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    GR01 - Whether and How to Adapt Treatment of NSCLC Oligometastatic Disease to… (ID 29)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Oligometastatic NSCLC
    • Presentations: 5
    • Now Available
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      GR01.01 - Definition and Minimal Staging in Oligometastatic Disease (Now Available) (ID 3298)

      13:30 - 15:00  |  Presenting Author(s): Anne Marie Clasina Dingemans

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oligometastatic non-small cell lung cancer (NSCLC) is perceived as a separate entity of metastatic NSCLC with limited metastatic potential and possibility of long term survival when treated with local radical treatment1-3. However, uniform definition of oligometastatic NSCLC does not exist. We showed in a recent systematic review (21 papers) that the number of metastasis, allowed in the definition of oligometastatic NSCLC, varies between 1 and 8, in only 2 out of 21 papers > 5 metastasis were allowed4. This has led to an European Organisation on Research and Treatment of Cancer (EORTC) –Lung Cancer Group (LCG) initiative to formulate a consensus definition of synchronous oligometastatic NSCLC. A pan-European multidisciplinary consensus group was established. Results from the systematic review, a European survey and real patient cases were taken into account when. It was concluded that the definition of synchronous oligometastatic NSCLC is relevant when a radical treatment is technically feasible for all tumor sites with acceptable toxicity, that may modify the disease course leading to long-term disease control. Based on the review, a maximum of 5 metastases and 3 organs is proposed. Mediastinal lymph node involvement is not counted as a metastatic site5.

      In addition staging with PET-CT and imaging of the brain is mandatory. This is in line with the advice of the EORTC-imaging group6.

      The eligibility criteria of recent and ongoing clinical trials in this setting will be discussed in this presentation.

      1. Gomez D, Tang C, Zhang J, et al. Local Consolidative Therapy (LCT) Improves Overall Survival (OS) Compared to Maintenance Therapy/Observation in Oligometastatic Non-Small Cell Lung Cancer (NSCLC): Final Results of a Multicenter, Randomized, Controlled Phase 2 Trial. ASTRO 2018 2018;abstract LBA3.

      2. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The lancet oncology 2016;17:1672-1682.

      3. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA oncology 2018;4:e173501.

      4. GiajLevra N, Levra MG, Durieux V, et al. Defining synchronous oligometastatic non-small cell lung cancer: a systematic review. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2019.

      5. Dingemans A, Hendriks L, Berghmans T, et al. MA25.02 - Searching for a Definition of Synchronous Oligometastatic (sOMD)-NSCLC: A Consensus from Thoracic Oncology Experts WCLC 2018. Toronto: 2018:abstract MA 25.02.

      6. deSouza NM, Liu Y, Chiti A, et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. European journal of cancer 2018;91:153-163.

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      GR01.02 - Local Stage of the Primary Disease? (Now Available) (ID 3299)

      13:30 - 15:00  |  Presenting Author(s): Valerie W. Rusch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      GR01.03 - Nodal Status of the Primary Disease? (Now Available) (ID 3300)

      13:30 - 15:00  |  Presenting Author(s): David Ball

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oligometastases from non-small cell lung cancer (NSCLC) can be classified as synchronous, which are diagnosed at the same time as the locoregional disease, or metachronous, developing after (successful) treatment of the locoregional disease. The title of this presentation implies that the nodes are present at the time of treatment, so the focus will be restricted to the treatment of synchronous oligometastases. In the absence of a universally accepted definition of oligometastatic disease we will assume that the term can be used where there are up to five metastatic sites.

      Nodal involvement as a prognostic factor in patients with oligometastatic disease.

      The earliest reports of attempting to improve survival outcomes for patients with limited metastastic disease were in patients with brain metastases either by resection (1) or by resection or stereotactic radiosurgery (2). Five year survivors were observed, vindicating aggressive treatment in this subset of stage IV patients with NSCLC, but patients with regional node involvement appeared to have worse survival than patients with N0 disease. This was confirmed in a subsequent large multicentre individual patient data meta-analysis reported by Ashworth et al of 757 patients who were treated with ablative treatments to all sites of disease (3). Factors that were important for survival in the meta-analysis were metachronous versus synchronous and histology (favouring adenocarcinoma) as well as N stage. Using recursive partitioning analysis, Ashworth et al were able to group patients with synchronous metastases into an intermediate risk group with N0 disease and a 5 year survival of 36.2% versus a high risk group with N1 or N2 disease and a 5 year survival of 13.8%. Why should regional node status be a prognostic factor in patients who already have distant metastatic disease? Most likely it is because nodal involvement is a surrogate for the volume of metastatic disease that may have been underestimated in the pre-PET era.

      Is regional nodal involvement a contraindication to an aggressive approach?

      Although Hu et al (2) recommended against an aggressive approach to the locoregional disease in patients with stage II or III NSCLC, the fact that 3 year survivors were observed in their cohort and 5 year survivors in the meta-analysis suggests that it is an option that should be discussed considered. in a retrospective study by Flannery et al if the thoracic disease was not treated definitively, survival at 5 years was 0% compared with 34.6% for surgical resection or chemoradiation (P < 0.0001) (4). Patients with N0 or N1 disease (grouped together) had longer survival than patients with N2 or N3 disease, but this was not statistically significant. A prospective phase II trial treated patients with up to 5 oligometastatic sites with chemotherapy followed by chemoradiation to the primary and involved nodes plus SABR or high dose radiotherapy (60 Gy in 30 fractions) to the metastases was associated with a median survival of 28 months, but there was no difference in survival whether nodes were or were not involved (5).

      Does nodal status influence whether locoregional disease should be treated by surgery, SABR or (chemo)radiotherapy?

      This will depend on the patient’s fitness for surgery, and the anatomical extent and location of disease. We have no evidence to support any one strategy. We use the same principles to select treatment to the locoregional disease as if there were no oligometastatic disease present. In the Ashworth meta-analysis, surgical management of the primary was a favourable prognostic feature with a hazard ratio of 0.74 (95% CI: 0.55 – 1.00) on univariable analysis, but not on multivariable analysis (3). In the first randomized trial in patients with NSCLC oligometatases the use of ablative treatments did improve disease free survival in patients with NSCLC who had up to 3 metastases and no evidence of progression after systemic therapy.(6) In this small trial, nearly all patients had synchronous oligometastases. Treatments used for the primary disease after first-line systemic therapy included surgery, stereotactic ablative body radiotherapy (SABR) and chemoradiation. Any involved regional nodes were regarded collectively as one “oligometastatic site”. There was no significant difference in progression-free survival comparing patients with N0-1 disease versus N2-3.

      Conclusion

      Where a patient has synchronous oligometastatic disease that is amenable to ablative therapy, definitive treatment to the primary site and any involved regional nodes taking into account the patient’s general condition and disease stage is a reasonable option, regardless of nodal stage.

      References

      1. Billing PS, Miller DL, Allen MS, Deschamps C, Trastek VF, Pairolero PC. Surgical treatment of primary lung cancer with synchronous brain metastases. J Thorac Cardiovasc Surg. 2001;122(3):548-53.

      2. Hu C, Chang EL, Hassenbusch SJ, 3rd, Allen PK, Woo SY, Mahajan A, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer. 2006;106(9):1998-2004.

      3. Ashworth AB, Senan S, Palma DA, Riquet M, Ahn YC, Ricardi U, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer. 2014;15(5):346-55.

      4. Flannery TW, Suntharalingam M, Regine WF, Chin LS, Krasna MJ, Shehata MK, et al. Long-term survival in patients with synchronous, solitary brain metastasis from non-small-cell lung cancer treated with radiosurgery. Int J Radiat Oncol Biol Phys. 2008;72(1):19-23.

      5. Petty WJ, Urbanic JJ, Ahmed T, Hughes R, Levine B, Rusthoven K, et al. Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2018;102(3):527-35.

      6. Gomez DR, Blumenschein GR, Jr., Lee JJ, Hernandez M, Ye R, Camidge DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-82.

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      GR01.04 - The Rationale for Local Consolidative Therapy in Oncogene-driven, Oligo-and Poly-metastatic NSCLC (Now Available) (ID 3301)

      13:30 - 15:00  |  Presenting Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      GR01.05 - Site of Oligometastases (Now Available) (ID 3302)

      13:30 - 15:00  |  Presenting Author(s): Paul Van Schil

      • Abstract
      • Presentation
      • Slides

      Abstract

      The concept of oligometastatic disease representing patients with only a few or “oligo”metastases, is a relatively new entity in thoracic oncology and surgery [1-2]. Most probably, an intermediate state exists between patients with locoregional disease without distant metastases and those with multiple metastatic involvement in one or more distant organs.

      The International Association for the Study of Lung Cancer (IASLC) adopted this concept and in the 8th Tumor-Node-Metastasis (TNM) edition a new category was introduced representing those patients with a single metastasis in a single distant organ, currently M1b involvement [3]. These patients belong to stage IVA, as well as patients with contralateral malignant nodules. In contrast, multiple metastases in a single or multiple distant organs are currently described as M1c disease, and they are grouped together in the new stage IVB category. In the IASLC database patients with clinical stage IVA disease had a median survival time (MST) and 5-year survival rate of 11.5 months and 10%, respectively, in contrast to 6.0 months and 0% for patients with stage IVB disease [4].

      No consensus exists on the precise definition of oligometastatic disease. For this reason the European Organisation of Research and Treatment of Cancer (EORTC) created a task force to propose a definition of synchronous oligometastatic disease based on consensus by thoracic oncology experts [5]. A maximum of 5 metastases and 3 organs is proposed. Diffuse serosal metastases (meningeal, pericardial, pleural, mesenteric) as well as bone marrow involvement are not accepted as specific site as these cannot be treated with radical intent.

      Is the specific organ involved important in management and prognosis of these patients? Patients with contralateral lung nodules, brain, bone and adrenal metastases are mostly reported in literature as these organs are quite accessible for local ablative treatment by surgical excision or stereotactic radiotherapy. For patients with bilateral / contralateral tumor nodules introduced in the IASLC prospective database by the electronic data capture (EDC) system, MST was 12 months, quite similar to patients with ipsilateral pleural/pericardial effusion. Although the numbers were quite small, for those patients with a single adrenal metastasis introduced by EDC, MST was 6.5 months, for a single bone metastasis 12.6 months, and for a single brain metastasis 12.1 months [3]. These survival times were significantly better than those for patients with multiple lesions at a single site. In general, most survival data are from retrospective series with an inherent selection or publication bias. For this reason, the EORTC decided not to consider the specific organ involved but this may change when more prospective data become available.

      Are there any predictive factors for survival in patients with oligometastatic disease? In an individual patient data meta-analysis of 757 patients with 1-5 synchronous or metachronous metastases from non-small cell lung cancer (NSCLC), predictive factors were synchronous versus metachronous metastases, N stage and adenocarcinoma histology [6]. Surgery was the most frequently used treatment, as well for the primary tumor as for the metastatic involvement. Low-risk patients had metachronous metastases, the intermediate risk group presented with synchronous metastases and N0 disease, and the high-risk group with synchronous disease and thoracic lymph node involvement. So, adequate lymph node staging should be performed in every patient [7].

      May combined modality therapy including locoregional ablative treatment by stereotactic radiotherapy or surgery improve prognosis in patients with oligometastatic disease? A recent landmark trial investigated the role of local ablative therapy in patients with stage IV NSCLC with three or fewer metastases remaining after first-line systemic therapy [8]. In this multicentre, controlled phase II study 49 patients were randomized between local consolidative therapy group consisting of surgery, radiotherapy or a combination with the aim of ablating all residual disease, and maintenance treatment which was chosen from a predefined list of regimens approved by the Food and Drug Administration (FDA). Primary endpoint was progression-free survival. Secondary outcomes were overall survival, safety and tolerability, time to progression of previous metastatic lesions, time to appearance of new metastatic lesions, and quality of life. Most frequent metastatic sites were brain, bone, adrenal gland, pleura and metastatic lung lesions. Significantly longer progression-free and overall survival rates were noted in the local consolidative therapy group than in the maintenance treatment group. Time to the appearance of a new lesion was longer among patients in the local consolidative therapy group than among patients in the treatment group. Survival after progression was also longer in the local consolidative group [8].

      Regarding specific management of oligometastatic disease related to the site of involvement, the European Society of Medical Oncology (ESMO) recently published clinical practice guidelines for metastatic NSCLC including oligometastatic disease [9]. In the presence of a solitary metastatic site on imaging studies, efforts should be made to obtain a cytological or histological confirmation of stage IV disease. Stage IV patients with one to three synchronous metastases at diagnosis may experience long-term disease-free survival following systemic therapy and local consolidative therapy (high-dose radiotherapy or surgery). Because of the limited evidence, these patients should be discussed within a multidisciplinary tumor (MDT) board and inclusion in clinical trials is preferred. Although operative risk is low and long-term survival may be achieved, current evidence for surgery in oligometastatic disease is limited, and the relative contribution of surgery versus radiotherapy as local treatment modality has not been established yet. Solitary lesions in the contralateral lung should, in most cases, be considered as synchronous secondary primary tumors and, if possible, treated with curative-intent therapy [9].

      Finally, even salvage surgery may be considered in highly selected patients with oligometastatic disease to improve long-term outcome [10].

      REFERENCES

      1. Pfannschmidt J. Lung Cancer. 2010;69:251-8

      2. Shields' General Thoracic Surgery, 8th edition 2019, pp. 1289-90

      3. Eberhardt WE. J Thorac Oncol. 2015;10:1515-22

      4. Goldstraw P. J Thorac Oncol 2016; 11:39-51

      5. Dingemans AM. IASLC 19th WCLC 2018; abstract MA25.02

      6. Ashworth AB. Clin Lung Cancer 2014;15:346-55

      7. Fernandez R. J Thorac Dis 2019; 11(Suppl.7):S969-S975

      8. Gomez DR. J Clin Oncol 2019 May 8; doi:10.1200/JCO.19.00201

      9. Planchard D. Ann Oncol 2018; 29(Suppl. 4):iv192-iv237

      10. Duchateau N. Ann Thorac Surg 2017;103:e409-e11.

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    IBS09 - Challenges in Translating Small Cell and Neuroendocrine Tumor Research into Clinical Practice (Ticketed Session) (ID 40)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 07:00 - 08:00, Seoul (2007)
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      IBS09.01 - Challenges in Translating Small Cell and Neuroendocrine Tumor Research into Clinical Practice (Now Available) (ID 3341)

      07:00 - 08:00  |  Presenting Author(s): Alex A Adjei

      • Abstract
      • Presentation
      • Slides

      Abstract

      Challenges in Translating Small Cell and Neuroendocrine Tumor Research into Clinical Practice

      Alex A. Adjei, MD;PhD

      Mayo Clinic, Rochester, MN, USA

      According to World Health Organization (WHO) classification of lung tumors in 2015, small cell lung cancer (SCLC) is one of four lung tumors of neuroendocrine origin. Key morphological features of SCLC are dense sheets of small cells, scant cytoplasm, ill-defined cell borders and distinctive nuclear quality. These tumors are typically high grade, manifesting a high proliferation rate, apoptosis and necrosis. Ki-67 is typically 50-100%, and there is neuroendocrine differentiation documented by expression of synaptophysin, chromogranin A, NCAM1 and insulinoma-associated protein 1 (INSM1). These tumors are very aggressive with high metastatic potential. While they are very responsive to initial therapy, there is invariably relapse and 5 year survival overall is less than 10%. A number of agents thought to be very promising, including the antibody drug conjugate Rova-T, and PARP inhibitors have yielded negative results. In this presentation we will review some of these studies to discern any lessons that can be learned from the failed studies. We will discuss promising new agents such as lurbinectedin, and EZH2 inhibitors and DNA damage response modifiers.

      A number of molecular vulnerabilities of SCLC have been identified. These include

      loss of TP53 and RB function, expression of the ASCL1, MYC, and Notch signaling pathways and unique neuronal characteristics. In addition, SCLC subtypes defined by differential expression of four key transcription regulators, the achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3), have been described. These new insights will be discussed in this presentation. The most significant advancements in the last year shown in Figure 1 below will be described

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      IBS09.02 - Immunotherapy for Small Cell and Neuroendocrine Tumors (Now Available) (ID 3342)

      07:00 - 08:00  |  Presenting Author(s): Sarah B. Goldberg

      • Abstract
      • Presentation
      • Slides

      Abstract

      A subset of patients with small cell lung cancer (SCLC) will achieve significant benefit from immunotherapy. Both nivolumab and pembrolizumab have demonstrated responses in patients with advanced SCLC, and atezolizumab in combination with chemotherapy results in an improvement in overall survival (OS) compared to chemotherapy alone. However, the ability to translate findings from the laboratory into patient care has been limited by several challenges.

      Though some patients will have durable response to PD-1 or PD-L1 agents, the majority of patients will not benefit. Combination strategies have been proposed and subsequently tested to potentially improve outcomes. Although ipilimumab was not effective as a single-agent for patients with SCLC, it has been combined with nivolumab in a phase I trial. The combination appears to be promising with response rates and OS that numerically exceeds that of single-agent PD-1 inhibitor therapy, although a randomized comparison trial has not yet been performed. Still, the majority of patients will not respond to the combination of PD-1 and CTLA-4 inhibition. Other immunotherapy targets have been explored pre-clinically though none have proven to be effective in patients to date.

      Another challenge in improving outcomes for patients with SCLC is that predictive biomarkers have been elusive. In contrast to non-small cell lung cancer, SCLCs rarely express PD-L1 on tumor cells and its presence has limited predictive value. However, immune cells in the tumor microenvironment more commonly express PD-L1 and may be predictive of benefit from immunotherapy. High tumor mutation burden (TMB) is also found in the majority of patients with SCLC likely due to the heavy smoking history in most patients with the disease. Patients with SCLC with a high TMB have been shown to have better outcomes with PD-1 inhibitors that those with lower TMB, however even those with the highest TMB have a fairly low chance of response or prolonged survival. Despite PD-L1 expression on immune cells and high TMB in most tumors, frequency of tumor infiltrating lymphocytes (TILs) is typically low in SCLC, possibly explaining the lack of response to immunotherapy in most patients with this disease.

      The benefit of immunotherapy for a subset of patients with SCLC has been proven, yet we are still faced with several challenges to optimize this treatment, including finding effective combination strategies that benefit more patients and developing predictive biomarkers to select those who are most likely to benefit.

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    IBS19 - Novel Approaches in Radiation Oncology for Small Cell and Neuroendocrine Cancers (Ticketed Session) (ID 50)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 07:00 - 08:00, Seoul (2007)
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      IBS19.01 - Novel Radiotherapy Approaches in Small Cell Lung Carcinoma – Applications to Thoracic, Oligometastatic and Cranial Tumor Control (Now Available) (ID 3372)

      07:00 - 08:00  |  Presenting Author(s): Andrea Bezjak

      • Abstract
      • Presentation
      • Slides

      Abstract

      Novel Radiotherapy Approaches in Small Cell Lung Carcinoma –

      Applications to Thoracic, Oligometastatic and Cranial Tumor Control

      Prof Andrea Bezjak, MDCM, MSc, FRCPC

      Radiotherapy (RT) plays a very important role in the management of Small cell Lung Cancer (SCLC), and jointly with chemotherapy can lead to cures in locally advanced SCLC1. Advances in RT techniques and understanding of its impact on tumor control are paving the way for a number of novel RT approached in the management of thoracic disease, as well as metastatic disease and brain control in SCLC.

      Thoracic radiation currently plays a role in extensive stage SCLC2, particularly in terms of reduction of symptomatic progression of intrathoracic disease. There is room to optimizing the indications, techniques, volumes and perhaps even dose of RT in that setting, and timing with respect to other treatments is worth exploring3-5.

      Whether there is an “oligometastatic” state in SCLC is not clear. One randomized trial of consolidative RT for patients with 1-3 extrathoracic metastases6 showed worse outcomes if all sites were treated with RT, so at this time we cannot recommend such an approach. However, immunotherapy is now part of systemic management of SCLC and studies have documented an important synergy of RT and immunotherapy7. Thus, the question of consolidative RT to areas of either residual disease, or to areas of oligo-progression, should be explored further, particularly if there are improved biological markers to differentiate patients with a lower burden of cancer, or slower natural history of disease.

      Prophylactic cranial irradiation (PCI) has been more controversial given some mixed evidence of its impact on survival from randomized controlled trials8,9, but all trials agree that PCI does reduce the risk of brain metastases in patients with SCLC. There are two current approaches to minimizing the risks of PCI – hippocampal sparing10 and omission of PCI, with MRI surveillance, and perhaps utilization of stereotactic RT if patients present with one or few brain metastases11. This approach, which has been of great benefit in reducing the negative impact of brain radiation while maximizing brain tumor control in non-small cell lung cancer, is emerging as a new paradigm in the management of patients with SCLC, although its applicability may be limited.

      References:

      1. Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18(8):1116–1125.

      2. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015; 385: 36–42.

      3. Slotman BJ, Faivre-Finn C, van Tinteren H, et al. Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial. Lung Cancer 108 (2017) 150–153.

      4. Palmer DA, Warner A, Louie AV et al. Thoracic Radiotherapy for Extensive Stage Small-Cell Lung Cancer: A Meta-Analysis. Clinical Lung Cancer, 2015, Vol. 17, No. 4, 239-44.

      5. Rathod S, Jeremic B, Dubey A. et al. Role of thoracic consolidation radiation in extensive stage small cell lung cancer: A systematic review and meta-analysis of randomised controlled trials. European Journal of Cancer 110 (2019) 110-119.

      6. Gore EM, Hu C, Sun AY, et al. NRG Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone To Prophylactic Cranial Irradiation And Consolidative Extra-Cranial Irradiation For Extensive Disease Small Cell Lung Cancer (ED-SCLC): NRG Oncology RTOG 093. J Thorac Oncol. 2017 October ; 12(10): 1561–1570.

      7. Bang A, Schoenfeld JD. “Immunotherapy and radiotherapy for metastatic disease”. Ann Palliat Med. 2018; (in press)

      8. Slotman B, Faivre-Finn C, Kramer G, et al. EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. (2007), 357(7):664-72.

      9. Takahashi T, Takeharu Y, Takashi S, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicenter, randomized, open-label, phase 3 trial. The Lancet Oncology 2017, 18: 663-71.

      10. Gondi V, Pugh SL, Tome WA, et al.Preservation of Memory With Conformal Avoidance of the Hippocampal Neural Stem-Cell Compartment During Whole-Brain Radiotherapy for Brain Metastases (RTOG 0933): A Phase II Multi-Institutional Trial J Clin Oncol. 2014 Dec 1; 32(34): 3810–3816.

      11. Robin TP, Jones BL, Amini A, et al. Radiosurgery alone is associated with favorable outcomes for brain metastases from small-cell lung cancer. Lung cancer (2018), 120, 88-90

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      IBS19.02 - Novel Radiotherapy Approaches in Small Cell Lung Carcinoma – Has SABR and Radionuclide Therapy Got a Role to Play? (Now Available) (ID 3373)

      07:00 - 08:00  |  Presenting Author(s): Gerard G Hanna

      • Abstract
      • Presentation
      • Slides

      Abstract

      Novel Radiotherapy Approaches in Small Cell Lung Carcinoma – has SABR and Radionuclide therapy got a role to play?

      Thoracic radiotherapy has been shown in to increase overall survival when added to systemic therapy in patients with small cell lung carcinoma (SCLC) and M0 stage. The dose, fractionation, treatment time and timing issues have not been fully resolved. A recent study did not show the superiority of 66Gy in 33 daily fractions over 6.5 weeks over twice-daily radiotherapy to a dose of 45 Gy in 30 fractions over 3 weeks twice daily [1]. For stage I non-small cell lung carcinoma (NSCLC), stereotactic ablative body radiotherapy (SABR) has been clearly shown to be superior to conventional fractionation [2]. Given the clear benefit seen in early stage NSCLC, it is postulated that SABR may have a role to play in early stage SCLC. A recent multi-institutional cohort study has reported favourable outcomes in this setting [3]. However, randomised data of equivalence or indeed superiority are lacking. Furthermore, questions remain as the timing and role of systemic therapy and prophylactic cranial irradiation when SABR is used in this setting.

      In advanced SCLC, many tumors display neuroendocrine clinical and cytological features and many SCLC tumors express somatostatin receptor and this can be imaged using radiolabeled somatostatin analogs such as 68Ga-DOTATATE [4]. Given the uptake by some SCLC tumors of 68Ga-DOTATATE, higher doses of the tracer have been used in an attempt to provide radiolabelled radiotherapy treatment in metastatic disease in what has been described as peptide receptor radionuclide therapy (PRRT) [5]. This molecularly target radiotherapy is a potentially exciting therapeutic approach, but the ideal positioning of such therapy in tumors which are suitable for treatment with PRRT and the safety of PRRT with systemic therapy have yet to be determined.

      References:

      1. Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18(8):1116–1125. doi:10.1016/S1470-2045(17)30318-2

      2. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small cell lung cancer (TROG 09.02. CHISEL): a phase 3, open-label, randomised controlled trial. The Lancet. 2019; 20: 494-503

      3. Verma V, Simone CB, 2nd, Allen PK, et al. Multi-Institutional Experience of Stereotactic Ablative Radiation Therapy for Stage I Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2017;97:362-71

      4. Sollini M, Farioli D, Froio A, et al. Brief Report on the Use of Radiolabeled Somatostatin Analogs for the Diagnosis and Treatment of Metastatic Small-Cell Lung Cancer Patients. J Thor Oncol 2013;8(8):1095-1101.

      5. Lapa C, Hänscheid H, Wild V, et al. Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. Oncotarget. 2016 Apr 12;7(15):20033-40.

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    IBS30 - Risk Assessment in CT Screening (Ticketed Session) (ID 61)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Screening and Early Detection
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/10/2019, 07:00 - 08:00, Seoul (2007)
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      IBS30.01 - Risk Assessment to Establish Screening Programs: The Australian Point of View (Now Available) (ID 3408)

      07:00 - 08:00  |  Presenting Author(s): Annette Maree McWilliams

      • Abstract
      • Presentation
      • Slides

      Abstract

      AustraIia has a multicultural community of 25 million people. (1) The ethnic background of Australians is predominantly Caucasian (83.6%) with 5.2% Chinese ancestry and 2.8% Indigenous Australian in 2016 census data.(1) It has one of the lowest current smoking rates in the world with only 14% of people >18 years being current smokers in 2017-2018.(2) Despite this, lung cancer remains the greatest cause of cancer death for women and men and is the fourth leading cause of all deaths in Australia. (2,3) Lung cancer cases continue to increase due to a variety of reasons including our growing and ageing population and the lag time between the tobacco epidemic and lung cancer occurrence.(4) Lung cancer rates in Indigenous Australians are approximately double compared to non-Indigenous Australians.(4)

      Overall, the majority of lung cancer in Australia is attributable to tobacco exposure but 20% of lung cancer occurs in never smokers.(4) There are known gender differences with ~90% of lung cancer in men attributable to tobacco exposure but only ~75% in women. (4) Other occupational exposures play an important role in lung cancer in Australia, with asbestos being one of the most important toxins contributing to lung cancer incidence.(1) A large longitudinal screening program in asbestos exposed individuals (>1700 participants) is ongoing in Western Australia, the Asbestos Review Project. The project has been utilising low dose chest computed tomography (CT) screening since 2012. Lung cancer rates in this cohort are similar to a high-risk smoking cohort despite lower tobacco exposures. The use of current screening enrolment criteria (USPSTF/NCCN) would have resulted in most lung cancer cases being missed. (5)

      Population based screening programs in Australia have been implemented for cervical, breast and bowel cancers but currently there is no national screening program for lung cancer. A proposed screening program must meet the Australian Screening Framework established in 2008 and be endorsed by the Standing Committee on Screening and the Australian Health Minister’s Advisory Council. (6) In their last published statement in 2015, implementation of a national program has not been supported.(7) The definition of the appropriate population to screen and the likely uptake of screening requires further evaluation in the Australian population.The reduction in mortality from lung cancer screening only occurs in those at high risk so the delineation of this cohort is crucial for minimisation of harm and a cost-effective program.(8) International work evaluating various risk prediction models to define the population that would most benefit from lung cancer screening have been published. (8,9)

      The performance of one of the most well validated models, the PLCOM2012 , has been retrospectively evaluated in the Australian population in a subset of the 45 and Up study.(10) In this large longitudinal cohort, 95 882 ever smokers, >45 years were included in the analysis. The predictive power of the PLCOM2012 risk model was assessed compared to other potential lung cancer screening enrolment criteria (NLST, USPSTF). This study showed that the risk model, although derived from a North American population, performed equally as well in the Australian population. It would reduce the proportion of ever smokers >55 years, potentially eligible for screening to ~29%. However, only 2% of the cohort were of Asian ancestry and 1.6% Indigenous Australian.

      The PLCO risk prediction model has been utilised prospectively in the PanCanadian study and further prospective validation is ongoing in Australia, Canada and Hong Kong in the International LungScreen Trial (ILST). The further refinement of a risk prediction model incorporating occupational/environmental carcinogen exposures such as asbestos and ethnicity is needed to further improve risk assessment for lung cancer screening.

      Supported by National Health and Medical Research Council and Cancer Australia.

      References:

      1. Australian Bureau of Statistics. 3101.0-Australian Demographic Statistics, Sep 2018. Dataset: 2016 Census-Cultural Diversity in Australia. Cited 7 June 2019

      2. Cancer in Australia 2019. https://www.aihw.gov.au/reports/cancer/cancer-in-australia-2019

      3. Deaths in Australia, Leading causes of death. https://www.aihw.gov.au/reports/life-expectancy-death/deaths-in-australia/contents/leading-causes-of-death

      4. Making Lung Cancer a fair fight: a blueprint for reform. Lung Foundation Australia, October 2018. https://lungfoundation.com.au/wp-content/uploads/2018/10/Information-paper-Making-Lung-Cancer-A-Fair-Fight-A-Blueprint-for-Reform-Oct2018.pdf

      5. Harris E, Murray C, Adler B, Ho A, Kong K, Reid A, Franklin P, De Klerk N, Musk A, Brims F. Malignant and non-malignant findings from 5 years of Low dose CT scans screening for lung cancer in the Western Australian Asbestos Review Program. American Thoracic Society Meeting 2019, Dallas, Texas, USA: Abstract 1001.

      6. http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/population-based-screening-framework

      7. http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/lung-cancer-screening

      8. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. The New England journal of medicine2013;369(3): 245-54.

      9. Tammemagi MC, Katki HA, Hocking WG, Church T, Caporaso N, Kvale P, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368:728-36.

      10. Weber M, Yap S, Goldsbury D, Manners D, Tammemagi M, Marshal H, Brims F, McWilliams A, Fong K, Kang, YJ, Carauna M, Banks E, Canfell K. Identifying high risk individuals for targeted lung cancer screening: independent validation of the PLCOm2012risk prediction tool. Int Journal of Cancer, 2017;141(2):242-253.

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      IBS30.02 - Risk Assessment to Establish Screening Programs: The European Point of View (Now Available) (ID 3409)

      07:00 - 08:00  |  Presenting Author(s): Marjolein A. Heuvelmans

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      IBS30.03 - Risk Assessment to Establish Screening Programs: The Canadian Point of View (Now Available) (ID 3410)

      07:00 - 08:00  |  Presenting Author(s): Stephen Lam

      • Abstract
      • Presentation
      • Slides

      Abstract

      Risk Assessment to Establish Screening Programs: The Canadian Point of View

      Stephen Lam MD, FRCPC

      BC Cancer Agency & University of British Columbia, Vancouver, Canada

      The Canadian Task Force on Preventive Health Care (CTFPHC) supports screening with low dose computed tomography (LDCT) of the chest to decrease lung cancer mortality.1 The Task Force recommends annual screening up to three consecutive years in high risk adults aged 55-74 years with at least a 30 pack-year smoking history, who currently smoke or quit less than 15 years ago. Pilot LDCT screening program or studies are being conducted in Canada to help determine how to best implement organized lung cancer screening for people at high risk at the population level. Based on emerging data that suggests both the CTFPHC and the US Preventive Services Task Force (USPSTF) age and pack-years selection criteria2 are suboptimal and that risk prediction tools such as the PLCOm2012 are more sensitive with better positive predictive power to identify ever smokers who will develop lung cancer with a lower number needed to screen to prevent one lung cancer death and are more cost-effective,3-8 pilot studies in Canada adopt the PLCOm2012 risk prediction tool to select high risk ever smokers for LDCT screening.

      A prospective study is being conducted in newly diagnosed lung cancer patients in the Greater Vancouver area. In 1,076 patients, 37% were never smokers reflecting the foreign-born ethnic distribution. Of the 683 ever smokers, 60% met the PLCOm2012 model 6-year risk ≥1.5% screening criteria while only 39.5% met the USPSTF screening criteria.

      The International Lung Screen Trial (ILST), a multi-center prospective trial in Canada (British Columbia, Alberta), Australia, Hong Kong, and the United Kingdom, offer screening to ever smokers age 55 to 80 years if they meet the USPSTF criteria or the PLCOm2012 model 6-year risk ≥1.5% criteria. Participants receive two annual screens and are followed for six years for lung cancer outcomes. Interim results in 4,863 participants with 101 lung cancers showed that PLCOm2012 identified 26.6% more lung cancers than USPSTF criteria (99% of all lung cancers versus 78% with USPSTF). However, PLCOm2012 screened 9.9% more people than USPSTF criteria. If 2% six-year lung cancer risk threshold were used for screening selection criteria as is currently used in the Cancer Care Ontario Pilot, PLCOm2012 would be 12.7% more sensitive identifying 88.1% of lung cancers while screening 11% fewer people compared to USPSTF criteria. A 1.7% six-year lung cancer risk threshold would be 24.1% more sensitive identifying 97% of all lung cancers while screening only 1% more people than USPSTF criteria. The 1.7% threshold may be a better screening selection criterion.

      The worldwide burden of lung cancer is significant and projected to rise during the coming years especially in East Asian countries, namely, China, Japan, South Korea and Taiwan because of the large population size, high stable incidence rates in male and significant upward trends in females many of whom are never smokers.9 With global migration and increasing number of new Canadians who are diagnosed with lung cancer are from Asian countries such as in Vancouver, better lung cancer risk assessment tools need to be developed that take into account ethnicity and other environmental exposures such as outdoor and household air pollution exposures.10

      Risk prediction tools may be perceived by some to be more complex to use than age and pack-years. The web based PanCan risk prediction tool, a precursor to the validated PLCOm2012 model, was tested in both English and French in 8 centers across Canada from coast to coast.7 The tool was found to be simple to use and took approximately 5 minutes to administer over the telephone. Similar experience was found with the web based PLCOm2012 risk assessment tool for enrollment into the International Lung Screen Trial and the Cancer Care Ontario pilot screening program. Risk assessment can be readily done by a navigator or a physician for enrollment into lung cancer screening programs as part of the shared decision process.

      Supported by the Terry Fox Research Institute, BC Cancer Foundation, the VGH-UBC Hospital Foundation, the Alberta Cancer Foundation, and the Australian NHMRC.

      References:

      1. Lewin G, Morissette K, Dickinson J, et al. Recommendations on screening for lung cancer. CMAJ. 2016;188(6):425-432.

      2. Moyer VA, Force USPST. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 160:330-8.

      3. Wang Y, Midthun DE, Wampfler, Deng B, Stoddard SM, Zhang S, Yang P. Trends in the Proportion of Patients With Lung Cancer Meeting Screening Criteria. JAMA 2015;313(8):853-855.

      4. Tammemagi MC, Katki HA, Hocking WG, Church T, Caporaso N, Kvale P, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368:728-36.

      5. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. The New England journal of medicine 2013; 369(3): 245-54.

      6. Tammemagi MC, Church TR, Hocking WG, et al. Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts. PLoS medicine 2014; 11(12): e1001764.

      7. Tammemagi MC, Schmidt H, Martel S, et al. Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study. Lancet Oncol 2017; 369: 910-919.

      8. Cressman S, Peacock SJ, Tammemagi MC, et al. The Cost-Effectiveness of High-Risk Lung Cancer Screening and Drivers of Program Efficiency. J Thorac Oncol 2017; 12(8): 1210-22.

      9. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424.

      10. Myers M, Brauer M, Ladhar S, et al. Association Between Outdoor Air Pollution and Lung Cancer in Female Never Smokers. J Thorac Oncol 2018; 13(10): S342.

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    IWS01 - Clinical Value of Diagnostic Agility in Managing Patients with Lung Cancer (ID 103)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
    • Now Available
    • Moderators:
    • Coordinates: 9/07/2019, 07:30 - 11:30, Seoul (2007)
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    MS08 - Management of Thymic Carcinoma (ID 71)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 5
    • Now Available
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      MS08.01 - Adjuvant Radiotherapy for Resected Thymic Carcinoma (Now Available) (ID 3481)

      14:00 - 15:30  |  Presenting Author(s): Anthony Brade

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma is a rare malignancy with peak incidence in the 4th-6th decade. In contrast to thymoma, it is commonly associated with higher rates of both lymph node and distant metastatic spread and also with shorter disease free survival. For localized or locally advanced disease, surgical resection, with the intention of complete disease extirpation, remains the standard of care. Due to its rarity however, definitive clinical trial data regarding optimal and appropriate addition of adjuvant therapy is lacking. Thus decision making for post-operative patients is guided by data from large institutional, national or international retrospective series or databases (evidence level IV or V).

      Recommendations for adjuvant therapy for thymic carcinoma are influenced principally by stage and adequacy of resection (R0 vs R1 vs R2). Thymic carcinoma is classically staged us the Masaoka-Koga (MK) system but, based on recommendation to the AJCC by the IASLC Staging Prognostic Factors Committee and the International Thymic Malignancy Interest Group (ITMIG), using a database of more than 10 000 patients (Detterbeck et al 2014), a TNM-based system has now been incorporated into the 8th Edition of the AJCC/UICC TNM Classification of Malignant Tumours. However, since much of the published data regarding thymic malignancies is based on the Masaoka-Koga system, at present this remains commonly used for clinical decision-making but, as data continues to accumulate, will likely be superseded by the TNM system over time.

      Post-operative radiotherapy is routinely recommended for patients with MK stage III (TNM Stage I – T1bN0, Stage II, IIIA/B) thymic carcinoma following R0 resection. Similarly, adjuvant radiation is recommended following R1 resection, regardless of stage, with adjuvant chemoradiation recommended following R2 resection.

      Adjuvant radiotherapy is not recommended for MK I or IIA (TNM Stage 1 T1aN0 with no extension to mediastinal fat) disease.

      Controversy exists regarding the utility of adjuvant radiotherapy in the management of MK IIB (TNM Stage I – T1aN0 with extension to mediastinal fat) disease but can be considered for this group of patients.

      The optimal adjuvant radiotherapy dose remains undefined for thymic carcinoma patients but typical doses reported in the literature for patients in the above recommended groups range from 45-50 Gy in 1.8-2 Gy per fraction daily. Following R1 resection, 50-54 Gy in 1.8-2 Gy per fraction is typically recommended. Following R2 resection, 60-70 Gy (with or without concurrent chemotherapy) is considered standard.

      Nodal involvement is much more frequent in patients with thymic carcinoma compared with thymoma. Resected, unexpectedly N+ patients are typically recommended to receive adjuvant RT to 45-60 Gy if complete resection was obtained or 60-70 Gy (with or without concurrent chemotherapy) if residual nodal disease is suspected/documented. Under the TNM staging system, N1 nodes are defined as those in the anterior mediastinal compartment (IASLC levels 1, 3a, 6 and/or supradiaphragmatic/inferior phrenics/pericardial) and N2 nodes are defined as deep intrathoracic or cervical nodes (IASLC levels 2, 4, 5, 7, 10 and/or internal mammary nodes). Whether inclusion of N1 or N2 nodal compartments in adjuvant RT target volumes is of benefit for N0 or completely resected N1 or N2 patients remains unknown but may be prudent to consider during radiotherapy planning based on clinical factors.

      Radiotherapy should conform to modern standards with CT-based simulation with photon-based 3D conformal or beam-modulated treatment delivery, motion management and image guidance to reduce margins and dose to organs at risk. The utility of adjuvant proton-based RT for patients with resected thymic malignancy remains the focus of ongoing study but may offer some dosimetric advantages with respect to OAR dose (e.g. lung or heart).

      Selected References:

      N. Girard et al., Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 26 (Supplement 5): v40–v55, 2015

      Imbimbo et al., Treatment guidelines: Best practices for the management of thymic epithelial tumors: A position paper by the Italian collaborative group for ThYmic MalignanciEs (TYME)
      Cancer Treatment Reviews 71 (2018) 76–87

      Detterbeck et al. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014; 9(Suppl 2): S65–S72.

      Shepherd et al. Thymic Carcinoma Management Patterns among International Thymic Malignancy Interest Group (ITMIG) Physicians with Consensus from the Thymic Carcinoma Working Group. J Thorac Oncol 2017;12:745-51

      Weksler et al., Impact of Positive Nodal Metastases in Patients with Thymic Carcinoma and Thymic Neuroendocrine Tumors. J Thorac Oncol. 2015;10: 1642–1647

      Willmann and Rimner. The expanding role of radiation therapy for thymic malignancies. J Thorac Dis 2018;10(Suppl 21):S2555-S2564.

      Vogel J, Lin L, Litzky LA, et al. Predicted rate of secondary malignancies following adjuvant proton versus photon radiation therapy for thymoma. Int J Radiat Oncol Biol Phys. 2017;99:427–433

      Vogel J, Lin L, Simone CB, et al. Risk of major cardiac events following adjuvant proton versus photon radiation therapy for patients with thymic malignancies. Acta Oncol. 2017;56: 1060–1064.

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      MS08.02 - Induction Therapy for Locally Advanced Thymic Carcinoma (Now Available) (ID 3482)

      14:00 - 15:30  |  Presenting Author(s): Robert Korst

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma (TC) is a rare mediastinal malignancy that occurs in approximately 10% of all patients with thymic epithelial tumors. There are several different histologic subtypes of TC with squamous cell carcinoma predominating. TC is an aggressive lesion, and frequently presents in more advanced stages and metastasizes to other organs compared to thymoma. This biologic behavior is reflected in the survival rates associated with TC, which are significantly shorter than that of thymoma. Clinical trials conducted exclusively in TC patients have been scarce with only a handful of studies reported in the literature, all focused on advanced, nonsurgical patients.

      Locally advanced, nonmetastatic disease is a common presentation of TC. In the largest retrospective series reported to date, locally advanced disease was the most common stage at presentation, accounting for 45% of patients in whom pathologic stage was recorded1. The importance of complete resection for patients with locally advanced TC cannot be overemphasized. Virtually all reported series of exclusively TC patients that undergo surgical resection have determined that the ability to perform a complete resection is an independent favorable prognostic factor. Despite this, the rate of complete resection in the large, aforementioned series for locally advanced TC was only 64%.

      Given that thymic epithelial tumors (thymoma and TC) are sensitive to both chemotherapy and radiotherapy, an approach that has been favored for patients with locally advanced disease is to administer one or both of these agents preoperatively (neoadjuvant therapy). This strategy is thought to increase the chances of performing a complete resection for marginally resectable or unresectable tumors. Although no clinical trials have been reported exclusively for TC patients using the neoadjuvant strategy, two retrospective reports in TC patients utilizing neoadjuvant chemotherapy or chemoradiation demonstrated complete resection rates of 86% and 69% in marginally resectable or unresectable locally advanced disease2,3. In a phase II clinical trial of neoadjuvant chemoradiotherapy for locally advanced thymic tumors, the complete resection rate for the seven patients that had thymic carcinoma was 71%4. Despite these data, the ability of neoadjuvant therapy to definitively enhance the resectability of locally advanced TC has not been demonstrated due to the absence of randomization and a control group in these studies.

      Some published data have also suggested that TC may respond better to neoadjuvant therapies when compared to the thymoma histotypes. In the previously described phase II trial of neoadjuvant chemoradiotherapy, the patients with TC not only had a better radiographic response to treatment, they were more likely to have a near complete pathologic response (<10% viable tumor) than the patients with thymoma (57% versus 8%)4. Similarly, in a retrospective pathologic analysis of 49 patients with unresectable thymic tumors that underwent neoadjuvant therapy followed by surgical resection at a single institution, the median percent viable tumor in the surgical specimen was significantly less in the TC specimens compared to thymoma (20% versus 91%)5. These two studies also suggest that TC may respond better to chemoradiotherapy than chemotherapy alone.

      Whether targeted or immune therapies can be used successfully in the neoadjuvant setting for TC remains to be determined. Active targeted agents against this disease have remained elusive and immunotherapy may be associated with autoimmune toxicities that may preclude their use in this approach6.

      In summary, the use of induction therapy for locally advanced TC is based on the premise that this approach may enhance resectability of these aggressive tumors, which is an overwhelmingly positive prognostic indicator. However, no published data has conclusively determined that this strategy is effective in enhancing resectability due to a lack of controlled studies. TC may respond better to induction therapy when compared to thymoma, and chemoradiotherapy may induce more radiographic and pathologic responses than chemotherapy alone, but these data are preliminary.

      References.

      Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: Results of an international analysis. J Thorac Cardiovasc Surg 2015;149:95-101.

      Kawasaki H, Taira N, Ichi T, et al. Weekly chemotherapy with cisplatin, vincristine, doxorubicin and etoposide followed by surgery for thymic carcinoma. Eur J Surg Oncol 2014;40:1151-1155.

      Shintani Y, Masayoshi I, Tomohiro K, et al. Multimodality treatment for advanced thymic carcinoma: outcomes of induction therapy followed by surgical resection in 16 cases at a single institution. Gen Thorac Cardiovasc Surg 2015;63:159-63.

      Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: A phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg 2014;147:36-46.

      Johnson GB, Aubry MC, Yi ES, et al. Radiologic response to neoadjuvant treatment predicts histologic response in thymic epithelial tumors. J Thorac Oncol 2016;12:354-67.

      Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018;19:347-355.

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      MS08.03 - Optimal Management of Metastatic Thymic Carcinoma (Now Available) (ID 3483)

      14:00 - 15:30  |  Presenting Author(s): Guiseppe Giaccone

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma represents approximately 10-15% of all thymic epithelial tumors, it is more aggressive than thymomas and also somewhat less sensitive to chemotherapy. More often than thymomas, thymic carcinomas are not resectable and therefore the use of systemic therapies and radiation are more often required than in thymomas. In general the sensitivity of thymic carcinomas to chemotherapy is lower than with thymomas, with response rates usually less than 50% in metastatic disease, and somewhat higher in locally advanced disease.

      In presence of borderline operable cases, neoadjuvant chemotherapy is indicated, in order to make the tumor more easily operable. Because thymic carcinomas often infiltrate surrounding tissues, radical resection are sometimes not achievable. The use of postoperative radiation is indicated even if margins are clear. Several chemotherapy regimens have been used, and the more commonly employed remain platinum combinations, with or without an anthracycline (mainly doxorubicin). More recently data the combination carboplatin-paclitaxel has been added to the potential chemotherapy regimens and it is often preferred becasue of its milder toxicity profile. When radiation is planned, the use of doxorubicin is contraindicated, becasue of the enhanced toxicity. The role of debulking surgery, reoperation and metastasectomy is much more controversial in thymic carcinomas than in thymomas, given the more aggressive behaviour. However, the histological diagnosis sometimes is not paralleled by an aggressive phenotype and individual treatment decisions should always be considered.

      Unfortunately thymic carcinoma have the tendency to metastatize wildly to virtually all organs, and brain metastases are all but rare. Complete staging procedures, including brain MRI are therefore indicated in patients with thymic carcinoma. In patients with metastatic disease, chemotherapy is indicated as first line therapy, and the CAP regimen (cisplatin, doxorubicin, cyclophosphamide) or carboplatin-paclitaxel, are the preferred regimens, with response rates in the range of 30-50%. Unfortunately, chemotherapy at this stage is not curative and most patients will require further systemic therapies after failure of chemotherapy. There have been a number of studies in recent years, which have established activity of a few agents, such as sunitinib and pembrolizumab in thymic carcinomas. Both of them are now listed in the NCCN guidelines and have a response rate of about 25%. Pembrolizumab however has a much longer duration of response, albeit the frequency of severe autoimmune disorders is higher than in other diseases in which immune checkpoint inhibitors are used. Further chemotherapy also has some activity, such and the combination gemcitabine-capecitabine and other single agents, with responses in the 20-30% range.

      The biology of thymic carcinoma does not appear to provide clues to specific treatments, although mutations in epigenetic genes have been found in a significant number of patients. No easily targetable mutations or genetic abnormalities have so far been found. The most common mutation is in the p53 gene, in about 30% of cases, which is not targetable and is associated with a poorer survival.

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      MS08.04 - Novel Biomarkers for Thymic Carcinoma (Now Available) (ID 3484)

      14:00 - 15:30  |  Presenting Author(s): Mirella Marino  |  Author(s): Beatrice Casini, Enzo Gallo, Enrico Melis, Fabiana Letizia Cecere, Valentina Laquintana, Virna Cerasoli, Francesco Facciolo, Edoardo Pescarmona, Francesco Fazi

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      Abstract

      Thymic carcinoma (TC), the rarer among Thymic Epithelial Tumors (TET), occur with an incidence rate of 0.2-0.5/million/yr. Difficulties in the evaluation of molecular aspects derive from the extreme rarity of these tumors. The Squamous cell carcinoma (SQCC) is the most frequently analyzed, however the other rarer histotypes could differ both in molecular pathogenesis and in clinical behaviour. The Cancer Genome Atlas Thymoma study (TCGA-THYM) in a series of ten TC cases including four SQCC, four undifferentiated carcinoma and both one large cell neuroendocrine carcinoma as well as one TC, NOS, identified a few genes rarely mutated, including KIT, HRAS, NRAS and TP53, reflecting the low mutational burden of these tumors (1). In the last years, only a limited number of TC has been investigated by other groups and only a limited number of relevant alterations has been identified. In addition to genomic events, however, epigenetic factors could contribute to TET carcinogenesis. Wang et al. in 2014 performed targeted sequencing of 197 cancer-associated genes in 78 advanced-stage TET patients, including 47 TC and 31 thymoma (THYM) cases. They reported that TC showed a higher incidence of somatic non-synonymous mutations than THYM. Moreover, they found that mutations of epigenetic regulatory genes involved in chromatin modification pathways are common in TC in comparison to THYM (2).

      In the last years we have been interested in the characterization of genomic and epigenetic findings related to TET development. In our earlier microRNA (miR) study, we reported, among other findings, preliminary data on mature microRNAs differentially expressed in TC vs THYM, as revealed by microarray-based unsupervised clustering analysis. Among the differentially expressed miRs, 3 were validated by RT-qPCR (miR128, miR142-5p and miR-181c-5p) (3). By a different approach, we analyzed by Next Generation Sequencing (NGS) thirteen TC cases and one Atypical Type A thymoma case. The tissues derived from Formalin-fixed, paraffin embedded (FFPE) material including biopsies/surgical specimens of tumors and a single case of matched peritumoral thymus. The percentage of neoplastic cells was not < 70-80% of total cells. The DNA was extracted using the QIAcube and QIAamp DNA FFPE Tissue Kit (Qiagen, Valencia, CA) from microdissected 5 μm FFPE tissue sections. The NGS platform Ion S5 (Thermofisher) and the Ion AmpliSeq™Cancer Hotspot Panel v2 were used. This panel is designed to amplify 207 amplicons covering over 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes. Libraries from Ion AmpliSeq Cancer Hotspot Panel v2 were prepared and sequenced by Ion Chef and S5 system. Data analysis was conducted by using the dedicated Ion Reporter Software. Among other genomic variants (polymorphysms and mutations were found in four cases), in one out of these four TC cases a KIT mutation (c.1900C>T; p.R634W, exon 13), already reported in TC, was identified. Moreover, a further KIT mutation ( c.1718C>T p.P573L, exon11) was found in a second case. In addition, a missense TP53 mutation ( c.824G>T; p.C275F), occurring in exon 8, was observed in a single case of TC, NOS. The patient harbouring a TC with this TP53 mutation had a R0 robotic-assisted thymectomy of a pT2 Thymic carcinoma (according to the 8th TNM edition), and after adjuvant chemotherapy and radiotherapy is alive and in complete remission with a follow-up of 22 months . The recent case of Atypical Type A thymoma showed a NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 of uncertain significance.

      Basing on the relatively few cases reported in the literature, analyzed by different techniques for their genomic alterations, it appears that the mutation status of TC is highly heterogeneous. In the cases examined so far by NGS we didn’t find recurrent genetic aberrations, but a variety of alterations. Each case, with the panel available, revealed either polymorphisms or, in few cases, mutations in cancer-associated genes, both oncogenic and oncosuppressor. Among the genes involved, both the KIT reported variants could be considered relevant for targeted therapy. Moreover, the tumor suppressor gene TP53 is already known for its importance and frequency of mutations particularly in TC. Moreira et al reported recurrent TP53 mutations with unfavorable prognostic value (4). The TP53 mutation found in one of our cases (previously reported in cases of SQCC of upper respiratory tract, in lung, head & neck and esophageal carcinoma) affects, among others, the DNA damage repair, the cell cycle and the apoptosis pathways. In human thymus, the Notch pathway, activated in thymic EC, is crucial to T cell differentiation; moreover the Notch signaling is also involved in hematological and in solid tumors. The NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 we reported in a Atypical case A thymoma was already described in lymphoid tissues. The clinical and prognostic value of the genomic alterations we observed needs to be definied.

      1) Radovich M, et al., The integrated genomic landscape of thymic epithelial tumors - Cancer Cell, 2018 Feb 12;33(2):244-258

      2) Wang Y, et al., Mutations of epigenetic regulatory genes are common in thymic carcinomas - Sci Rep. 2014 Dec 8;4:7336

      3) Ganci F, et al., MicroRNAs Expression Profiling of Thymic Epithelial Tumors - Lung Cancer 2014, 85 (2) 197–204

      4) Moreira AL, et al, Massively parallel sequencing identifies recurrent mutations in TP53 in thymic carcinoma associated with poor prognosis - J Thorac Oncol. 2015 Feb;10(2):373-80

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      MS08.05 - Basic Pathological Features (Now Available) (ID 3485)

      14:00 - 15:30  |  Presenting Author(s): Cesar Moran

      • Abstract
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      Abstract

      IASLC WCLC 2019

      MS08 – Management of Thymic Carcinoma

      Cesar A. Moran, MD

      Professor of Pathology

      M D Anderson Cancer Center

      Houston, TC

      USA

      Pathologic Features

      The basic pathological features of thymic carcinomas are essentially those seeing in other tumors elsewhere and require the presence of conventional features such mitotic activity, cellular and nuclear atypia, and necrosis among others. However, the diagnosis of thymic carcinoma contrary to the diagnosis of carcinomas in other anatomical areas requires a more strict radiological correlation, as thymic carcinoma can show similar histological features as other tumors such lung or head and neck area. Therefore, the clinical information of an anterior mediastinal mass in the absence of tumor elsewhere becomes an important diagnostic tool in the assessment of thymic carcinoma.

      The histopathological features of thymic carcinomas are vast and highly heterogeneous. It is possible that such heterogeneity may be due the different cell types that may be encountered in the normal thymus. However, in general terms, thymic carcinomas can be separated into neuroendocrine and non-neuroendocrine carcinomas, and further sub-divided into: 1) low grade and 2) high grade carcinomas (see table 1). Among the neuroendocrine carcinomas, similar spectrum as in other organ systems has been recognized, including: low grade, intermediate grade, and high grade neuroendocrine carcinoma. Some of these tumors may have special association with particular syndromes. Aside from the neuroendocrine carcinomas, the vast majority of thymic carcinomas are of the squamous type, which can show diversity in their growth pattern from well-differentiated keratinizing to the high-grade lymphoepithelioma-like carcinoma and anaplastic/pleomorphic carcinoma. In addition, the tumors may show different cell types and growth patterns that may include: papillary, micropapillary, clear cell, sarcomatoid carcinomas, and micronodular among others. In addition, it is important to highlight the occurrence of salivary gland type carcinomas in the thymus, examples of that include: mucoepidermoid carcinoma, adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. More interesting is the fact that a small subset of thymic carcinomas will belong to the adenocarcinoma type, with similar features as those adenocarcinomas in other organ systems – mainly a malignant glandular proliferation. These tumors may also show variability in their growth pattern and may show a solid glandular proliferation or a predominantly mucinous component. Needless to say, these thymic adenocarcinomas can mimic metastatic disease from other organ systems such as lung or colon. Therefore, a close clinical correlation is also highly suggested before determining site of origin. It is due to this heterogeneity that the diagnosis of primary thymic carcinoma requires more strict clinical-radiological-pathological criteria, as there are no pathognomonic features that can define a thymic carcinoma, mainly in cases in which there is only a small mediastinoscopic biopsy for evaluation.

      From the immunohistochemical point of view, thymic carcinomas commonly express keratin, keratin 5/6, p63, p40, CD5. In addition, it is also well known that some neuroendocrine markers such as synaptophysin may be seen positive in otherwise conventional thymic carcinomas. On the other hand, thymic adenocarcinomas may express different immunohistochemical phenotype that may include: keratin 7, keratin 20, CDX-2, and CEA. In cases of neuroendocrine carcinomas the use of neuroendocrine markers including chromogranin, synaptophysin, and CD56 may prove useful. However, the grade of differentiation still can be done on morphological grounds. More recently, it has been identified a poorly differentiated carcinoma the so-called NUT carcinoma that by histology most likely represents a poorly differentiated squamous carcinoma but that shows positive staining using the immunohistochemical stain for NUT and also may show more specific cytogenetic and chromosomal abnormalities. Such diagnosis should be suspected in poorly differentiated carcinomas.

      Regarding the prognosis of thymic carcinoma, it has been identified that the presence of lymph node metastasis, regardless of the location of the lymph node, plays an important role in the clinical outcome of these patients. Therefore, thymic carcinomas are best suited for a TNM staging, contrary to the use of the TNM for thymomas.

      TABLE 1

      Histological Variants of Thymic Carcinoma

      Low grade High grade Neuroendocrine

      Mucoepidermoid carcinoma lymphoepithelioma-like Low grade (carcinoid)

      Basaloid carcinoma P.D. squamous cell Ca Intermediate (atypical carcinoid)

      Epithelial-myoepithelial Ca Anaplastic Ca High-grade (Small cell Ca)

      Well-diff. Squamous cell Ca Sarcomatoid Ca

      Rhabdoid Ca

      Hepatoid Ca

      Micronodular Ca

      Papillary/micropapillary Ca

      Clear Cell Ca

      NUT carcinoma

      Adenocarcinoma

      REFERENCES

      1.Shimosato Y, Kameya T, Nagai K, Suemasu K. Squamous cell carcinoma of the thymus. Analysis of 8 cases. Am J Surg Pathol 1977; 1:109-121.

      2.Snover DC, Levine GD, Rosai J. Thymic carcinoma. Five distinctive histological variants. Am J Surg Pathol 1982; 6:451-470.

      3.Suster S, Moran CA. Thymic carcinoma. Spectrum of differentiation and histologic types. Pathology 1998; 30:111-112.

      4.Moran CA, Suster S. Thymic carcinoma. Current concepts and histological features. Hematol Oncol Clin N Am 2008; 22:393-407.

      5. Suster S, Rosai J. Thymic carcinoma. A clinicopathologic study of 60 cases. Cancer 1991; 67:1025-1032.

      6.Weissferdt A, Moran CA. Thymic carcinoma, part I. A clinicopathologic and immunohistochemical study of 65 cases. Am J Clin Pathol 2012; 138: 103-114.

      7.Weissferdt A, Moran CA. Thymic carcinoma, part 2. A clinicopathologic correlation of 33 cases with a proposed staging system. Am J Clin Pathol 2012; 138:115-121.

      8.Kalhor N, Moran CA. Primary thymic adenocarcinomas: a clinicopathological and immunohistochemical study of 16 cases with emphasis on the morphological spectrum of differentiation. Hum Pathol 2018; 74:73-82.

      9.Moran CA, Suster S. Neuroendocrine carcinomas (Carcinoid Tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000; 114:100-110.

      10. Kalhor N, Moran CA. Mediastinal Pathology, Springer 2019, Chapter 8, pp 237-286.

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    MS13 - Immunotherapy for Mesothelioma (ID 76)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 6
    • Now Available
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      MS13.01 - Immunotherapy and Mesothelioma: Rationale and Strategies (Now Available) (ID 3514)

      11:30 - 13:00  |  Presenting Author(s): Jan P Van Meerbeeck

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      Abstract

      Unresectable malignant pleural mesothelioma (MPM) is a uniformly fatal rare cancer with increasing incidence worldwide. Combination chemotherapy with platinum/antifolate –either pemetrexed or raltitrexed- is the only standard of care 1st line treatment with proven improvement of survival, which varies according to series and patient selection between 12-16 months median overall survival (mOS), with corresponding 1 year survival rate of 50-60%. After a median progression-free survival of ~ 3 months, patients relapse and few if any drugs have any proven efficacy at this stage. Survival after progression varies from 3-18 months according to tumors’ biological behavior and patient’s prognostic factors. Therefore, innovative drugs are urgently needed.

      Although called ‘immunologically cold tumours’ and presenting with a low mutational burden, MPM express distinct targetable antigens (WT1, mesothelin), contain tumour-infiltrating lymphocytes (TILs) and PDL-1 expression is variably present, mostly on the sarcomatoid subtype. Experimental models have demonstrated chronic inflammation and local tumor suppression as crucial to MPM pathogenesis. This led to the investigation of immunotherapy in MPM.

      Monoclonal antibodies against immune check point inhibition (ICI-) molecules have been evaluated as salvage therapy after first-line chemotherapy in several phase 2 trials, either as single agent or in combination. The randomized DETERMINE trial evaluated in 564 patients the anti–CTLA-4 antibody tremelimumab versus placebo in second or third line and found no benefit in outcome (hazard ratio 0.92; p = 0.408). Results from the anti–PD-1 or anti–PD-L1 trials with nivolumab, pembrolizumab and durvalumab are fairly consistent with a response rate of 19-30%, a median PFS of 3.5 – 6.0 months and mOS of 12-18 m, all uncontrolled in selected patients with good prognostic features. Addition of CTLA-4 inhibitors to PD(L)-1 seem to increase efficacy and prolong the time-to-event endpoints. Preliminary results suggest that PD-L1 tumour proportional score (TPS) is both a predictive and prognostic biomarker.

      Several trials are underway investigating ICI alone or in combination with SOC-chemotherapy as frontline treatment. The DREAM trial, a single-arm, open-label phase II trial of durvalumab with cisplatin/pemetrexed, followed by durvalumab maintenance therapy for 1 year. The primary endpoint was PFS at 6months. Interim results in the first 54 patients show a mPFS of 6.2 months, with 48% achieved a partial response based on immune-modified RECIST. The -immature- 1-year OS estimate is 65% at a median follow-up of 14.4 months.

      Other randomized studies of triplet combinations are ongoing, including SOC-chemotherapy w/wo pembrolizumab (NCT02784171) or durvalumab (NCT02899195). The phase III CheckMate743 (NCT02899299) trial randomly selected 600 patients with treatment-naïve MPM to nivolumab plus ipilimumab -until progression or unacceptable toxicity- versus up to six cycles of SOC-chemotherapy.

      Surgical management in resectable MPM represents an excellent opportunity for window-of-opportunity trials when treating patients with neo-adjuvant immunotherapies to improve resectability, fight residual disease and improve patient outcome. Several studies are ongoing with anti–PD(L)-1 with or without CTLA-4 inhibitors or chemotherapy in the neo-adjuvant setting, but results have not yet been published.

      Immunotherapy beyond ICI have been also tested in MPM but with discordant results. Several randomized phase II trials have targeted mesothelin, including amatuximab, an antimesothelin chimeric monoclonal antibody, anetumab-ravtansine, an antibody drug conjugate, and CRS-207, a vaccine targeting mesothelin: these have not yet shown any efficacy in MPM (unpublished data). Cell therapies in phase I trials are being investigated in MPM, including chimeric antigen receptor (CAR) T cells targeting surface antigens such as mesothelin, given both intravenously (NCT02159716) and intrapleuraly (NCT02414269).

      Vaccines targeting the Wilms tumor-1 (WT-1) antigen have also been tested in MPM with variable results. Dendritic cell vaccination was found to be efficacious in small trials of MPM, providing the rationale for ongoing trials, such as the large randomized phase II trial (DENIM) with dendritic cell therapy as maintenance after P/P frontline chemotherapy or a phase I/II trial testing autologous dendritic cells loaded with WT-1 tumor antigen following standard first-line chemotherapy. Autologous tumor infiltrating lymphocytes and interleukin-2 (IL-2) infusion after lympho-depletion are also currently under investigation in a phase I/II trial in MPM. Immune-gene therapy using intrapleural delivery of adenovirus-expressing interferon-α combined with celecoxib and chemotherapy was well tolerated and provided a remarkable mOS of 21.5 months as second-line treatment. Finally, oncoviral therapy is being assessed in a phase I trial with intrapleural injection of measles virus (NCT01503177), or with an oncolytic adenovirus coding for GM-CSF combined with chemotherapy and cyclophosphamide versus chemotherapy alone in a randomized phase II trial (NCT02879669).

      In conclusion, immunotherapies are being investigated in different settings of MPM. Regulatory approval is anticipated soon for ICI (anti–PD-1 with or without anti–CTLA-4) as salvage treatment in MPM. However, state of the art phase III trials comparing ICI with SOC-chemotherapy are needed to firmly establish immunotherapy, either alone or in combination with standard treatment, and to validate biomarkers for patient selection.

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      MS13.05 - CaR T Cell in Mesothelioma (Now Available) (ID 3516)

      11:30 - 13:00  |  Presenting Author(s): Prasad S Adusumilli

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      Abstract

      Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in hematological malignancies and was approved by FDA for the treatment of leukemia and lymphoma patients. Adotpive cell therapy by use of CARs involves transducing patient's own T lymphocytes with antigen-specific CAR by retro or lenti virus, and infusing back to the patient following Cyclophosphamide preconditioning. This presentation will dicuss the challenges in developing CAR T-cell therapy, progress to date in translation of CAR T-cell therapy for thoracic cancers.

      Advances in understanding thoracic cancers tumor immune microenvironment and successes with checkpoint blockade agents has opened doors to devlop combiantion immunotherapy for thoracic cancer patients. Our laboratory has shown that in the presence of high tumor burden as in patients with metastases, a low-dose of CAR T cells adminsitered in phase I clinical trials can be exhausted. Addition of anti-PD-1 agents can rescue functionally exhausted CAR T cells and prolong their anti-tumor efficacy. Based on this strong rationale, our laboratory has translated mesothelin-targeted CAR T-cell therapy for patients with malignant pleural mesothelioma and demonstrated anti-tumor efficacy in addition to safety in combination with anti-PD-1 agents. The results of the ongoing trials will be discussed.

      While extrinsic anti-PD-1 agent administration requires multiple doses and potential off-tumor side effects, we have developed T-cell intrinsic anti-PD-1 strategies which are in translation. The preclinical and clinical data supporting this upcoming clinical trial will be presented.

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      MS13.02 - Pro - Hedy Kindler Is Right (Immuno Works for Mesothelioma) (Now Available) (ID 3512)

      11:30 - 13:00  |  Presenting Author(s): Hedy Lee Kindler

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      Abstract not provided

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      MS13.03 - Con - Raphael Bueno Is Right (It Does Not Work) (Now Available) (ID 3513)

      11:30 - 13:00  |  Presenting Author(s): Raphael Bueno

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      Abstract

      Mesothelioma is a heterogeneous cancer and it is not always correctly staged in the absence of surgical extirpation. While some clinical trials utilizing a remarkably small number of patients showed some response to immunotherapy in mesothelioma, the response rate is relatively low (in the 10% rate) and it is unclear how durable. The heterogeneity of the tumor makes interpretation of such small number difficults leading to the conclusion that at this time immunotherapy remains experimental in mesothelioma

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      MS13.04 - Biomarkers of Anti-PD1 Therapy in Mesothelioma (Now Available) (ID 3515)

      11:30 - 13:00  |  Presenting Author(s): Paul Baas

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      Abstract

      Biomarkers of Anti-PD1 Therapy in Mesothelioma.

      Biomarkers have attracted attention for their usefulness in selecting the right treatment for the right patient. There are different types of biomakers; blood based, clinical markers and histological markers. Most of the biomarker studies have focused on the prognosis of patients while only a limited number examined the predictive value of a marker; to correctly predict the outcome of a certain treatment.

      After the reported successes of check-point inhibitors in melanoma and NSCLC (1-4), the use of these agents have found its way to mesothelioma(5-8).
      Since 2015 many studies have been initiated whit a comparable efficacy compared to NSCLC outcomes. Around 20-25% of cases do respond favorably to this approach. This is considered to be of great importance since there is a limited 2 years survival rate (8) and no standard second line therapy has yet been defined. There are a number of factors that have to be considered before embarking on Immuno-Oncology (IO) therapies as single agent or in combination. The choice of the drug or combination; the expected outcome in short time; the toxicity profile and the costs. Because of the lack of registration, there is a limited availability and patients can only join in studies or be part of a compassionate use program. When registration is a fact we merely have to deal with the questions; who will benefit, who will experience toxicity and is the treatment cost effective?

      In a series of studies we performed in patients with pleural mesothelioma we have collected samples to be used as biomarkers (6,7). Currently we are analyzing the predictive value of these biomarkers.
      1. Histological biopsies: It is well known that the expression PD-L1 can be predictive in NSCLC of a success while in melanoma there is a better correlation with tumor mutational burden. For mesothelioma the expression of PD-L1 varies between the different subtypes of mesothelioma (with sarcomatoid type expressing higher PD-L1 levels) (9). In general the high expression correlates with a worse survival. In addition, the expression of PD-L1 on tumor stroma also influences the outcome of IO treatment. In our study of 34 patients (7), we observed a clinical benefit of 18% in PD-L1 tumor negative patients compared with 15% in the (TIL+) stroma and 32% versus 35% in stroma for any PD-L1 expression. When analyzed for PD-L1 > 50% the stromal T+ cells showed a factor of 2 higher clinical benefit. This implies that a single analysis of the PD-L1 of the tumor cells might underestimate the effect of IO therapy.

      2. eNose analyses. The use of exhaled air has attracted clinical interest since early data indicate that the Volatile Organic Compounds (VOCs) can predict an outcome of IO therapy (11). These VOCs probably represent a complex combination of tumor and immune cell interactions. Ongoing studies focus on the use of these electronic noses to select only patients for whom a treatment has a high chance of success.

      3. Blood based biomarkers have been tested in many studies in mesothelioma. For well-known markers such as mesothelin, cyfra 21-1, osteopontin and fibulin-3 no positive outcomes have been reported in prediction studies.

      4. MicroRNAs. These short, non-coding RNA sequences have attracted attention because of their prognostic capability in mesothelioma and other cancers. The huge number of miR’s identified and the lack of comparative studies to date indicate that these markers can only be used for diagnostic and perhaps treatment purposes. (12)

      5. BAP1 is a nuclear deubiquitinase which regulates the ubiquitination of selected histones and other translational factors. This mutation is occurring both in germline or, more frequently, as a somatic mutation in mesothelioma. It has different functions and can influence the inflammation status of the microenvironment. Although not tested in a proper study setting this marker may well have a predictive potential(13).

      6. Other biomarkers. Finally there are a number of interesting biomarkers including chemokines like IL-6 which acts as a pro-inflammatory cytokine and is closely related to T cell function. Ongoing studies will try to elucidate the predictive effect of this and other markers.

      To date there is a lot of activity ongoing in mesothelioma and the introduction of the IO drugs have been welcomed full-heartedly. Although we have identified an abundant number of prognostic factors in cancer, the high costs of IO therapies presses us to find solid predictive markers. The combination therapies of IO drugs now proposed do increase the toxicity profile and we must not lose precious time of patients and doctors spend on ineffective and costly therapies.

      References are available at the author at request

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      MS13.06 - Role of Second Line Chemotherapy and New Target Treatment in Recurrent Mesothelioma (Now Available) (ID 3517)

      11:30 - 13:00  |  Presenting Author(s): Silvia Novello  |  Author(s): Paolo Bironzo

      • Abstract
      • Presentation
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      Abstract

      Malignant pleural mesothelioma (MPM) is a highly lethal disease, with a median overall survival (OS) between 12 and 18 months. Following first-line treatment, neither chemotherapy nor target treatments have clearly shown to increase overall survival (OS), to date. Historically, second-line cytoxic drugs, such as gemcitabine and vinorelbine have been the backbone in pre-treated patients, with response rates ranging from 7% to 16% [Zucali PA, Perrino M, Lorenzi E, et al. Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Lung Cancer 2014; 84:265-270; Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009; 63:94-97; van Meerbeck JP, Baas P, Debruyne C, et al. A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organisation for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999;85(12):2577-2582]. Pemetrexed rechallenge was assessed in small retrospective studies, suggesting its role, especially when combined with platinum compounds, in selected patients with a pemetrexed-free interval of at least 3 to 6 months [Zucali PA, Simonelli M, Michetti G, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung cancer 2012; 75: 360-367]. “Omics” studies have enlarged our knowledge of MPM, describing high prevalence of TP53, NF2, BAP1 and cyclin dependent kinase inhibitor 2A (CDKN2A) mutations, along with the lack of tyrosine receptor kinase (TRK) activating mutations [Lo Iacono M, Monica V, Righi L, et al. Targeted next-generation sequencing of cancer genes in advanced malignant pleural mesothelioma: a retrospective study.J Thorac Oncol 2015;10(3):492-9]. For this reason, the development of target treatment approaches in MPM has been more difficult and slower as compared to non-small-cell lung cancer (NSCLC), for example. However, many drugs have been tested, while others are currently under evaluation. Among the first studied agents, mTOR inhibitors failed to show activity in pre-treated MPM patients [Ou SH, Moon J, Garland LL, et al.SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). J Thorac Oncol 2015;10(2):387-91]. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is upregulated in MPM with BAP1 inactivation and its inhibition showed to be syntethic lethal in BAP1-negative tumors. The EZH2 inhibitor tazemetostat demonstrated a 51% disease control rate (DCR) in 74 MPM patients (95% with BAP1 inactivation) enrolled in a phase 2 study [Zauderer MG, Szlosarek P, Le Moulec S, et al. Phase 2, multicenter study of the EZH2 inhibitor tazemetostat as monotherapy in adults with relapsed or refrectory (R/R) malignant mesothelioma (MM) with BAP1 inactivation. J Clin Oncol 36, 2018 (suppl.abstr 8515)]. As BAP1 loss leads to homologous repair deficiency, PARP inhibitors are currently being tested in this subgroup [NCT03531840; NCT03207347; NCT03654833]. Neurofibromin 2 (NF2) inactivation, which encodes for merlin, has been proposed to be synthetic lethal to focal adhesion kinase (FAK) inhibition. However, the COMMAND trial, exploring the use of the FAK inhibitor defactinib as a maintenance treatment after first-line chemotherapy in MPM patients stratified for merlin expression, failed to show any improvement as compared to placebo [Fennell DA, Baas P, Taylor P, et al. Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND-a double-blind, randomized, phase II study. J Clin Oncol 2019;37(10):790-798]. Defactinib is currently under investigation in combination with anti programmed-death 1 (PD-1) monoclonal antibody pembrolizumab in a phase I/IIA clinical trial enrolling pretreated MPM patients along with pancreatic cancer and NSCLC ones [NCT02758587]. The identification of argininosuccinate synthetase 1 (ASS1) loss in MPM, leading to arginine auxotrophy, paved the way to the use of the arginine depletor pegylated adenosine deiminase ADI-PEG20 in a phase 2 randomized trial in 70 ASS1-deficient patients [Szlosarek PW, Steele JP, Nolan L, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol 2017;3(1):58-66]. Among the 68 treated patients, the drug improved progression free survival (PFS) as compared to best supportive care (BSC) (HR 0.56, 95% CI, 0-33-0.96), although by only 1.2 months (median PFS 3.2 vs 2.0 months for ADI-PEG20 and BSC, respectively; p=0.03). Currently, ADA-PEG20 is being explored in combination with first-line chemotherapy in biphasic and sarcomatous MPM only [NCT02709512]. Recent studies described novel prognostic MPM subsets with specific genomic characteristics that could further shape personalized treatment approaches, especially when looking at immunotherapic approaches [Hmljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov 2018;8(12):1548-1565]. Indeed, the high expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) negative immune-checkpoint in epithelioid MPM reported in this study, suggests a possible of role of specific inhibitors alone or in combination with other agents in advanced MPM.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 8
    • Now Available
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      OA02.01 - Alectinib in Previously Treated RET-Rearranged Advanced Non-Small-Cell Lung Cancer: A Phase 1/2 Trial (ALL-RET) (Now Available) (ID 1651)

      10:30 - 12:00  |  Presenting Author(s): Noriko Yanagitani  |  Author(s): Shinji Takeuchi, Toshinori Murayama, Kenichi Yoshimura, Yasuhito Imai, Shizuko Takahara, Takahiro Kawakami, Takashi Seto, Yoshihiro Hattori, Kadoaki Ohashi, Masahiro Morise, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Makoto Nishio, Seiji Yano

      • Abstract
      • Presentation
      • Slides

      Background

      RET rearrangements occur in 1–2% of non-small cell lung cancers (NSCLCs). Alectinib (300 mg twice daily) has been approved for the treatment of ALK-rearranged NSCLC in Japan; it also has a high activity against RET in vitro. A global trial (ALEX study) showed the efficacy and safety of alectinib (600 mg twice daily) in ALK-rearranged NSCLC patients. We conducted a phase 1/2 study of alectinib to establish the recommended dose (RD) and examined its activity in RET-rearranged Japanese NSCLC patients.

      Method

      This study was a single-arm, open-label, multi-institutional phase 1/2 trial. RET-rearranged NSCLC patients treated with at least one regimen of chemotherapy were recruited. RET rearrangements were screened using LC-SCRUM-Japan, a nationwide genomic screening network. In phase 1, alectinib (600 or 450 mg twice daily) was administered, following a 3 + 3 design. The primary endpoint was safety. During phase 2, alectinib at the RD defined in phase 1 was administered. The primary endpoint was the objective response rate in RET inhibitor-naïve patients.

      Result

      Between March 8, 2016 and January 29, 2018, 35 patients were enrolled, and 34 patients were administered alectinib. KIF5B-RET was the most common fusion gene (22 cases [63%]), and the CCDC6-RET fusion was identified in 8 cases. The remaining 5 cases were not distinguishable. In cohort 1 (600 mg twice daily), we observed 5 DLTs (grade 3 rash, increased aspartate aminotransferase, erythema multiforme, thromboembolic event, and increased CPK) in 3 of 6 patients. In accordance with the protocol, we moved to cohort 2 (450 mg twice daily) and observed no DLTs in 3 patients. Additionally, pharmacokinetic analysis indicated that the mean exposure (AUC0–10) of 600 mg twice daily was higher than that previously reported in AF-002JG trial (global phase 1 study). Therefore, we determined 450 mg twice daily as the RD for phase 2. Twenty-five RET inhibitor-naïve patients were treated with the RD, of whom 1 achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%) as determined by central review. The median progression-free survival was 3.4 months (95% CI 2.0-5.4), and the median overall survival was 19.0 months (5.4-NE). We observed grade 3 neutropenia, pneumonitis, diarrhea, hyponatremia, increased CPK and blood bilirubin (4%) in patients treated with 450 mg alectinib twice daily; no grade 4 adverse events were observed.

      Conclusion

      Alectinib had limited activity in patients with RET-rearranged NSCLC. Further investigation of new targeted therapeutics is required to improve outcomes for these patients.

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      OA02.02 - Phase 1 Study of Safety, Tolerability, P­­K and Efficacy of AMG 510, a Novel KRAS G12C Inhibitor, Evaluated in NSCLC (ID 1020)

      10:30 - 12:00  |  Presenting Author(s): Ramaswamy Govindan  |  Author(s): Marwan G Fakih, Timothy J Price, Gerald S Falchook, Jayesh Desai, James C Kuo, John H Strickler, John C Krauss, Bob T Li, Crystal S Denlinger, Greg Durm, Jude Ngang, Haby Henary, Gataree Ngarmchamnanrith, Erik Rasmussen, Phuong Khanh Morrow, David S. Hong

      • Abstract
      • Slides

      Background

      The KRASG12C mutation is found in approximately 14% of lung adenocarcinoma and 11% of NSCLC pts. Currently, no approved therapy targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state.

      Method

      A phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult pts with locally-advanced or metastatic KRASG12C mutant solid tumors, including NSCLC pts. Safety is the primary endpoint; ORR (assessed every 6 wks), DOR, PFS, and PK are key secondary endpoints. Important inclusion criteria: KRASG12C mutation identified through DNA sequencing; measurable or evaluable disease; progression on standard therapy; ECOG PS ≤2; life expectancy >3 mo. Important exclusion criteria: active brain metastases; myocardial infarction within 6 mo. The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) will be identified during the dose exploration. Once identified, additional pts with advanced solid tumors carrying the KRASG12C mutation will be enrolled during dose expansion. AMG 510 is given PO until disease progression, intolerance, or consent withdrawal.

      Result

      As of 4 April 2019, thirteen [5 men and 8 women; median age 63 yrs (range: 53–77)] of 35 pts enrolled in 4 dose exploration cohorts have NSCLC. These pts had a median of 3 (range: 1–5) prior lines of treatment (tx). On-study tx duration had a median of 59 days (range:9–192 d). No DLTs have been reported. Six NSCLC pts reported 10 treatment-related AEs (6 grade 1; 2 grade 2; 2 grade 3). The grade 3 related AEs were anemia in a pt with baseline grade 2 anemia and diarrhea lasting 2 d in a second pt. The most frequently reported AEs were decreased appetite (n=4 subjects) and diarrhea (n=3 subjects). Best tumor response has been evaluated in 10 NSCLC pts; 3 pts have not reached their first assessment. Of these 10 evaluable pts, 5 pts had a PR (2 of which are confirmed PRs), 4 had SD and 1 had PD. Of 13 NSCLC pts, 11 pts remain on-study and continue their AMG 510 and 2 pts have discontinued treatment due to PD during study wks 6 and 26.

      Conclusion

      AMG 510 has been well tolerated at all 4 dose levels explored and has shown antitumor activity when administered as monotherapy to pts with advanced KRASG12C mutant NSCLC. Enrollment is on-going.

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      OA02.03 - The Third Generation EGFR Inhibitor (EGFR-TKI) HS-10296 in Advanced NSCLC Patients with Resistance to First Generation EGFR-TKI (Now Available) (ID 766)

      10:30 - 12:00  |  Presenting Author(s): Shun Lu  |  Author(s): Qiming Wang, Guojun Zhang, Xiaorong Dong, Cheng-Ta Yang, Yong Song, Gee-Chen Chang, You Lu, Hongming Pan, Chao-Hua Chiu, Zhehai Wang, Jifeng Feng, Jianying Zhou, Xingxiang Xu, Renhua Guo, Jianhua Chen, Haihua Yang, Yuan Chen, Zhuang Yu, Her-Shyong Shiah, Chin-Chou Wang, Nong Yang, Jian Fang, Ping Wang, Kai Wang, Yanping Hu, Jianxing He, Ziping Wang, Jianhua Shi, Shaoshui Chen, Ying Cheng, Wu-Chou Su, Te-Chun Hsia, Jiuwei Cui, yuping Sun, Chih-Hsin Yang

      • Abstract
      • Presentation
      • Slides

      Background

      HS-10296 is an oral, potent, high selective third generation EGFR tyrosine-kinase inhibitor (EGFR-TKI) for sensitizing mutations, and the EGFR Thr790Met (T790M) resistance mutation which has been demonstrated by phase I study. This phase II, open-label, multicenter single-arm study was designed to confirm the efficacy and safety of HS-10296 in a large population of non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation, who had progressed after first generation EGFR-TKI treatment.

      Method

      Patients aged at least 18 years with centrally confirmed EGFR T790M-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC after first generation EGFR-TKI treatment received HS-10296 110 mg orally once daily until disease progression, or intolerable toxicity, or patient withdrawal. Patients with asymptomatic, stable brain metastases not requiring steroids were allowed to enroll. The primary endpoint was the objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1 every 6 weeks. Response endpoints (ORR and disease control rate [DCR]) were assessed in response analysis set. Secondary end points including progression-free survival (PFS), duration of response (DoR), depth of response (DepOR), overall survival (OS) and safety were evaluated in full analysis set. The final data cutoff was on Jan 5, 2019. The study is still ongoing.

      Result

      Totally, 244 patients (median age 60.8) entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients) between May 16, 2018 to Oct 23, 2018. 2 patients were excluded from the evaluable for response analysis set (n=242) due to absence of measurable disease at baseline by independent central review. At data cutoff, 182 (74.6%) patients remained on treatment. The median duration of follow-up was 4.7 months. 160 of 242 patients achieved confirmed partial responses by independent central review. The ORR was 66.1% (95% CI: 59.8-72.1). The DCR was 93.4% (95% CI: 89.5-96.2). The most common adverse reactions (≥ 10%) were blood creatine phosphokinase increased (43 [17.6%]), aspartate aminotransferase increased (29 [11.9%]), pruritus (28 [11.5%]), rash (28 [11.5%]) and alanine aminotransferase increased (26 [10.7%]). The most common all-causality grade 3 and 4 adverse events were blood creatine phosphokinase increased (14 [5.7%]) and hyponatraemia (4 [1.6%]). Serious adverse events were reported in 30 (12.3%) patients, of which 19 (7.8%) were investigator assessed as possibly treatment-related to HS-10296. Three deaths were due to adverse events; one was related to cardiopulmonary failure, other two events occurred after disease progression. There was no interstitial lung disease during study treatment.

      Conclusion

      HS-10296 has demonstrated good clinical benefit with minimal toxicity in patients with EGFR T790M-positive NSCLC patients who have progressed after first generation EGFR-TKI treatment. The Phase III study has already launched comparing HS-10296 with gefinitib in advanced NSCLC patients with EGFR sensitizing mutations. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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      OA02.04 - Discussant - OA02.01, OA02.02, OA02.03 (Now Available) (ID 3726)

      10:30 - 12:00  |  Presenting Author(s): Jon Zugazagoitia

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA02.05 - First-In-Human Phase 1/2 Trial of Anti-AXL Antibody–Drug Conjugate (ADC) Enapotamab Vedotin (EnaV) in Advanced NSCLC (Now Available) (ID 343)

      10:30 - 12:00  |  Presenting Author(s): Suresh S Ramalingam  |  Author(s): Juanita Lopez, Morten Mau-Sorensen, Fiona Thistlethwaite, Sarina Piha-Paul, Shirish Gadgeel, Yvette Drew, Pasi A Jänne, Aaron S. Mansfield, Guang Chen, Ulf Forssmann, Hrefna Kristin Johannsdottir, Nora Pencheva, Annette Ervin-Haynes, Ignace Vergote

      • Abstract
      • Presentation
      • Slides

      Background

      AXL, a transmembrane receptor tyrosine kinase, is aberrantly expressed in various cancers, and associated with poor prognosis and treatment resistance. AXL overexpression is associated with resistance to PD-1 immune checkpoint inhibitors (Hugo et al. 2016). EnaV, a novel ADC of anti-AXL human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in preclinical models, including NSCLC (Boshuizen et al. 2018). In a phase 1, dose escalation, multi-cohort trial (NCT02988817) in heavily pretreated patients with relapsed or refractory solid tumors, EnaV 2.2 mg/kg once every 3 weeks (1Q3W; recommended phase 2 dose) showed preliminary anti-tumor activity. Here we present initial results from patients with NSCLC in the phase 2a, expansion phase of this trial.

      Method

      We analyzed data from EnaV 2.2 mg/kg 1Q3W, in the cohort of pretreated patients with stage III/IV NSCLC without sensitizing EGFR mutations (EGFR WT) or ALK rearrangements (ALK-) who had failed ≤4 prior lines of therapy, including platinum-based chemotherapy and PD-1/PD-L1 inhibitor (either in combination or sequentially). Endpoints include safety, objective response rate (ORR; RECIST 1.1), and AXL expression in fresh tumor biopsies (immunohistochemistry).

      Result

      In the EGFR WT/ALK- cohort, 26 patients (median age 65.5 years, range 38–74; 57.7% male) with ECOG PS of 0 (11.5%) or 1 (88.5%) have been enrolled. Most patients (23/26) were treated with a checkpoint inhibitor. At a median follow-up of 18 weeks (range: 2–54), the most common (≥20%; any grade) treatment-emergent adverse events (TEAEs) were fatigue, constipation, nausea, decreased appetite, decreased weight, diarrhea, and vomiting. Two patients had a TEAE leading to dose reduction. Grade ≥3 TEAEs occurred in 12 patients, with the most common being gastrointestinal disorders in eight patients (constipation [n=1]; colitis, diarrhea, nausea, vomiting [n=2 each]; abdominal distension [n=1]. The confirmed ORR is 19% (95% CI: 8.5%, 37.9%). The disease control rate (CR+PR+SD) is 50% (13/26). Nine of 12 (75%) evaluable fresh biopsies were positive for AXL tumor cell staining.

      Conclusion

      In this high unmet need patient population, with advanced EGFR WT and ALK- NSCLC who are pretreated with PD-1/PD-L1 inhibitors and platimum-based therapies, EnaV monotherapy demonstrated a manageable safety profile and encouraging preliminary clinical activity. This cohort has expanded to allow up to 60 patients to gain further knowledge of AXL as a potential biomarker for responsiveness to EnaV and to gather additional data on safety and efficacy. Funding: Genmab A/S

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      OA02.06 - The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L) (Now Available) (ID 2145)

      10:30 - 12:00  |  Presenting Author(s): Satomi Watanabe  |  Author(s): Takeharu Yamanaka, Kentaro Ito, Shinya Sakata, Haruko Daga, Takashi Kijima, Katsuya Hirano, Isamu Okamoto, Atsushi Nakamura, TOSHIYUKI Kozuki, Mikiko Ishihara, Koichi Azuma, Takashi Seto, Toshihide Yokoyama, Yuko Oya, Haruki Kobayashi, Kazumi Nishino, Yoshihiro Hattori, Kazuhiko Nakagawa, Nobuyuki Yamamoto

      • Abstract
      • Presentation
      • Slides

      Background

      Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of CRZ followed by other ALK-inhibitorcan provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.

      Method

      We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of CRZ followed by ALEC, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the TTF of CRZ plus the TTF of ALEC if patients were treated with ALEC followed by CRZ. In the ALEC group, the TTF of ALEC was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group.

      Result

      Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P=0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P=0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P<0.0001.

      Conclusion

      The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown.

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      OA02.07 - Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses (Now Available) (ID 2267)

      10:30 - 12:00  |  Presenting Author(s): Juergen Wolf  |  Author(s): Åslaug Helland, In-Jae Oh, Maria Rita Migliorino, Rafal Dziadziuszko, Javier De Castro Carpeno, Julien Mazieres, Frank Griesinger, Marijana Chlistalla, Andres Cardona, Thorsten Ruf, Kerstin Trunzer, Vlatka Smoljanovic, Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background

      The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile.

      Method

      Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59).

      Result

      Final efficacy data confirmed those of the primary analysis (table). Grade ≥3 treatment-emergent adverse events were lower with alectinib (37.7%) than with chemotherapy (43.2%); adverse events causing treatment discontinuation were lower with alectinib (5.2% versus 10.8% chemotherapy), despite alectinib’s longer treatment duration. ALK fusions were confirmed retrospectively in 26/33 (78.8%) tissue and 41/59 (69.5%) plasma (post-crizotinib) samples. ORR in alectinib-treated patients with ALK fusions was 72.2% (13/18, tissue) and 63.0% (17/27, plasma) versus 0% for chemotherapy (tissue [0/8], plasma [0/14]). ALK secondary mutations were detected in 16/59 (27.1%) patients (plasma, both arms). ORR in the alectinib arm (plasma) was similar in patients with ALK fusions with (60.0%, 6/10) or without (64.7%, 11/17) ALK secondary mutations, but lower in patients with gene mutations other than ALK (23.1%, 3/13).

      Conclusion

      Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and safety with alectinib versus chemotherapy in post-crizotinib ALK+ NSCLC. The role of reconfirming ALK status upon sequential ALK inhibitor treatment requires further investigation, due to the limited data and known technical challenges of plasma testing.

      Funding: F. Hoffmann-La Roche Ltd.

      table.jpg

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      OA02.08 - Discussant - OA02.05, OA02.06, OA02.07 (Now Available) (ID 3727)

      10:30 - 12:00  |  Presenting Author(s): Michael Duruisseaux

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 9
    • Now Available
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      OA12.01 - PCI for Radically Treated Non-Small Cell Lung Cancer: A Meta-Analysis Using Updated Individual Patient Data of Randomized Trials (Now Available) (ID 2624)

      15:45 - 17:15  |  Presenting Author(s): Willem Witlox  |  Author(s): Dirk De Ruysscher, Benjamin Lacas, Cecile Le Pechoux, Jean-Pierre Pignon, Matthias Guckenberger, Alexander Sun, Mary Redman, Si-Yu Wang, Chen Hu, Vincent Van Der Noort, Ning Li, Harm Van Tinteren, Harry JM Groen, Manuela Joore, Bram Ramaekers

      • Abstract
      • Presentation
      • Slides

      Background

      In localized non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduced the incidence of brain metastases (BM) (relative risk 0.35), but without a demonstrated effect on overall survival (OS). This may be due to the small sample size in these individual randomized clinical trials (RCTs).

      Therefore, we aimed to assess the impact of PCI on long term OS for radically treated stage III NSCLC patients compared to observation using updated individual patient data (IPD) from RCTs.

      Method

      The main endpoint was OS and secondary endpoints were progression-free survival (PFS), BM-free survival (BMFS) and toxicity. All analyses were performed based on the intention-to-treat principle. The median follow-up was estimated using the inverse Kaplan-Meier method. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Heterogeneity was studied using the Cochrane test and I2. Survival curves and 5-year difference between arms were estimated using the Peto method. Interaction between prognostic factors (age, performance status, and histology) and treatment allocation were assessed using Cox proportional hazards models. Toxicities grade ≥ 3 were reported descriptively.

      Result

      Data on four of the seven eligible trials (SWOG 8300, RTOG 0214, Guangzhou 2005 and NVALT-11) were available for this IPD meta-analysis. In total, 924 patients were analyzed of which 68% was male, median age was 61 years, 94% of the patients had a performance status ≤ 1 and 37% had squamous histology. The median follow-up was 8.1 years. All trials provided sufficient IPD for the three endpoints, except for the SWOG 8300 trial (OS only). This trial explained inter-trial heterogeneity. Because of the qualitative interaction with the other trials (p=0.0062) it was separately analyzed (N=254). Compared to observation, OS was significantly lower for PCI in the SWOG 8300 trial (HR 1.38, 95% CI [1.07 to 1.79] p=0.013, 5-year absolute difference -0.9%, 95% CI [-5.9 to 4.1]). However, for the other trials (N=670) no significant OS difference was observed (HR 0.90, 95% CI [0.76 to 1.07] p=0.228, 5-year absolute difference 1.8%, 95% CI [-5.2 to 8.8]). PFS (HR 0.78, 95% CI [0.65 to 0.92] p=0.004, 5-year absolute difference 4.8%, 95% CI [-1.2 to 10.8]) and BMFS (0.38, 95% CI [0.27 to 0.53] p<0.001, 5-year absolute difference 20.7%, 95% CI [12.2 to 29.2]) were significantly higher in the PCI arm. There was no interaction between prognostic factors and treatment allocation for OS. Toxicity data for the PCI arm was available in all trials except the SWOG 8300 trial. The total number of patients with at least one grade ≥3 toxicity (for the adverse events pre-specified in the protocol) in the PCI arm was 19/456, including 11/86 in the NVALT-11 trial. Toxicity for the observation arm was only available in the NVALT-11 trial, including 4/88 patients with at least one grade ≥3 toxicity.

      Conclusion

      Although PFS and BM-free survival were improved for patients who received PCI, no significant PCI benefit for OS was observed.

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      OA12.02 - Randomized Phase II Study of CDDP+S-1 vs CDDP+PEM Combined with Thoracic RT for Locally Advanced Non-Sq NSCLC: SPECTRA Study (Now Available) (ID 428)

      15:45 - 17:15  |  Presenting Author(s): Takashi Seto  |  Author(s): Seiji Niho, Tatsuya Yoshida, Tetsuo Akimoto, Kentaro Sakamaki, Akira Ono, Makoto Nishio, Noboru Yamamoto, Toyoaki Hida, Hiroaki Okamoto, Takayasu Kurata, Yoshihiro Hattori, Koichi Goto, Takeharu Yamanaka, Yuichiro Ohe

      • Abstract
      • Presentation
      • Slides

      Background

      SPECTRA, a multicenter, randomized phase II study of CDDP+S-1 versus CDDP+pemetrexed (PEM) combined with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer (NSCLC), previously reported that toxicities were tolerable and manageable in both arms; however, febrile neutropenia was more frequently observed in the CDDP+S-1 arm (9.6%/2%). Completion rate of TRT (60Gy) and chemotherapy (4 cycles) was 92%/98% and 73%/86%, respectively. Response rate was 60%/64% (WCLC 2017, MA17.06). Here, we present primary analysis of 2-year survival data.

      Method

      Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. The sample size was set at 100 patients.

      Result

      Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n=17 (33%)/n=17 (34%); stage IIIB, n=21 (40%)/n=20 (40%); ECOG PS of 1, n=14 (27%)/n=14 (28%); never smoker, n=12 (23%)/n=12 (24%); and adenocarcinoma, n=47(90%)/n=45(90%); activating EGFR mutation, n=9 (17%)/n=4 (8%); ALK fusion, n=2 (4%)/n=3 (6%). A total of 72 PFS events were observed at the data cut-off (28 November 2018). After a median follow-up of 32.1 months, median PFS was 12.7/13.8 months (HR=1.16, 95% CI, 0.73-1.84, p=0.538), and 2-year PFS rate was 36.5% (95% CI, 23.5-49.6)/32.1% (95%CI, 18.9-45.4). Disease progression was observed in 33 and 36 patients. Distant metastases were the first site of failure in 24 and 31 patients. Local relapse as the first site of failure was observed in 14 and 13 patients. After a median follow-up of 34.6 months, 44 OS events were observed. Median OS was 48.3/59.1 months (HR=1.05, 95%CI, 0.58-1.90, p=0.883), and 2-year OS rate was 69.2% (95%CI, 56.7-81.8)/66.4% (95%CI, 53.0-79.9). 27 patients in each arm received post-study chemotherapy including EGFR-TKIs (n=7/n=5), ALK-TKIs (n=0/n=3), and immune checkpoint inhibitors (n=6/n=10).

      Conclusion

      2-year PFS rate in the CDDP+S-1 arm was better than that in the CDDP+PEM arm. We will select the CDDP+S-1 arm as the investigational arm in a future phase III study. UMIN000009914 (release date: 31/Jan/2013)

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      OA12.03 - Initial Reporting of NRG-LU001, Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC (Now Available) (ID 1868)

      15:45 - 17:15  |  Presenting Author(s): Heath Skinner  |  Author(s): Chen Hu, Theodoros Tsakiridis, Rafael Santana-Davila, Bo Lu, Jeremy Erasmus, Anthony Doemer, Gregory Videtic, James Coster, Alex Xuexhong Yang, Richard Lee, Maria Werner Wasik, Phillip Schaner, Steven McCormack, Benjamin Esparaz, Rondal McGarry, Jose Bazan, Timothy Stuve, Jeffrey D Bradley

      • Abstract
      • Presentation
      • Slides

      Background

      Preclinical and retrospective clinical data, have shown that metformin, an inexpensive diabetes drug, has the potential to improve response to chemotherapy and radiation in several solid tumors, including non-small cell lung cancer (NSCLC). These findings led to NRG-LU001, a multi-institutional, international randomized Phase II clinical trial to determine whether metformin can improve outcomes of curative chemoradiation (CRT) in locally advanced NSCLC (LA-NSCLC).

      Method

      Unresectable stage IIIA/B NSCLC patients were randomized to either concurrent chemoradiation to 60 Gy with weekly carboplatin-paclitaxel (CP), followed by consolidation CP (Control) or the same regimen combined with metformin (2000 mg/day) (Experimental). The primary endpoint was 1-year progression free survival (PFS). PFS and overall survival (OS) were estimated using the method of Kaplan-Meier. Time to loco-regional progression (TTLRP) or distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded using CTCAE v4.0.

      Result

      170 patients were randomized between Aug. 2014-Dec. 2016, with planned analysis at 102 events. No significant difference in toxicity was observed between Control and Experimental arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Experimental arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). On multivariable analysis including treatment arm, performance status, histology and stage, only higher stage (IIIA vs. IIIB) was associated with worse PFS (HR 1.79, 95% CI:1.19, 2.69, p=0.0054). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP (HR 1.01, 95% CI: 0.57, 1.79, p=0.98) or TTDM (1.38, 95% CI: 0.76, 2.5, p=0.29). 63.4% of patients in the experimental arm received the complete course of metformin, with the most common cause of discontinuation being side effects or complications (13.4%).

      Conclusion

      In NRG-LU001, concurrent CRT and metformin presented no noticeable safety concerns. However, this combination failed to improve PFS at the hypothesized effect size. Additionally, no effect on OS or patterns of failure were identified. Blinded central review of imaging based PFS is ongoing. Somewhat unexpectedly, 37% of patients did not complete the prescribed course of metformin. Additionally, deaths due to disease were less in the experimental arm compared to control.

      Acknowledgements: This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). HS and TT are Co-Principal Investigators in this trial.

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      OA12.04 - Discussant - OA12.01, OA12.02, OA12.03 (Now Available) (ID 3789)

      15:45 - 17:15  |  Presenting Author(s): Everett E. Vokes

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA12.05 - Imaging-Guided Target Volume Reduction in Radiotherapy of Lung Cancer: The Prospective Randomized Multinational PET-Plan Trial (Now Available) (ID 2558)

      15:45 - 17:15  |  Presenting Author(s): Eleni Gkika  |  Author(s): Ursula Nestle, Tanja Schimek-Jasch, Stephanie Kremp, Andrea Schaefer, Andreas Kuesters, Marco Tosch, Thomas Hehr, Martina Eschmann, Yves-Pierre Bultel, Peter Hass, Jochen Fleckenstein, Alexander Thieme, Marcus Stockinger, Matthias Miederer, Gabriele Holl, Christian Rischke, Sonja Adebahr, Jochem Koenig, Anca-Ligia Grosu

      • Abstract
      • Presentation
      • Slides

      Background

      Advanced medical imaging offers a chance for target volume reduction in modern radiotherapy, which may lead to more effective local treatments with reduced toxicity and offer the protection of draining lymph nodes and large vessels, possibly of importance for the upcoming combination of radiotherapy and immunotherapy. Locally advanced non-small cell lung cancer (NSCLC) with improvable local control and high toxicity is an excellent model to investigate this topic.

      Method

      In the prospective randomised controlled PET-Plan trial (NCT00697333), patients with inoperable stage II/III NSCLC and an indication for radiochemotherapy were randomized at a 1:1 ratio. In conventional arm A target volumes were informed by FDG-PET and CT plus elective nodal irradiation and in experimental arm B they were solely informed by FDG-PET. In both arms, quality assured isotoxically dose-escalated IMRT or 3D-CRT (60 - 74Gy, 2Gy per fraction) was planned and applied to the respective target volumes along with simultaneous platinum-based chemotherapy. The primary objective was time to locoregional progression (LRP) in terms of non-inferiority of experimental arm B.

      Result

      311 patients were recruited, 205 patients included in the intent to treat (ITT) (A: n=99, B: n=106) and 172 patients in the per protocol (PP) analysis (A: n=84, B: n=88). Median FU time in the PP set was 16 months. Non-inferiority of experimental arm B was confirmed for the pre-specified non-inferiority margin. The risk of LRP was lower in the experimental arm B (2y-LRP 0.20 vs. 0.39; HR=0·57; 95% CI: 0·30–1·06; p=0·039) with no difference between study arms concerning survival (2y-OS 0.57 vs. 0.54), out-field recurrence and toxicity.

      Conclusion

      In radiochemotherapy for locally advanced NSCLC PET-Imaging based reduction of radiotherapy target volumes is feasible and may improve local control without increasing toxicity. However, in this trial there was no impact on survival. The procedures established in this clinical trial provide a radiotherapy standard for future NSCLC-trials including immunotherapy and may furthermore inspire trials on imaging based target volume reduction for other types of tumours.

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      OA12.06 - A Prospective Randomized Phase Ⅲ Study of Precise PORT for Patients with pⅢA-N2 NSCLC After Complete Resection and Adjuvant Chemotherapy (Now Available) (ID 2487)

      15:45 - 17:15  |  Presenting Author(s): Zhouguang Hui  |  Author(s): Yu Men, Chen Hu, zongmei Zhou, Jun Liang, qinfu Feng, Bi Nan, Xin Wang, Dongfu Chen, zefen Xiao, Jima Lv, Lei Deng, Tao Zhang, wenqing Wang, Shugeng Gao, Jie He, Luhua Wang

      • Abstract
      • Presentation
      • Slides

      Background

      For patients with completely resected pⅢA-N2 non-small cell lung cancer (NSCLC), the role of postoperative radiotherapy (PORT) is not well defined. 3D-conformal or simplified intensity modulated radiotherapy (3D-CRT/sIMRT) can precisely deliver high dose to the target volume while decreasing the toxicity of normal tissues, which may improve the treatment outcomes. This phase III randomized clinical trial (NCT00880971) is designed to evaluate the effect of precise PORT on survival and failure pattern in patients with pⅢA-N2 NSCLC after complete resection and adjuvant chemotherapy.

      Method

      After complete resection and four cycles of platinum based chemotherapy, patients with pⅢA-N2 NSCLC were randomized equally into PORT group or observation group. Using 3D-CRT/sIMRT techniques, PORT of 50 Gy by 25 fractions was given to the ipsilateral hilum, subcarinal region and ipsilateral mediastinum. The primary endpoint was disease free survival (DFS). Secondary endpoints include overall survival (OS), loco-regional recurrence free survival (LRFS), distant metastasis free survival (DMFS) and toxicity. Targeted accrue was 360 patients. With at least 230 DFS events it was designed to detect an improvement in 3-year DFS from 30% to 44% (equivalent to HR=0.69) at 1-sided type 1 error of 0.025 with 80% power. Intent-to-treat populations is used for primary analyses, supplemented with sensitivity analyses using per-protocol population. Log-rank test is used for time-to-event data comparisons.

      Result

      Between Jan. 2009 and Dec. 2017, 364 consecutive eligible patients were randomized, including 184 in the PORT group and 180 in the observation group. For this initial reporting of planned final analysis, as Jan 31, 2019, 230 DFS events were reported and the median follow up time was 53.3 months. The clinical features were comparable between the two groups. The 3-year DFS rates in PORT and observation were 42.7% vs. 34.5% (mDFS: 26.5 vs 22.7 months, HR=0.85, 95% CI: 0.65-1.10, 1-sided p=0.10), with OS of 81.5% vs. 85.4% (mOS: not reached vs 90.9 months, HR=1.01, 95% CI: 0.68-1.51, 2-sided p=0.94), LRFS of 69.8% vs. 62.4% (HR=0.71, 95% CI: 0.51-0.97, 2-sided p=0.03), and DMFS of 44.8% vs. 43.5% (HR=0.93, 95% CI 0.71-1.22, 2-sided p=0.60), respectively. For 310 per-protocol patients (140 with PORT and 170 without PORT), PORT marginally improve the DFS (44.8% vs 32.6%, HR=0.76, 95% CI: 0.57-1.00, 2-sided p=0.05), but not OS (85.7% vs 85.0%, HR=0.83, 95% CI: 0.53-1.30, p=0.41). Relapses of any type were observed in 110 (59.8%) and 116 patients (64.4%) in the PORT and observation groups, respectively. Forty-seven over 50 deaths (94.0%) in the PORT group and 42 over 47 deaths (89.4%) in the observation group died of cancer progression, respectively. No radiotherapy-related grade 5 AE was observed.

      Conclusion

      For pⅢA-N2 NSCLC patients after complete resection and adjuvant chemotherapy, precise PORT has not been shown to significantly improve DFS or OS , though it can significantly improve LRFS.

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      OA12.07 - Radicality of Lymphadenectomy in Lung Cancer According to Surgical Approach. Results from the Spanish Group of Video-Assisted Thoracic Surgery (Now Available) (ID 1062)

      15:45 - 17:15  |  Presenting Author(s): Carme Obiols  |  Author(s): Sergi Call, Ramon Rami-Porta, Angeles Jaen, David Gomez De Antonio, Silvana Crowley, Iñigo Royo, Raúl Embún

      • Abstract
      • Presentation
      • Slides

      Background

      The minor standard of systematic nodal dissection (SND) in lung cancer surgery, which is the minimum recommended by the Union for International Cancer Control, requires the resection/sampling of, at least, 3 mediastinal (including subcarinal station) and 3 hilar/intrapulmonary lymph nodes (LN). The objective of this study is to analyze differences in intraoperative LN assessment in patients with surgically treated non-small cell lung cancer (NSCLC) according to surgical approach (open vs VATS), from the results of the Spanish Group of Video-Assisted Thoracic Surgery (GEVATS) database.

      Method

      Prospective multicenter cohort study of anatomic pulmonary resections (n=3533) performed from 20/12/16 to 20/03/18. Exclusions criteria were: indications different from NSCLC, previous lung cancer, synchronous tumors and induction therapy. Patients who did not meet the criteria for SND but had no nodal involvement were coded as pathologic (p)Nx (instead of pN0). Corresponding tests for homogeneity were performed. Multiple logistic regression analysis was used to determine the odds ratio (OR) and 95% confidence interval (95%CI). Stata/SE vs 13 statistical package was used for data analysis. Significance was considered when p<0.05.

      Result

      2532 patients were analyzed (1801 men [71.1%]; median age: 67 years). SND was performed in 65%, with a median of LN resected/sampled of 7 (IQR 4-12) and a rate of pN2 of 9.5%. Table1 summarizes results from bivariate analysis.Independent risk factors for thoracotomy at multivariate analysis (OR; 95%CI) were: squamous cell carcinoma vs adenocarcinoma (1.3; 1.04-1.68), staging mediastinoscopy (2.8; 1.83-4.22), LN resected (1.02; 1.00-1.04), SND (1.4; 1.07-1.8), tumour >3cm (1.8; 1.5-2.2), central tumour (2.5; 2.0-3.1); pN1 (1.5; 1.1-2.1) and pN2 (1.6; 1.1-2.3). A significantly higher proportion of nodal upstaging was observed in thoracotomy group: from cN0 to pN1/pN2, and from cN1 to pN2 (table1).

      figure1.jpg

      Conclusion

      The intensity of lymphadenectomy in GEVATS was superior in the thoracotomy approach. Therefore, intraoperative lymph node evaluation performed at VATS should improve to have better prognostic information and indicate adjuvant therapy.

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      OA12.08 - Discussant - OA12.05, OA12.06, OA12.07 (Now Available) (ID 3790)

      15:45 - 17:15  |  Presenting Author(s): José Belderbos

      • Abstract
      • Presentation
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      Abstract not provided

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      OA12.09 - James D. Cox Lectureship Award for Radiation Oncology (Now Available) (ID 3902)

      15:45 - 17:15  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    PC01 - Reinventing Clinical Trials (ID 83)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advocacy
    • Presentations: 5
    • Now Available
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      PC01.01 - Setting the Stage: Tension Between Patient Safety, Scientific Purity and Patient Inclusion (Now Available) (ID 3555)

      11:00 - 12:30  |  Presenting Author(s): Jacob Sands

      • Abstract
      • Presentation
      • Slides

      Abstract

      Clinical trials are important to the process of better understanding the therapeutic potential of new drugs while also serving as treatment options for individuals seeking the best possible treatment. When writing protocols, we think about how best to determine the effectiveness and side effect profile of the treatment being studied. This can lead to more limited eligibility in an effort to reduce complications not related to the disease or drug. When seeing patients in clinic, we think about how best to treat each individual, which can lead to preferring less strict eligibility. These two perspectives can sometimes seem to be at odds. How do we best define eligibility in a way that both provides scientific rigor while also providing the trial as an option to as many people as possible? This session sets the stage for an in-depth discussion of these 2 important aspects of clinical trials and how to strike the ideal balance for enrollment eligibility criteria.

      As part of this introduction, a highlight of the process of drug development through different phases of clinical trials from “pre-clinical work” to phase 3 studies is helpful. The following is a general structure. Any prospective drug must demonstrate compelling results at one phase to then be studied in the next phase. This starts with lab studies and often treatment of mice with prospective drugs. Any studies before treatment of humans is called “pre-clinical.” When results in this setting are promising, treatment in humans starts with phase 1. In this setting the focus of the study is to find the most appropriate dose, and there are often multiple diagnoses allowed for enrollment within that one study. The strategy for dose finding generally includes starting treatment for a few individuals at a low starting dose. After verifying tolerability, another group starts treatment on the study at a higher dose and so on. Less commonly, studies will allow dose increases for each individual that is tolerating the lower dose with ongoing disease control. Dose escalation often continues until finding the “maximum tolerated dose.” Although the side effects of the drug often weigh heavily in determining the dose for further study, responses to the treatment are certainly considered. After determining a dose for future study, this drug may enter a phase 2 study. In this phase, many more individuals are treated at the determined dose, and the effectiveness of the treatment is studied within a specific clinical setting. Results that suggest efficacy often lead to a phase 3 study, which includes randomization to the new drug, or the standard of care treatment, within a specific clinical setting. Although placebo is sometimes utilized, all individuals should get at least the best known therapy. For example, KEYNOTE-189 enrolled individuals with metastatic nonsquamous, non-small cell lung cancer (without sensitizing EGFR or ALK mutations) to the standard of care first line chemotherapy, pemetrexed and a platinum, with randomization to also include either pembrolizumab or placebo. Although people received placebo, it was given along with the chemotherapy, as was pembrolizumab.

      This introduction is followed by two related session. One is focused on crafting trials to allow more broad enrollment with the acknowledgment of trials as a treatment option. The other is focused on trial development with full attention toward scientific rigor and study of the drug. A discussion of the balance of these goals follows.

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      PC01.02 - Real World Research Groups - ROS1ders (Now Available) (ID 3556)

      11:00 - 12:30  |  Presenting Author(s): Merel Hennink

      • Abstract
      • Presentation
      • Slides

      Abstract

      Presentation Title: Real World Research Groups - ROS1ders
      Session: Reinventing Clinical Trials

      Merel Hennink

      Lung cancer research has made great progress in the last decade. Discovery of more treatable mutations have paved the way to more treatment options. We are moving away from a “one-size-fits-all” chemotherapy towards personalized medicine. (1)

      However, these developments require accurate diagnostics to identify the right treatment options. Furthermore, as a common cancer like lung cancer is split into rare subgroups, it also poses additional challenges. Rare mutations in NSCLC (for instance ROS1) result in small patient populations for trials and less bio-materials for research. The main question here is how to navigate this changing landscape.

      The ROS1ders – a community

      The ROS1 rearrangement was first described in 2007 and occurs in about 1% of patients with NSCLC. Of the estimated 1.5 million new cases of NSCLC worldwide each year, approximately 15,000 may be driven by oncogenic ROS1 fusions.(2) In 2015, little was known about the ROS1 rearrangement and only a single drug was available to treat the disease. Also in 2015, a group of ROS1 positive lung cancer patients formed an international community on social media, The ROS1ders, allowing them to connect with each other. Through social media, patients are becoming increasingly engaged, and discussing the diagnostic and treatment options available in their countries or hospitals. In addition, these national and global online communities, where information is shared, can highlight (inter)national disparities in treatment access.

      Treatments
      Crizotinib is currently the only FDA- and EMA–approved agent for the treatment of ROS1-rearranged NSCLC. Unfortunately several healthcare systems across the world have difficulty with reimbursing the drug due to lack of data from randomized clinical trials (UK, South Africa, Canada, New Zealand). In Canada, Real World Data from the ROS1 Facebook group helped in the approval process. “The Committee expressed that they were impressed with the patient input of 259 ROS1 positive patients and caregivers from 32 countries who supported the use of crizotinib. Overall, from the perspectives of patients with ROS1-positive NSCLC, they value a chance to extend their life and spend more time with their families by having a treatment that is effective, and improves their symptoms and outcomes.”(3)

      Global ROS1 initiative – from advocacy to active research

      The ROS1ders transitioned from advocacy to active research in the past few years. Reaching out to academic cancer centers, they strove to increase the amount of cancer models available to stimulate ROS1 research. The Global ROS1 Initiative is a partnership connecting researchers, patients, caregivers, and physicians worldwide. Patients who have an upcoming biopsy contact the national study nurse, and can choose to donate extra material to generate a cell line, a patient-derived xenograft (PDX) mouse model, or both. The goal is to create models and data accessible to all researchers. All models and characterization data will be made available as an open access database to researchers and collaborators. The Global ROS1 initiative has already generated four cell lines at the University of Colorado, and three PDX mouse models are in development. Patients are in the driver seat!(4)

      Europe

      Diagnostics

      Testing is essential to select the right treatment. Nevertheless, systematic diagnostic testing for ROS1 in metastatic NSCLC is not yet included in the European Society of Medical Oncology recommendation, but only suggested. (5) In Europe, access to molecular testing and new medicines differs between individual countries, even within the same country. In the Netherlands, a retrospective study in all patients that tested negative for EGFR and KRAS, showed an increase in ROS1 testing between 2013 (10%) and 2017 (61%) (6). Given the demonstrated added value of patient-driven organizations, both for patients and research, we need a more systematic testing for ROS1, in order to offer effective treatment to more ROS1 patients and strengthen our international community.

      ROS1 patients as research partners in Europe

      The Global ROS1 Initiative requires streamlined protocols to be successful. Currently, European ROS1ders cannot donate tissue for a variety of reasons. Therefore, a pan-European collaboration should be implemented, that centralizes expertise on the small number of potential tissue donations. In this network, tissue processing should be centralized in a single lab, and the resulting data and models could be distributed to collaborating partners. However, the setup of such network is very difficult, in part due to national differences in legislation.

      Furthermore, although we are a European Union, patients are not really united, and bringing together the European ROS1ders is not an easy task. We deal with language, boundary and policy issues. Due to European public health systems, all responsibility is given to doctors. Most patients see less benefit in getting informed and organized. Data protection laws and less use of social media make it more difficult to connect patients. Next, the number of non-governmental organizations supporting lung cancer patients is small - in particular in Europe. And finally, fundraising activities are rather uncommon in Europe. Overall these aspects make it harder for patient advocates to make a difference. As such, international networking and solidarity become even more important.

      In the Netherlands, www.stichtingmerelswereld.nl was founded to raise awareness and accelerate research. As a result, research on drug resistance has been initiated in cell lines and PDX mouse models. In parallel, drug resistance is also studied in France and Germany. Combining these individual studies might result in a 1+1 equals 3 scenario.

      We strive to unite our national voices to influence European policies and use our European voices to connect national studies.

      Understanding the role of personalized medicine https://www.lungcancer.org

      Jessica J. Lin MD & Alice T. Shaw (2017) “Recent Advances in Targeting ROS1 in Lung Cancer” in Journal of Thoratic Oncology . https://doi.org/10.1016/j.jtho.2017.08.002

      Xalkori for ROS1 positive advanced lungcancer. 2019 (4)

      https://ros1cancer.com/ros1-patient-driven-research

      D. Planchard et al. (2018) “Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.” Annals of Oncology 29 (Supplement 4): iv192–iv237, 2018 doi:10.1093/annonc/mdy275

      Kuijpers Chantal C.H.J. et al (2018). “National variation in molecular diagnostics in metastatic lung cancer. “ Nederlands Tijdschrift voor Geneeskunde 162:D1607

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      PC01.03 - Real World Research Groups - ALK+ Group (Now Available) (ID 3557)

      11:00 - 12:30  |  Presenting Author(s): Linnea Olson

      • Abstract
      • Presentation
      • Slides

      Abstract

      There is a natural tension inherent to clinical trials—between scientific rigor and a participant’s hope that an experimental therapy shall prove effective. However, it is important to never lose track of the reason for clinical trials. To quote Dr. Richard Pazdur, Director of the FDA’s Oncology Center of Excellence, ‘We have to understand that the clinical trials are here to serve the patients. The patients are not here to serve the clinical trials.’ (1)

      The decision to enroll in a clinical trial—particularly phase I where both maximum tolerable dose and the safety profile are being ascertained—is not a casual one. Generally the prospective participant has exhausted traditional therapies. With the emergence of actionable mutations and targeted therapies, the paradigm for participation is evolving. It is foreseeable that a participant can have a response to a therapy measured not only in months but in years. And when progression does occur, that same participant may enroll in yet another clinical trial.

      For many patients with advanced lung cancer, clinical trials now offer the best option for therapeutic treatment.

      It is critically important to find the balance between advancing medical research and extending individual lives.

      To this end, exclusion criteria need to be reevaluated. A patient who is desperately ill is often willing to tolerate a far higher degree of risk. Arguments for exclusion criteria fail to take into account the fact that this is a representative population; should the drug receive FDA approval, this will be the consumer profile. (2,3)

      It is also vital to understand the burden that clinical trial participants take on. First, financial. There is an overriding misperception that participation in a clinical trial is cost free. In reality, it is often only the experimental therapeutic that is provided free of charge.

      Clinical trials are procedure rich—from pharmacokinetics to additional scans/MRIs/EKGs/biopsies. In most cases a participant’s insurance is billed for these procedures, resulting in quickly maxed out deductibles and added copays. More frequent visits to the site of the trial require additional time and travel on the part of the participant. Transportation, lodging and meals are often the responsibility of the patient. There are lost wages, for either the patient or their caregiver or both. Often there is also the burden of childcare.

      The financial toll adds to the high degree of stress that a patient and their families are already living under. It also means that clinical trials are an option only for those with both the financial means and a solid support system in place. As economically distressed families are unevenly distributed among minorities, the clinical trial population is not representative. Not only does this mean there is an inherent disparity in access to clinical trials, it also impacts the science, as clinical trial participants in an ethically diverse country such as the US are overwhelmingly caucasian. In addition, it is important to point out that healthy volunteers to clinical trials are almost always compensated for both their time and even small things that are typically not covered in a clinical trial for oncology patients—such as parking. (4,5,)

      And then there is the physical toll upon a patient. Excessive scanning, multiple biopsies, exhaustion associated with additional visits to the site.


      “When you begin to look at a trial from the patient’s perspective and consider the complexity of the trial and what we are asking them to do, is it any wonder that so many patients are refusing to participate? And is it any wonder why so many patients choose to withdraw from a clinical trial?” (6)

      As accrual is an ongoing issue in clinical trials, it is imperative for both the sake of patients as well as medical science, that the voice of the patient be heard. Patient reported outcomes (7) often fail to capture the actual experience of a trial participant. Rather than being the one size fits all that is commonly handed to participants at each visit now, why not write the PRO with the assistance of actual participants? Humans, unlike their rodent counterparts in the lab, are sentient beings. Potentially a wealth of anecdotal information is being lost simply because no one thinks to ask.

      Clinical trials cannot happen without the cooperation of human participants. That cooperation is referred to as compliance. A patient who is noncompliant risks ejection from a trial. This creates a relationship that is inherently unbalanced.

      It is possible to address both accrual and the needs of the participant if clinical trials become truly patient centric. To do so one must consider the burden of participation. A clinical trial should be viewed as an opportunity, albeit one that is not risk free. Lessening the burden and removing some of the barriers to participation will better address the needs of both patients and the field of medical research.

      1. NCCS Celebrates “Focus on the Care” Reception in Honor of Dr. Richard Pazdur and Ellen Goodman Oct 22 2015 https://www.canceradvocacy.org/news/nccs-celebrates-focus-on-the-care-reception-in-honor-of-dr-richard-pazdur-and-ellen-goodman/

      2. Clinical Trial Patient Inclusion and Exclusion Criteria Need an Overhaul, Say Experts
      April 23, 2018 Redfearn, S https://www.centerwatch.com/cwweekly/2018/04/23/clinical-trial-patient-inclusion-and-exclusion-criteria-need-an-overhaul-say-experts/

      3. You Can’t Sit With Us for This Study: Exclusion Factors in Clinical Trials Feb 4, 2019 Krebill, C, NU SCI https://nuscimag.com/you-cant-sit-with-us-for-this-study-exclusion-factors-in-clinical-trials-44a8f6efbd8

      4. Clinical Trials and Their Financial Barriers: Increasing Participation, Lowering Financial Toxicity Jan 07, 2019 Rolleri,C, ASCO Communications https://connection.asco.org/magazine/features/clinical-trials-and-their-financial-barriers-increasing-participation-lowering

      5. Payment for participation in clinical research: Review of proposals submitted to the ethics committees Perspect Clin Res. Apr-Jun, 2018 9(2): 64–69. Marathe, PA; Tripathi, RK; Shetty, YC; Kuyare, SS; Kamat, SK; That, UM; atte2https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950612/

      6. Merck Changes The Paradigm On Clinical Trials May 11, 2016 Miseta, E Clinical Leader https://www.clinicalleader.com/doc/merck-changes-the-paradigm-on-clinical-trials-0001

      7. Patient involvement in clinical research: why, when and how Apr 27, 2016 Sacristán, JA; Aguarón, A; Avendaño-Solá, C; Garrido, P; Carrión, J; Carrión, A; Kroes, R; Flores, A; NCBI PMC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854260/

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      PC01.04 - Lung Cancer Patients Should Have Better Access to Clinical Research: Relax the Eligibility Criteria (Now Available) (ID 3558)

      11:00 - 12:30  |  Presenting Author(s): Janet Freeman-Daily

      • Abstract
      • Presentation
      • Slides

      Abstract

      Clinical trials are essential for improving treatment of cancer patients. However, only 2%-3% of adult cancer patients participate in clinical trials, and many trials close because they do not enroll enough patients. Others are slow to accrue patients, which prolongs the time required to obtain results. Those trials that meet accrual goals often have cohorts that don’t reflect the demographics or performance status of the real-world population of patients who have the disease.

      Why do trials have trouble enrolling enough patients? Some of the significant barriers to clinical trial participation stem from over-restrictive trial eligibility criteria. Unger et al (2019) found 21.5% of patients did not enroll in a clinical trial because they were not eligible. A Kaiser Permanente study of non-small cell lung cancer patients found 80% of the patients were not eligible for two NSCLC treatment studies.

      Trial eligibility must balance opposing factors. It must be narrow enough to ensure the effect of the treatment can be determined, yet broad enough that the population of patients is meaningful. Researchers often use “common” eligibility criteria without giving due consideration to how those criteria may impact trial recruitment and the real-world applicability of their study. A population of younger patients with no health issues other than lung cancer might make it easier to identify the effect of the experimental treatment, but this population gives no real insight into how the treatment affects the typical population of lung cancer patients (which has an average age of 71).

      Recommendations to modernize eligibility criteria have been recently published by a joint effort of the American Society for Clinical Oncology and Friends of Cancer Research, as well as the US Food and Drug Administration and the National Cancer Institute. The recommendations include relaxing restrictions on brain metastases, minimum age, HIV/AIDS, organ dysfunction, and prior and concurrent malignancies while ensuring patient safety.

      Other aspects of a trial may cause patients to decide not to enroll even if they meet the eligibility requirements. Locations of trial sites might require the patient to travel, yet the patient might not be able to afford time or cost of travel, or their insurance might not cover treatment at any trial site. The trial protocol may prohibit certain previous treatments, or require weeks of washout from previous tyrosine kinase inhibitor (TKI) treatments (which raises the possibility of TKI flare).

      Preliminary evidence shows that relaxing trial eligibility requirements could result in a greater number of patients becoming eligible for clinical trials. Harvey et al (2019) conducted a retrospective study of 10,500 CancerLinq records of patients with lung adenocarcinoma. They found 47.7% of patients were excluded from clinical trials by traditional exclusion criteria (no brain metastases, no other malignancies, and creatinine clearance greater than 60 mL/minute), while only 1.5% of patients were excluded by the ASCO-Friends recommended expanded criteria that removed these restrictions.

      Relaxing clinical trial eligibility while maintaining safety is in the best interest of the patient. Patients are not for clinical trials. Clinical trials are for the patient.

      References:

      Gore, L, et al. (2017). "Modernizing Clinical Trial Eligibility: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Minimum Age Working Group." Journal of Clinical Oncology 35(33): 3781-3787

      Harvey RD, et al. (June 2019). “Impact of broadening clinical trial eligibility criteria for advanced non-small cell lung cancer patients: Real-world analysis.” Presentation at ASCO Annual Meeting 2019, Chicago, IL. https://meetinglibrary.asco.org/record/178360/abstract

      Jin, S, et al. (2017). "Re-Evaluating Eligibility Criteria for Oncology Clinical Trials: Analysis of Investigational New Drug Applications in 2015." Journal of Clinical Oncology 35(33): 3745-3752.

      Lichtman, SM, et al. (2017). "Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group." Journal of Clinical Oncology 35(33): 3753-3759.

      Lin, NU, et al. (2017). "Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Brain Metastases Working Group." Journal of Clinical Oncology 35(33): 3760-3773.

      Sharpless NE, Doroshow JH. “Modernizing Clinical Trials for Patients With Cancer.” JAMA. Published online January 23, 2019. 321(5):447–448. doi:10.1001/jama.2018.18938

      Uldrick, TS, et al. (2017). "Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group." Journal of Clinical Oncology 35(33): 3774-3780.

      Unger JM, Hershman DL, Fleury ME, Vaidya R. “Association of Patient Comorbid Conditions With Cancer Clinical Trial Participation.” JAMA Oncol. Published online January 10, 2019 5(3):326–333. Doi:10.1001/jamaoncol.2018.5953

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      PC01.05 - Representation of Minorities and Women in Oncology Clinical Trials (Now Available) (ID 4059)

      11:00 - 12:30  |  Presenting Author(s): Narjust Duma

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      Abstract not provided

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