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  • WCLC 2018

    19th World Conference on Lung Cancer

    Access to all presentations that occur during the 19th World Conference on Lung Cancer in Toronto, ON

    Presentation Date(s):
    • Sept 23 - 26, 2018
    • Total Presentations: 2384

    To review abstracts of the presentations below, narrow down your search by using the Filter options below, and then select the session listing of your choice. Click the "+" for a presentation to expand & view the corresponding Abstract details.

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    GR01 - Thymic Malignancies Tumor Board (ID 777)

    • Type: Grand Rounds Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 206 F
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      GR01.01 - Pathology (Now Available) (ID 11386)

      10:30 - 10:45  |  Presenting Author(s): Anja C Roden

      • Abstract
      • Presentation
      • Slides

      Abstract

      The pathologist is an integral member of the thymic malignancies tumor board team as he/she provides information on diagnosis, tumor stage, completeness of resection, and potential performance of biomarkers which is necessary for the team to decide on the optimal treatment for each individual patient. Information that will be expected from the pathologist differs dependent on whether a preoperative biopsy, a resection specimen or a specimen from a recurrence/metastasis is discussed (Table 1).

      For preoperative biopsies it is important to establish a histologic diagnosis including thymoma, thymic carcinoma, thymic neuroendocrine tumor, or benign thymic gland. Morphologic mimickers of thymic epithelial tumors (TET) such as lymphoma or germ cell tumors also need to be considered. Thymoma are not further subtyped on biopsies given the potential heterogeneity of these tumors. Moreover, the subtype of a thymoma in general does not play a role for treatment decisions. In contrast, the subtype of a thymic carcinoma might be of value at the time of biopsy as some subtypes behave in a very aggressive manner and might be treated differently from a squamous cell carcinoma, the most common subtype of thymic carcinomas. For instance NUT carcinoma commonly have already metastasized at time of diagnosis(1). Similarly, SMARCA4-deficient tumors (even though not included in the current WHO) are highly aggressive tumors(2). Lymphoepithelioma-like carcinoma can also behave more aggressively(3). Although these subtypes of thymic carcinoma are quite rare, they should be kept in mind and the threshold of ordering ancillary tests such as immunohistochemical stains for NUT and/or BRG1 or an EBV in situ hybridization should be low. As some TET are unresectable, suggestions for biomarker testing might also be expected from the pathologist.

      If a resection specimen of a TET is discussed stage and resection status are critical as they are the most important prognostic parameters and guide additional treatment decisions. To stage TET the recently introduced 8th edition of the UICC/AJCC TNM should be used. Currently, in many centers, both, Masaoka-Koga stage(4) and TNM stage(5) are reported simultaneously as some treatment protocols are still based on the Masaoka-Koga stage. The histologic classification also plays a role especially if the TET was not previously biopsied (which is the most common scenario in thymoma). In resection specimens the histologic classification should include the distinction between thymoma, thymic carcinoma and thymic neuroendocrine tumor vs benign thymic gland (i.e., thymic follicular hyperplasia, true thymic hyperplasia) vs mimickers of TET. In resection specimens the thymoma should be further subtyped, which is usually performed according to the 2015 WHO classification.(6) If the patient underwent neoadjuvant therapy, a comment on treatment effect of the resection specimen might be made(7).

      Although uncommon, biopsies or resections of recurrences or metastases of TET are performed and are discussed during tumor board. Based on the type of specimen (biopsy vs resection specimen) similar issues as described above will be discussed. In addition, especially in resection specimens, the WHO subtype of the TET should be mentioned as it might differ from the original specimen.

      In conclusion, the pathologist will contribute important information in regards to histologic diagnosis, stage, completeness of resection and biomarker testing of TET to the tumor board discussion which will be crucial for further treatment decision.

      References:

      1. Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Luer SC, et al. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Canc Res. 2012;18(20):5773-9.

      2. Sauter JL, Graham RP, Larsen BT, Jenkins SM, Roden AC, Boland JM. SMARCA4-deficient thoracic sarcoma: a distinctive clinicopathological entity with undifferentiated rhabdoid morphology and aggressive behavior. Mod Pathol. 2017;30(10):1422-32.

      3. Gomez JMD, Syed G, Co MLF, Bayoumi M, Abrams R. A rare highly aggressive tumour: lymphoepithelioma-like thymic carcinoma. BMJ Case Rep. 2017;2017.

      4. Koga K, Matsuno Y, Noguchi M, Mukai K, Asamura H, Goya T, et al. A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int. 1994;44(5):359-67.

      5. Amin MB, American Joint Committee on Cancer., American Cancer Society. AJCC cancer staging manual. Eight edition / editor-in-chief, Mahul B. Amin, MD, FCAP ; editors, Stephen B. Edge, MD, FACS and 16 others ; Donna M. Gress, RHIT, CTR - Technical editor ; Laura R. Meyer, CAPM - Managing editor. ed. Chicago IL: American Joint Committee on Cancer, Springer; 2017. xvii, 1024 pages p.

      6. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015.

      7. Johnson GB, Aubry MC, Yi ES, Koo CW, Jenkins SM, Garces YI, et al. Radiologic Response to Neoadjuvant Treatment Predicts Histologic Response in Thymic Epithelial Tumors. J Thorac Oncol. 2016.

      Table 1: Pathology discussion points at thymic malignancies tumor boards
      Time / type of specimen Important information from pathology
      Presurgical / initial biopsy

      Histologic subtype of thymic epithelial tumor

      Subtype of thymic carcinoma

      Mimicker of thymic epithelial tumor

      Biomarker testing

      Resection specimen

      Stage

      Resection status

      Thymic epithelial tumor histologic subtype including thymoma subtype

      Treatment effect

      Biomarker testing
      Recurrence / metastasis

      Histologic subtype of thymic epithelial tumor including thymoma subtype (especially if resection)

      Resection status if excision

      Biomarker testing

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      GR01.02 - Surgical Oncology (Now Available) (ID 11387)

      10:45 - 11:00  |  Presenting Author(s): Pier Luigi Filosso  |  Author(s): Enrico Ruffini, Francesco Guerrera, Paolo Olivo Lausi, Paraskevas Lyberis, Alberto Oliaro

      • Abstract
      • Presentation
      • Slides

      Abstract

      The treatment strategy for Thymic Epithelial Tumors (TETs) is based first on the tumour resectability. If complete resection is deemed feasible upfront, as it is the case in Masaoka-Koga stage I/II as well as for some stage III tumours, surgery represents the first step of the treatment, sometimes followed by postoperative radiotherapy and, less frequently, chemotherapy. Pretreatment biopsy is not always required, if the diagnosis of thymic tumour is highly probable and upfront surgical resection is achievable. Biopsy is therefore required in all other clinical situations: approaches may consist of percutaneous core-needle biopsy or incisional surgical biopsy through mediastinotomy or mini-thoracotomy. Pleural spaces should be respected to avoid tumour cell seeding. Fine-needle aspiration is generally not recommended.

      The standard approach is median sternotomy, which allows the complete opening of the mediastinum and both pleural cavities, and the evaluation of tumour macroscopic capsular invasion, infiltration of perithymic and mediastinal fat, peritumoural and pleural adherences and possible involvement of surrounding anatomical structures. Generally, complete thymectomy including the tumour, the residual thymus gland and perithymic fat is preferred because local recurrences have been sometimes observed after partial thymectomy, when a part of the thymus gland is left behind. However, thymomectomy alone is an option in stage I tumours and in non-myasthenic patients. If the tumour is widely invasive (stage III/IV), en bloc removal of all affected structures, including lung parenchyma (usually through limited resection), pericardium, great vessels, nerves and pleural implants, should be carried out. Resection of venous vascular structures (innominate vein(s) and superior vena cava) includes partial resection with suturing or complete resection and vessel reconstruction using vascular prosthesis. Areas of uncertain resection margins are marked with clips to allow a precise postoperative radiotherapy delivery.. Phrenic nerve preservation does not affect survival, but increases the risk of local recurrence, and should be balanced with the achievement of a complete resection, especially in patients with severe and uncompensated myasthenia gravis. Frozen sections to assess tumour involvement of resection margins are not always recommended, since the risk of false-negative results is high. Minimally invasive surgery is an option for presumed stage I and possibly stage II tumours in the hands of appropriately trained thoracic surgeons. This includes transcervical, extended transcervical, video-assisted thoracoscopy (VATS) and robotic approaches (right or left, right and left, right and cervical, left and cervical, subxiphoid and right and left, cervical and subxiphoid); furthermore, robotic surgery may allow a better visualisation of the tumour when compared with VATS. The choice for minimally invasive resection should not jeopardise or change the principles that are deemed appropriate for an open approach, especially the achievement of complete resection that may ultimately require switching to an open procedure. Minimally invasive surgery is not recommended for stage III tumours, because the lack of long-term follow-up. Lymphadenectomy has historically rarely performed after resection of thymic tumours. The new IASLC/ITMIG TNM staging system of thymic tumours, however, leads to the recommendation that locoregional lymphoadenectomy should be carried out during resection of all types of thymic tumours. A proposed nodal map is available from ITMIG. Routine removal of anterior mediastinal nodes and anterior cervical nodes is also recommended. Systematic sampling of other intrathoracic sites is encouraged (i.e. paratracheal, aortopulmonary window and subcarinal areas, depending on tumour location) in stage III/IV tumours. Systematic lymphadenectomy (N1 + N2) is strongly recommended in case of thymic carcinoma due to the high rate of lymphatic spread (20% versus 3% in thymomas)

      If complete resection is deemed not to be achievable upfront on the basis of imaging studies, as it is frequently the case in Masaoka-Koga stage III/IVA tumours, a biopsy should be carried out, followed by primary/induction chemotherapy as part of a curative-intent sequential strategy that integrates subsequent surgery or radiotherapy. Patients not eligible for local treatment should receive palliative chemotherapy only.

      Recurrences of thymic epithelial tumours are not uncommon (10%–15% of all-stage resected tumours) and should be managed according to the same strategy as newly diagnosed tumours. Complete resection of recurrent lesions represents a major predictor of favourable outcome, and surgery is then recommended in case of resectable lesions.

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      GR01.03 - Surgical Oncology (Now Available) (ID 11388)

      11:00 - 11:15  |  Presenting Author(s): David Waller

      • Abstract
      • Presentation
      • Slides

      Abstract

      In this section we will address the controversial areas of surgical management in the more advanced stages of thymoma.

      Using case-based discussion we will debate the following clinical scenarios :

      Stage III Thymic tumours ( with invasion of great vessels)

      Is there a role for primary surgical debulking leaving an intentional R2 resection ?

      There is little survival evidence to support intentional debulking but such procedures may reduce the dose and extent of radiotherapy subsequently required and therefore the associated morbidity [1]. However, there is a lack of supportive evidence for debulking surgery in thymic carcinoma. [2,3]

      Should primary treatment be chemoradiotherapy followed by consolidation surgery ?

      Induction therapy is feasible in locally advanced thymic tumours and has been reported to achieve around a 50% partial response. A complete pathological response has not been seen but such treatment can facilitate a high rate (over75%) of R0 resection.[4]

      Stage IVa Thymic tumours – pleural/pericardial deposits

      Is there a role for radical surgery ?

      The International Thymic Malignancies Interest Group have recommended that in locally-advanced Stage IVa patients with pleural involvement, major pleural resections, including pleurectomy/decortication or extrapleural pneumonectomy are indicated, provided a complete resection of the pleural deposits is anticipated, usually in a multidisciplinary setting [5]

      Should this be extrapleural pneumonectomy or thymectomy and extended pleurectomy/decortication ?

      As in other disease, extrapleural pneumonectomy (EPP) is associated with a high 30 day mortality of up to 17% (6). Providing a complete resection can be achieved there is no difference between EPP and extended pleurectomy decortication (EPD) (7] and median survival may exceed 4 years. The contribution of occult nodal metastases must be recognized and radical resection must include lymph node dissection.

      Stage migration due to lymph node metastases, WHO-classification type C, and T3/4-status are associated with inferior survival but extended surgery has been found to be the only independent significant prognosticator in multivariate analysis [8,9].

      Which surgical incision is best ?

      Radical resections can be facilitated by extended approaches which are well tolerated and adequate exposure is necessary to ensure a complete resection

      Recurrent thymic tumour – after previous resection

      Is there evidence that extending local control prolongs overall survival over systemic therapy alone ?

      Survival is acceptable and superior to non surgical treatment if complete resection of recurrence is achieved. There is no evidence to support debulking of recurrent thymoma [10]

      A significant poorer prognosis is associated with multiple versus single relapses, Masaoka stage III primary tumour versus Masaoka stage I-II primary tumour, distant versus loco-regional relapses and B3 histotype versus other. On multivariate analysis, completeness of resection, number of metastases, Masaoka stage of primary tumour and site of relapse were identified as the only independent predictors of prognosis [10]

      Conclusions

      The relative rarity of thymic neoplasms has contributed to the lack of high grade evidence from randomized controlled trials of large numbers of patients. Most supportive evidence for radical surgery in advanced thymic malignancies has therefore been provided by relatively small selected case series. However, the formation of larger collaborative groups with cumulative databases has provided more robust support for extended surgical procedures that many have avoided previously. The superiority of resection as part of multimodality treatment over non-surgical treatment alone seems to be justified provided high quality surgical standards are maintained.

      References

      1. Ried M et al. Extended surgical resections of advanced thymoma Masaoka stages III and IVa facilitate outcome. Thorac Cardiovasc Surg. (2014)

      2. Hamaji M et al A meta-analysis of debulking surgery versus surgical biopsy for unresectable thymoma.. Eur J Cardiothorac Surg. (2015)

      3. Attaran S et al , Does surgical debulking for advanced stages of thymoma improve survival? Interact Cardiovasc Thorac Surg. 2012 Sep;15(3):494-7

      4. Korst RJ, et a. lNeoadjuvant chemoradiotherapy for locally advanced thymic tumours: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg. 2014 Jan;147(1):36- 44

      5. Ruffini E et al, Optimal surgical approach to thymic malignancies: New trends challenging old dogmas. Lung Cancer. 2018 Apr;118:161-170.

      6. Fabre Det al.Long-term outcome of pleuropneumonectomy for Masaoka stage IVa thymoma. Eur J Cardiothorac Surg. 2011 ;39:e133-8

      7. Moser B et al, Surgical therapy of thymic tumours with pleural involvement: an ESTS Thymic Working Group Project. Eur J Cardiothorac Surg. 2017 Aug 1;52(2):346-355

      8. Kaba E et al, Role of Surgery in the Treatment of Masaoka Stage IVa Thymoma. Ann Thorac Cardiovasc Surg. 2018:20;24:6-12.

      9.. Bölükbas S et al, Extended thymectomy including lung-sparing pleurectomy for the treatment of thymic malignancies with pleural spread. Thorac Cardiovasc Surg. 2015 Apr;63(3):217-22.

      10. Dai J et al, Is it valuable and safe to perform reoperation for recurrent thymoma? Interact Cardiovasc Thorac Surg. 2015 Oct;21(4):526-31

      11. Marulli G et al, Surgical treatment of recurrent thymoma: is it worthwhile? Eur J Cardiothorac Surg. 2016 Jan;49(1):327-32

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      GR01.04 - Medical Oncology (Now Available) (ID 11389)

      11:15 - 11:30  |  Presenting Author(s): Nicolas Girard

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic malignancies represent a heterogeneous group of cancers, which are classified according to the World Health Organization (WHO) histopathologic classification, that distinguishes thymomas from thymic carcinomas; thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the relative proportion of the non-tumoral lymphocytic component, and the resemblance to normal thymic architecture. Thymic carcinomas are similar to their extra-thymic counterpart, the most frequent subtype being squamous cell carcinoma. Neuroendocrine tumors may occur in the thymus, for which the management is similar to that of advanced neuroendocrine tumors originating from other anatomic locations.

      The management of thymic epithelial tumors is a paradigm of cooperation between clinicians, surgeons, and pathologists from establishing the diagnosis to organizing the multimodal therapeutic strategy. Data related to the systemic treatment of thymic malignancies are mostly based on non-randomized studies, retrospective data, and recommendations rely on expert opinion; this is related to the rarity of the disease, precluding large clinical trials to be developed.

      Systemic treatment may be delivered in a curative-intent approach, for patients presenting with locally-advanced tumor at time of diagnosis, with invasion of intra-thoracic neighboring structures, and/or dissemination to the pleura and the pericardium, precluding upfront complete resection to be achieved. In such cases, chemotherapy has been used both to reduce the tumor burden - possibly allowing subsequent surgery and/or radiotherapy- and to achieve prolonged disease control. In this setting, cisplatin-based combination regimens should be administered; combinations of cisplatin, adriamycin, and cyclophosphamide, and cisplatin and etoposide have been recommended, based on historical studies.

      When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable, or because of poor performance status or co-existent medical condition, definitive radiotherapy is recommended part of a sequential chemoradiotherapy strategy. Combination with chemotherapy may be considered as well.

      Chemotherapy is also a palliative-intent treatment of unresectable, metastatic, and recurrent tumors, which are more frequently thymic carcinomas than thymomas. Again, cisplatin-based combination regimens with anthracyclins and/or etoposide are standard. No randomized studies have been conducted, and it is unclear which regimens are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination; however, the effect of corticosteroids to deplete the lymphocytic component of thymomas, without any antitumor effect, may significantly impact radiologic response assessment, and hamper comparisons between chemotherapy regimens. Combination of carboplatin and paclitaxel is an option for thymic carcinoma, based on results of recent phase II trials.

      Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. In non-resectable recurrences, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. The re-administration of a previously effective regimen has to be considered, especially in case of previous response, late occurring recurrence. Preferred regimens for second-line treatment include carboplatin plus paclitaxel, and platin plus etoposide; capecitabine plus gemcitabine is an option. These regimens were evaluated in dedicated phase II trials. Options for subsequent lines include pemetrexed, oral etoposide. Sunitinib is an off-label option in the second-line setting, based on its antiangiogenic activity. Everolimus may be another option for refractory disease.

      Several trials assessing the efficacy of PD-1 checkpoint inhibitors are currently ongoing. Phase II studies of pembrolizumab were recently reported, collectively enrolling 63 patients, showing response rates of 24%, but occurrence of serious, autoimmune adverse events in 20% to 30% of patients. The off-label use of checkpoint inhibitors is currently not recommended.

      The management of patients requires continuous multidisciplinary expertise at any step of the disease. A dramatic improvement in our knowledge has occurred in the last few years, through the development of databases, translational research programs, and clinical trials. While access to innovative strategies represents a major challenge, as the rarity of the tumor precludes specific approval of drugs to be obtained, patient-centered initiatives, such as the establishment of dedicated networks to provide expertise for the actual management of patients, are warranted.

      In France, RYTHMIC (Réseau tumeurs THYMiques et Cancer; www.rythmic.org) is a nationwide network for thymic malignancies, which was appointed in 2012 by the French National Cancer Institute, as part of its rare cancer program. Since then, the management of all patients diagnosed with thymic tumors has been discussed on a real-time basis at a national multidisciplinary tumor board (MTB), which is organized twice a month basis using a web-based conferencing system. Decision-making is based on consensual recommendations, that were originally established based on available evidence, and are updated and approved each year by all members of the network. A prospective database of all patients is hosted by the French Thoracic Cancer Intergroup. Overall, more than 2,500 patients have been enrolled, demonstrating the feasibility of a national MTB for thymic malignancies, that, besides ensuring patients an equal access to highly specialized management, provides with a comprehensive tool to monitor dedicated actions to improve the management of patients, and enroll patients in clinical trials. Similar thymoma-dedicated and mesothelioma-dedicated networks are now being implemented in France and in other European countries, such as Spain and Italy (the TYME collaborative group).

      Within the European Reference Network EURACAN, the rare thoracic tumor domain – referred as to G8 domain - handles a network of 20+ healthcare providers; the objectives of EURACAN include the updating and the assessment of current guidelines, the development of educational programs, dissemination and communication with patients groups, and the establishment of research projects, from the diagnosis workup of the disease to the therapeutic strategies. Achieving the highest quality of patient care is the main objective of EURACAN, and the RYTHMIC model provides some practical tools to be implemented at the European level, including Clinical Patient Management System. The European network also provides an infrastructure for collaboration with diagnosis and pharmaceutical companies; one example may be the opening of dedicated cohorts in basket studies assessing new drugs, for which the network allows a better identification of patients and facilitates the recruitment in the trials.

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      GR01.05 - Radiation Oncology (Now Available) (ID 11390)

      11:30 - 11:45  |  Presenting Author(s): Anthony Brade

      • Abstract
      • Presentation
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      Abstract not provided

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    MA10 - Considerations in Immunotherapy / Real World (ID 911)

    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 11
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 105
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      MA10.01 - Antibiotic Use and PD-1 Inhibitors: Shorter Survival in Lung Cancer, Especially When Given Intravenously. Type of Infection Also Matters (Now Available) (ID 13542)

      10:30 - 10:35  |  Presenting Author(s): Xabier Mielgo-Rubio  |  Author(s): Luis Enrique Chara, Miguel Jhonatan Sotelo-Lezama, Rafael Lopez Castro, Judit Rubio-Martínez, Alejandro Velastegui, Clara Olier-Garate, Sandra Falagan, Isabel Gómez-Barreda, Pilar Bautista-Sanz, Jorge Silva-Ruiz, Juan Moreno Rubio, Cynthia López, Ana Cardeña-Gutiérrez, Elia Pérez-Fernández, María Sereno Moyano

      • Abstract
      • Presentation
      • Slides

      Background

      Some studies found that cancer patients treated with PD-1 immune checkpoint inhibitors (ICI) who receive antibiotics (ATB) had worse efficacy outcomes because ATB can dysregulate gut microbiota. AvaiIable data in NSCLC are contradictory. In addition it’s unknow whether route of administration, type of the ATB and reason for its use, can affect survival outcomes.

      Method

      This is a multicenter retrospective study. We included consecutive patients with advanced non-small-cell lung cancer (NSCLC) treated with nivolumab or pembrolizumab in second line or beyond between March 2015 and April 2018, from 7 hospitals in Spain. The aim of the study was to evaluate if patients taking ATB 2 months before or within the first month after starting ICI had worse OS, and if OS was affected by the route of administration, type of ATB, and the reason for its use.

      Result

      168 patients were evaluated. Median age was 65 years (39-85). 134(79,8%) were male and 121 (72%) had PS>=1. Predominant histologies were adenocarcinoma (50%) and squamous-cell carcinoma (42,9%). 92,3% received nivolumab and 7,7% pembrolizumab. The median number of prior lines was 1 (1-5), median number of cycles 11 (1-68). Median follow: 6,3m. Most were current or former smokers (94,6%). Only 2,9% had driver mutations. PD-L1 was available in 25% (<1%: 36,6%; 1-49%: 39%; >=50%: 24,4%). Response rate (RR) was 30,4%. 47,9% received ATB, 30% of them intravenously and 70% orally. Median PFS and OS were 5,6 months (m) (95%CI, 3,9-7,3) and 11,4 m (95%CI, 9,4-13,5). Patients who received ATB had shorter OS (8,1m (95%CI, 3,6-12,5) vs 11,9m (95%CI 9,1-14,7); p=0,026) and PFS (5m (95%CI,3,1-6,9) vs 7,3m (95%CI,2-12);p=0,028). Those patients receiving ATB intravenously had shorter OS than orally (2,9m (95%CI, 1,6-4,1) vs 14,2m (95%CI, 7,9-20,6); p=0,0001) and shorter PFS (2,2m (95%CI,0,6-3,7) vs 5,9m (95%CI,3,9-8); p=0,001). Patients treated for a lower respiratory tract infection (LRTI) and urinary infection had significantly shorter OS (6m (95%CI2,2-9,7) vs 26m (95%CI, 7,9-44); p=0,006).

      Conclusion

      Our results suggest that use of antibiotics (mainly intravenously) has a negative impact on survival outcomes in patients with pretreated advanced NSCLC receiving ICI. To our knowledge, this is the biggest retrospective study evaluating the impact of ATB on the efficacy of ICI in NSCLC patients and the first one evaluating route of administration of ATB. We also found worse outcomes when ATB were administered for low respiratory or urinary tract infection.

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      MA10.02 - Impact of Antibiotics on Outcome of Metastatic Non Small Cell Lung Cancer Patients Treated with Immunotherapy (Now Available) (ID 14021)

      10:35 - 10:40  |  Presenting Author(s): Giulia Galli  |  Author(s): Marta Poggi, Giovanni Fucà, Martina Imbimbo, Claudia Proto, Diego Signorelli, Milena Vitali, Nicoletta Zilembo, Monica Ganzinelli, Filippo De Braud, Marina Chiara Garassino, Giuseppe Lo Russo

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy (IO) is effective against metastatic non small cell lung cancer (mNSCLC). Gut microbioma has a strong impact on immune functions and its imbalance due to antibiotics (atbs) may impair the efficacy of IO. Recent works on other malignancies supported this evidence, but data are still lacking. We studied this topic in a case series of mNSCLC patients (pts) treated with IO.

      Method

      Data about all consecutive pts with mNSCLC treated with IO at Istituto Nazionale dei Tumori, Milan, Italy, between 04/2013 and 01/2018 were retrospectively collected. Pts were stratified according to atb use between 1 month (mo) before and 3 mos after the beginning of IO, and to atb exposure (AEx) defined as the ratio “days under atb/days under IO”. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analysis was performed with Cox proportional model.

      Result

      One hundred fifty-seven pts were analyzed, for a median follow-up of 28.6 mos. IO consisted in an anti-PD1 agent in 62.4% of cases, in an anti-PDL1 agent in 32.5% of cases, in a combination anti-PDL1+anti-CTLA4 in 5.1% of cases. First-line IO was administered in 25 cases, second-line IO in 66 cases, third- or more advanced-line IO in 66 cases. Twenty-seven pts received atbs. The 3 most commonly used atbs were levofloxacin (55.6%), amoxicillin/clavulanate (25.9%), and ceftriaxone (14.8%). No differences in either response rate, progression free survival (PFS) and overall survival (OS) were observed between the subgroups defined by atb use (p .14, .18 and .24, respectively). Median AEx of the treated pts was 5%. The pts with an AEx longer than the median one had significantly worse PFS (2.2 vs 7.7 mos, p<.0001) and OS (4.9 vs 16.3 mos, p .0004) than the others. This result maintained significance after correction for IO line (p .0003) and performance status (p .0002), which were the only other variables influencing PFS and OS.

      Conclusion

      Though no differences in outcome could be observed in our population according to simple atb use, a significant disadvantage in PFS and OS became evident for pts with a higher AEx. If confirmed, these data may suggest to carefully weigh the prescription of atbs to mNSCLC pts treated with IO.

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      MA10.03 - Plasmatic Evaluation of the Intestinal Barrier and Blood Microbiota, and Antibiotic Use in Non-Small Cell Lung Cancer Patients Treated with Nivolumab (Now Available) (ID 13863)

      10:40 - 10:45  |  Presenting Author(s): Etienne Giroux Leprieur  |  Author(s): Julia Ouaknine, Pierre Helly De Tauriers, Coraline Dumenil, Nathalie Neveux, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Julie Tisserand, Jean-François Emile, Thierry Chinet

      • Abstract
      • Presentation
      • Slides

      Background

      Recent data suggest that gut microbiota and antibiotic use affect the efficacy of immune checkpoint inhibitors. We aimed to evaluate the predictive role of blood microbiota, plasma citrulline (marker of the intestinal barrier), and the impact of early (from 2 months before until 1 month after beginning of nivolumab) and late (after 1 month of nivolumab) antibiotic use on nivolumab efficacy in NSCLC patients.

      Method

      We included consecutive patients with advanced NSCLC treated with nivolumab between July 2014 and December 2017. Plasma tests were taken prospectively during treatment. The microbial population present in the plasma samples was determined using sequencing of variable regions of the 16S rRNA bacterial gene at M0. Plasma citrulline concentrations were evaluated by ion exchange chromatography at month (M) 0, M2, M4 and M6 of nivolumab.

      Result

      Seventy-two patients were included (male: 62%; smokers: 87%; adenocarcinoma: 63%). Early use of antibiotics (EUA) (n=28/72) was associated with poor overall survival (OS) (median 5.1 months, versus 13.4 months without EUA, p=0.03), whereas later use of antibiotic during treatment had no significant effect. Thirty-six patients (50%) had serial plasma samples available for analyses. The composition of blood microbiota at M0 was associated with tumor response and long-term benefit of nivolumab, with a significant impact of Paludibacilum, Gemmatimonadaceae and Nocardioides. Patients with long-term benefit of nivolumab had significantly higher plasma citrulline concentrations than other patients, at M0, M2 and M4, and maintained high citrulline concentrations at M6. Median progression-free survival (PFS) and OS for patients with citrulline ≥20µM at M0 were 7.9 months and not reached, versus 1.6 months (p<0.0001) and 2.2 months (p<0.0001) for patients with citrulline <20µM, respectively. Patients with EUA had lower median citrulline concentrations at M0 (17µM [IQR 15-30] versus 31µM [IQR 21.3-40.5]; p=0.06).

      Conclusion

      This study confirms the negative impact of EUA during nivolumab treatment, and suggests that plasma evaluation of the intestinal barrier and blood microbiota may help to predict the outcome of NSCLC patients treated with nivolumab.

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      MA10.04 - Discussant - MA 10.01, MA 10.02, MA 10.03 (Now Available) (ID 14611)

      10:45 - 11:00  |  Presenting Author(s): Bertrand Routy

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA10.05 - Effect of Early Steroids use in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 14163)

      11:00 - 11:05  |  Presenting Author(s): Giovanni Fucà  |  Author(s): Marta Poggi, Giulia Galli, Martina Imbimbo, Giuseppe Lo Russo, Claudia Proto, Milena Vitali, Monica Ganzinelli, Nicoletta Zilembo, Filippo De Braud, Marina Chiara Garassino, Diego Signorelli

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy (IO) radically improved patients (pts) outcomes in advanced non-small cell lung cancer (NSCLC). Because of their immunosuppressive activity, the use of steroids as supportive care medications or for mild adverse events, even if at anti-inflammatory dosage, is debatable. In this study we assessed the effect of early steroids use on clinical outcomes of pts with advanced NSCLC treated with IO.

      Method

      We retrospectively collected demographics, clinical and pathological data of pts with advanced NSCLC treated with IO at our institution with at least one instrumental response assessment. Early use of steroids was defined as the use of a daily prednisone-equivalent dose 10 mg for at least 1 day within 28 days from the start of IO. Chi-square test or Fisher's exact test were used to analyze the association of early use of steroids with pts’ characteristics. The Kaplan-Meier method and the Cox proportional-hazards model were used for survival analyses while the reverse Kaplan-Meier method was used for follow-up quantification.

      Result

      We included 151 pts, 35 (23 %) of whom recurred to an early use of steroids. Six pts (4%) received combinatorial PD-L1+CTLA-4 blockade while 145 (96%) received single agent anti PD-1/PD-L1. Early use of steroids was positively associated with ≥2 metastatic sites (OR 3,08, 95% CI 1.33-7.89; P = .01) and ECOG PS 2 (OR 4.57; 95% CI 1.10-20.37; P = .03) and negatively associated with disease control (OR 0,32; 95% CI 0.14-0.71, P = .006). With a median follow-up of 28.61 months, early use of steroids characterized a poorer median OS (4.86 vs 15.14 months; HR 2.60; 95% CI 1.70-4.10; P < .0001). In the multivariable model including the only other covariate significantly associated with survival (ECOG PS), the early use of steroids was confirmed to independently worsen OS (HR 2.38; 95% CI 1.49-3.81; P = .0003). Early use of steroids was also associated with a poorer median progression-free survival (PFS) (1.98 vs 3.94 months; HR 1.80; 95% CI 1.20-2.80; P = .003).

      Conclusion

      In our analysis, the early use of steroids significantly affected disease control, PFS and OS in advanced NSCLC patients treated with IO. If our findings will be further prospectively confirmed, early use of steroids should be avoided in this setting.

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      MA10.06 - Impact of Immune-Related Adverse Events on Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Nivolumab (Now Available) (ID 13039)

      11:05 - 11:10  |  Presenting Author(s): Biagio Ricciuti  |  Author(s): Carlo Genova, Andrea De Giglio, Marta Brambilla, Maria Bassanelli, Maria Giovanna Dal Bello, Sara Baglivo, Giulio Metro, Francesco Grossi, Rita Chiari

      • Abstract
      • Presentation
      • Slides

      Background

      Anti PD1 and anti PD-L1 monoclonal antibodies represent the standard of care for platinum-pretreated advanced non-small cell lung cancer (NSCLC) patients, having shown to prolong survival compared to chemotherapy in second-line setting in phase III clinical trials. Patients treated with these drugs not infrequently experience immune-related adverse events (irAEs), which we hypothesize might reflect antitumor response. In this study we investigated whether the development of irAEs was associated with nivolumab efficacy in patients with advanced NSCLC.

      Method

      We conducted a multicenter retrospective study of patients with advanced NSCLC treated with nivolumab between October 2013 and September 2017. IrAEs were defined as AEs having immunological basis that required intensive monitoring and interventions. We evaluated nivolumab efficacy according to the development of irAEs.

      Result

      Among 195 patients (median [range] age, 63 [30-40] years; 128 men [65.6%], 67 women [34.4%]), irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events. Median PFS was 5.7 months in patients with irAEs compared to 2 months of those without irAEs (P < 0.0001). Median OS was 17.8 months compared to 4.04 months of no-irAEs group (P < 0.0001). The survival benefit of irAEs was consistent also in 12- and 6-weeks landmark analysis. Patients who developed ≥ 2 irAEs (n: 37) had a significantly longer median PFS and OS compared to those with one AE (n: 48) or none (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2, P < 0.0001; OS: 26.8 months vs. 11.9 vs. 4, P < 0.0001). Multivariable analysis revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.48 (95%CI, 0.34-0.77; P < 0.0001) for PFS and 0.38 (95%CI, 0.26-0.56; P < 0.0001) for OS.

      Conclusion

      This is the largest study conducted to date aimed to evaluate whether the development of irAEs is predictive of nivolumab efficacy in pre-treated NSCLC patients. In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients who had received nivolumab in ≥ 2 line setting. This data was consistent in the 12- and 6-weeks landmark analysis, suggesting that an early onset of irAEs might be predictive of durable clinical benefit in NSCLC patients treated with nivolumab. Moreover, patients who experienced ≥ 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE. Further studies are required to investigate the molecular mechanisms underlying this association.

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      MA10.07 - Discussant - MA 10.05, MA 10.06 (Now Available) (ID 14614)

      11:10 - 11:25  |  Presenting Author(s): Kenneth O’byrne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA10.08 - Choice of Taxane and Outcomes in the KEYNOTE-407 Study of Pembrolizumab Plus Chemotherapy for Metastatic Squamous NSCLC (Now Available) (ID 14698)

      11:25 - 11:30  |  Presenting Author(s): Balazs Halmos  |  Author(s): Alexander V Luft, Margarita Majem, Rina Hui, Romain Corre, Mahmut Gümüş, Konstantin Laktionov, Barbara Hermes, İrfan Çiçin, Andrew G Robinson, Terufumi Kato, Ying Cheng, Dariusz Kowalski, Xiaodong Li, Gregory M Lubiniecki, Bilal Piperdi, Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      In the randomized, double-blind, phase 3 KEYNOTE-407 study (NCT02775435), pembrolizumab plus chemotherapy with carboplatin and paclitaxel or nab-paclitaxel significantly prolonged OS (HR 0.64, 95% CI 0.49-0.85, P=0.0008) and PFS (HR 0.56, 95% CI 0.45-0.70, P<0.0001) compared with placebo plus chemotherapy in patients with previously untreated, metastatic squamous NSCLC. The benefit of pembrolizumab plus chemotherapy was observed irrespective of PD-L1 TPS. Pembrolizumab plus chemotherapy also had a manageable safety profile. We performed an exploratory analysis of outcomes by investigator’s choice of paclitaxel or nab-paclitaxel, which was a randomization stratification factor.

      Method

      559 eligible patients were randomized 1:1 to pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus 4 cycles of carboplatin AUC 6 mg/mL/min Q3W and investigator’s choice of paclitaxel 200 mg/m2 Q3W or nab-paclitaxel 100 mg/m2 QW. Primary end points were OS and PFS; ORR and safety were secondary.

      Result

      Paclitaxel was the chosen taxane in 60% of patients. The addition of pembrolizumab to chemotherapy improved OS, PFS, and ORR regardless of choice of carboplatin and paclitaxel or carboplatin and nab-paclitaxel (Table). Incidence of grade 3-5 AEs in the pembrolizumab plus chemotherapy arm vs placebo plus chemotherapy arm was 63.9% vs 59.3% in paclitaxel recipients and 78.9% vs 81.4% in nab-paclitaxel recipients. AEs led to discontinuation of all treatment in 13.6% vs 8.4% of paclitaxel recipients and 12.8% vs 3.5% of nab-paclitaxel recipients and led to discontinuation of any treatment in 19.5% vs 13.2% and 29.4% vs 9.7%, respectively. Immune-mediated AEs occurred in 29.6% vs 9.6% of paclitaxel recipients and 27.5% vs 7.1% of nab-paclitaxel recipients.

      Conclusion

      Adding pembrolizumab to chemotherapy with carboplatin and a taxane improved efficacy and was generally tolerable compared with chemotherapy alone as first-line therapy in patients with metastatic squamous NSCLC regardless of whether paclitaxel or nab-paclitaxel was the chosen taxane.

      Carboplatin plus Paclitaxel Carboplatin plus Nab-Paclitaxel

      Pembrolizumab + Chemotherapy

      N = 169

      Placebo + Chemotherapy

      N = 167

      Pembrolizumab + Chemotherapy

      N = 109

      Placebo + Chemotherapy

      N = 114

      OS, median

      (95% CI), mo

      14.0 (12.6-16.6) 10.3 (8.2-14.8) NR (NE-NE) 12.6 (9.6-NE)
      HR (95% CI)a 0.67 (0.48-0.93) 0.59 (0.36-0.98)

      PFS, median

      (95% CI), mo

      6.4 (6.0-8.3) 4.4 (4.2-5.1) 6.5 (6.2-8.5) 5.9 (4.4-6.9)
      HR (95% CI)a 0.52 (0.40-0.68) 0.65 (0.45-0.94)
      ORR, % (95% CI) 57.4 (49.6-65.0) 37.7 (30.4-45.5) 58.7 (48.9-68.1) 39.5 (30.4-49.1)
      aBased on a Cox regression model with treatment as a covariate.

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      MA10.09 - NECPAL 2: A Multicentre Descriptive Study of Primary and Continuous Attention in Palliative Care in Argentina: Lung Cancer Cohort (Now Available) (ID 12928)

      11:30 - 11:35  |  Presenting Author(s): Carolina Gabay  |  Author(s): Mara Bonet, Monica Castro, Romina Tranier, Sol Sandijian, Silvina De Lellis, Alvaro Sauri, Vilma Tripodoro, Gustavo De Simone

      • Abstract
      • Presentation
      • Slides

      Background

      In Argentina Lung cancer is the most deadly neoplasm (9230 annuals death). Early identification of palliative care (PC) needs has proven benefits in terms of quality of life, survival, and decision making in Lung cancer patients. The NECPAL CCOMS-ICO© tool is face and content-validated instrument to identify patients likely in need of PC.

      Method

      To implement and evaluate a demonstration multicenter program for early and continuous PC for Lung cancer patients in Buenos Aires using the NECPAL-CCOMS-ICO© tool (multifactorial assessment) in every level of attention. We reported the results of one University Cancer center lung cancer cohort (2016-2018).

      We categorized patients as surprise question positive (SQ+), (Would you be surprised if this patient were to die in the next 12 month?). If the healthcare professional answered ‘NO’, the patient was considered SQ+ and they were also considered NECPAL+ when they presented at least one additional parameter from the NECPAL tool. All patients classified as NECPAL+ were considered to be in need of PC. Then using a Cox regression model analyzed predictors for overall survival (OS).

      Result

      82 patients out of 206 were SQ+ and NECPAL +. Median age 64 (35-82). 46 % had stage IVB (8th ) ,18 % IVA , 19.5% locally advanced, and 7 ptes early stage. 6 ptes presented SCLC . Male were 59%. 78 ptes were analyzed for overall survival; n=4 were excluded due lost of follow up. 56% had died with a Median OS of 11 months (7.2-14.7). 5/82 ptes did not receive any kind of oncology treatment due ECOG, comorbidities or patients’ choice. Median OS was 17 months (10.5-23.4) for men and 10 months (3.7-16.2) for females (p=0.08).

      In the univariate analyses, only metastasis in vital organs (nervous central system, liver, massive lung) was predicted of survival (17 vs 8 months; p=0.035). The other NECPAL indicators did not met the criteria for significance.

      The multivariate analysis, did not find a statistically significant combination of predictors for overall survival except metastasis in vital organs. It was noted an small number of low PPS score (11/78), as well as nutritional (14/78) or severe functional deterioration (5/78), in spite of the majority of the cohort had advanced disease.

      Conclusion

      This Program adds a prospective direct method of measuring prevalence of PC needs including a Palliative approach. The results presented support consideration of the NECPAL tool as a prognostic tool in our setting.

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      MA10.10 - Lung Cancer Stigma: A Ten-Year View of Patient, Provider, and Public Attitudes About Lung Cancer. (Now Available) (ID 13413)

      11:35 - 11:40  |  Presenting Author(s): Jennifer C King  |  Author(s): Maureen Rigney, Lisa Carter-Harris

      • Abstract
      • Presentation
      • Slides

      Background

      The presence of lung cancer stigma is well documented (Chapple, 2004; Chambers, 2012; Marlow, 2015) and impacts the care and treatment of lung cancer survivors (Tod, 2008; Carter-Harris, 2014). In 2008, a large survey of patients, oncologists, and general public revealed that most participants felt lung cancer was principally caused by external factors, was preventable, and lung cancer patients were partly to blame for their illness (Weiss 2014; 2017). We replicated the survey to understand whether perceptions have changed over the last decade.

      Method

      1001 members of the general public, 208 lung cancer patients, and 205 oncologists who treat lung cancer were surveyed with the identical instrument as 2008 plus 3-11 questions at the end including Cataldo Lung Cancer Stigma Scale (Cataldo, 2011) strongest-loaded items for the patient survey. The survey was administered by phone and online during summer 2018.

      Result

      General lung cancer awareness has significantly improved in a decade with 94% of the public reporting familiarity with lung cancer, every segment reporting increased media visibility (65%, 78%, 85% for public, patients, and oncologists, respectively), and patients reporting significantly increased use of advocacy organizations (39% vs 18%, p<.05). Additionally, significantly more oncologists reported having adequate treatment options to prolong patients’ lives (52% vs 31%, p<.05) and most patients reported satisfaction with medical care (87%) and treatment options (71%).

      Despite these advances, stigma remains a critical problem. In 2018, significantly more of the public believed lung cancer patients are viewed/treated differently than other cancer patients (37% vs 31%, p<.05) and a similar proportion (56%) felt patients are partly to blame for their illness. Oncologists continue to believe there is stigma associated with lung cancer (68%) although more felt stigma was lower for never-smokers. More oncologists indicated patients blame themselves (67% vs 57%). Patients reported significant increases (p<.05) in presence of stigma associated with lung cancer (70% vs. 54%), lung cancer patients being treated differently by society (63% vs. 45%), having personally been treated different by society (43% vs 25%), and loved ones would be more supportive if they had a different type of cancer (25% vs. 11%).

      Conclusion

      After a decade of lung cancer research progress, results indicate considerably elevated awareness. Unfortunately, disease stigma remains. Interestingly, stigma is reported more frequently by lung cancer patients and may be felt more acutely, perhaps due to increased awareness and empowerment. This work underscores the need to address stigma with proactive multilevel approaches (Hamann, 2018).

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      MA10.11 - Discussant - MA 10.08, MA 10.09, MA 10.10 (Now Available) (ID 14616)

      11:40 - 11:55  |  Presenting Author(s): Antoinette Wozniak

      • Abstract
      • Presentation
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      Abstract not provided

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    MA11 - Biomarkers of IO Response (ID 912)

    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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      MA11.01 - Comparative Efficacy of T-Cell Intrinsic Versus Extrinsic PD-1 Blockade to Overcome PD-L1+ Tumor-Mediated Exhaustion (Now Available) (ID 14194)

      10:30 - 10:35  |  Presenting Author(s): Jordan Dozier  |  Author(s): Nan Chen, Jasmeen Saini, Navin Chintala, Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD-1 agents are effective in overcoming PD-L1+ mediated T-cell exhaustion. Effective therapeutic regimens include multiple, long-term administration. We hypothesized that a single dose of T-cell intrinsic PD-1 blockade by expression of a dominant negative receptor (PD1-DNR) can be equally effective as multiple doses of anti-PD-1 agent administration in the treatment of PD-L1 overexpressing thoracic cancers.

      Method

      Human T cells engineered to target the cancer-antigen mesothelin (MSLN) by expression of a chimeric antigen receptor (CAR) with or without co-transduction with a PD1-DNR underwent repeated antigen stress with cancer cells with constitutive overexpression of PD-L1. For comparative efficacy evaluation, anti-PD-1 antibody was co-administered with CAR T cells (CARs). In vitro efficacy was evaluated by cytotoxicity (chromium-51 release assay). In vivo, mice with established pleural tumor were treated with either a single dose of MSLN CARs (with and without anti-PD-1 agent) or MSLN PD1-DNR CARs. Tumor burden regression by bioluminescence imaging and median survival were evaluated.

      Result

      In vitro, constitutive PD-L1 overexpression (Fig. A) inhibits MSLN CAR effector function as evidenced by a decrease in cytotoxicity following repeated stimulation with MSLN+PD-L1hi tumor cells (Fig B). MSLN PD1-DNR CARs had increased cytotoxicity when compared to MSLN CARs with or without high frequency anti-PD-1 antibody supplementation. In vivo, mice treated with MSLN CAR (with or without anti-PD-1 antibody) or MSLN PD1-DNR CARs demonstrated enhanced tumor regression (Fig C) and prolonged median survival (Fig D) compared to MSLN CARs alone. Furthermore, a single low dose of MSLN PD1-DNR CARs shows equal anti-tumor efficacy compared to MSLN CARs with multiple doses of anti-PD-1 antibody.

      dozier_figure 1.png

      Conclusion

      Our results demonstrate that CAR T cells engineered to express a cell-intrinsic PD-1 dominant negative receptor overcome PD-L1 mediated T-cell inhibition equally compared to multiple doses of anti-PD-1 antibody administration. A clinical trial with MSLN CAR PD1-DNR CAR T cells is being initiated.

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      MA11.02 - Increased CD3+ TIL Infiltration and Low FOXP3+/CD8+ TIL Ratio Can Predict Anti-PD-1 Therapeutic Response in Non-Small Cell Lung Cancer Patients (Now Available) (ID 12553)

      10:35 - 10:40  |  Presenting Author(s): Hyojin Kim  |  Author(s): Hyun Jung Kwon, Yeon Bi Han, Soo Young Park, Eun Sun Kim, Jin-Haeng Chung

      • Abstract
      • Presentation
      • Slides

      Background

      To determine whether distinct tumor microenvironments differentially affect the clinical response to anti-PD-1 therapy in non-small cell lung cancer (NSCLC), we investigated the expression level of PD-L1 and tumor infiltrating lymphocytes (TILs) and elucidate their predictive role.

      Method

      Forty pretreated specimens (including 21 resected and 19 biopsied tissues) from 36 advanced, treatment-refractory NSCLC patients who underwent PD-1 blockade therapy were analyzed. PD-L1 expression by tumor cells and the distribution of CD3, CD8, CD4, FOXP3 and PD-1 positive TILs were immunohistochemically assessed. The mean number of cells positive for each marker in covered total fields was expressed in density per mm2 using digital image analyzer. In addition, CD8+/CD3+, CD8+/CD4+, FOXP3+/CD8+, and PD-1+/CD8+ ratios were calculated for each specimen using the mean number of total fields.

      Result

      CD3+ and CD8+ TILs were distributed more in PD-L1 positive group compared to PD-L1 negative group. Inversely, EGFR mutant group showed fewer CD3+ TILs than EGFR-naïve group. The patients in the clinical benefit group with PD-1 blockade showed a higher number of CD3+, CD8+ TILs and a higher CD8+/CD3+ TIL ratio (p=0.003, p=0.001, and p =0.042) and a lower FOXP3+/CD8+ TIL ratio compared to non-responders (p=0.001). We analyzed the effects of TIL, PD-L1 and clinicopathologic factors in PD-1 blockade therapeutic response using logistic regression. In multivariate analysis, increased CD3+ TIL infiltration and low FOXP3+/CD8+ TIL ratio were found to be independent predictors of clinical benefit with PD-1 blockade. (p=0.014 and p=0.03, respectively). Using receiver operating characteristic curves, levels of CD3+ TIL and FOXP3+/CD8+ TIL ratio that provide the best distinguishing point between responder versus non-responder to PD-1 blockade were 617.5/mm2 and 25%, respectively (p=0.007 and p=0.003). Considering that 1 mm2 is about 5 high power fields (HPF), a good response to the PD-1 blockade can be expected when CD3 + TIL is observed in 120 per 1 HPF and CD8 + TIL : FOXP3 + TIL are greater than 4 : 1. In addition, there were no difference between sample acquisition method (resection vs. biopsy) and duration (3, 6, and 12 months before PD-1 blockade treatment), and TIL expression.

      Conclusion

      Based on our results, TIL is an independent predictive factor of response to PD-1 blockade and we suggested a cutoff value of TIL to predict responder group. In addition, properly sampled small biopsy tissue and well preserved archival specimens are feasible to evaluate TIL status.

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      MA11.03 - Interaction of Tumor Infiltrating Lymphocytes and Cancer Nuclei Predicts Response to Nivolumab in Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 14143)

      10:40 - 10:45  |  Presenting Author(s): Xiangxue Wang  |  Author(s): Cristian Barrera, Cheng Lu, Vamsidhar Velcheti, Anant Madabhushi

      • Abstract
      • Presentation
      • Slides

      Background

      Immune checkpoint inhibitors, particularly drugs targeting the Programmed death-1 (PD-1) pathway, are promising agents in NSCLC. These drugs however are effective in only a small subset of patients. Programmed death Ligand-1 (PDL1) expression in the tumor predicts response to these agents but is not an optimal biomarker because of spatial and temporal heterogeneity associated with PDL1. PD-L1 is upregulated in response to inflammation in the tumor and strongly correlates with Tumor-infiltrating lymphocytes (TILs). In this work, we evaluated whether quantitative measurements relating to the spatial interplay and arrangement of TILs and cancer nuclei from diagnostic biopsy tissue slide images (H&E) was predictive of response to Nivolumab.

      Method

      Tumor biopsies of total 82 NSCLC patients previously treated with Nivolumab from two different institutions were employed in this study. The RECIST criteria was used to define response. [vv1] The 492 features characterizing the global interaction of TILs and cancer cells through graph interplay metrics are extracted from tumor regions delineated by two expert pathologists to interrogate the difference of phenotypes. Top 5 features were learnt on learning set by random forest classifier from one institution (n=32) and independently validated on patients from a second site (n=50).

      Result

      The most predictive features comprised of difference of characteristic path length between lymphocyte graph and cancer nuclei graph and cosine similarity between lymphocyte node and cancer nuclei node based on their node centrality index. The random forest classifier yielded an area under the receiver operating characteristic curve (AUC) of 0.76 on the training cohort and 0.68 on the validation set (Figure 1).til40.png

      Conclusion

      Our results showed that quantitative measurements relating to the spatial interplay and arrangement of lymphocyte and cancer nuclei from H&E slide images were predictive of response to Nivolumab in NSCLC. Additional independent multi-site validation of these features is needed.

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      MA11.04 - Discussant - MA 11.01, MA 11.02, MA 11.03 (Now Available) (ID 14619)

      10:45 - 11:00  |  Presenting Author(s): Donald Morris

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA11.05 - Indoleamine 2,3-Dioxygenase Expression in Non-Small-Cell Lung Cancer: Analyses of Prevalence, Clinical Correlations and Prognostic Impact (Now Available) (ID 13309)

      11:00 - 11:05  |  Presenting Author(s): Francesco Agustoni  |  Author(s): Hui Yu, Kim Ellison, Derek Smith, Paul Mitchell, Gareth Rivalland, Rafal Dziadziuszko, Dexiang Gao, Kenichi Suda, Shengxiang Ren, Christopher J. Rivard, Charles Caldwell Jr, Leslie Rozeboom, Kristine Brovsky, Diego Cortinovis, Paolo Bidoli, Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Indoleamine 2,3-dioxygenase-1 (IDO-1) is a cytosolic enzyme involved in the catabolism of tryptophan; IDO-1-related immune suppression is due to decreased tryptophan availability and to the generation of tryptophan metabolites, culminating in substantial suppression of T-lymphocytes. Here we investigate IDO-1 expression in a cohort of non-small-cell lung cancer (NSCLC) specimens, both in tumor cells and in immune infiltrate, with correlation of IDO-1 to PD-L1 expression, clinical patient demographics and outcomes.

      Method

      A cohort of 1.200 NSCLC samples were obtained from 437 patients who underwent surgical lung resections at Austin Health, Melbourne, Australia. IDO-1 expression was evaluated by immunohistochemistry. Correlations were assessed using Spearman and Kendall tests. A Cox proportional hazards (PH) model was used to assess if overall survival (OS) was associated with IDO-1 positivity in univariate and multivariable settings.

      Result

      Samples from 437 patients were analyzed for IDO-1 expression, with 111 (25.4%) determined as positive (H-Score 1) and 326 patients (74.6%) as negative (H-Score: 0). IDO-1 expression was determined to be greater in tumor immune infiltrate, with 406 patients (93.8%) determined as positive, while just 27 (6.2%) were IDO-1 negative. There was a significant positive correlation between IDO-1 positive tumor cells and immune cells (0.2167, p < 0.001). Both continuous and binary versions of tumor H-Score showed a significant positive correlation with the amount of tumor immune infiltrate (0.1806 and 0.1698, p < 0.0001, respectively). None of the analyzed variables (age, sex, histology, stage, EGFR, KRAS and PD-L1 status) were found to display a significant correlation with IDO-1 positivity in tumor and immune cells. IDO-1 positivity in tumor cells was found to be significantly associated with OS in the univariate setting and in the multivariable model where variables age, sex, histology, stage, EGFR, KRAS and PD-L1 status were included [P-value = 0.009 and 0.021, respectively; HR: 0.72 (95% CI: 0.55-0.95)]. IDO-1 positivity in immune cells was found to be significantly associated with OS in the univariate setting and was borderline significant in the multivariable model [P-value = 0.006 and 0.053, respectively; HR: 0.798 (95% CI: 0.635-1.003)].

      Conclusion

      To our knowledge, this is the most extensive analysis of IDO-1 expression in NSCLC patients reported in the literature. Our results suggest the possible prognostic role of IDO-1 expression in tumor and immune cells, highlighting the relevance of IDO-1 detection in tumor tissue. Since new compounds targeting IDO-1 are actually under investigation, the identification of potential prognostic and predictive biomarkers will be needed.

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      MA11.06 - Prognostic Value of Complement System in NSCLC and its Association with PD-1 and PD-L1 Expression (Now Available) (ID 12372)

      11:05 - 11:10  |  Presenting Author(s): Luis M Montuenga  |  Author(s): Daniel Ajona, María José Pajares, Javier Freire, Javier Gomez-Roman, Elena Martinez-Terroba, Sergio Ortiz-Espinosa, Ana Lledo, Elisabeth Arenas-Lazaro, Jackeline Agorreta, Fernando Lecanda, Ruben Pio

      • Abstract
      • Presentation
      • Slides

      Background

      Recent research has unveiled novel molecular mechanisms linking imbalanced complement activation and cancer progression. In this context, complement inhibition has emerged as a treatment option for maximizing the clinical efficacy of current immunotherapies that target the PD-1/PD-L1 immune checkpoint.

      Method

      Lung cancer tissues were obtained from 140 patients treated by surgery at the Clinica Universidad de Navarra. Inclusion criteria were: NSCLC histology, complete resection of the primary tumor, absence of cancer within the five years previous to the lung cancer surgery, and no treatment with chemo- or radiotherapy prior to surgery. Resected primary lung tumors were fixed in formalin and embedded in paraffin. After antigen retrieval samples were incubated with anti-human C4d, C5aR1, C1q, PD-1 and anti-PD-L1 followed by detection with the Envision system (Dako). Peroxidase activity was visualized with 3,3’-diaminobenzidine. Sections were slightly counterstained with hematoxylin. Two independent and blinded observers calculated an H -score based on intensity and extension of the staining. Survival curves were generated using the Kaplan–Meier method, and statistically significant differences were analyzed with the log rank test.

      Result

      Immunohistochemistry of complement proteins in NSCLC was performed for C1q, the target recognition of the complement pathway in NSCLC, C4d, a split product of complement activation, and C5aR1, the complement C5a anaphylatoxin receptor. Immunohistochemical analysis showed positive staining for all these proteins, indicating complement activation in primary lung tumor cells. Importantly, high levels of C1q, C4d, and C5aR1 predict poor disease-free survival (P=0.004; P=0.044; and P=0.02; respectively) and poor overall survival (P=0.031; P=0.022; and P=0.048; respectively) in NSCLC patients. A significant association between PD-1 expression levels in immune cells and disease-free survival was found (P=0.002) but this association was not significant for overall survival. PD-L1 expression levels in both immune cells and tumor cells were not associated with prognosis in NSCLC patients. Interestingly, those patients with high levels of C4d presented a significant decrease of PD-L1 expression in tumor cells (P<0.001) suggesting a link between complement activation and the immune homeostasis of the tumor microenvironment.

      Conclusion

      Complement activity in primary NSCLC tumors predicts poor prognosis. C4d, a marker of complement activation, is associated with low levels of PD-L1 expression in tumor cells. Harnessing complement system as therapeutic target may enhance PD-1/PD-L1 immune checkpoint-based immunotherapies.

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      MA11.07 - Expression of LAG-3 and NY-ESO-1 In Tumor Cells is Promising Biomarker Predicting Durable Clinical Benefit of PD-1 Blockade in Advanced NSCLC (Now Available) (ID 12403)

      11:10 - 11:15  |  Presenting Author(s): Hee Ryeong Jang  |  Author(s): Se Hyun Kim, Kyoung Jin Suh, Yu Jung Kim, Mi So Kim, Bhumsuk Keam, Tae Min Kim, Jin-Haeng Chung, Dong-Wan Kim, Dae Seog Heo, Jong-Seok Lee

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD-1 antibodies are currently used in treating advanced non-small cell lung cancer (NSCLC). PD-L1 expression in tumor cell or immune cell is the only available predictive biomarker in the clinic. Lymphocyte activation gene-3 (LAG-3) is an inhibitory checkpoint in immune cells and NY-ESO-1 is an antigen expressed in tumor cells. We investigated LAG-3 and NY-ESO-1 protein expression and its relationship to response to anti-PD-1 therapy in NSCLC.

      Method

      We retrospectively reviewed the medical records of 38 patients with advanced NSCLC who were enrolled in prospective clinical trials of nivolumab or pembrolizumab monotherapy (NCT01295827, NCT01905657, and NCT02175017) between October 2013 and April 2016 at Seoul National University Hospital and Seoul National University Bundang Hospital. Immunohistochemial staining (IHC) of NY-ESO-1(E978, Invitrogen), and PD-L1 (22C3, Dako) in tumor cell and LAG-3(EPR4392, Abcam) in immune cell was performed to determine protein expression.

      Result

      LAG-3 and NY-ESO-1 protein expression were assessed in 38 patients. LAG-3, NY-ESO-1 and PD-L1 were expressed in 76.3% (29/38), 50% (19/38) and 18.5% (7/36, 50% cut-off value), respectively. Sixteen patients with durable clinical benefit (DCB, anti-PD-1 therapy more than 6-month) were grouped as responder. NY-ESO-1 expression (DCB 11/19 vs 5/19, p= .05) and LAG-3 expression (DCB 16/29 vs 0/9, p= .003) were significantly correlated with the DCB to Anti-PD-1 therapy, while PD-L1 expression was identified in 5 patients with DCB (5/7 vs 11/29, p= .12). Patients with both NY-ESO-1 and LAG-3 expression had high rate of DCB (73.3%, 11/15 pts). With the results of the interaction with DCB, the calculation of positive predictive value and negative predictive value about durable clinical benefit is assessed and the significance of each measurement was proven by Fisher’s exact test. As a result, NPV of LAG-3 expression in tumor cell was 100% and PPV of each protein expression was LAG-3 (55.17%), NY-ESO-1(57.89%) and PD-L1 (71.43%) respectively. In survival analysis, LAG-3 expression was a significant predictor for PFS (HR 0.170; CI 0.066-0.437; p< .0001) and OS (HR 0.250; CI 0.140-0.599; p= .002).

      Conclusion

      NY-ESO-1 expression on tumor tissue and LAG-3 expression on tumor microenvironment may be useful for identifying advanced NSCLC patients for the treatment of anti-PD-1 therapy. These protein markers seem quite promising and warrant further investigation in large sample size.

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      MA11.08 - Discussant - MA 11.05, MA 11.06, MA 11.07 (Now Available) (ID 14620)

      11:15 - 11:30  |  Presenting Author(s): Erin Schenk

      • Abstract
      • Presentation
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      Abstract not provided

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      MA11.09 - Single-Cell Characterization of the Immunologic Microenvironment in Advanced-Stage, Oncogene-Driven NSCLC (Now Available) (ID 12122)

      11:30 - 11:35  |  Presenting Author(s): Julia Rotow  |  Author(s): Caroline McCoach, Ashley Maynard, David Naeger, Yaron Gesthalter, K Pallav Kolli, Spyros Darmanis, Trever G Bivona, Collin Blakely, Jonathan Weissman

      • Abstract
      • Presentation
      • Slides

      Background

      The immunologic microenvironment in oncogene-driven non-small cell lung cancer (NSCLC) is poorly understood. Despite high initial response rates to tyrosine kinase inhibitors (TKIs) in patients with oncogene-driven NSCLC, responses are incomplete and transient. Furthermore, response rates to subsequent checkpoint inhibitor immunotherapies are very low. Understanding the immunologic microenvironment may facilitate understanding treatment resistance in this population.

      Method

      From October 2016 to March 2018 we performed single-cell sequencing on 35 tissue samples from 28 patients with NSCLC. Fresh tissue samples were obtained at time of standard of care biopsies and as research sample collections. Single-cell level whole transcriptome RNA sequencing was performed using SmartSeq2. Cells were clustered into distinct cell states on a multi-dimensional gene expression space and visualized using t-distributed stochastic neighbor embedding (t-SNE) for further dimensionality reduction. Cellular identities for each cluster were established by examining the enrichment of known cell-type specific genes across all distinct clusters.

      Result

      Tumor samples were obtained from predominantly stage IV lung adenocarcinoma (90.6%) harboring an oncogenic driver (EGFR-mutant 50%, ALK-rearranged 21.9%, BRAF V600E 9.4%, ROS1-rearranged 9.4%, MET exon 14 skipping 6.3%, and KRAS-mutant 3.1%). Samples were collected prior to treatment (21.9%), during treatment (46.9%), and at disease progression on therapy (31.3%). All patients with a targetable oncogenic driver received a standard of care TKI and the KRAS-mutant patient received pembrolizumab monotherapy. A total of 6048 cells were isolated, including 3457 immune cells, with an average of one million reads and 2500 genes per cell. The immunologic microenvironment (average 108 immune cells/sample) included macrophages/monocytes (33% of cells), T cells (31.9%), and B cells (11.6%), as well as a smaller fraction (<10%) of dendritic cells, Langerhans cells, mast cells, neutrophils, and NK cells. Unbiased gene expression-based subclustering of T cells identified 7 distinct T cell populations, including naïve (22.6%), cytotoxic and/or memory T cells (44.1%), and T regulatory cells (5.6%), as well as 6 tumor-associated macrophage populations with distinct gene expression patterns.

      Conclusion

      Single-cell RNA sequencing to identify immune cell populations is feasible in advanced-stage NSCLC biopsy specimens across multiple time points during treatment. Here, we describe the heterogeneity of infiltrating immune cell phenotypes including T cell and macrophage subtypes. An improved understanding of the immunologic microenvironment in oncogene-driven NSCLC may facilitate patient selection for immunotherapy treatment and aid in the rational design of alternative or combination immunotherapy strategies for a patient population rarely responsive to current immunotherapeutic agents.

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      MA11.10 - Identification of Mismatch Repair Deficient Lung Adenocarcinomas Using Targeted Next-Generation Sequencing (Now Available) (ID 12439)

      11:35 - 11:40  |  Presenting Author(s): Navin Rajput Mahadevan  |  Author(s): Priyanka Shivadasani, Jonathan Nowak, Mark M. Awad, Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Background

      Mismatch repair (MMR) deficiency/microsatellite instability (MSI) results from the inactivation of DNA mismatch repair proteins. Due to the defect in DNA repair, MMR-deficient (D) tumors display an elevated tumor mutation burden (TMB) and a characteristic increase in small insertions/deletions within homopolymer tracts (“homopolymer indels”), a signature that can be detected using next generation sequencing methods. MMR-D/MSI predicts response to immune oncology (IO) agents (Le et al., 2017) and is an approved biomarker for pembrolizumab therapy in the relapse setting irrespective of histologic diagnosis. In this study, we retrospectively analyzed a large cohort of non-small cell lung carcinomas using targeted next generation sequencing to examine the prevalence and clinicopathologic associations of MMR-D in this tumor type.

      Method

      TMB and MSI status was derived from a 309-447 gene targeted next generation sequencing panel (OncoPanel) using an internally validated method (Nowak et al., 2017), that relies on an empirically defined homopolymer indel cutoff of >=1.52/Mb to identify candidate MMR-D tumors. MMR/MSI status was confirmed using MSI PCR (5 marker panel) and/or immunohistochemistry (IHC) for MLH1, PMS2, MSH2, and MSH6. When indicated, MLH1 promoter methylation status was evaluated by methylation-specific PCR.

      Result

      2242 lung tumors, including 1835 non-squamous non-small cell lung carcinomas (NSCLC), were interrogated. A total of three lung tumors (all adenocarcinoma) with confirmed MSI/MMR-D by orthogonal methods were identified, for a prevalence of 0.1% of all lung tumors and 0.2% of non-squamous NSCLC. The TMB of these tumors averaged 42.5 mutations/Mb with 7-10 homopolymer indels /Mb. All three tumors showed loss of MLH1 and PMS2 staining by IHC; two cases had somatic loss-of-function MLH1 variants and one showed MLH1 promoter methylation. All were from female patients whose mean age was 68 years (range: 53-83). All showed a poorly-differentiated histology with moderate to brisk lymphoid infiltrates. One patient was a never-smoker; her tumor had a concomitant EML4-ALK rearrangement. The other two patients had moderate/heavy smoking histories (12.5-80 pack-years) both showed RASA1 and NF1 inactivating mutations. One tumor evolved in the context of usual interstitial pneumonia.

      Conclusion

      MMR-D is very rare in lung tumors, where it appears to arise as somatic event and is enriched in adenocarcinoma. MMR-D may coexist with other relatively uncommon driver alterations, including those not traditionally associated with IO response. Additional investigation is needed to determine if MMR-D confers sensitivity to IO in lung carcinomas.

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      MA11.11 - Discrepancy of Tumor Neoantigen Burden Between Primary Lesions and Matched Metastases in Lung Cancer (Now Available) (ID 12289)

      11:40 - 11:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Personalized vaccine based on tumor neoantigens showed the striking antitumor effect on several solid tumors, suggesting its significant and potential role in curing cancer. However, whether tumor neoantigens identified from primary lesions were similar to their matched metastases remain unknown. Here, we aimed to compare the tumor neoantigen burden (TNB) between primary lesions and matched metastases in lung cancer.

      Method

      Primary lung cancers, matched metastatic sites and peripheral blood (10 mL, EDTA) were collected before any systemic therapy as part of the standard clinical care. Genomic DNA was extracted from all included samples. The matched peripheral blood leukocytes were used as the source for germline DNA control. DNA libraries were subjected to whole-exome capture and then sequenced on an Illumina HiSeq X-TEN platform. The criteria for tumor neoantigen identification were tumor specific mutations (missense, frameshift, inframe insertion or deletions), fold change > 10, high predicted affinity (IC50 < 500 nM) and predicted peptide of 9-10 amino acids in length.

      Result

      Totally, 14 cases with matched lung primary lesions and metastases were enrolled, including 10 patients with liver metastases and 4 with brain metastases. A wide range of TNB were identified in both primary lesions (median 157, range 21-1156) and metastases (median 135, range 35-1902). We observed a large discrepancy of TNB between primary lesions and matched metastases, with a median unique percentage of 82.20% (74.03%-95.24%) in primary lesions and 84.50% (77.45%-97.14%) in metastases. In patients with brain metastases, primary lesions had a percentage of 90.98% (79.57%-95.24%) unique tumor neoantigens, while metastases had 86.03% (77.45%-97.14%). For those with liver metastases, the median unique percentage of tumor neoantigens was 80.58% (74.03%-88.66%) in primary lesions and 83.35% (78.49%-91.14%) in metastases. Smoking history and histological types had no impact on the discrepancy of TNB (P > 0.05, P > 0.05; respectively). TNB of primary lesions was similar to matched metastases (P = 0.733). However, primary lesions of brain metastases had a significantly higher percentage of unique tumor neoantigen than that of liver metastases (P = 0.025).

      Conclusion

      There is a large percentage of different tumor neoantigens between primary lesions and matched metastases in lung cancer. Whether this discrepancy could affect the efficacy of following personalized vaccine on primary lesions or matched metastases need further investigation.

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      MA11.12 - Discussant - MA 11.09, MA 11.10, MA 11.11 (Now Available) (ID 14621)

      11:45 - 12:00  |  Presenting Author(s): Ignacio Gil-Bazo

      • Abstract
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      Abstract not provided

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    MA12 - Mesothelioma Surgery and Novel Targets for Prognosis and Therapy (ID 913)

    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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      MA12.01 - The Information Pathway to Randomisation: Patients Experience of the Mesothelioma and Radical Surgery (MARS2) Feasibility Trial (Now Available) (ID 11200)

      10:30 - 10:35  |  Presenting Author(s): Angela Mary Tod  |  Author(s): Clare Warnock, Karen Lord, Liz Darlison

      • Abstract
      • Presentation
      • Slides

      Background

      The Mesothelioma and Radical Surgery 2 (MARS 2) trial was established in the UK to evaluate the role of radical surgery, (Pleurectomy decortication), for the treatment of malignant pleural mesothelioma (MPM). It compares chemotherapy and surgery to chemotherapy alone. The feasibility trial included a nested qualitative sub-study. The sub study aimed to 1) understand the patient experience of MARS2 trial process and interventions and 2) Identify any information and support needs required by patients. We present here the results related to MARS2 participant’s information experiences and needs at the point of randomisation. Implications for information provision to enhance patient experience and overcome recruitment barriers1 within MPM trials are considered.

      Method

      41 in-depth longitudinal qualitative methods were used with 15 participants following randomisation. 9 participants received chemotherapy and surgery and 6 received chemotherapy alone. Interviews were conducted following randomisation, and at 6 and 12 months after the initial interviews. Participants randomised to surgery also had an interview after post-operative discharge. Data was collected between August 2015 and March 2017 and analysed using Framework analysis2

      Result

      The findings provide insight into the challenging context within which potential participants have to assimilate knowledge about a trial such as MARS2. Prior to hearing about the trial participants had encountered a diverse range of new and concerning experiences. These included worrying symptoms, diagnostic tests, investigations and the drainage of litres of fluid from the lung. They had to absorb an array of life-changing facts in a short time including that they had a rare incurable cancer with a poor prognosis; their illness was an occupational disease with legal and financial implications due to asbestos exposure. Participants attended their trial consultation soon after this challenging diagnostic information provision. The study reveals variations in understanding of the trial procedures, specifically decision-making regarding treatments, equipoise and the process of randomisation. Motivations for participating in the trial were identified along with preferences for information formats.

      Conclusion

      This study provides unique insight into the information pathway of MPM trail participants, from diagnosis to randomisation. Results suggest that improvements in presentation of trial information and the development of formats that can be tailored to individual needs and preferred ways of learning, many enhance experience of and recruitment to MPM trials. Working with patients to co-produce information that communicates challenging concepts effectively, (such as randomisation and equipoise), may be a useful approach to meeting this challenge.

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      MA12.02 - Quality of Life Following Pleurectomy Decortication and Extrapleural Pneumonectomy for Pleural Malignant Mesothelioma (Now Available) (ID 12983)

      10:35 - 10:40  |  Presenting Author(s): Wil Lieberman-Cribbin  |  Author(s): Andrea Wolf, Rebecca Schwartz, Raja Flores, Emanuela Taioli

      • Abstract
      • Presentation
      • Slides

      Background

      Few studies have focused on quality of life (QoL) after treatment of malignant pleural mesothelioma (MPM). Questions remain as to which surgical procedure, extrapleural pneumonectomy (EPP) or pleurectomy (P/D), is most effective and results in better outcomes for survival and involves fewer complications. A comprehensive review was conducted on MPM patients to assess differences in QoL following P/D and EPP.

      Method

      Original research studies on QoL after mesothelioma surgery were identified through May 2018: 17 articles, 14 datasets encompassing 659 patients, were retrieved. Measures of lung function (FEV, FVC) and EORTC QLQ-C30 were compared 6 months following surgery with preoperative values.

      Result

      QoL data was available for 102 EPP patients and 432 P/D patients. Two studies directly compared QoL between the two techniques. While QoL was still compromised 6 months following surgery, P/D patients fared better than EPP patients across all QoL measures. Physical function, social function, global health and dyspnea were higher at follow-up for PD than for EPP, while other indicators such as pain and cough were similar. FEV and FVC were higher at follow-up for P/D compared to EPP, although only one study reported FEV and FVC following EPP.

      Conclusion

      QoL is better for patients undergoing P/D compared to EPP for an extended period following surgery. Given the need for multimodality therapy and the aggressive nature of MPM, QoL outcomes should be strongly considered when choosing type of surgery for MPM.

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      MA12.03 - The Impact of Malignant Pleural Mesothelioma Histology on the Use of Surgery and Survival in a Population-Based Analysis (Now Available) (ID 14406)

      10:40 - 10:45  |  Presenting Author(s): Chi-Fu Jeffrey Yang  |  Author(s): Nicholas Mayne, John Z Deng, Sarah J Commander, Thomas A. D'Amico, Mark Berry

      • Abstract
      • Presentation
      • Slides

      Background

      Histologic subtype for malignant pleural mesothelioma (MPM) is known to be an important determinant of both treatment and survival. This study aimed to quantify the impact of MPM histology on the use of surgery and survival in a population-based analysis.

      Method

      Overall survival (OS) of patients with stage I-III epithelioid, sarcomatoid, and biphasic MPM in the National Cancer Database from 2004 to 2015 was evaluated using Kaplan-Meier survival analysis and multivariable Cox proportional hazard models.

      Result

      Of the 3,346 patients who met inclusion criteria, the histologic subtype was epithelioid in 2,326 patients (70%), biphasic in 482 patients (14%), and sarcomatoid in 538 patients (16%). Median survival was 16.2 [95% CI: 15.3 – 17.2] months in the epithelioid group, 10.9 [95% CI: 9.8 – 11.9] months in the biphasic group, and 5.3 [95% CI: 4.7 – 6.0] months in the sarcomatoid group (p<0.001). Cancer-directed surgery was utilized more often in epithelioid (31%, n=718) and biphasic patients (38%, n=181) compared to sarcomatoid patients (17%, n=91) (p<0.001). Among patients who underwent surgery, median survival was significantly better for epithelioid (22.6 [95% CI: 21.2 – 24.8] months) and biphasic (14.7 [95% CI: 12.6 – 17.3] months) histologies compared to sarcomatoid histology (7.7 [95% CI: 6.4 – 8.6] months) (p<0.001). Surgery was associated with better survival in multivariable analysis for epithelioid (HR 0.81; [95% CI: 0.72 – 0.93], p=0.002) and biphasic histologies (HR 0.69; [95% CI: 0.53 – 0.89], p=0.004), but not for sarcomatoid type mesothelioma (HR 0.87; [95% CI: 0.65 – 1.16, p=0.34). Further, the absolute difference in median survival between surgical and non-surgical therapy was more clinically significant for the epithelioid (22.6 vs 15.8 months; p <0.001 and biphasic (14.7 vs 10.4 months; p=0.001) patients compared to the sarcomatoid (7.7 vs 7.2 months; p=0.13).

      Conclusion

      In this U.S. national analysis of patients with malignant pleural mesothelioma, surgery was most commonly used for epithelioid and biphasic histologies and was associated with a median survival of nearly 2 years and over 1 year, respectively. However, surgery was also used in almost 1 in 5 patients with sarcomatoid mesothelioma but was associated with a median survival of less than 8 months. These results suggest that the specific mesothelioma histology should be firmly established before surgery, and it is reasonable to aggressively treat select patients with epitheloid and biphasic mesothelioma with surgery, but that surgery should not be performed for most patients with sarcomatoid mesothelioma.

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      MA12.04 - Discussant - MA 12.01, MA 12.02, MA 12.03 (Now Available) (ID 14623)

      10:45 - 11:00  |  Presenting Author(s): Marc De Perrot

      • Abstract
      • Presentation
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      Abstract not provided

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      MA12.05 - Phase 1 Study of HSP90 Inhibitor Ganetespib with Pemetrexed and Cisplatin/Carboplatin Chemotherapy for Pleural Mesothelioma (Now Available) (ID 11921)

      11:00 - 11:05  |  Presenting Author(s): Dean A Fennell  |  Author(s): Sarah Danson, Martin Forster, Denis Talbot, Penella Woll, Jennifer Child, Yenting Ngai, Laura Farrelly, Allan Hackshaw, Annabel Sharkey, Sara Busacca, Robert Hastings, Dan Barnes, Marianne Nicolson, Paul Taylor, Samreen Ahmed, Graham Mark Wheeler

      • Abstract
      • Presentation
      • Slides

      Background

      There have been no new licenced therapies for mesothelioma in over a decade. Ganetespib is a small-molecule heat-shock protein 90 (Hsp90) inhibitor, with significant activity for down-regulating Hsp90 client protein levels. Prior evidence indicates efficacy for ganetespib in mesothelioma through critical survival pathways and synergies with antifolates and platinum chemotherapy.

      Method

      We conducted a dose-escalation study of ganetespib in patients with pleural malignant mesothelioma and ECOG 0-1. Ganetespib was combined with standard pemetrexed/platinum therapy, using either cisplatin (GCisP), or carboplatin (GCarbP). Three ganetespib cohorts were: 100, 150 & 200mg/m2 given days 1 and 15, every 21 days. GCisP was evaluated using a 3+3 design. GCarbP followed an accelerated titration run-in using single patients, switching to a 3+3 design after one dose limiting toxicity (DLT). DLT was assessed during cycles 1-2 for GCisP and cycle 1 for GCarbP. Genomic instability was inferred by array-based analysis of somatic copy number.

      Result

      27 patients were treated (GCisP, n=16; GCarbP, n=11). Median age 66 (range 37-76), 6 PS-0/21 PS-1, and 25 male. Only 3 patients experienced DLTs, all at 200mg/m2: grade 3 nausea (GCisP, n=1; GCarbP, n=1); grade 2 infusion-related reaction (GCarbP, n=1). This dose was the maximum tolerated dose. Partial tumour response rate was 61% (14/23 evaluable patients); 7 patients had tumour burden reduction of >50% (Figure). PFS was better using 200mg/m2 versus 100mg/m2 (hazard ratio 0.32, 95%CI 0.11-0.95, p=0.04). One patient remains progression-free even after 37 months. Total loss of heterozygosity (LOH) was correlated with increased tumour burden (n=7, correlation=0.7, p=0.078).

      meso02abstract_bestresponse.png

      Figure. Best tumour response (% change in tumour burden from baseline)

      Conclusion

      Ganetespib plus pemetrexed and platinum chemotherapy was well-tolerated in patients with pleural mesothelioma, with evidence of activity, particularly at the recommended dose of 200mg/m2. LOH correlated with poorer response to this triplet combination.

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      MA12.06 - STELLAR – Final Results of a Phase 2 Trial of TTFields with Chemotherapy for First-Line Treatment of Malignant Pleural Mesothelioma (Now Available) (ID 13806)

      11:05 - 11:10  |  Presenting Author(s): Giovanni L Ceresoli  |  Author(s): Joachim G.J.V. Aerts, Jaroslaw Madrzak, Rafal Dziadziuszko, Rodryg Ramlau, Susana Cedres, Birgitta Hiddinga, Jan P Van Meerbeeck, Manlio Mencoboni, David Planchard, Antonio Chella, Lucio Crinò, Maciej Krzakowski, Federica Grosso

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. In-vitro, human mesothelioma cells were highly susceptible to TTFields. TTFields have been shown to significantly extend survival of patients with glioblastoma when added to chemotherapy.

      Method

      The trial accrued 80 patients with unresectable, previously untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria included ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. The primary endpoint was overall survival (OS) and secondary endpoints were response rate, progression free survival (PFS) and toxicity. This prospective, single arm study assumed an historical control with a median survival of 12.1 months (Vogelzang et al. 2003). The sample size provides 80% power with a two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months.

      Result

      All 80 patients were enrolled between 2016 and 2017, with a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 56% smokers. 16% (13 patients) had metastatic disease and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy and 63% (50 patients) received carboplatin.

      Median OS was 18.2 months (95% CI 12.1-25.8) compared to 12.1 months in the historical control. Median PFS was 7.6 months (95% CI 6.7-8.6) compared to 5.7 months in the historical control. Partial responses were seen in 40.3% of patients and clinical benefit (PR+SD) was seen in 97.2% of patients. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Only 4 patients (5%) had grade 3 dermatitis. The following grade 3-4 systemic AEs were reported in >3% of patients: hematological AEs (15%) and fatigue (4%).

      Conclusion

      The study met its primary endpoint of significant extension of survival for previously untreated mesothelioma patients. Secondary efficacy endpoints were also improved compared to historical control. The study demonstrated no safety concerns for the combination of TTFields to the thorax together with standard chemotherapy. These results support the addition of TTFields to standard chemotherapy in the treatment of first-line malignant pleural mesothelioma.

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      MA12.07 - gC1qR Expression is Independently Prognostic for Survival Benefit Following Chemotherapy in Mesothelioma (Now Available) (ID 13284)

      11:10 - 11:15  |  Presenting Author(s): Xiaoyu Li  |  Author(s): Takashi Eguchi, Rania G Aly, Navin Chintala, Kay See Tan, John Messinger, Marjorie G. Zauderer, Berhane Ghebrehiwet, Prasad S. Adusumilli, Ellinor I.B. Peerschke

      • Abstract
      • Presentation
      • Slides

      Background

      Overexpression of gC1qR, a multicompartmental and multifunctional cellular protein, has been shown to promote chemotherapy-induced apoptosis in cancer cells, but compromise CD4 T-cell proliferation in viral infections. The goal of this study was to investigate the overexpression of gC1qR, and its prognostic association with chemotherapy and CD4 T-cell infiltration in malignant pleural mesothelioma (MPM).

      Method

      Tissue microarrays comprising 6 tumoral and 3 stromal cores from 265 patients with MPM (216 epitheloid, 26 biphasic, and 23sarcomatoid, 1989-2010) were investigated by immunohistochemistry for gC1qR expression (intensity and distribution by H-score, range 0-300), and CD4 T-cell infiltration. Overall survival (OS) was analyzed by the Kaplan-Meier method (high versus low gC1qR expression delineated by median score). Multi-variable analysis included clinical, pathological factors and stage (T, N).

      Result

      In comparison to benign and reactive mesothelial cells (median H-score 30), gC1qR is overexpressed (median H-score 155) in all histological types of MPMs (263/265, 99.2%). In epithelioid MPM patients – 1) among patients who received neoadjuvant chemotherapy (NAC), high gC1qR was associated with better median OS (25 vs.11 months, Fig1A), 2) among patients without NAC, high gC1qR was associated with better survival, survival benefit is pronounced in patients who received postoperative chemotherapy (median OS 38 vs.19 months, Fig1B), and 3) in multivariate analysis, high gC1qR was an independent factor for better OS. gC1qR expression did not correlate with CD4 T cell infiltration. However, among patients without NAC, high CD4+ T cell infiltration-high gC1qR expression was associated with better OS (26 vs 18,12, and11 months, Fig1C).

      gc1qr.jpg

      Conclusion

      gC1qR is overexpressed on MPM cells. MPM patients with high gC1qR expression have a significant survival benefit particularly following chemotherapy; or in the presence of high CD4 T-cell infiltration.

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      MA12.08 - Discussant - MA 12.05, MA 12.06, MA 12.07 (Now Available) (ID 14625)

      11:15 - 11:30  |  Presenting Author(s): Quincy Chu

      • Abstract
      • Presentation
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      Abstract not provided

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      MA12.09 - Preclinical Investigations of Folate Receptor Targeted Nanoparticles for Photodynamic Therapy of Malignant Pleural Mesothelioma (Now Available) (ID 11277)

      11:30 - 11:35  |  Presenting Author(s): Tatsuya Kato  |  Author(s): Cheng S Jin, Hideki Ujiie, Kosuke Fujino, Daiyoon Lee, Hironobu Wada, Hsin-pei Hu, Licun Wu, Rober A Weersink, Juan Chen, Hiromi Kanno, Yutaka Hatanaka, Kanako C Hatanaka, Yoshihiro Matsuno, Marc De Perrot, Brian C Wilson, Gang Zheng, Kazuhiro Yasufuku

      • Abstract
      • Presentation
      • Slides

      Background

      Photodynamic therapy (PDT) following lung-sparing extended pleurectomy (EPD) for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression of folate receptor 1 (FOLR1) has been reported in MPM, and targeting the FOLR1 has been considered as a new potential strategy. We have developed FOLR1-targeting porphyrin-lipid nanoparticles (folate-porphysomes; FP) for PDT. The inhibition of survival pathways of activated epidermal growth factor (EGFR) also enhance the PDT efficacy. Here, we have combined these approaches by using FP based PDT together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

      Method

      The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1-targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and the therapeutic efficacy were then examined. The effect of EGFR-TKI was assessed in vitro. The in vivo combined anti-tumor effect of EGFR-TKI and FP-PDT was then evaluated.

      Result

      FOLR1 and EGFR were expressed in 79 % and 89 % of the MPM samples, respectively. The intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated in FP and then irradiated at 671 nm, there was significant in vitro cell kill, which was inhibited in the presence of free folic acid, suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pre-treatment with EGFR-TKI plus FP-PDT showed further marked improvement of treatment responses.

      Conclusion

      Folate-porphysome based PDT shows selective destruction of MPM cells based on FOLR1 targeting, and pre-treatment with EGFR-TKI further enhances the therapeutic response.

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      MA12.10 - Long-Term Impact of Radiotherapy Before Surgery for Mesothelioma on the Distribution of Memory T Cell Subsets (Now Available) (ID 12728)

      11:35 - 11:40  |  Presenting Author(s): Junichi Murakami  |  Author(s): Licun Wu, Mikihiro Kohno, Mei-Lin Chan, Yidan Zhao, Zhihong Yun, Marc De Perrot

      • Abstract
      • Presentation
      • Slides

      Background

      Postoperative recurrence remains one of the critical issues in treatments for mesothelioma. We previously reported that non-ablative, hypo-fractionated radiation before surgery generated an antigen-specific activation of the immune system and could provide an in situ vaccination with long-term protection against mesothelioma in our murine model. An effective immunological protection depends on memory T cell subset diversification. However, limited work has been done to address the distribution of memory T cell subsets and its effects on the immune system after radiotherapy followed by surgery for mesothelioma.

      Method

      C57BL/6 mice bearing AE17-OVA tumor were treated with local radiotherapy (LRT). LRT 5Gy was delivered on days 10, 11 and 12. We performed radical tumor resection 7 days after LRT. The mice were re-challenged under the skin or into thoracic cavity with AE17-OVA 28 days after surgery and defined as immunological protective memory model if the tumors were completely rejected. Memory model received subcutaneous tumor inoculation once again (second rechallenge), samples were harvested on day 0, 3, 10. We investigated memory T cell subsets using flow cytometry. In addition, the harvested total splenocytes (effector) were co-cultured with CFSE-labeled AE17-OVA (target) for three days. Each of their cytotoxic potential was analyzed by evaluating a number of AE17-OVA and its early or late apoptosis.

      Result

      8 out of 10 mice completely rejected the subcutaneous tumor in mice treated with LRT and surgery after re-challenged. We observed significantly better survival in the memory model re-challenged into the thoracic cavity compared with no treatment mice. After subcutaneous tumor inoculation, central memory T cells (CD44[+]CD62L[+]KLRG1[-]) on day 0, effector memory T cells (CD44[+]CD62L[-]KLRG1[-]) and terminal effector T cells (CD44[+]CD62L[-]KLRG1[+]) on day 0, 3, 10 increased significantly in CD8[+] splenocytes of memory model compared with no treatment mice. This observation was also seen in draining and non-draining lymph nodes. The MFI of CFSE reflecting a number of AE17-OVA cells decreased, whereas the proportion of early (Annexin V[+]FVD[low]) or late (Annexin V[+]FVD[high]) apoptotic cells in CFSE[+] cells increased, depending on time passage and effector/target ratio after tumor inoculation in both memory model and naïve mice. However, during time passage, memory model always had a stronger cytotoxicity (even at Day 0) as compared to naïve mice.

      Conclusion

      Our data raise an important possibility that non-ablative, hypo-fractionated radiotherapy followed by surgery for mesothelioma contributes to the development and long-term maintenance of memory T cell subsets, which could remain poised to rapidly recall effector functions upon antigen re-exposure.

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      MA12.11 - Analysis of Angiogenic and Stromal Biomarkers in a Large Malignant Mesothelioma Cohort (Now Available) (ID 12234)

      11:40 - 11:45  |  Presenting Author(s): Puey Ling Chia  |  Author(s): Prudence Russell, Khashayar Asadi, Carmel Murone, Marzena Walkiewicz, Ulf Eriksson, Andrew Scott, Thomas John

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other mesothelium membranes. Agents targeting vascular endothelial growth factor (VEGF) receptor such as bevacizumab; and multi-kinase inhibitors like nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM. In the setting of these new therapies, it is important to evaluate angiogenic and stromal markers in MM to assess their associated prognostic implications.

      Method

      Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients who underwent surgical resection or biopsy for MM between 1988 and 2014. PDGF-CC, FGFR-1, VEGF and CD31 expression were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0–300 to each sample, based on the percentage of cells stained at different intensities. The discriminatory threshold was set for each IHC stain (usually the median score) and samples were classified as low (below median) or high expression (above median). CD31 was evaluated via Chalkley’s method to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM.

      Result

      The histological subtypes comprised of 203/325 (62.5%) epithelioid; 72/325 (22.2%) biphasic; 42/325 (12.9%) sarcomatoid, or indeterminate. The median age was 67 (range 24-88) with Male: Female ratio of 266: 53.

      CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology (13/31 (42%) epithelioid; 10/31 (32%) sarcomatoid; 7/31 (23%) biphasic; 1/31 indeterminate).

      PDGF-CC high (≥150) was seen in 203/310 (65%) of all samples but was higher in epithelioid subtype [129/203 (64%)]. VEGF high (≥80) was seen in 219/322 (68%) of all MM with 143/209 (68%) of epithelioid histology.

      FGFR-1 high (≥40) was seen in 127/310 (41%) of all MM and 73/127 (57.5%) are of epithelioid histology.

      There was no association of VEGF and FGFR-1 IHC with survival nor differences between histological subtypes.

      There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGF-CC expression (OS 18.5 vs 13.2 months; HR 0.7928; 95%CI 0.5958 to 1.055, P=0.1110).

      High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95%CI 0.2873 to 0.7941, P=0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-CC and 20/31 (64%) with high VEGF scores.

      Conclusion

      High PDGF-CC expression and CD31 scores are associated with poor survival in MM. Abrogating these pathways may have prognostic implications.

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      MA12.12 - Discussant - MA 12.09, MA 12.10, MA 12.11 (Now Available) (ID 14627)

      11:45 - 12:00  |  Presenting Author(s): Masaki Anraku

      • Abstract
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      Abstract not provided

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    MA13 - Interventional Pulmonology (ID 914)

    • Type: Mini Oral Abstract Session
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 206 AC
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      MA13.01 - CT-Guided Transthoracic Needle Biopsy for Evaluation of PD-L1 Expression: Comparison of 22C3 and SP263 Assays (Now Available) (ID 11312)

      10:30 - 10:35  |  Presenting Author(s): Kyongmin Sarah Beck  |  Author(s): Kyo Young Lee, Su Jin Hong

      • Abstract
      • Presentation
      • Slides

      Background

      Although there are a few studies about concordance of different assays testing PD-L1 expression using surgical specimens, there hasn’t been any such concordance study using real-world biopsy specimens. However, many of the patients requiring immunotherapy and thus PD-L1 testing have unresectable lung cancer and have to rely on small biopsy results. Although phase 2 of Blueprint phase 2 does include core biopsy specimens, they are mixed with bronchial biopsy specimens and the absolute number is very small (n=20). We sought to evaluate the concordance of 22C3 and SP263 assays in a larger number CT-guided transthoracic needle biopsy (TNB) specimens.

      The purpose of this study was to assess the concordance of two commercially available diagnostic assays (22C3 and SP263) in evaluating programmed cell death ligand-1 (PD-L1) expression using specimens from CT-guided TNB in a routine clinical setting.

      Method

      This retrospective analysis reviewed 202 non-small cell lung cancer (NSCLC) patients who underwent CT-guided TNB at our institution from April 2017 to February 2018. Among these, biopsy specimens tested with both 22C3 and SP263 assays were included for review. Concordance of PD-L1 expression levels determined by the two assays was assessed using intraclass correlation coefficient, and the agreement of dichotomized values at various cut-offs (1%, 25%, and 50%) were assessed using Cohen’s κ coefficient of agreement. Clinical characteristics and biopsy-related factors were also assessed for the association of concordance of PD-L1 expression detected by different assays

      Result

      In total, 80 patients (M:F =47:33, mean age: 68.0 years) were included in the study. Concordance of PD-L1 expression levels was high (intraclass coefficient: 0.892) between 22C3 and SP263 assays. Agreements at cut-off levels of 1%, 25%, and 50% were also good, with κ values of 0.878, 0.698, and 0.790 respectively. Positive percent agreement was 93.2%, 100.0%, and 95.2% for agreements at 1%, 25%, and 50%. At multivariate analysis, the presence of emphysema was significantly related to discordant PD-L1 results (odds ratio: 0.059, p= 0.005).

      Conclusion

      There is a high concordance of PD-L1 expression evaluated with 22C3 and SP263 assays using CT-guided TNB specimens.

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      MA13.02 - PD-L1 Expression in EBUS-Guided Cytology Specimens of Non-Small Cell Lung Cancer is Not Affected by Type of Fixation: A Study of Matched Pairs (Now Available) (ID 11867)

      10:35 - 10:40  |  Presenting Author(s): Alexander Haragan  |  Author(s): John Roy Gosney, Claire Chadwick, Tom Giles, Seamus Grundy, Victoria Tippett, Krishna Gumparthy, Andrew Wight, Hock Tan

      • Abstract
      • Presentation
      • Slides

      Background

      No previous trials of immune modulators (IMs) to treat non-small cell lung cancer (NSCLC) have included ‘cytology’ specimens, dispersed cells aspirated from a tumour deposit or body cavity, for immunochemical assessment of PD-L1, a useful complementary or compulsory companion diagnostic test. This has led to the widely-held view that, in the absence of such ‘validation’, cytology specimens cannot be used to assess it. In many centres, endobronchial ultrasound (EBUS)-guided aspiration of the tumour or intra-thoracic lymph nodes is the preferred means of diagnosis and staging of NSCLC and such specimens account for the majority received for analysis. Failure to asses them has serious implications for appropriate management and might deny patients effective therapy. Much of this reluctance centres on the alleged effect of fixation in alcohol-based fixatives, the preferred method of cytopathologists, rather than formalin, the standard fixation medium for tissue specimens, on the expression of PD-L1 on the cell surface.

      Method

      We compared expression of PD-L1 in 50 paired specimens of NSCLC, one fixed in an alcohol-based fixative and one in neutral-buffered formalin, taken from the same tumour deposit or lymph node during the same procedure. All were spun down and formed into a cell block before assessment for PD-L1 expression, which was by two appropriately-trained pathologists with extensive experience in its interpretation.

      Result

      In none of the 50 pairs studied was there any significant difference, qualitative or quantitative, in the pattern or extent of PD-L1 expression and, in the great majority, it was identical irrespective of fixation.

      Conclusion

      There is no evidence from this study that the use of alcohol-based fixatives has any effect on the expression of PD-L1 or its interpretation. Notwithstanding the general challenges in accurately assessing such expression, which are common to specimens of tissue as well as dispersed cells, pathologists should feel able to interpret cytology specimens with confidence and clinicians able to rely on the results.

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      MA13.03 - Heterogeneity Analysis of EBUS-TBNA-Derived Specimens for Evaluation of PD-L1 Expression and Copy Number Alterations in Patients with NSCLC (Now Available) (ID 12664)

      10:40 - 10:45  |  Presenting Author(s): Katsuhiro Yoshimura  |  Author(s): Yusuke Inoue, Kazuo Tsuchiya, Masato Karayama, Yuji Iwashita, Tomoaki Kahyo, Akikazu Kawase, Masayuki Tanahashi, Hiroshi Ogawa, Koshi Yokomura, Naoki Inui, Kazuhito Funai, Kazuya Shinmura, Hiroshi Niwa, Takafumi Suda, Haruhiko Sugimura

      • Abstract
      • Presentation
      • Slides

      Background

      Most patients with non-small cell lung cancer (NSCLC) are diagnosed at advanced stages and only small biopsy specimens are available for diagnosis in the majority of the patients. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a useful diagnostic modality and is becoming more relevant and essential procedure in the real-world clinical setting. However, it is poorly elucidated whether EBUS-TBNA-derived small specimens are suitable for evaluation of biomarkers such as PD-L1 alterations, because heterogeneity of PD-L1 expression limits the power as a guide to select patients who are likely to benefit from the PD-1/PD-L1 blockade therapy. In addition, PD-L1 copy number alterations (CNAs) have been proposed to potentially complement the predictive performance of PD-L1 expression. We here evaluated the utility of EBUS-TBNA-derived specimens in the assessment of PD-L1 protein and CNAs focusing on the heterogeneity with other biopsy/resected samples.

      Method

      PD-L1 protein expression and CNAs in 71 EBUS-TBNA specimens of NSCLC were assessed. Corresponding 68 transbronchial biopsy (TBB) specimens, 13 resected primary tumors, and 6 resected metastases were comparatively analyzed. PD-L1 expression on tumor cells was assessed by immunohistochemistry (E1L3N). Positivity of ≥1% was used as the cut-off. PD-L1 CNAs were assessed with fluorescent in situ hybridization, and were classified into three categories: amplification, polysomy, and disomy. Concordance between EBUS-TBNA and other specimens were calculated.

      Result

      The median age was 68 years (38-90 years). The cohort comprised 48 men (67.6%), 15 never-smokers (21.1%), and 39 adenocarcinomas (54.9%). The concordance of PD-L1 positivity between EBUS and the other specimens was moderate; κ=0.63 for EBUS vs TBB, κ=0.68 for EBUS vs the resected primary tumors, and κ=1.00 for EBUS vs the resected metastases. The concordance of PD-L1 CNA statuses was comparable with that of PD-L1 expression: κ=0.60 for EBUS vs TBB, and κ=0.74 for EBUS vs the resected primary tumors. When the PD-L1 copy number was assessed as a continuous variable, the correlation was also good/moderate: ρ=0.60 for EBUS vs TBB specimens, ρ=0.56 for EBUS vs the resected primary tumors, and ρ=0.80 for EBUS vs the resected metastases. Intratumorally, PD-L1 expression was significantly heterogeneous in whole sections of resected tumors, but PD-L1 CNAs was less heterogeneous than protein expression.

      Conclusion

      EBUS-TBNA-derived specimens can be used for the assessment of PD-L1 alterations including CNAs. The concordance of PD-L1 CNAs between EBUS-TBNA and TBB/resected specimens were comparable with that of PD-L1 expression. However, spatial heterogeneity should be taken into account to interpret both PD-L1 protein expression and CNAs.

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      MA13.04 - Discussant - MA 13.01, MA 13.02, MA 13.03 (Now Available) (ID 14629)

      10:45 - 11:00  |  Presenting Author(s): John Roy Gosney

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA13.05 - The Canada Lymph Node Sonographic Score: National Validation of a Sonographic Score to Determine Mediastinal Lymph Node Malignancy (Now Available) (ID 12084)

      11:00 - 11:05  |  Presenting Author(s): Danielle Alexandria Hylton  |  Author(s): Julie Huang, Simon Turner, Daniel French, Chuck Wen, James Masters, Biniam Kidane, Jonathan David Spicer, Jenelle Taylor, Christian Finley, Yaron Shargall, Christine Fahim, Forough Farrokhyar, Kazuhiro Yasufuku, John Agzarian, Waël C. Hanna

      • Abstract
      • Presentation
      • Slides

      Background

      At the time of endobronchial ultrasound (EBUS) staging for Non-Small Cell Lung Cancer (NSCLC), 6 ultrasonic criteria (Fig. 1) are used to assign a Lymph Node Sonographic Score (LNSS) that is predictive of malignancy. The LNSS has not gained widespread use due to lack of research demonstrating its validity and reliability among endoscopists. We hypothesized that LNSS correlates well with the probability of malignancy, potentially guiding decisions for lymph node (LN) biopsy.

      iaslc abstract lnss - figure 1_jpg.jpg

      Method

      We conducted a prospective study to assess the validity and reliability of the LNSS. The validation cohort comprised LN that were video-recorded from patients with NSCLC, and assigned a LNSS by an experienced endoscopist. Videos were then circulated to thoracic surgeons and interventional respirologists across Canada, who were asked to assign a score to each LN. All raters had demonstrated proficiency using our online education module, were blinded to staging information, and to each other. Each LN was scored by at least 3 independent raters. Pathological specimens were used as the gold standard for determination of malignancy. Regression, receiver operator curve (ROC), and Gwet’s AC1 analyses were used to test LNSS score performance, discriminatory capacity, and inter-rater reliability.

      Result

      A total of 300 LNs (18% malignant) from 140 patients were analyzed by 11 endoscopists across 7 Canadian centres. LNSS=0 was strongly predictive of benign LN (NPV= 95.69%, OR=49.2, p=0.001). LNSS ≤2.5 (OR=44, p=0.001) was determined as the cutoff for malignancy based on ROC analysis (c= 0.7757, 95%CI: 0.70281-0.84853). Inter-rater reliability for LNSS=0 was 0.8553 (95%CI:0.8158-0.8947, p=0.0001) and 0.46 for LNSS ≤2.5 (95%CI=0.3521-0.5012, p=0.0001).

      Conclusion

      The Canada LNSS shows excellent performance in identifying benign LN at the time of EBUS. A cutoff ≤2.5 has the potential to inform decision-making regarding biopsy or repeat biopsy/mediastinoscopy if the initial results are inconclusive. Further teaching and education are required to improve inter-rater reliability.

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      MA13.06 - Endosonography with Lymph Nodes Sampling for Restaging the Mediastinum in Lung Cancer: A Systematic Review and Pooled-Data Analysis (Now Available) (ID 11918)

      11:05 - 11:10  |  Presenting Author(s): Long Jiang  |  Author(s): Jun Liu, Wenlong Shao, Kassem Harris, Lonny Yarmus, Weizhe Huang, Jianxing He

      • Abstract
      • Presentation
      • Slides

      Background

      Mediastinal restaging after induction treatment is still a difficult and controversial issue. We aimed to investigate the diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for restaging the mediastinum after induction treatment in patients with lung cancer.

      Method

      Embase and PubMed databases were searched from conception to July 2017. Data from relevant studies were analyzed to assess sensitivity and specificity of EBUS-TBNA and EUS-FNA, and to fit the Hierarchical Summary Receiver-Operating Characteristic curves.

      Result

      A total of nine studies consisting of 542 patients fulfilled the inclusion criteria. All patients were restaged by EBUS-TBNA, EUS-FNA or both. Negative results were confirmed by subsequent surgical approaches. There were no complications reported during any endosonography approaches reviewed. The pooled sensitivities of EBUS-TBNA and EUS-FNA were 66%(95% CI, 60%-72%) and 73%(95% CI, 52%-87%), respectively; and specificities were 100%(95% CI, 98%-100%) and 99%(95% CI, 90%-100%), respectively. The area under the HSROC curves(AUC) were 0.84(95% CI, 0.81-0.87) for EBUS-TBNA and 0.99(95% CI, 0.98-1) for EUS-FNA. Moreover, for patients who received chemotherapy alone, the pooled sensitivity of endosonography with lymph node sampling for restaging was 69% (95% CI, 63%-75%), and specificity was 100% (95% CI, 97%-100%); and for patients who received chemoradiotherapy, the results seemed similar with sensitivity of 65% (95% CI, 50%-78%) and specificity of 100% (95% CI, 96%-100%).

      Variables

      No. of patients

      Pooled sensitivity (95% CI)

      Pooled specificity (95% CI)

      Negative Likelihood Ratio

      AUC

      In all mediastinal stations

      Overall

      543

      0.70 (0.65-0.75)

      1.00 (0.98-1.00)

      0.30 (0.21-0.43)

      0.93 (0.91-0.95)

      EBUS-TBNA

      424

      0.66 (0.60-0.72)

      1.00 (0.98-1.00)

      0.38 (0.26-0.54)

      0.84 (0.81-0.87)

      EUS-FNA

      226

      0.73 (0.52-0.87)

      0.99 (0.90-1.00)

      0.27 (0.14-0.53)

      0.99 (0.90-1.00)

      Combine

      106

      0.67 (0.53–0.79)

      0.96 (0.86–0.99)

      N/A

      0.81 (0.73–0.87)

      Subgroup analysis

      Chemo alone

      365

      0.69 (0.63-0.75)

      1.00 (0.97-1.00)

      0.35 (0.26-0.48)

      0.90 (0.88-0.94)

      Chemo radiotherapy

      130

      0.65 (0.50-0.78)

      1.00 (0.96-1.00)

      0.25 (0.06-1.02)

      0.97 (0.95-0.98)

      If negative Likelihood Ratio(LR-) is smaller: essentially a definite diagnosis when negative result.

      Conclusion

      Endosonography with lymph node sampling is an accurate and safe technique for mediastinal restaging of lung cancer. For nondiagnostic results, a further more invasive approach should be thoroughly considered.

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      MA13.07 - Diagnostic Yield of N3 Hilar Staging by Endobronchial Ultrasonography (EBUS) in Lung Cancer (Now Available) (ID 12565)

      11:10 - 11:15  |  Presenting Author(s): Antoni Rosell  |  Author(s): Jaume Bordas Martinez, Jose Luis Vercher Conejero, Guillermo Rodriguez Gonzalez, Cristina Martin Cabeza, Noelia Cubero De Frutos, Rosa-Maria Lopez Lisbona, Marta Diez Ferrer, Paula Notta, Roger Llatjos Sanuy, Jordi Dorca Sargatal

      • Abstract
      • Presentation
      • Slides

      Background

      Systematic lung cancer staging with EBUS has proven to be equivalent to cervical mediastinoscopy. Nevertheless, in the daily practice it is common to explore and sample negative PET-CT hilar N3 lymph nodes (LN). This study aims to explore if there is enough evidence to support this clinical practice.

      Method

      Retrospective study from our database including 1,013 explorations over the last 5 years. Including criteria were patients with lung cancer staged by PET-CT and EBUS-TBNA. Mediastinal and hilar N3 LN with a short axis ≥ 5 mm were sampled with a 21G needle and assessed by rapid on site evaluation (ROSE). A single nuclear medicine expert reviewed blindly all PET-CT scans and determined the SUVmax of every LN. Those that were ≥ 5 SUVmax by PET-CT and/or ≥ 10mm in short axis by EBUS were considered abnormal.

      Result

      87 patients were included, of which 87% were male with a mean age of 66 years (SD 12.6). The final histopathology diagnoses were adenocarcinoma (46%), squamous cell carcinoma (39%) and other histology (14%). EBUS-TBNA was performed 30 days (SD 16.9) after PET-CT. None of the 61 normal hilar and normal mediastinum N3 LN, and none of the 7 normal N3 hilar LN with abnormal mediastinal LN (3 by PET-CT, 3 by EBUS and 1 for both) resulted positive for lung cancer. Of the 19 patients with abnormal N3 hilar LN (6 by PET-CT, 8 by EBUS and 6 for both) malignancy was found in 16.7% , 25% and 60% for both techniques, respectively.ryywawmo--450186-1-any.png

      Conclusion

      In absence of abnormal N3 hilar LN (PET: SUVmax<5; EBUS<10mm in short axis) it seems there is not enough evidence to sample them, regardless of N3 mediastinal status.

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      MA13.08 - Discussant - MA 13.05, MA 13.06, MA 13.07 (Now Available) (ID 14631)

      11:15 - 11:30  |  Presenting Author(s): Nicole Bouchard

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA13.09 - Electromagnetic Navigation Bronchoscopy as an Integrated Approach to Aid in Diagnosis and Treatment of Pulmonary Lesions (Now Available) (ID 12623)

      11:30 - 11:35  |  Presenting Author(s): Sandeep Khandhar  |  Author(s): Septimiu Murgu, Kyle Hogarth, William Krimsky, Javier Flandes, Otis Rickman, Momen Wahidi, Eric Sztejman, Philip Linden, Sadia Benzaquen, Sandeep Bansal, Erik Folch

      • Abstract
      • Presentation
      • Slides

      Background

      Electromagnetic navigation bronchoscopy (ENB) is an image-guided localization approach to guide endoscopic tools to lung targets. In a single procedure, ENB aids in localizing lung lesions for biopsy or molecular profiling, fiducial placement for stereotactic body radiation therapy (SBRT), or dye marking for surgical resection. The multidisciplinary utility of ENB in a large, prospective, multicenter study is unknown.

      Method

      NAVIGATE (clinicaltrials.gov, NCT02410837) is a prospective, multicenter, observational cohort study of ENB using the superDimension™ navigation system. From April 2015 to August 2016, 1,215 consecutive subjects were enrolled at 29 United States sites. Two-year follow-up is ongoing. A prespecified 1-year interim analysis is presented.

      Result

      ENB was used to aid in lung lesion biopsy (n=1157 subjects), fiducial placement (n=258), pleural dye marking (n=23), and/or lymph node biopsy (n=30). EBUS-guided lymph node staging was conducted in the same procedure in 448 subjects. The median lesion-to-pleura distance was 9mm. The median lesion size was 20mm; most were in the middle (30%) and peripheral (67%) thirds of the lung. Pathology results were malignant in 44.3% (484/1092) (54.1% Stage I, 11.1% Stage II, 17.0% Stage III, 17.7% Stage IV). Molecular testing was attempted in 30.7% (80/261) of adenocarcinoma or NSCLC-not-otherwise-specified cases overall and 57.9% (33/57) of Stage IIIB/IV cases. Tissue was adequate in 87.5% (70/80) of cases. EGFR mutations (14.7%) and ALK translocations (4%) were the most frequently observed genetic alterations. The ENB procedure was well-tolerated; 2.9% of subjects had procedure-related pneumothorax requiring hospitalization or intervention, lower than published rates for CT-guided core biopsy (25%) and CT-guided fine needle aspiration (19%). Subject-reported impact of ENB on daily activities was 0.9 out of 10 (0 = no impact).

      Conclusion

      In the largest prospective, multicenter study to date, ENB aided in lesion biopsy in the middle and periphery of the lung and tissue collection for molecular testing, with a very low morbidity. ENB facilitates a multidimensional approach to lung biopsy and mediastinal/hilar staging, offering the opportunity for multiple sites/tissues to be safely sampled in one anesthetic event.

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      MA13.10 - Comparison of Pulmonary Nodule Location Between Preprocedural CT and Intra-Procedural Cone-Beam CT During Guided Bronchoscopy (Now Available) (ID 14216)

      11:35 - 11:40  |  Presenting Author(s): Michael A. Pritchett

      • Abstract
      • Presentation
      • Slides

      Background

      Electromagnetic navigation bronchoscopy relies on pre-procedural CT scans to create a virtual airway reconstruction that is used as a roadmap during bronchoscopy. These systems assume similarity between the position of the nodule during bronchoscopy and the pre-procedure CT scan. However, there are multiple factors that suggest that such assumption maybe inaccurate. These include differences in positioning, breathing motion, and the presence of atelectasis. In this study, we evaluated the lung nodule position between pre-procedural CT to interprocedural cone-beam CT (CBCT). In addition, we assessed the ability of a novel augmented endobronchial fluoroscopic guidance system (LungVision, Body Vision Medical Ltd, Israel) to overcome those differences in real-time.

      Method

      This was a prospective study of 21 patients with 23 peripheral pulmonary nodules. CT scans were imported into the planning software and the physician identified the nodule and navigation pathway. CBCT (Philips Allura Xper FD20) was used to scan the patient during the procedure. LungVision was used for real-time navigation and guidance during biopsy. The divergence in nodule location between the pre-procedural CT and the interprocedural CBCT was measured.

      Result

      The average patient age was 69 ± 8.6, median nodule size was 18mm with 74% of the nodules in the upper lobes. The average divergence of the nodule was 14.11 ± 9.9mm. Successful navigation was verified by CBCT in 91% of cases. Malignancy was diagnosed in 20 of 23 nodules for a diagnostic yield of 87%. No adverse events were reported.

      Conclusion

      This study demonstrates a significant divergence in lesion location between pre-procedural CT and intra-procedural CBCT during guided bronchoscopy. This finding indicates that the change in nodule position between the CT and bronchoscopy could have a great impact on the diagnostic success of the procedure. This movement, sometimes greater than the size of the nodule itself, can lead to an inaccurate localization when relying solely on virtual bronchoscopic or electromagnetic navigation.

      CT to patient divergence does not appear to influence the accuracy of this novel navigation platform. The system is capable of tracking the nodules dynamically and can compensate for changes in patient positioning and respiratory motion during both navigation and biopsy which leads to a high diagnostic yield.

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      MA13.11 - Photodynamic Therapy for Peripheral-Type Lung Cancer in a Multi-Center Clinical Trial (Now Available) (ID 13691)

      11:40 - 11:45  |  Presenting Author(s): Jitsuo Usuda

      • Abstract
      • Presentation
      • Slides

      Background

      Photodynanic therapy (PDT), is a treatment modality for many cancers, and uses a tumor-specific photosensitizer and laser irradiation. Recently, we have developed a new minimally invasive laser device using a 1.0 mm in diameter composite-type optical fiberscope (COF), which could transmit laser energy and images for observation in parallel.In this study, we aimed to develop a new endobronchial treatment for peripheral cancer using PDT and a COF, and we evaluated the feasibility of PDT using COF for peripheral lung cancer.

      Method

      This phase I study enrolled 3 patients with peripheral lung cancers (primary tumor< 20 mm, stage IA), which were definitively diagnosed by bronchoscopic modalities such as EBUS-GS and brocnhoscopic navigation system. We conducted irradiation using a diode laser (664 nm) and a COF 4 hours after the administration of NPe6 40 mg/m2. We evaluated the tumor lesions using EBUS, and then we introduced the COF into the peripheral lung cancer, and irradiated of red light 664 nm (120 mW, 50 J/cm2 or 100J/cm2). 

      Result

      We performed PDT for 3 patients with c-stage IA peripheral lung cancer, using a laser dose (120mW, 50J/cm2), and confirmed the feasibility of the dose. We escalated the laser dose and performed 4 patients using a laser dose (120mW, 100J/cm2).

      Seven patients met our criteria, and 5 cases were adenocarcinoma and 2 case squamous cell carcinoma. We were able to observe the cancer lesions at the peripheral lung by the COF, and feasibly irradiated. Two weeks and 3 months after NPe6-PDT, complications such as pneumonia and pneumothorax were not found, but one mildly found light skin-photosensitivity. Six months later, we found CR in 3 cases and SD in 4 cases.

      Conclusion

      The 1.0 mm COF was a very useful device of NPe6-PDT for peripheral lung cancers, and PDT was a feasible and non-invasive treatment for a peripheral type early lung cancer. In the future, for non-invasive adenocarcinoma such as AIS, NPe6-PDT will become a treatment modality.

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      MA13.12 - Discussant - MA 13.09, MA 13.10, MA 13.11 (Now Available) (ID 14632)

      11:45 - 12:00  |  Presenting Author(s): Antoni Rosell

      • Abstract
      • Presentation
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      Abstract not provided

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    MA14 - Survivorship, Socioeconomic and End-of-Life Considerations (ID 915)

    • Type: Mini Oral Abstract Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 205 BD
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      MA14.01 - Life Sustaining Procedures, Palliative Care and Hospital Cost Trends in Dying Lung Cancer Patients in U.S. Hospitals: 2005-2014 (Now Available) (ID 14134)

      10:30 - 10:35  |  Presenting Author(s): Jinwook Hwang  |  Author(s): Ji won Yoo, Jay Shen, Sun Jung Kim, Sung Youn Chun

      • Abstract
      • Presentation
      • Slides

      Background

      Little is known about the extent to which dying patients with lung cancer receive life-sustaining treatments and palliative care services at the end-of-life in U.S. hospitals. We examine hospital cost trends and the impact of palliative care utilization on the use of life-sustaining procedures in this population.

      Method

      Retrospective nationwide cohort analysiswas performed using National Inpatient Sample (NIS) data from 2005 and 2014. We examined the receipt of both palliative care and life-sustaining procedures, defined as systemic procedures, local procedures, or surgeries using the International Classification of Diseases, 9th revision (ICD-9-CM).

      Result

      Figure 1.

      스크린샷 2018-05-05 05.44.27.png

      We used compound annual growth rates (CAGR) to determine temporal trends and multilevel multivariate regressions to identify factors associated with hospital cost. Among 77,394,755 hospitalizations, 120,144 patients were examined. During 10 years, the CAGR of hospital cost was 7.05% (p<.0001). In contrast, the CAGR of hospital lengths of stay was -3.77% (p<.0001). The CAGRs of palliative care was over ten percentage (13.30 %, p<.0001). However, the CAGRs of systemic procedures, local procedures, and surgeries were less than around one percentage (-1.13%, -1.07% and 1.42%, each p<.0001). Systemic procedures, local procedures and surgeries were associated with increased hospital cost and lengths of stay by 50.6%, 74.4%, 68.5%, and 7.4%, 50.6%, 4.6% respectively (each p<.001). Palliative care was associated with decreased hospital cost and length of stay by 28.6% and 4.6% (each, p<.001).

      Conclusion

      The volume of life-sustaining treatments is the biggest driver of cost increase although there is a cost-saving effect from greater palliative care utilization at the end-of-life in dying lung cancer patients.

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      MA14.02 - Use and Impact of A Systematic Advanced Care Planning in Hospitalized Lung Cancer Patients: A Prospective Study. (Now Available) (ID 13997)

      10:35 - 10:40  |  Presenting Author(s): Anne Claire Toffart  |  Author(s): Natacha Denis, Matteo Giaj Levra, Linda Sakhri, Michaël Duruisseaux, Julian Pinsolle, Léonie Ferrer, Denis Moro-Sibilot, Jean-François Timsit

      • Abstract
      • Presentation
      • Slides

      Background

      End-of-life communication is crucial, particularly for cancer patients. In usual practice, advanced care planning discussions with the patients are uncommon and rarely documented. The aim of this study was to investigate the impact of advanced care planning on intensity of care in cases of organ failure in lung cancer patients.

      Method

      This prospective study was performed at the Grenoble University Hospital in France. Consecutive patients hospitalized in thoracic oncology unit between 01/28/2014 and 03/31/2016 were included and followed up to 12/31/2016. At each hospital admission, lung cancer patients benefited from advanced care planning. We defined 3 intensities of care: intensive care, maximal medical care and exclusive palliative care. The propositions of care could be modified during the hospitalization. Patients’ wishes should be received.

      Result

      Data of 715 hospitalizations corresponding to 473 patients were studied. Hundred fifty nine patients had a second hospitalization and 69 a third. At first admission, 247 (52%) patients had a performance status of 0 to 2, 186 (39%) were not yet treated for the cancer and 165 (35%) in progression. Main reasons of admission were an acute disease (n=208, 44%) and supportive care of cancer symptoms (n=167, 35%).

      During the three first admissions, 173 (25%) patients developed an organ failure. Among them, 56 (32%) had intensive care proposition, 104 (61%) maximal medical care, and 13 (7%) exclusive palliative care. Median time between admission and organ failure was 9 days [IQR 25%-75%, 3-13]. All patients benefited from intensity of care equal or lower than the proposed intensity of care. Among patients planed for intensive care, 17 (30%) patients received intensive care, 22 (39%) maximal medical care and 17 (30%) exclusive palliative care. Thirteen of the 39 patients not admitted in ICU despite organ failure and previous proposition of intensive care were considered too well by the oncologist. Patients’ wishes were recorded for 158 (91%) patients, and a discussion about end of life conditions was led with 116 (73%) patients or families.

      Conclusion

      In case of organ failure, an advanced care planning appears helpful to provide reasonable intensity of care. The proposition of care seems to be adapted to the patient’s general condition and cancer characteristics. 3/4 of the patients with an organ failure benefited from a discussion about end of life conditions.

      ClinicalTrials.gov Identifier: NCT02852629

      Funding from the publicly funded nonprofit organization Cancéropole Lyon Auvergne Rhône-Alpes (CLARA).

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      MA14.03 - Aggressiveness of Cares on the Month Before Death of Patients with Lung Cancer: A French National Database Survey (Now Available) (ID 12005)

      10:40 - 10:45  |  Presenting Author(s): Olivier Bylicki  |  Author(s): Charlène Tournier, florence Canoui-Poitrine, Cecile Blein, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Prior studies have demonstrated that high-intensity end of life (EOL) cares improves neither survival nor quality of life for cancer patients. The National Quality Forum endorses markers of poor EOL care for cancer patients but there is little data’s concerning lung cancer patients (1). The aim of this study was to assess, the quality of management during the last month of life of lung cancer patients managed in France and factors associated EOL aggressiveness.

      Method

      Using a French hospital discharge database (PMSI, Programme de Médicalisation des Systèmes d’Information), all patients with lung cancer who died between January 1, 2010 and December 31, 2011 (cohort 1) and between January 1, 2015 and December 31, 2016 (cohort 2) were identified through the International Classification of Diseases 10th version (ICD-10). Aggressiveness of EOL cares was assessed by the following criteria’s 1) chemotherapy administrated within last 14 days of life (DOL); 2) > 1 hospitalization within 30 DOL; 3) ICU admission within 30 DOL; and 4) Palliative care < 3 days before death. Multivariate analysis was performed to identify individual determinants EOL aggressiveness.

      Result

      A total of 90,827 incident adult patients were identified (cohort 1: 43,862, cohort 2: 46,965): men: 74%, median age: 67 years], metastatic at diagnosis: 70%; 57% have at least one marker of aggressiveness of EOL cares (repeated hospitalizations: 49%, ICU admissions: 12%, chemotherapy within 14 DOL: 9%, palliative care < 3 days before death: 5%). A significant increase was observed between 2010/2011 and 2015/2016 for repeated hospitalizations (48% vs 51%, p<.001) and ICU admissions (11% vs 13%, p<.001); the two other markers have remained stable. In multivariate analysis of cohort 2, the risk of aggressiveness of care in EOL was increased by the presence of COPD (OR: 1.08, 95%CI: 1.02-1.14) and a management in an anti-cancer center (OR: 2.32,95%CI 2.05-2.61) while advanced age (OR: 0.51, 95%CI 0.47-0.55), female sex (OR: 0.86 95%CI: 0.82-0.90), malnutrition (OR: 0.72, 95%CI:0.68-0.76) were protective factors for EOL aggressiveness of cares.

      Conclusion

      Despite growing focus on providing appropriate EOL cares, in this analysis 57% of deceased lung cancer patients in France received aggressive EOL cares. Research must be undertaken to better identify patients at risk of aggressive EOL cares and to improve the quality of cares of last days of life these patients.

      1.McNiff KK, . Measuring supportive care in medical oncology practice: lessons learned from the quality oncology practice initiative. JCO 2008;

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      MA14.04 - Discussant - MA 14.01, MA 14.02, MA 14.03 (Now Available) (ID 14636)

      10:45 - 11:00  |  Presenting Author(s): Gouri Shankar Bhattacharyya

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.05 - Social Isolation Increases Psychological Distress in Patients With NSCLC (Now Available) (ID 11959)

      11:00 - 11:05  |  Presenting Author(s): Cheryl Ho  |  Author(s): Bonnie Leung, Jonn Wu, Janessa Laskin, Heather Rennie, Alan Bates

      • Abstract
      • Presentation
      • Slides

      Background

      The Psychosocial Screen for Cancer (PSSCAN-R) questionnaire is a validated screening tool used to identify the psychosocial needs of patients with cancer. The questionnaire assesses patients’ perceived social supports and identifies patients at risk for developing psychological distress. The study goal was to examine patients with NSCLC who reported risk factors for social isolation and their risk for developing psychological distress.

      Method

      All patients with NSCLC referred to BC Cancer from 2011-2015 who completed a prospective PSSCAN-R questionnaire at the time of first visit were included in the study. Perceived social support questions include: if patients live alone, lost a life partner recently, have no help with IADLs, have no regular contact with friends and family or have no emotional support from others. Demographics were collected retrospectively. Chi-squared test and logistical regression were used to compare patient groups based on age, gender and perceived social support factors.

      Result

      The study cohort was comprised of 4428 patients who completed the PSSCAN-R questionnaire. Female 50%, patients ≥65 years 69%, live alone 29%, lost life partner 13%, no help with IADLs 9%, no regular contact 3% and no emotional support 5%.table1.png

      Conclusion

      Female patients and patients younger than 65 are more at risk for developing moderate to severe anxiety and depression. Lack of perceived social support also contributes to the risk of developing psychological distress. In addition to developing gender and age-based resources for patients addressing their psychosocial needs, greater efforts in assessing patients’ perceived social supports and allocating community and institutional resources to isolated patients should also become an important part of the patients’ comprehensive and holistic care.

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      MA14.06 - Predictors of Financial Toxicity, an Under-Recognized Patient-Reported Outcome (Now Available) (ID 13571)

      11:05 - 11:10  |  Presenting Author(s): Doreen Anuli Ezeife  |  Author(s): Josh Morganstein, Sally C Lau, Jennifer Law, Lisa Le, Penelope Bradbury, Geoffrey Liu, Frances A Shepherd, Natasha B Leighl

      • Abstract
      • Presentation
      • Slides

      Background

      In contemporary cancer care, financial distress has been established as a clinically relevant patient-reported outcome (PRO) associated with worse mortality and quality of life, but remains under-recognized by health care providers. Our goal was to define predictors of patient financial toxicity (FT) in a public healthcare system.

      Method

      Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FT was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, an 11-item survey scored from 0-44 with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP) and extended insurance coverage (EIC) were collected. Associations between variables and COST score were evaluated using multivariable regression analyses.

      Result

      Of 249 patients approached, 200 (80%) participated. Median age of the cohort was 65 years; 44% were male, 36% immigrants, 67% employed or on pension, with median OOP between $1000-5000 CAD. Median COST score was 21 (range 0-44). FT was associated with age, with patients <65 years reporting greater FT than older patients (COST 18 vs. 25; P<0.0001). Employed patients or those receiving pension income reported less FT than unemployed patients (22 vs. 19; P=0.01). Less FT occurred in patients with EIC compared to those without (23 vs. 19; P=0.03). Patients with higher OOP reported more FT (P<0.0001). Patients on clinical trials reported less FT than others (25 vs. 20; P=0.04). In multivariable linear regression, younger age was a predictor of higher FT, when adjusting for income, employment status, OOP and EIC (P<0.0001).

      Conclusion

      Age is a predictor of FT in the Canadian (Ontario) public healthcare system, with younger lung cancer patients reporting greater financial distress. This study highlights priority patient populations where FT should be routinely assessed and appropriate resources for support offered.

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      MA14.07 - The Impact of Socioeconomic Status and Geographic Location on Palliative Chemotherapy Uptake in Patients with Metastatic NSCLC  (Now Available) (ID 13098)

      11:10 - 11:15  |  Presenting Author(s): Zamzam Salam Al-Hashami  |  Author(s): Bonnie Leung, Janessa Laskin, Jonn Wu, Heather Rennie, Alan Bates, Cheryl Ho

      • Abstract
      • Presentation
      • Slides

      Background

      Socioeconomic status (SES) and geographic factors may impact patient treatment choices. Canada has a publically funded health care system and in BC, there are 35 community oncology network sites that delivery treatment in patients’ local communities. We studied the impact between SES and geographic location upon delivery of chemotherapy/survival in metastatic NSCLC.

      Method

      All patients with metastatic NSCLC referred to BC Cancer centres from 2011-2015, who completed a prospective Canadian Problem Checklist questionnaire at the time of their first visit and for which chemotherapy data was available were included in the study. The CPC assesses patient distress in 6 domains including practical aspects of cancer care. The Postal Code Conversion File Plus uses data from Statistics Canada 2011 census to determine population size and income quintiles. Baseline characteristics and chemotherapy treatments were collected retrospectively. Univariate analysis using the Chi-squared test and Fisher’s exact test were used for analysis.

      Result

      1113 patients were included with median age of 69 years, 54% female and 77% were former/current smoker and 47% received palliative chemotherapy. Uptake of chemotherapy did not differ between lowest + mid-lowest 44%, middle 51% /mid-highest + highest 49% income quintiles (p=0.18). Chemotherapy use was also similar between patients reporting financial concerns 50% versus none 47% (p=0.51). Uptake of chemotherapy was lower in patients who lived in rural communities population<10 37% (P 0.00), 10K-1.5M 41%, >1.5 million 53% (p<0.001). Chemotherapy use was lower for patients with concerns about getting to appointments (39% vs 49%, p=0.008) or accommodations (33% vs 48%, p=0.012).

      Conclusion

      This dataset provide evidence that patients from rural communities were less likely to receive palliative chemotherapy treatment for metastatic NSCLC in BC despite the availability of multiple local community oncology services. SES did not appear to impact the proportion of patients treated, congruent with a government funded health care system. An in depth assessment of distances to local cancer services and treatment delivery is warranted to investigate these differences and their effect on mortality.

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      MA14.08 - Discussant - MA 14.05, MA 14.06, MA 14.07 (Now Available) (ID 14637)

      11:15 - 11:30  |  Presenting Author(s): Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.09 - Mortality of Lung Cancer as a Second Primary Malignancy among Cancer Survivors: A Study of Surveillance, Epidemiology, and End Results Database (Now Available) (ID 11862)

      11:30 - 11:35  |  Presenting Author(s): Lei Deng  |  Author(s): Huan Song, Zhengrui Xiao, Changchuan Jiang, Qian Wang, Haiying Cheng, Donghao Lu

      • Abstract
      • Presentation
      • Slides

      Background

      Cancer survivors are at increased risk of developing a second primary malignancy, including lung cancer. However, the prognosis of lung cancer as a second primary malignancy (lung-2) remains largely unknown.

      Method

      Primary lung cancer patients diagnosed from 1988 to 2014 in the SEER program were included. Lung-2 was ascertained by a previous diagnosis of primary malignancy in SEER. Hazard ratios (HRs) of overall and lung cancer specific mortality were estimated among patients with lung-2 compared to lung-1.

      Result

      679,541(88.8%) and 85,758 (11.2%) patients were identified as lung-1 and lung-2, respectively. The median time from first primary malignancy to lung-2 diagnosis was 4.8 years. Compared to lung-1, patients with lung-2 were more likely to be diagnosed at localized stage, with smaller primary tumor, and treated with surgery. Lung-2 patients were at lower risk of lung cancer specific mortality in the first five years (HR 0.77, 95% CI 0.76 - 0.78 at < 1 year; HR 0.87, 95% CI 0.86 - 0.89 from 1 to < 5 years) but at higher risk thereafter. Patients with lung-2 were associated with reduced risk of overall mortality during the first year after diagnosis (HR 0.91, 95% CI 0.91 - 0.92), but with significantly increased risks thereafter.

      Table Hazard ratios (HRs) of overall and lung cancer specific mortality among patients with lung-2

      N (%) of patients

      From 0 to <1 year after diagnosis

      From 1 year to < 5 years after diagnosis

      From 5 years to 10 years of follow-up after diagnosis

      N (IR)

      HR (95% CI) *

      N (IR)

      HR (95% CI)*

      N (IR)

      HR (95% CI)*

      Overall mortality

      First primary lung cancer

      679,541

      383,208 (99.9)

      1.00

      135,513 (29.3)

      1.00

      16,821 (9.8)

      1.00

      Second primary lung cancer

      85,758

      44,288 (84.1)

      0.91 (0.91-0.92)

      20,073 (29.4)

      1.10 (1.08-1.12)

      3,133 (14.6)

      1.32 (1.27-1.37)

      Lung cancer specific mortality

      First primary lung cancer

      679,541

      325,633 (84.9)

      1.00

      111,348 (24.1)

      1.00

      8,147 (4.7)

      1.00

      Second primary lung cancer

      85,758

      31,247 (59.3)

      0.77 (0.76-0.78)

      12,485 (18.3)

      0.87 (0.86-0.89)

      1,158 (5.4)

      1.10 (1.03-1.17)

      N, number of deaths; IR, incidence rate per 100 person-years

      * HR was adjusted for age and calendar period at diagnosis, sex, race, cohabitation status, percentile of cost of living and high-school education in county of residence, tumor stage, histology, tumor grade, surgery, radiation therapy, and chemotherapy.

      Conclusion

      Lung-2 is associated with favorable lung cancer specific and overall survival within early period of diagnosis. Inferior overall survival afterwards cannot be attributed to aggressiveness of lung-2, highlighting the importance of managing first malignancy and comorbidities.

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      MA14.10 - QTc Interval-Prolonging Medications in Lung Cancer: Implications for Clinical Trial Eligibility and Routine Clinical Care (Now Available) (ID 12305)

      11:35 - 11:40  |  Presenting Author(s): David E Gerber

      • Abstract
      • Presentation
      • Slides

      Background

      Concomitant medication use, including agents that prolong the QTc interval, may exclude cancer patients from clinical trials. To estimate potential impact on accrual, we determined the prevalence of QTc-prolonging medication prescriptions in a national patient cohort.

      Method

      We identified adult patients in the United States Veterans’ Affairs system diagnosed with lung cancer 2003-2016. QTc-interval prolonging medications and risk category were obtained from CredibleMeds®. We calculated prevalence of prescriptions for QTc-prolonging medications with known or possible risk of torsades de pointes (the most common criteria employed as trial exclusion criteria) in the 3 months up to and including date of cancer diagnosis. Rates across patient groups and time periods were compared using Chi-square test.

      Result

      280,068 patients were included in the study. Mean age was 70 years, 98% were male, and 72% were white. Overall, 29.7% were prescribed a QTc-prolonging medication. Patients receiving QTc-prolonging medications were marginally younger (mean age 68.9 years versus 70.9 years; P<0.001) and more likely to be black (14.1% versus 11%; P<0.001). The most commonly prescribed QTc-prolonging medications were antimicrobials (14.0%), psychiatric agents (10.2%), antiemetics (2.6%), and cardiovascular medications (1.7%). Seven percent of patients were prescribed two or more QTc-prolonging medications. Over the period of study, the rate of QTc-prolonging medication use increased 20% (25% in 2004 versus 31% in 2016; P<0.001).

      Conclusion

      A substantial and growing proportion of individuals with lung cancer are prescribed QTc-prolonging medications. These prescriptions may limit eligibility for clinical trials and complicate the administration of standard cancer therapies. Given the prevalence of chronic and/or multiple QTc-prolonging medication prescriptions, it may be challenging to address this obstacle to trial enrollment simply through prescription substitution or discontinuation. Further research into the actual clinical risks and optimal management of QTc-prolonging medications in cancer populations is warranted.

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      MA14.11 - Factors Associated with Early Mortality in Non-Small Cell Lung Cancer Patients Following Systemic Anti-Cancer Treatment (Now Available) (ID 12970)

      11:40 - 11:45  |  Presenting Author(s): Amanda Jane Williams Gibson  |  Author(s): Haocheng Li, Adrijana D'Silva, Roxana A. Tudor, Anifat A. Elegbede, Shannon Mary Otsuka, Winson Y Cheung, Gwyn Bebb

      • Abstract
      • Presentation
      • Slides

      Background

      To determine a 30-day mortality rate benchmark and assess factors associated with early mortality of non-small cell lung cancer (NSCLC) patients following receipt of systemic anti-cancer therapies (SACT).

      Method

      In a 10-year population-based analysis, NSCLC patients receiving SACT in 2005-2014, with or without other treatments, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data were reviewed. 30-day mortality after most recent SACT cycle was calculated, and end-of life (EOL) regimen changes in the last 14 days of life were identified. Univariate analysis and multivariable logistic regression were used to identify demographic, tumor or treatment-related factors that correlated with mortality risk.

      Result

      1044 eligible NSCLC patients receiving at least one cycle of SACT in 2005-2014 were identified. 51% were female, 62% adenocarcinoma, 79% current/former smokers, 83% advanced stage at diagnosis, and 77% receiving palliative-intent treatment. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt, and 32 (13.7%) EOL regimen changes identified. Risk of early mortality decreased for never-smokers and those receiving SACT between 2010-2014, and increased in association with male gender, advanced disease at diagnosis, palliative-intent treatment, and use of EGFR-targeting agents. No factors were associated with a decreased risk of EOL regimen change. (Table 1). The predominant SACT-modality among those experiencing 30-day mortality was EGFR-targeting agents (54%).
      abstract #12790 table.jpg

      Conclusion

      Our findings from a real-world population identify several factors which affect the risk of early mortality in NSCLC patients following SACT, and establish a 30-day mortality benchmark for Canadian NSCLC populations. Evolving SACT modalities may facilitate an increased use of SACT at EOL and associated early mortality; however, in this cohort, decreased early mortality risk in the 2010-2014 timeframe suggests concomitant evolution of decisions regarding EOL SACT and/or palliative and EOL care may be underway at our centre, but represents an area for ongoing investigation.

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      MA14.12 - Discussant - MA 14.09, MA 14.10, MA 14.11 (Now Available) (ID 14638)

      11:45 - 12:00  |  Presenting Author(s): Amanda Tufman

      • Abstract
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      Abstract not provided

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    MS13 - Novel Mediators of Lung Cancer Metastasis (ID 792)

    • Type: Mini Symposium
    • Track: Biology
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 201 F
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      MS13.01 - Liquid Biopsy-mediated Identification of Metastatic Variants (Now Available) (ID 11453)

      10:30 - 10:45  |  Presenting Author(s): Philip Christopher Mack

      • Abstract
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      Abstract not provided

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      MS13.02 - Capicua Inactivation Drives Lung Cancer Metastasis (Now Available) (ID 11454)

      10:45 - 11:00  |  Presenting Author(s): Trever G Bivona

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      Abstract not provided

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      MS13.03 - Ubiquilin as a Novel Mediator of Lung Cancer Invasion and Metastasis (Now Available) (ID 11455)

      11:00 - 11:15  |  Presenting Author(s): Levi J. Beverly

      • Abstract
      • Presentation
      • Slides

      Abstract

      Data from large, publicly available datasets indicate multiple somatic non-synonymous recurrent mutations in Ubiquilin (UBQLN) family genes or loss of either UBQLN1 or UBQLN2 loci in over 50% of human lung adenocarcinoma patient samples. The UBQLN family consists of 5 related proteins (UBQLN1-4 and UBQLNL) that all contain ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains. Our work was the first to show that UBQLN proteins regulate processes involved in tumorigenesis. In fact, our work now conclusively demonstrates that Ubiquilin1 is a bona fide metastasis suppressors in human lung adenocarcinoma. Importantly, since the vast majority of patients that succumb to lung cancer, die from the metastatic disease and not from the primary tumor burden the combination of these data suggest that nearly 700,000 people die world-wide every year from lung cancers that have decreased or altered UBQLN function. The exact mechanism by which loss of UBQLN proteins leads to metastatic progression remains unclear, however metastatic cancer progression requires cells to acquire new aggressive properties, such as increased migration, invasion, survival and growth at the metastatic site. The identification of regulators of these properties will be crucial for our future success in decreasing metastatic progression and thus cancer mortality rates. The goal of our lab is to understand the detailed mechanisms by which disruption of UBQLN proteins contributes to the metastatic progression of hLAC. We demonstrate that (i.) loss of UBQLN1 or UBQLN2 increases proliferation, EMT, migration and invasion of hLAC cells, in vitro; (ii.) loss of UBQLN1 activates multiple signaling pathways known to regulate cell motility, such as IGF1R and Integrin/FAK; (iii.) inhibition of SRC kinase blocks migration, but not proliferation of cells lacking UBQLN1; (iv.) and finally, loss of UBQLN1 increases metastasis of hLAC cells in vivo. By understanding how UBQLN1 functions to protect cells from tumor progression and metastatic dissemination we may be able to use UBQLN1 status as a predictive biomarker for disease staging or as an indicator for which patients will respond to a given therapeutic. Further, by understanding how UBQLN1 alters signaling pathways that contribute metastatic progression, we may be able to target these downstream pathways specifically in tumors with altered UBQLN1 function to block metastasis, thus potentially affecting millions of lung cancer patients in the coming decades.

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      MS13.04 - Tracking the Evolution of Non-Small-Cell Lung Cancer (Now Available) (ID 11456)

      11:15 - 11:30  |  Presenting Author(s): Charles Swanton  |  Author(s):

      • Abstract
      • Presentation
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      Abstract

      Increasing evidence supports complex subclonal relationships in solid tumours, manifested as intratumour heterogeneity. Parallel evolution of subclones, with distinct somatic events occurring in the same gene, signal transduction pathway or protein complex, suggests constraints to tumour evolution that might be therapeutically exploitable. Emerging data from TRACERx, a longitudinal lung cancer evolution study will be presented. Drivers of tumour heterogeneity change during the disease course and contribute to the temporally distinct origins of lung cancer driver events. APOBEC driven mutagenesis appears to be enriched in subclones in multiple tumour types. Oncogene, tumour suppressor gene and drug induced DNA replication stress are found to drive APOBEC mutagenesis. Evidence that intratumour heterogeneity and chromosomal instability is finely tuned will be presented, to create sufficient diversity for adaptation mitigating the risks of excessive genome instability resulting in cell autonomous lethality. On-going chromosomal instability, manifested as Mirrored Subclonal Allelic Imbalance (MSAI) is found to be a major driver of intratumour heterogeneity in non-small cell lung cancer, contributing to parallel evolution and selection. The finding of subclonal driver events, evidence of ongoing selection within subclones, combined with genome instability driving cell-to-cell variation is likely to limit the efficacy of targeted monotherapies, suggesting the need for new approaches to drug development and clinical trial design and integration of cancer immunotherapeutic approaches. The clonal neo-antigenic architecture may act as a tumour vulnerability, targeting multiple clonal neo-antigens present in each tumour to mitigate resistance and treatment failure. The role of cancer genome instability driving immune evasion and HLA/MHC loss and immune escape will be presented.

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      MS13.05 - Discussant (Now Available) (ID 11457)

      11:30 - 11:45  |  Presenting Author(s): David Beer

      • Abstract
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      Abstract not provided

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    MS14 - IO in Early Stage NSCLC (ID 793)

    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 107
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      MS14.01 - Basic Science Rationale of IO in Early Stage NSCLC? (Now Available) (ID 11458)

      10:30 - 10:45  |  Presenting Author(s): Johan F. Vansteenkiste  |  Author(s): Christophe A. Dooms

      • Abstract
      • Presentation
      • Slides

      Abstract

      The 5-year overall survival (OS) of patients with surgically treated early stage NSCLC ranges from 92% (stage IA) to 36% (stage IIIA). Numerous clinical trials over the last decades tried to improve on these results by either adding adjuvant therapy (i.e. in addition after a radical local therapy) or neoadjuvant therapy (i.e. cytoreductive before a radical local therapy).

      Adjuvant setting

      Adjuvant therapy for resected NSCLC came into place in 2004, when the large International Adjuvant Lung cancer Trial (IALT) demonstrated OS benefit with cisplatin-based chemotherapy. No further progress with other types of adjuvant therapy has been made since then. The progress in patients with advanced NSCLC in stage IV with pemetrexed, bevacizumab and EGFR-directed TKIs was not translated in the adjuvant setting [1].

      As for immunotherapy, the MAGRIT trial assessed antigen-specific immunotherapy directed to the MAGE-A3 antigen in completely resected MAGE-A3 positive NSCLC [2]. The adjuvant setting – where the aim is to eliminate sparse tumor cells remaining after surgery – was judged to be the ideal setting for this approach. Unfortunately, the trial did not improve survival. One of the hypotheses why is that the generated MAGE-A3 directed T-cells with cancer killing properties did not travel nor enter easily in tumors, and even if they did, they encountered checkpoints that blocked their potential benefit.

      Immune checkpoint inhibitor (ICI) immunotherapy, which revolutionized the approach to metastatic NSCLC, is now tested in the post-surgical setting with micrometastatic disease and low tumor burden. In contrast to directly cytotoxic chemotherapy, however, agents blocking the PD-1/PD-L1 axis require an interaction between antigen-presenting cells, CD8+ T cells, and tumor cells. It is far from certain that these intercellular interactions will occur sufficiently in patients with micrometastatic disease, where low tumor (mutation) burden may not sufficiently incite the tumor microenvironment. Because of the adjuvant setting, without detectable disease, no early effectiveness read-outs of efficacy nor translational tissue research is feasible. The results of the different ongoing trials with adjuvant ICI therapy in early stage NSCLC needs to be awaited.

      Neoadjuvant setting

      Because of the aforementioned limitations, the neoadjuvant use of PD-1/PD-L1 blockade is of greater interest for several reasons.

      From a biologic perspective, PD-1/PD-L1 blockade before surgery, when the tumor mass and intact locoregional lymph nodes with ongoing activation of T cells may be present, might be more rational. In a breast cancer model in mice, it has been suggested that neoadjuvant ICI is more effective than adjuvant ICI [3]. In the neoadjuvant setting, there was a stronger systemic antitumor T-cell response with maintenance of tumor specific CD8+ T cells in the blood early after immunotherapy. High levels of CD8+ T cells predicted long-term survival in this mouse model. Moreover, induction of this systemic immune response could lead to immune memory that may prevent metastatic relapse over time.

      From a clinical perspective, the neoadjuvant strategy has advantages, as we learned from the chemotherapy era. The systemic therapy has better distribution because of the intact vascularization, which may reduce the locoregional tumor extension. There is an early attack microscopic metastatic disease and the effectiveness can be evaluated in vivo with pre- and post-imaging.

      From a clinical trial perspective, a big advantage is the possibility to study surrogate endpoints. The crucial outcome in this setting is OS, but this endpoint requires many years of follow-up. Here as well, lessons learnt from neoadjuvant chemotherapy followed by surgical resection are of use. Tumor-free lymph nodes and pathological response in the primary tumor have been associated with significantly better outcome. In a dedicated study on the prognostic impact of morphometric tissue analysis of tumor regression, the latter was graded in I: no regression; II: remaining vital tumor tissue ≥10% (grade IIa) or <10% (grade IIb); and III: no evidence of vital tumor tissue [4]. Patients with tumors of regression grades IIb or III showed significantly longer OS than the others (3-year OS 52% vs 9%, P=0.02). These findings, however, do not help to select patients for surgery, as they are post-hoc analyses on the resection specimen. Ideally, one should have pre-surgical (pre-hoc analysis) predictors, but the standard clinical restaging with repeat CT after neoadjuvant only is a raw tool for this purpose. Our group first demonstrated that morphometric tissue analysis of mediastinal lymph nodes after induction was a strong prognosticator in that setting [5]. This was then validated in a prospective multi-center setting, using the first video-mediastinoscopy after neoadjuvant chemotherapy [6]. Patients with a grade IIA or III regression (<10% viable tumor) had much better outcome than the others: 5-year OS 43% versus 19%.

      A recent pilot study evaluated the clinical, pathological, and immunologic effects of short-term neoadjuvant PD-1 blockade in NSCLC [7]. Here again, major pathological response was defined as ≤10% residual viable tumor on sections of the resected tumor. With this criterion, 45% of the patients had a major pathological response, with clear infiltration of CD8+ T cells in regressing tumors. Moreover, a systemic immune response with T-cells of similar T-cell receptor repertoire as in the tissue were described. Even with its small sample (N=21), this strategy has a strong mechanistic principle, both in the tumor and on distant sites, and has resulted in a promising surrogate endpoint effect. Whether this will translated in better 5-year OS now needs to be defined in larger multi-center phase 3 trials, several of which are currently started.

      References

      1. Deslypere G. et al. Ther Adv Med Oncol 2018; 10: 1-11.

      2. Vansteenkiste J. et al. Lancet Oncol 2016; 17: 822-35.

      3. Liu J et al. Cancer Discov 2016; 6: 1382-99.

      4. Junker K et al. Chest 2001; 120: 1584-91.

      5. Dooms C et al. J Clin Oncol 2008; 26: 1128-34.

      6. Dooms C et al. J.Thorac.Oncol. 12 Suppl 1, 460S. 2017.

      7. Forde P et al. N Engl J Med 2018; 378: 1976-86.

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      MS14.02 - Adjuvant / Neoadjuvant IO Therapy (Now Available) (ID 11459)

      10:45 - 11:00  |  Presenting Author(s): Julie R. Brahmer

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      Abstract not provided

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      MS14.03 - Concerns About IO for the Thoracic Surgeon? (Now Available) (ID 11460)

      11:00 - 11:15  |  Presenting Author(s): Bernward Passlick

      • Abstract
      • Presentation
      • Slides

      Abstract

      Perioperativ immunotherapy is a relative new field in thoracic oncology. Although several studies are ongoing, there are until now only two publications describing the effect of preoperative immunotherapy and the intraoperative and the postoperative course of patients with thoracic malignancies.

      The first study is a publication by Forde and colleagues (1), dealing with patients with resectable lung cancer who received one or two preoperative doses of PD-1-inhibitior Nivolumab. The immunotherapy was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The authors described an acceptable side-effect profile and no delays in surgery. Treatment-related adverse events of any grade occurred in 5 of 22 patients (23%) an only one event was a 3 grades side effect. This was a patient with a pneumonitis who could be resected thereafter that without any complications. The median interval between the administration of the second dose of Nivolumab and surgery was 18 days (range 11 to 29). Twenty of 21 eligible patients underwent a complete resection. The preoperative imaging showed that the majority of the patients (86 %) had stable disease.

      The other report (2) deals with the safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors. This is a retrospective study on 19 patients treated between 2012 and 2016. The majority of them had lung cancer (47 %) followed by metastatic melanoma. Various types of immunotherapeutic agents were used. Anatomic resections (lobectomy or greater) were performed in 11 patients. Complications occurred in 32 % but the majority of them were again only minor. One patients developed postoperative pneumonitis in the contralateral lung approximately 2 weeks after VATS-resection on the other side.

      In summary, preoperative immunotherapy seems to be applicable with only minor side effects. However, there are only few reports and theoretically other complications might occur. Especially if the side effect spectrum in patients with metastatic disease and immunotherapy is considered (3). Frequent side effects are pneumonitis, hepatitis or even myocarditis. The development of such side effects should be excluded in each patient undergoing surgery after immunotherapy.

      References

      1. Forde PM, Chaft JE, Smithe KN et al. Neoadjuvant PD-1-Blockade in Resectable Lung Cancer. N Engl J MED 2018 378;21.

      2. Matthew JB, Cools-Lartigue J, Tan KS et al. Safety and Feasibility of Lung Resection after Immunotherapy for Metastatic or Unresectable Tumors. Ann Thorac Surg 2018; …..

      3. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med 2018 378;22.

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      MS14.04 - IO - New Standards in Stage III NSCLC (Now Available) (ID 11461)

      11:15 - 11:30  |  Presenting Author(s): Rafal Dziadziuszko

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      Abstract not provided

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      MS14.05 - Do Biomarkers used in Metastatic Setting Apply in Earlier Stages (Now Available) (ID 11462)

      11:30 - 11:45  |  Presenting Author(s): Naiyer A Rizvi

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      Abstract not provided

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    MS15 - Disruptive Technology and Lung Cancer Risk (ID 794)

    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 201 BD
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      MS15.01 - Just Water Vapor? Toxicology Perspectives on Electronic Cigarettes (Now Available) (ID 11463)

      10:30 - 10:45  |  Presenting Author(s): Maciej Lukasz Goniewicz

      • Abstract
      • Presentation
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      Abstract

      Electronic cigarettes (e-cigarettes) were introduced to the global market in the mid 2000’s. While it is common to hear the term “e-cigarettes”, this label is a broad term referring to a heterogeneous class of devices that differ in shape, size, and functional characteristics. Common features of e-cigarettes include a heating element that heats a propylene glycol and/or vegetable glycerin based solution (“e-liquid” /“e-juice”) that contains stabilizers, flavorings and often, nicotine. Numerous flavors are available, including tobacco, menthol, fruit, and sweet flavors. Heating of e-liquids produces an aerosol, which is then inhaled by the user. Due to their relatively short existence, data on the long-term health effects of e-cigarette use are not currently available. In the interim, evidence from animal studies, in vitro and in vivo laboratory studies, observational studies, and small-scale clinical trials may provide important information on the potential harms of e-cigarette use [1].

      Many studies conducted on e-cigarettes have focused on the measurement of potentially harmful chemicals that may be produced by these products. Chemicals identified in e-cigarette aerosol include nicotine, tobacco‑specific nitrosamines (TSNAs), metals, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and aldehydes. Within these classes, there are several respiratory irritants and toxicants, as well as carcinogenic substances linked to the development of respiratory cancers. In our work, we have tested emissions from numerous e-cigarette brands [2] and identified the presence of formaldehyde, acetaldehyde, and acrolein in e-cigarette emissions. Overall, concentrations of toxicants identified in e-cigarette aerosols were 9 to 450 times lower than in tobacco smoke [2]. Concerns have also been raised about the presence of metal particles in e-cigarette aerosol (particularly nickel and chromium, two main elements in heating coils).The inhalation of these metals in larger quantities may cause respiratory diseases, bronchitis, and pneumonia [3], however, these effects have not been definitively elucidated.

      The size of particulate matter generated from e-cigarettes affects pulmonary nicotine absorption and determines settlement of particulate matter into various parts of the upper or lower airways. There is likely substantial variation across generations of e‑cigarette devices, and across brands. Results from laboratory studies indicate that e-cigarettes may expose users to small particles and lower amounts of particulate matter in general. While inhalation of high levels of particulate matter has been linked to greater mortality risk from cardiopulmonary illnesses, the available data indicate that e-cigarette particulate emissions expose users at a level akin to WHO guidelines and are far lower than those of conventional cigarettes.

      Issues raised about toxicological effects mostly question effects on cells, with a special interest in lung epithelial cells. For instance, many flavorings used in e‑cigarettes (e.g. cinnamaldehyde, benaldehyde, diacetyl) are already approved for use in food, yet their impact on respiratory health via repeated inhalation is currently unknown. Several studies have shown that e-cigarette flavorings could lead to lung cell damage (mostly by releasing free radicals) and inflammation in lung tissue [4]. Studies on cytotoxic effects of e-cigarette constituents have also identified negative effects on DNA. In one in vitro research, e-cigarette liquids aerosolized at biologically relevant doses induced increased DNA strand breaks and apoptosis while decreasing survival in both normal epithelial and head and neck squamous cell carcinoma cell lines [5]. Moreover, in experiments conducted by Yu et al. [6] e-cigarettes aerosol has shown cytotoxic effects on epithelial cell lines and acted as a DNA-breaking agent.

      Given multiple potential etiologic mechanisms related to incident case development coupled with the long latency period in developing illness, there is currently no definitive evidence to commenting on the role of e-cigarettes in increasing lung cancer risk. As an intermediate assessment, cross-sectional biomarker data can be suggestive of possible carcinogen exposures related to cancer development. For instance, Shahab et al. [7] examined a large panel of biomarker data among e-cigarette users, cigarette users, and users of both products (“dual users”). The e-cigarette–only users had significantly lower metabolite levels for tobacco-specific nitrosamines (TSNAs), particularly NNAL, a metabolite of potent lung carcinogen NNK. Several observational longitudinal studies also showed a substantial reduction in exposure to NNK and several VOCs, including respiratory toxicants like acrolein, acrylamide, acrylonitrile, 1,3-butadiene (human carcinogen), and ethylene oxide among smokers who switched to e-cigarette [8]. Although evidence from biomarker studies are insufficient to evaluate causative mechanisms, but show users of e-cigarettes display lower levels of exposure to biomarkers of lung carcinogens when compared to smokers, such as NNK.

      Since e-cigarettes have only been on the market for a decade, it is presently not possible to assess all potential long-term harmful effects of e-cigarette use. To date, findings from clinical studies have demonstrated that e-cigarettes are likely less harmful compared to conventional tobacco cigarettes, and any harmful side effects are noticeably milder compared with regular cigarettes. Furthermore, it is also clear that e-cigarette aerosols are not “a harmless water vapor”, as claimed by manufacturers and retailers, and potential health effects from vaping may emerge after long-term use.

      References

      1. National Academies of Sciences, Engineering and Medicine. Public health consequences of e-cigarettes. Washington, DC: The National Academies Press; 2018.

      2. Goniewicz et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control. 2014;23:133-139

      3. Lerner et al. Environmental health hazards of e cigarettes and their components: oxidants and copper in e-cigarette aerosols. Environ Pollut. 2015;198:100-107

      4. Leigh et al. Flavourings significantly affect inhalation toxicity of aerosol generated from electronic nicotine delivery systems (ENDS). Tob Control. 2016;25(Suppl 2):ii81-ii87.

      5. Welz et al. Cytotoxic and genotoxic effects of electronic cigarette liquids on human mucosal tissue cultures of the oropharynx. J Environ Pathol Toxicol Oncol. 2016;35:343-354.

      6. Yu et al. Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines. Oral Oncol. 2016;52:58-65.

      7. Shahab et al. Nicotine, carcinogen, and toxin exposure in long-term e-cigarette and nicotine replacement therapy users: a cross-sectional study. Ann Intern Med. 2017;166:390-400.

      8. Goniewicz et al. Exposure to nicotine and selected toxicants in cigarette smokers who switched to electronic cigarettes: a longitudinal within-subjects observational study. Nicotine Tob Res. 2017;19:160-167.

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      MS15.02 - PRO- Electronic Cigarettes: A Cessation Tool (Now Available) (ID 11464)

      10:45 - 11:00  |  Presenting Author(s): K. Michael Cummings

      • Abstract
      • Presentation
      • Slides

      Abstract

      Should clinicians recommend electronic cigarettes (e-cigarettes) to their lung cancer patients who continue to smoke? For many clinicians the answer to this question is a resounding NO WAY. However, I hope to persuade you that there are good reasons why clinicians should strongly consider recommending e-cigarettes to at least some of their patients who smoke. No one disputes the enormous health risks posed by cigarette smoking, or the need to find better treatments to help smokers overcome addiction to cigarettes. In theory, a product that can deliver nicotine like a cigarette without the toxins found in smoke could be used instead of cigarettes would be a welcome invention. E-cigarettes were first introduced into the marketplace in 2003 and were initially promoted as an aid to help smokers to stop smoking. However, concerns have been raised about whether e-cigarettes are an effective cessation aid or if they would actually reduce successful quitting by adult smokers, whether they are safe to use, and if they may be a gateway into smoking for youth. Admittedly, the science is in a state of flux and evolving rapidly. The National Academy of Sciences, Engineering, and Medicine (NASEM) report on the public health consequences of e-cigarettes, and a new evidence review on e-cigarettes and heated tobacco products commissioned by Public Health England (PHE) both come to similar conclusions. Both reports acknowledge that available evidence indicates that e-cigarette use is less risky than use of combustible tobacco cigarettes; that e-cigarettes may be helpful to smokers who are trying to stop smoking cigarettes, and that e-cigarettes should not be used by non-smokers, especially youth. However, both reports also state that e-cigarettes contain constituents that are not inert and are likely to have some negative health effects on their own. Given uncertainties regarding e-cigarettes, clinicians should advise cigarette smokers seeking to stop smoking to use evidence-based, FDA-approved, safe, and effective smoking cessation pharmacotherapies as first-line treatments in preference to e-cigarettes. So why consider e-cigarettes as a treatment option? First, many patients have already tried the evidence based methods and have found them not to be helpful. We need better treatments and e-cigarettes, in theory, might work for some patients. Second, nicotine seeking is the primary motivation for continued smoking so providing addicted smokers with an alternative that delivers nicotine without most of the harmful toxins in smoke makes sense. Nicotine is not the problem, it is the smoke. E-cigarettes are not lit, they do not burn, and do not produce cigarette smoke. Finally, many smokers simply prefer e-cigarettes over other aids to quitting. It is great to have government approved stop smoking treatments, but if smokers are unwilling to use them, they don’t do much good. Sales of e-cigarettes have grown exponentially over the past decade, and they have become the most popular quitting aid used by smokers in many countries. For those smokers and ex-smokers who are already using the e-cigarettes, clinicians need to be informed and prepared to answer questions regarding potential harms and benefits and to advise patients about use.

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      MS15.03 - CON- Electronic Cigarettes: Not Evidence Based Cessation (Now Available) (ID 11465)

      11:00 - 11:15  |  Presenting Author(s): Alison Wallace

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      Abstract not provided

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      MS15.04 - The Rise of Heat-Not Burn Tobacco in Japan: A “Hot” Issue for Tobacco Control (Now Available) (ID 11466)

      11:15 - 11:30  |  Presenting Author(s): Junji Yoshida

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      Abstract

      Just like in other developed countries, public health has been of major public interest in Japan. Reduced-risk tobacco alternative that exposes smokers who cannot quit and non-smokers around them to lower levels of harmful and potentially harmful constituents (HPHC) has long been a goal. In many countries, electronic nicotine delivery systems (ENDS) have been introduced into the market for that purpose. However, there is a high hurdle for ENDS in Japan. Nicotine is classified as a medicinal drug, and devices using nicotine require governmental approval under the pharmaceutical affairs law. Although Japanese citizens can privately import ENDS as an unapproved pharmaceutical product for private use, bureaucratic formalities are troublesome, and the monthly amount able to be imported is limited.

      In 1997, Japan Tobacco (JT) started to sell AIRS®, the R.J. Reynolds’ Premia® product but with a slight modification. AIRS® had a charcoal heat source at one end, and heated air was inhaled through tobacco leaves. This product did not sell well and was discontinued in 2004. Then in 2010, the next alternative was ZERO STYLE STIX®, also by JT. This product has no heat source. It is a snuff variant, and ambient air is simply inhaled through tobacco leaf powder. When its nicotine was measured by ISO metrics, the amount of inhaled nicotine was shown to be less than a half of low nicotine cigarette.

      Following these alternatives, heat-not burn tobacco (HNBT) came into the market. Tobacco manufacturers aimed at public tobacco harm reduction in total by reducing HPHC emissions from their products and encouraging public acceptance of such products. The tobacco manufacturers understood that Japanese value cleanliness and physical fitness. Most Japanese people are very anxious about their reputation within their community. An American anthropologist Ruth Benedict described it as “Shame Culture” in her book “The Chrysanthemum and the Sword” in 1946. Many Japanese smokers feel shame at releasing HPHC and ash. The manufacturers also know Japan is a country of electric gadget geeks.

      The first of the updated or more recent heated tobacco products was Ploom® from JT in 2013, which was updated to Ploom TECH® in 2016. These were bought from a Californian company Ploom Inc. They are not HNBT but aerosol-not burn or e-cigarette, to be precise. Glycerin, propylene glycol and water vapor passes through a tobacco capsule at the maximum temperature of 30. Philip Morris International introduced their true HNBT, iQOS®, to the Japanese market in 2015, and British American Tobacco product named glo® in 2016. All these HNBT’s were sold in limited areas of Japan at first and gradually extended to nation-wide sales, in response to the demand for HNBT, expanding their production lines. HNBT sales increased rapidly, and heated tobacco category usage among all tobacco users grew up to over 30% in early 2018 from about 4% in late 2015.

      Cigarette ads on TV, radio, or Internet have been allowed in Japan if it is technically possible to restrict access only to the adults, and this is true for the HNBT ads. According to the guidelines set down by the Ministry of Finance, access to HNBT advertising/information web sites and purchase at virtual/real shops have been strictly restricted, requiring proof of age such as a driving license. In their web sites and on product packages, there are always some messaging to the effect of reduced HPHC, but not necessarily guaranteeing less harm to health, which is in accordance with the Ordinance for Enforcement of the Tobacco Business Act.

      Reduction in HPHC exposure and lower levels of biomarker responses have been vigorously reported in peer-reviewed journals, but many of them are funded, studied and reported by the tobacco manufacturing companies themselves. There have been several contradictory articles and in media coverage suggesting that some HPHC are released more from HNBT than from cigarettes. However, manufacturers refute the findings by pointing out inappropriate methods, evaluation and data presentation in these reports. The truth will need to wait for the academic and public health community to sort out the reality of the potential for HNBT to reduce the morbidity and mortality caused by tobacco product use.

      Currently, it seems reasonable to understand that HNBT is likely to expose users and bystanders to lower levels of most HPHC. Although the extent of the reduction found so far varies between studies, reduced exposure to some HPHC is reported to be associated with less short-term harm. To this extent, HNBT might be beneficial for smokers who cannot quit and non-smokers around them. However, less is not zero. It will take 15-20 years to confirm long-term health harm caused by reduced HPHC, such as clinical carcinogenesis. It requires tremendous effort to maintain and watch a large cohort of HNBT users for that long period of time. It is questioned which party ought to do and publish the study. Another question is who pays the cost and whether the study is worth the cost. Because zero is zero, tobacco products including HNBT are desired to be completely abandoned in the future, eliminating the need for long-term harm studies.

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      MS15.05 - Heat-Not-Burn Tobacco: Real Risk Reduction or Industry’s Next Promise (Now Available) (ID 11467)

      11:30 - 11:45  |  Presenting Author(s): Carolyn Dresler

      • Abstract
      • Presentation
      • Slides

      Abstract

      So, the question is: what are we to think about the products emerging from the global tobacco manufacterers that are being marketed in upper income countries? To be clear the topic is not about electronic nicoitne delivery systems (ENDS) that have been sweeping the world’s marketplaces - those arise from a multitude of mostly small companies. ENDS are an interesting topic that is quickly changing also - but, not the topic of this dissertation.

      Rather the topic for this paper will discuss the current market-disrupters which are the so-called ‘heat not burn’ cigarettes (HNB). The tobacco control community tends to call them ‘heated tobacco products’ (HTP), as some of them do come close to ‘burning’ (combusting) the tobacco, so, HTP is a more accurate, broad term for the category. The question to be addressed is whether they are less harmful than cigarettes or are they the usual ‘oversell’ or untrue marketing claims that have been the usual practice of the global tobacco manufacturers.

      A brief review: the global tobacco manufacturers are: Philip Morris, International. (PMI-Switzerland); British American Tobacco (BAT-UK); Imperial Tobacco (UK); Altria (USA) and Japan Tobacco International (JTI- Japan).(see: https://www.statista.com/statistics/259204/leading-10-tobacco-companies-worldwide-based-on-net-sales/). Altria is really just a spin-off from Philip Morris International who sells their products in the USA, including trying to do so for their HNB product (iQOS). Each of them have their own offerings in the HNB category: PMI/Altria is the current leader with iQOS, quipped as standing for: I quit ordinary smoking; BAT has ‘glo’; and Imperial has not embraced/marketed a HNB product but had thought to stay with their ENDS (blu) product. Reportedly, Imperial is considering getting their own HNB, as this category appears to be growing (commerically renumerative). JTI has PloomTECH.

      IQOS and glo use a lithium battery to heat compressed/powdered tobacco to around 300 Celsius which creates an aerosol for inhalation. PloomTech heats a liquid that has nicotine in it (closer to an ENDS)

      A recent paper by Farsalinos et, tested iQOS, an ENDS and a regular cigarette for emitted carbonyls, like formaldehyde and acrolein. (1) They found that iQOS emitted 82-98% less carbonyls compared to smoking 20 tobacco cigarettes. The ENDS emitted 92-99.8% less carbonyls. So, iQOS were better than cigarettes by alot, but the ENDS was better still.

      In a webpage hosted by RIVM (National Institute for Public Health and the Environment, misistry of Health, Welfare and Sport), their research to date is quoted as:

      “Heated tobacco products are newly available on the market. An example of such a product is the heatstick which is heated with an iQOS, a device that looks like an e-cigarette. Heating the heatstick leads to the formation of carcinogenic and other harmful substances. The use of heatsticks with the iQOS is harmful to health, but probably less harmful than smoking tobacco cigarettes. This is RIVM’s conclusion, based on its research into heated tobacco products (HTPs).”(2)

      In another recent paper from Japan, HTPs (iQOS, glo and Ploom TECH) were compared with ‘reference cigarettes’(research cigarettes that are well-defined and not for human consumption (as if any should ever be)). (3) Chemists interested in these findings should check out this paper. For the rest of us - it just demonstrates the tremendous variability in the products. Cigarettes deliver nicotine better than the other tested products, and iQOS does better than glo which does better than PloomTech. Since users are going for the nicotine, it seems that the order of preference will be cigarettes, iQOS, glo and PloomTech. However, the manufacturers are constantly changing their products, so they could be different next month. (This is the problem of unregulated products)

      Most of the published/available research is by the tobacco industry. For the hardy, there is a very large amount of scientific information from PMI on their iQOS submission to the USA FDA. (4) This is all publicly available information - and actually, a very interesting read. The question always remains when reviewing tobacco industry research - can it be verified?

      Overall, however, it does seem that heated tobacco products (or, ENDS) deliver lower levels of most toxicants to the human lung. Low enough to prevent disease is a different question. BUT, cigarettes kill more than half of the people who use them, cause a huge amount of morbidity and healthcare costs - and, are addictive. So, the question facing society - or, public health - is it possible or probable that if people who are already addicted to nicotine and using cigarettes switch (completely) to HTP products - would there be lower morbidity and mortality than we currently experience from cigarttes? No one knows the answer at present - and, we are unlikely to know for a few decades the real answer.

      However, are we horrified enough at the currently greater than 7 million deaths globally per year from cigarettes to radically alter our passionless inactivity and push, by regulation (and social pressure) for people to quit cigarettes. If they use HTPs (or ENDS) to quit the unacceptably deadly cigarettes, so be it. I don’t know how they could be worse than what we currently allow.

      {Disclaimer: I am still passionate about the standard tobacco control measures that are working in some countries, per the Framework Convention for Tobacco Control. I do not trust the global tobacco manufacturers that they are willing to help everyone in the world to quit cigarettes, particularly in low income countries, where these HTP products would be more expensive (unaffordable?) for their current customers. I believe the industry is still intersted in maintaining tobacco addiction - I want to ultimately reduce it as far as possible. First however, I want people who are nicotine addicted to stop dying from that addiction.}

      1. Farsalinos KE at al. Addiction 2019 June 19. doi: 10.1111/add 14365

      2. https://www.rivm.nl/en/Documents_and_publications/Common_and_Present/Newsmessages/2018/Addictive_nicotine_and_harmful_substances_also_present_in_heated_tobacco (accessed 6/29/2018)

      3. Uchiyama S. et al. Simple Determination of gaseous and particulate compounds generated from heated tobacco products. Chem. Res. Toxicol 2018.

      4. https://www.fda.gov/tobaccoproducts/labeling/marketingandadvertising/ucm546281.htm (accessed 6/29j/2018)

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    OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)

    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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      OA10.01 - Patient Preferences for Tyrosine Kinase Inhibitor Treatments for EGFR Mutation Positive Metastatic NSCLC (Now Available) (ID 13735)

      10:30 - 10:40  |  Presenting Author(s): John F.P. Bridges  |  Author(s): Marie De La Cruz, Melissa Pavilack, Emuella Flood, Ellen Janssen, Nabil Chehab, Ancilla W. Fernandes

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR mutation positive (EGFRm) NSCLC responds to EGFR-tyrosine kinase inhibitors (TKIs). First-, second-, and third-generation EGFR-TKI treatment attributes vary in efficacy, side effects, and dosing regimen. We used two different methods to explore treatment preferences among patients with EGFRm metastatic NSCLC.

      Method

      Patients with EGFRm metastatic NSCLC were recruited in the US to participate in an online survey containing two complimentary preference elicitation methods. First, preferences were assessed through direct elicitation exercises where participants chose between competing treatment profiles. The first exercise compared two profiles with a large difference in progression-free survival (PFS) (6 vs 18 months). The second exercise compared two profiles with a smaller difference (10 vs 18 months). Both exercises compared the same side effect risks (0–1% vs 2–16% risk). Second, a discrete choice experiment (DCE) was used to assess preferences for variation in treatments in terms of PFS, severity of side effects (mild/moderate/severe), and mode of administration. These attributes and levels were varied based on a D-efficient design. Participants completed 10 DCE choice tasks where they saw pairs of hypothetical treatments with different attribute levels and selected their preferred treatment. A choice model was estimated using conditional logit regression.

      Result

      Between 10/2017 and 03/2018, 90 patients with EGFRm metastatic NSCLC were recruited and completed the survey: 42% female; 79% white; 76% taking first-line or second-line EGFR-TKIs at time of survey. Median time since diagnosis: 2.1 years (inter-quartile range: 1.1–2.7). In the direct elicitation exercise, participants opted for shorter PFS in exchange for more favorable side effects, but were less likely to do so for a large difference in PFS (52% of participants) vs a smaller difference (66%; p<0.001). Participants who chose shorter PFS when difference in PFS was large were more likely to be taking EGFR-TKIs (odds ratio: 21.4; 95% confidence interval: 2.24, 204.88). No relationship between choice and treatment characteristic was observed when difference in PFS was small. In the DCE, conditional logit regression indicated that to avoid severe levels of nausea/vomiting, diarrhea, rash, or fatigue, participants on average would accept reductions in PFS of 13, 11, 9, and 8 months, respectively. Participants would accept reduction in PFS of 7 months for oral treatment taken with/without food vs IV.

      Conclusion

      In this online survey of patients with EGFRm metastatic NSCLC, some patients were willing to accept shorter PFS for a better safety profile and dosing convenience; however, PFS remained an important attribute in treatment choice.

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      OA10.02 - Oncogene-Driven Patient Groups: A New Era For Research Partnerships (Now Available) (ID 13519)

      10:40 - 10:50  |  Presenting Author(s): Janet Freeman-Daily  |  Author(s): Ivy Elkins, Laura Greco, Marcia K Horn, Bonnie Addario, David LeDuc, Robert C. Doebele, Christine Lovly

      • Abstract
      • Presentation
      • Slides

      Background

      Genomic alterations drive more than 60% of non-small cell lung cancer (NSCLC). About 20% of NSCLC cases (EGFR, ALK, ROS1, BRAF) will have an oncogenic driver that can be treated with approved targeted therapy drugs, and more have clinical trial options. In some cases, patients on targeted therapies will have years of good quality of life. However, targeted therapies do not cure, and these patients will eventually see their cancer progress. Patients and caregivers dealing with cancers driven by EGFR, ALK, ROS1 and Exon20 oncogenes have organized globally into online groups and are building partnerships that seek to provide support, increase awareness and education, accelerate and fund research, and improve access to effective diagnosis and treatment.

      Method

      Each patient-caregiver group forms using social media, patient blogs, websites, fliers, newsletters, and contacts with clinicians. Each has a private Facebook group or other network to inform and educate patients and caregivers of approved and experimental treatments, share common experiences, provide information and tips from expert clinicians and researchers, and enable real-life connections. Each group sets its own priorities such as creating websites, raising funds for research, donating tissue, developing studies of demographics and treatment sequences, and creating biorepositories with annotated specimens that will be made widely available. These projects are accomplished in patient-driven partnership with researchers, clinicians, advocacy groups, and industry. None of the patient-caregiver groups are corporations or other types of legal entities.

      Result

      The ROS1ders focus on ROS1+ cancers of all types and include over 275 members from 21 countries across 8 cancer types. They have partnered in two studies to create ROS1+ cancer models. ALK Positive focuses on ALK+ NSCLC and other cancers, and includes over 1000 members from 38 countries. They have raised nearly $400,000 for research and will announce two grants in May. Exon 20 Group focuses on EGFR and HER2 insertions in Exon 20, and includes 110 members from 19 countries. They created an Exon 20 molecular tumor board and awarded two grants. The EGFR Resisters focus on EGFR+ NSCLC and cancers that develop resistance to EGFR targeted therapies, and include over 450 members from 20 countries.

      Conclusion

      Oncogene-driven patient-caregiver groups are creating a new paradigm in cancer research and have demonstrated that their partnerships with advocacy organizations, clinicians, researchers and industry, combined with social media outreach, can increase available patient data, specimens, cancer models and research funding for geographically distributed, oncogene-driven cancer populations.

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      OA10.03 - Discussant - OA 10.01, OA 10.02 (Now Available) (ID 14564)

      10:50 - 11:05  |  Presenting Author(s): Zofia Piotrowska

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA10.04 - Afatinib With or Without Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Safety and Efficacy Results from SWOG S1403 (Now Available) (ID 14014)

      11:05 - 11:15  |  Presenting Author(s): Sarah B Goldberg  |  Author(s): Mary W. Redman, Rogerio Lilenbaum, Katerina Politi, Thomas E. Stinchcombe, Leora Horn, Everett H. Chen, Sandeep Mashru, Scott N. Gettinger, Mary Ann Melnick, Jieling Miao, James Moon, Karen Kelly, David R. Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      Several EGFR tyrosine kinase inhibitors (TKIs) are used for the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), however resistance inevitably develops. The combination of the irreversible ErbB family TKI afatinib and the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to first-line EGFR TKIs. To attempt to delay resistance, we conducted a randomized trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722).

      Method

      Patients with previously-untreated EGFR-mutant NSCLC were randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks or afatinib 40mg PO daily. The study was designed to accrue a total of 212 patients, comparing progression-free survival (PFS) between the arms at the 1-sided 0.025 level when 134 PFS events had been observed. Secondary objectives included comparison of overall survival (OS), time to treatment discontinuation (TTD), and toxicity. An interim analysis evaluating early stopping for futility occurred when at least 64 PFS events were reported.

      Result

      Between March 26, 2015 and April 23, 2018, 170 eligible patients were accrued: 86 to afatinib/cetuximab and 84 to afatinib. Median age was 66.4 years, 66% were female, 64% had an EGFR exon 19 deletion mutation and 36% had an L858R point mutation. With 109 events observed, there was no improvement in PFS with the combination compared to single-agent (HR 1.17, 95% CI 0.80-1.73, P = 0.42, median 10.6 months vs 13.1 months). OS was also not improved with the addition of cetuximab (HR 1.23, 95% CI 0.62-2.44, P = 0.55, median 26.9 months vs not reached). TTD was similar between the two groups (HR 0.95, 95% CI 0.64-1.39, P = 0.79, median 12.5 months vs 12.2 months). Grade > 3 treatment-related adverse events (AEs) were more common among patients treated with afatinib/cetuximab, and more patients in the combination arm required at least 1 dose reduction of afatinib (57% vs 26%). However, treatment discontinuations due to AEs were similar between the two groups (11.6% vs 10.7%).

      Conclusion

      There was no difference in PFS, OS or TTD with the addition of cetuximab to afatinib for treatment-naïve patients with EGFR-mutant NSCLC. The trial was closed to accrual at the interim analysis having met the criteria for futility. Correlative analysis of tumor tissue and blood from patients is ongoing.

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      OA10.05 - An Open-Label, Multicenter, Phase II Single Arm Trial of Osimertinib in NSCLC Patients with Uncommon EGFR Mutation(KCSG-LU15-09) (Now Available) (ID 14365)

      11:15 - 11:25  |  Presenting Author(s): Jang Ho Cho  |  Author(s): Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Keon Uk Park, Eun Joo Kang, Yoon Hee Choi, Ki Hwan Kim, Ho Jung, An An, Hyun Woo Lee, Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Background

      Approximately 10% of EGFR mutants harbor uncommon mutations, which represent a heterogeneous group of rare molecular alterations within exons 18-21 and the sensitivity to EGFR TKIs is variable. Osimertinib is a potent irreversible inhibitor of both sensitizing EGFR mutation and T790M. In preclinical data, osimertinib was found to be active against most uncommon EGFR mutants, apart from the exon 20 insertion variant. Here we present the efficacy and safety of osimertinib in patients with uncommon EGFR mutation positive NSCLC.

      Method

      Patients with histologically confirmed metastatic or recurrent NSCLC with activating EGFR mutation other than exon 19 deletion, L858R, T790M and insertion in exon 20 were eligible. Patients received 80mg of osimertinib orally, once daily until progression or unacceptable toxicity. Response was assessed every 8 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT03424759.

      Result

      Between Mar 2016 and Oct 2017, 35 patients were enrolled. Median age was 59, 63% male, 43% never smoker, 97% adenocarcinoma. 63% of patients were treated as first-line therapy. The mutations identified were G719A/C/D/S/X (19, 54.3%) followed by L861Q (9, 25.7%), S7681 (8, 22.9%), and others (3, 8.6%). The overall response rate was 50.0% (95% CI 32.8-67.2) and DCR was 88.9% (95% CI 78.1-99.7). Seven patients (77.8%) with L861Q mutation achieved partial response; 10/19 (52.6%) with G719A/C/D/S/X mutation; 3/8 (37.5%) with S768I mutation. At data cutoff (Apr, 2018), the median PFS was 8.2 months (95% CI 1.9- 14.4) and median duration of response was 9.8 months (95% CI 7.6-12.0). The most common adverse events were rash (n=11, 31.4%), anorexia (n=8, 22.9%), and diarrhea (n=7, 20.0%). Grade 3 or 4 AEs were reported in 8 of 35 patients (23%), but all of AEs were manageable.

      Conclusion

      Osimertinib showed highly active in NSCLC patients harboring uncommon EGFR mutation with manageable safety profile, consistent with previous reports. Further analysis will be provided.

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      OA10.06 - A First-in-Human Phase 1 Trial of the EGFR-cMET Bispecific Antibody JNJ-61186372 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 13006)

      11:25 - 11:35  |  Presenting Author(s): Keunchil Park  |  Author(s): Myung-Ju Ahn, Se-Hoon Lee, Hye Ryun Kim, Min Hee Hong, Dawn Millington, Martin Curtis, Spyros Triantos, Sandra Chaplan, Nahor Haddish-Berhane, Roland Knoblauch, Zuleima Aguilar, Sylvie Laquerre, Matthew V. Lorenzi, Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Background

      JNJ-61186372 (JNJ-372) is a bispecific antibody targeting both EGFR and cMET. In preclinical studies, JNJ-372 demonstrated efficacy in EGFR and cMET driven tumor xenograft models (including EGFR T790M and MET-amplified/HGF secretion), consistent with inhibition of ligand binding, receptor degradation, and ADCC activity. The goal of Part 1 of this study (reported here) was to assess the safety, pharmacokinetics (PK), and preliminary efficacy of JNJ-372 and to identify the recommended phase 2 dose(s) to be explored in Part 2.

      Method

      Patients with previously treated, advanced NSCLC were enrolled at two sites and treated with escalating doses of JNJ-372 administered IV weekly for the first 4-week cycle, then biweekly for each subsequent cycle. PK sampling was taken at multiple time points within cycle 1 and 2. Disease assessments were performed every 8 weeks. Tumors were characterized at baseline through next-generation sequencing of circulating tumor DNA (Guardant 360).

      Result

      25 patients were treated with JNJ-372 during dose escalation: 140mg (n=3), 350mg (n=3), 700mg (n=9), 1050mg (n=7), 1400mg (n=3). Median age was 63y, 48% were male, 100% were Asian, 84%/12%/4% had adenocarcinoma/squamous/other histology, and median prior therapies was 4. No dose-limiting toxicities were observed at any dose level tested. The most frequent treatment-emergent AEs were infusion-related reactions (76%), rash/acneiform dermatitis (40%), dyspnea (24%), paronychia (24%), pruritus (20%), fatigue (20%), and nausea (20%); incidence of peripheral edema (cMET-related toxicity) was 12%. Infusion-related reactions were grade ≤2 severity, observed primarily with the first dose. The worst severity of rash/acneiform dermatitis was grade 2 (16%). One treatment-related AE of grade ≥3 severity was reported (neutropenia grade 3, possibly related). JNJ-372 demonstrated linear PK at dose levels 350 mg and above with non-linear PK at lower concentrations, suggesting target-mediated drug disposition. Doses ≥700mg resulted in average steady-state concentrations at or above the preclinically established therapeutic target level. Preliminary evidence of efficacy (maximum change from baseline in sum of target lesion diameters) was observed in a patient with squamous cell carcinoma (-20%), a patient with wtEGFR adenocarcinoma (-20%), and 4 patients with EGFR-mutant adenocarcinoma (≥-30%).

      Conclusion

      JNJ-372 is a novel EGFR-cMET bispecific antibody. The manageable safety profile and preliminary evidence of clinical activity support active accrual of patients with previously treated EGFR-mutant NSCLC. The first recommended dose of 1050mg is being evaluated in Part 2.

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      OA10.07 - Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer Patients: Analysis from AURA17 Trial (Now Available) (ID 12693)

      11:35 - 11:45  |  Presenting Author(s): Caicun Zhou  |  Author(s): Min Hu, Xuehua Zhu, Yun Sun, Xuesong Lu, Jia Wang, Mengzhao Wang, Ying Cheng, Yuan Chen, Yanqiu Zhao, Yuan-Kai Shi, You Lu, Meiqi Shi, He-Long Zhang, Xiangning Huang, Zheng Wang, Zhijie Ding, Heyan Li, George Chen, Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is approved for metastatic NSCLC patients with EGFR T790M mutation after progression from TKI therapy. Despite impressive tumor responses, drug resistance usually develops. The resistance mechanisms of osimertinib are emerging but studies with large cohorts of Chinese patients and association with clinical outcomes are lacking. Here we report a biomarker study of osimertinib using plasma samples from 107 Chinese patients who had progressed by 24 months after LSFD (Oct. 2017) of AURA17 (NCT02442349), the 2nd-line pivotal trial in China.

      Method

      Serial plasma cell-free DNA (cfDNA) were collected from baseline until progressive disease (PD) by investigator assessment. Capture-based 75-gene NGS panel with unique molecular index (UMI) system was used to identify resistance mechanisms to osimertinib by comparing paired cfDNA at baseline and PD. Droplet digital PCR (ddPCR) was used to dynamically monitor EGFR mutation changes (L858R, Ex19Del, T790M and C797S) during treatment course. Association of cfDNA biomarkers based on valid test results with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) from DCO3 (Mar. 20, 2018) was analyzed.

      Result

      The 107 patients were with ORR of 68.2%, median PFS of 8.2 months, and median OS of 21.5 months. Eight-two had detectable EGFR sensitizing mutations (L858R or Ex19Del) in their PD cfDNA samples. Among them, 15 had acquired EGFR C797S, all in cis with T790M, and with no enrichment for L858R or Ex19Del (6 and 9, respectively). The median time of C797S detection from plasma was 2.8 (1.2-8.4) months prior to PD. EGFR L718Q, I744T, C775Y, G796S/D, T854I mutations, or amplification were found in 11 patients. Aberrations in bypass tracks including AKT2, ALK, DDR2, ERBB2/3, HRAS, JAK1/2, KRAS, MET, NTRK1, PIK3CA, RIT1, etc. were observed in 45 patients.

      Clearance of EGFR sensitizing mutations at weeks 3 of treatment was associated with favorable ORR (78.7% vs. 33.3%), PFS (9.6 vs. 4.0 months, p<0.001) and OS (21.5 vs. 11.7 months, p<0.001). Clearance of EGFR sensitizing mutations at weeks 6 of treatment was also associated with favorable ORR (80.0% vs. 36.8%) and PFS (8.3 vs. 4.2 months, p<0.001). Presence of T790M at PD was correlated with longer PFS (12.3 vs. 5.5 months, p<0.001) and OS (21.3 vs. 13.2 months, p=0.045). Acquired or enriched TP53 alterations at PD were associated with worse PFS (4.2 vs. 8.3 months, p=0.008).

      Conclusion

      Our study revealed diverse resistance mechanisms to osimertinib in Chinese NSCLC patients and urged for new drug discovery or combination strategies to overcome this clinical challenge.

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      OA10.08 - Discussant - OA 10.04, OA 10.05, OA 10.06, OA 10.07 (Now Available) (ID 14565)

      11:45 - 12:00  |  Presenting Author(s): Linda Coate

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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