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Manuel Cobo

Moderator of

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    ES22 - Immunotherapy - Discovering New Areas (ID 25)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Immuno-oncology
    • Presentations: 5
    • Now Available
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      ES22.01 - Immunotherapy in Resectable NSCLC (Now Available) (ID 3275)

      15:45 - 17:15  |  Presenting Author(s): Patrick M. Forde

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune checkpoint blockade with inhibitors of the PD-1/PD-L1 interaction have improved survival substantially for patients with advanced non-small cell lung cancer. Despite many clinical trials of different combination regimens, the benefit from perioperative platinum doublet chemotherapy in resectable lung cancer is modest with an approximate 5% improvement in 5 year survival over surgery alone.

      This session will review the background of systemic therapy for resectable lung cancer and data reported to date with single agent PD-1 blockade, PD-(L)1-based immunotherapy combinations, and chemotherapy combined with anti-PD-1. Ongoing phase 3 clinical trials of neoadjuvant and adjuvant immunotherapy will be discussed and future directions both in novel science and clinical trials explored.

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      ES22.02 - A Milestone in Locally Advanced NSCLC (Now Available) (ID 3276)

      15:45 - 17:15  |  Presenting Author(s): Solange Peters

      • Abstract
      • Presentation
      • Slides

      Abstract

      Stage III NSCLC encompasses locally advanced tumours with infiltration of locoregional nodes and central thoracic structures and accounts for about a third of newly diagnosed NSCLC[1]. It represents the most advanced stage of NSCLC in which treatment is delivered with curative intent, but eventually more than 60% of patients die from their disease.

      Stage III NSCLC patients must strictly be discussed in a multidisciplinary tumor board, whereat the definition of resectability suffers from a certain heterogeneity across centers. Resectability is usually defined by the degree of invasion of lymph nodes, most often excluding multilevel or bulky N2 and N3 disease as well as invasion of the oesophagus, aorta and myocardium. Controversy exists on the role of surgery in stage III NSCLC since two large randomized trials investigated either induction chemoradiation therapy followed by resection versus radiotherapy[2], or induction chemotherapy followed by resection versus radiotherapy[3]. Both studies failed to demonstrate a difference in survival[2-5], however these treatment strategies are evidence-based and can be pursued in restectable NSCLC[6].

      In the surgical scenario, randomised trials and meta-analyses have consistently shown that either adjuvant or neoadjuvant chemotherapy added to surgery results, with a better survival than surgery alone[7,8]. Adding preoperative radiotherapy to chemotherapy in patients with stage IIIA/N2 NSCLC did not improve the clinical outcome in a phase 3 randomised trial[9]. The role of adjuvant radiotherapy in stage IIIA/N2 after neoadjuvant chemotherapy followed by surgery has been evaluated in a unique randomized trial with awaited results (Lung ART, NCT00410683).

      Early NSCLC stages offer a theoretical unique curative scenario for the development of immunotherapy startegies, with limited disease volumes, a relative immune system preservation as well as unique oportunities for the investigation and assessment of new biomarkers.

      Perspectives, rational, hopes and ongoing attempts to combine immunotherapy in the surgical setting or alterenatively complementary to chemoradiation will be discussed, with a focus on locally advanced disease.

      References

      1. Detterbeck FC. The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg 2018;155:356-9.

      2. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86.

      3. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-50.

      4. O'Rourke N, Roque IFM, Farre Bernado N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010:CD002140.

      5. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-90.

      6. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv1-iv21.

      7. Group NM-aC. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71.

      8. Group NM-aC, Arriagada R, Auperin A, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;375:1267-77.

      9. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015;386:1049-56.

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      ES22.03 - New Hope in SCLC? (Now Available) (ID 3277)

      15:45 - 17:15  |  Presenting Author(s): Leora Horn

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) accounts for approximately 15-20% of cases. This aggressive tumor is characterized by rapid growth, early development of disseminated disease and dramatic responses to first line chemotherapy. For decades, first line therapy has traditionally included four to six cycles of platinum-based chemotherapy. While up to 80% of patients respond to first-line chemotherapy, the majority eventually relapse with a median survival of 8 to 12 months for patients with extensive stage disease and 12 to 20 months for those with limited stage disease. Until recently, topotecan was the only FDA approved second line therapeutic option. The shortcomings of traditional chemotherapy, as well as the limited role of targeted therapy in SCLC, led to the investigation of novel mechanisms to target lung cancer and specifically the discovery of immune checkpoint inhibitors.

      Immune checkpoint inhibitors work by blocking interactions between T cells and antigen presenting cells (APCs) or tumor cells. By inhibiting this interaction, the immune system is effectively upregulated and T-cells become activated against tumor cells. There are three major classes of checkpoint inhibitors. Ipilimumab and tremelimumab inhibit T-lymphocyte antigen-4 (CTLA-4); nivolumab and pembrolizumab target the programmed cell death-1 receptor (PD-1); and atezolizumab, durvalumab, and avelumab block PD-L1, the ligand of PD-1. Prior studies have shown lack of PD-L1 expression on tumor cells in patients with pulmonary and extra pulmonary SCLC. While PD-1 and PD-L1 are expressed in the tumor stroma of small cell carcinomas.[1] In addition PD-L1 has been shown to be prognostic in patients with SCLC.[2] The aggressive nature of SCLC is underscored by its high mutational burden, including loss of the tumor suppressor genes p53 in 75%–90% and retinoblastoma in almost 100% of tumors.[3] Higher tumor mutation burden has been associated with outcome in patients with select tumors treated with checkpoint inhibitor therapy, including non-small cell lung cancer. [4]

      Recently singly agent nivolumab and combination nivolumab and ipilimumab were shown to have activity in the second and third line setting for patients with advanced SCLC with response rates of approximately 10% and 20% respectively. Combination nivolumab and ipilimumab appeared particularly promising in patients with tumors with high tumor mutation burden and in 2018 nivolumab received approval in the third line setting for patients with advanced SCLC. [5] However, disappointingly Chekckmate 331, a large phase III trial of patients who had progressed on first line platinum-based chemotherapy, found nivolumab was not superior to topotecan or amrubicin in the second line setting. Recently a combined analysis of patients treated on the Keynote 158[6] and 028 trial[7] with pembrolizumab in the second line setting demonstrated a response rate of approximately 20% in patients, with a greater benefit in patients with tumors that were PD-L1 positive.

      In the first line setting, a single arm phase II trial demonstrated no benefit to maintenance pembrolizumab following induction chemotherapy in patients with advanced SCLC with a progression free survival of less than 2 months. [8] Earlier this year, a phase III trial (Checkmate 451) also found maintenance nivolumab with or without ipilimumab following induction chemotherapy in patients with advanced small cell lung cancer was not superior to placebo, suggesting this is not the optimal strategy in patients with advanced stage disease.

      Importantly, he Impower 133 phase III trial demonstrated combination chemotherapy with carboplatin, etoposide and atezolizumab was superior to chemotherapy alone in patients with advanced SCLC with a significant improvement in progression free and overall survival leading to FDA approval and a new standard of care for patients with advanced disease. [9] Two large phase III trials Keynote 604 and Poseidon are comparing a similar strategy with pembrolizumab and durvalumab respectively, with data anticipated in the upcoming year.

      While progress has finally been made. Limited tissue specimens in patients with SCLC remain a challenge and many unanswered questions remain including the optimal patient population in which these agents will have benefit (PD-L1 positive or negative, tumor mutation high or low), the optimal duration of therapy, the appropriate combinations (can we improve upon chemotherapy with a different checkpoint inhibitor), and the safety of these agents long term, particularly in patients with comorbid disease.

      References:

      1. Schultheis, A.M., et al., PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer, 2015. 51(3): p. 421-6.

      2. Ishii, H., et al., Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol, 2015. 10(3): p. 426-30.

      3. Byers, L.A. and C.M. Rudin, Small cell lung cancer: where do we go from here? Cancer, 2015. 121(5): p. 664-72.

      4. Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.

      5. Antonia, S.J., et al., Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol, 2016. 17(7): p. 883-895.

      6. Chung, H.C., et al., Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol, 2019. 37(17): p. 1470-1478.

      7. Ott, P.A., et al., Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol, 2017. 35(34): p. 3823-3829.

      8. Gadgeel, S.M., et al., Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC). J Thorac Oncol, 2018. 13(9): p. 1393-1399.

      9. Horn, L., et al., First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med, 2018. 379(23): p. 2220-2229.

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      ES22.04 - Any Chance in Mesothelioma (Now Available) (ID 3278)

      15:45 - 17:15  |  Presenting Author(s): Giorgio Vittorio Scagliotti

      • Abstract
      • Presentation
      • Slides

      Abstract

      Section not applicable

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      ES22.05 - Role in Thymic Epithelial Tumours (Now Available) (ID 3279)

      15:45 - 17:15  |  Presenting Author(s): Rina Hui

      • Abstract
      • Presentation
      • Slides

      Abstract

      Although thymic epithelial tumours (TETs) are rare, they are the commonest primary tumours of the anterior mediastinum. TETs are heterogenous with histological classification into thymoma and thymic carcinoma. Subtypes of thymomas include A, AB, B1, B2 and B3 depending on the presence of spindle cells, the relative proportion of lymphocytes and abnormal epithelial cells. The commonest histological subtype of thymic carcinoma is squamous cell, others include sarcomatoid, adenocarcinoma, basaloid etc. The traditional Masaoka-Koga staging system is widely used to stage TETs (I: no breaching of capsule; II: invasion through capsule to involve surrounding fatty tissue; III: invasion into nearby organs; IV: pleural/pericardial spread or distant metastases), while TNM staging (T1a: with or without invasion into mediastinal fat; T1b: mediastinal pleura; T2: pericardium; T3/T4: nearby organs; N1: peri-thymic anterior mediastinal nodes; N2: deep thoracic or cervical nodes; M1a: separate pleural or pericardial nodules; M1b: distant metastases) has been introduced more recently. The prognosis of TETs depends on both histology and disease extent. Thymomas are usually more indolent with 10- year overall survival rate of >80% for stage I and II, but thymic carcinoma confers poorer prognosis with 5-year survival of around 50% for stage III and 25% for stage IVa.

      The treatment of choice for early stage disease is surgical resection with curative intent. Concurrent chemoradiation can be considered for unresectable locally advanced TETs. 10-15% of resected TETs recur and radical radiation may be appropriate for local recurrence. In unresectable stage III and IV disease with spread to pleural and pericardial cavities or beyond, standard first-line systemic treatment is platinum-based chemotherapy, usually with cisplatin, doxorubicin and cyclophosphamide. Although TETs are reported to be chemo-sensitive with a response rate (ORR) of 50% for thymomas and around 20% for thymic carcinoma, they ultimately will progress and research into second-line treatments besides chemotherapy is important. Targeted therapies including sunitinib and everolimus with disease control rate (DCR) of >80% in previously treated TETs have been reported.

      Cancer treatment landscape has been rapidly evolving in recent years due to the successful development of PD1 blockade in many cancer types including melanoma, non-small cell lung cancer, bladder cancer, renal cell cancer, head and neck cancer, etc. The function of thymus during childhood in the production, differentiation and maturation of immunocompetent T cells together with the observation of high level of PD-L1 expression in normal thymus and TETs suggest a possible role of immunotherapy in TETs. Of 40 eligible patients with chemotherapy refractory thymic carcinoma in a phase 2 study, pembrolizumab provided an ORR of 22.5%, DCR of 75%, median progression-free survival (PFS) of 4.2 months, and median overall survival (OS) of 24.9 months with 1-year OS rate of 71%. Exploratory analysis in this study suggested an association of high-level PD-L1 with longer PFS and OS. A similar phase 2 study of pembrolizumab after at least 1 line of chemotherapy in Korea included 7 patients with thymoma and 26 patients with thymic carcinoma achieving an ORR of 27% with DCR of 100% in thymoma and ORR of 19% with DCR of 73% in thymic carcinoma. A phase 1 study with avelumab showed confirmed ORR of 29% with DCR of 86% in 7 thymoma patients and stable disease in the 1 thymic carcinoma patient.

      As thymus is involved in positive and negative T cell selection process for self-major histocompatibility complex molecules, thereby inducing self-tolerance avoiding auto-immunity, one third of thymoma is associated with autoimmune diseases, the commonest being myasthenia gravis. Other associated autoimmune conditions include systemic lupus erythematosus, pure red cell aplasia, syndrome of inappropriate anti-diuretic hormone secretion, bullous dermatoses autoimmune blistering diseases, polymyositis, dermatomyositis, pernicious anaemia, haemolytic anaemia, scleroderma, Sjogren’s syndrome, rheumatoid arthritis, ulcerative colitis, Takayasu syndrome, Grave’s disease etc. However, autoimmune disorders are much less likely to occur in thymic carcinoma. It is not surprising that a significant incidence of immune-related adverse events (irAE) is evident with immune-checkpoint inhibitors in the treatment of TETs with higher frequency of irAE in thymoma than in thymic carcinoma. 71% of patients with thymoma and 15% of patients with thymic carcinoma treated with pembrolizumab in the Korean study experienced grade 3-4 irAE including 12% hepatitis, 9% myocarditis, 6% myasthenia gravis, 3% thyroiditis, colitis, nephritis and myoclonus. The other phase 2 pembrolizumab study in patients with thymic carcinoma also reported similar incidence of 15% severe irAE with 5% myocarditis. IrAE was observed in 63% of patients in the phase 1 avelumab study with 38% myositis and 13% enteritis. PD-L1 status did not predict irAE.

      In conclusion, the main issue of PD1 blockade in TETs is common irAEs with higher frequency in thymomas. Therefore, immunotherapy is still not standard of care, needing further research to identify possible biomarkers to spare patients with less likelihood to benefit taking the risk of serious irAEs. There may be a role of immunotherapy in advanced TETs with aggressive pathology after failing chemotherapy, but thorough discussion with patients about the potential irAEs is warranted.

      References:

      Girard N, Ruffini E, Marx A, et al. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v40-v55.

      Miyamoto K and Acoba J. Thymomas and thymic carcinomas: a review on pathology, presentation, staging, treatment, and novel systemic therapies. EMJ Respir. 2017;5:100-107.

      Detterbeck F, Stratton K, Giroux D, 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:S65-S72.

      Shelly S, Agmon-Levin N, Altman A, et al. Thymoma and autoimmunity. Cell Mol Immunol. 2011;8:199-202.

      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.

      Cho J, Kim K, Ku B, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial. J Clin Oncol. 2018;36:1-8.

      Rajan A, Heery C, Mammen A, et al. Safety and clinical activity of avelumab in patients with advanced TETs. J Thorac Oncol. 2017;12:1S:OA18.03.

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Author of

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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-28 - Real World Use of Afatinib in NSCLC EGFRm+ Patients Outside Clinical Trials: A FAETT Experience (Now Available) (ID 655)

      08:00 - 18:00  |  Author(s): Manuel Cobo

      • Abstract
      • Slides

      Background

      Epidermal growth factor receptor (EGFR) tyrosine kynase inhibitors (TKIs) remain the standard of care as first-line therapy for patients with non-small cell lung cancer (NSCLC) harboring an EGFR mutation. These drugs have been associated with improvements in both clinical outcomes and tolerability, compared with platinum-based chemotherapy.

      Three generations of TKIs are currently approved in the first-line setting, though only first (erlotinib and gefitinib) and second generation blockers (mainly afatinib, but also dacomitinib) have been extensively used in clinical practice nowadays.

      Method

      We reviewed 105 patients with NSCLC with advanced or recurrent stages that harbour EGFR mutations, treated with afatinib as first´line therapy among the academic hospitals adhered to the FAETT network.
      The information of clinical, pathological and treatment characteristics of the patients was collected retrospectively and the statistical analysis was performed with the software SPSS software version 21.0, considering the statistical significance if p-value <0.05.

      Result

      The characteristics of the patients are reflected in Table 1.
      The mean age at the beginning of treatment with afatinib was 61 (37-81) years. 48.6% of the patients were older than 65 years. 27.6% were older than 70 years. With a median follow-up of 15 months (0-82), the median progression-free survival was 14 months (10.74-17.26) Fig 1, and the median overall survival was 31 months (24.00) -37.99).
      The median PFS and OS among patients older than 65 years, and even those older than 70 years, is not statistically significant (14 vs 13 and 30 vs 31 months, repectively. P-value:0,83 and 0,78
      On the other hand, the toxicities between both groups remain similar, with diarrhea and skin rash standing out as the most frequent, as reflected in the data published to date. Table 2

      tablas2.jpg

      tabla3.jpg

      Conclusion

      This retrospective study shows no differences in the use of afatinib among older patients in terms of both efficacy and tolerability.

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    MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA02.01 - Reccurrence Pattern After Adjuvant Customized Chemotherapy Based on BRCA Expression Level (SCAT Trial) (Now Available) (ID 2760)

      10:30 - 12:00  |  Author(s): Manuel Cobo

      • Abstract
      • Presentation
      • Slides

      Background

      •Postop platinum-based CT improves outcomes in completely resected NSCLC with nodal involvement, (St II-IIIA). Customization is feasible in adjuvant setting (tissue availability) . Analysis of expressionin genes involved in DNA repair could be use to select CT regiment. •BRCA1 plays an important role in DNA repair pathways and functions as a differential regulator of response to cisplatin and antimicrotubuleagents. SCAT trial results found that for low BRCA1 levels subgroup Cis-Gemcitabine was superior to Cis-Docetaxel and in high BRCA1 levels subgroup Docetaxel single agent without platinum achieved similar survival to Cis-Doc. Analysis of recurrence pattern in different subgroups of the trials has been performed

      Method

      From Jun/2007 to May/2013 591 patients were screened and 500 p were included (108 in Control arm treated with Cisplatin-Docetaxel and 392 in Experimental arm treated with Cisplatin-Gemcitabine, Cisplatin-Docetaxel or Docetaxel alone according terciles BRCA1 expression level). With a cut-off September 30th 2018 and a median follow-up of 60 months, recurrence pattern are analysed in each arm and subgroup treatment and comparison are made for incidence of risk of recurrence, single/multiple recurrence, thoracic/extrathoracic and site of metastases (liver, bone, brain)

      Result

      Cumulative recurrence 232/456 evaluable patients (p) (50.8%). Recurrence were seen in 182/354 patients treated in experimental arm and in 50/102 p treated in the control arm (RR 1.04; 0.83-1.30) (p=0.672). Majority of recurrences 159/232 (68.5%) were single site recurrence. Intrathoracic recurrences in 121/232 (52%) while extrathoracic metastatic disease 111/232 (47.8%). No significant differences were seen for single/multiple, intra/extrathoracic recurrences between experimental and control arm. More frequent distant metastatic sites were: bone (42 p), brain (38 p) and liver (11 p) In the experimental group between different treatments no significant differences were found for the overall metastatic rate or for the single/multiple, intrathoracic/extrathoracic recurrences. For specific metastatic sites related to experimental treatment a significant reduction of risk of brain metastases were found in the experimental group with high level BRCA1 treated with Docetaxel single agent (p=0.0016)

      Conclusion

      For NSCLC resected patients with lymph node involvement (Stages II-IIIA) risk of recurrence remains high with cumulative rate > 50%. There were no differences in the Relative Risk (1.04) of recurrence when control and experimental arm are compared. Majority of recurrences were single site (68.5%) and intrathoracic (52%) but distant metastases developed in 47.8% os p. More frequent metastatic site was bone, followed by brain and liver. Brain metastases risk were significant lower for patients with low BRCA1 expression treated with single agent Docetaxel

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    MS14 - Molecular Subsets and Novel Targeted Approaches to Small Cell and Neuroendocrine Cancers (ID 77)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      MS14.03 - Targeting Transcription (Including Lurbinectedin) (Now Available) (ID 3521)

      11:30 - 13:00  |  Presenting Author(s): Manuel Cobo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      OA13.05 - NADIM Study: Updated Clinical Research and Outcomes (Now Available) (ID 1670)

      11:30 - 13:00  |  Author(s): Manuel Cobo

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months

      Method

      A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC in adult patients with CT plus IO as neoadjuvant treatment: 3 cycles of nivolumab (NV) 360 mg IV Q3W + paclitaxel 200 mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After completing neoadjuvant therapy, all patients underwent tumor assessment prior to surgery. Surgery was performed during the 3rd or 4th week after day 21 of the 3rd neoadjuvant treatment cycle. The study aimed to recruit 46 patients. The primary endpoint was Progression-Free Survival (PFS) at 24 months. Efficacy was explored using objective pathologic response criteria. Here we present the final data on all study patients that underwent surgical assessment.

      Result

      At the time of submission, the 46 patients had been included. None of the patients were withdrawn from the study preoperatively due to progression or toxicity. 41 patients had undergone surgery and all tumors were deemed resectable with R0 resection in all cases. Intention to treat analysis shows 35 patients (85%; 95% CI, 71; 94%) achieved major pathologic response (MPR) of which 25 (71%; 95% CI, 54; 85%) were complete pathologic responses (CPR). Downstaging was seen in 38 (93%; 95% CI, 80; 98%) of cases. The median follow-up was 13.8 months (P25; P75: 11.7; 16.6 months) for both the whole series and resected patients, and 12 month PFS was 95.7% (95% CI, 84; 99%).

      Conclusion

      This is the first multicentric study to test CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a complete pathologic response rate that is higher than ever seen previously, together with a promising PFS which may translate into increased overall survival. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-93 - Metastases Sites as a Prognostic Factor in a Real-World Multicenter Cohort Study of Spanish ALK-Positive NSCLC Patients (p) (ID 1377)

      09:45 - 18:00  |  Author(s): Manuel Cobo

      • Abstract

      Background

      ALK gene rearrangements are detected in 3-7% of Non-Small-Cell-Lung-Cancer (NSCLC) p. EML4-ALK translocation was first identified as an oncogene in NSCLC p in 2007. To date, published real-world data on the prognostic factors of patients with ALK-positive advanced NSCLC in Spain are limited. We aim to evaluate the effect of number of metastases (M1) organs on overall survival (OS) in a multicenter cohort of Spanish ALK-positive NSCLC p diagnosed between 2008 and 2017.

      Method

      We included p with stage IV at diagnosis since 2011 to April 2018. OS (months [m]) was estimated with the Kaplan-Meier method. Survival curves were compared between groups of p using the log-rank test. Hazard risk (HR) to death was estimated with multivariable Cox model, adjusted by site of metastases, gender, age and first line type of treatment.

      Result

      Out of the 163 p in the cohort a total of 98 p were included, with a median follow-up of 28.6 m and 45 deaths reported. Characteristics at diagnosis were median age 58 years, female 46.9%, never-smokers 59.2%, 50% with comorbidities, PS by ECOG 0-1 93%, 58.2% lung M1, 45.9% central nervous system M1, 42.9% bone M1, 22.4% liver M1 and 29.6% pleural M1.

      54.3% p and 89.4% p were treated with ALK inhibitors as first line and second line respectively. The median OS was 34.4 months, being 46.9 months in p treated with ALK inhibitors and 38.8 months in p treated with chemotherapy as first line (p= 0.9).

      There were 72 p who presented M1 in more than one organ and 26 p in a single organ. The risk of death increased with greater number of organs involved at diagnosis (HR= 3.0, p=.016), and presenting liver M1 at diagnosis (HR=2.2, p=.046, with OS of 19.1 m), compared to p single site involvement (OS: 45.4 m).

      Conclusion

      OS was worse with increased metastatic sites involved at diagnosis in p with ALK positive NSCLC, being liver M1 associated with the highest risk of mortality. Brain metastases at diagnosis were not a prognostic factor for OS in our series.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-16 - Agreement Between Different Methodologies for Non-Invasive p.T790M and EGFR Sensitizing Mutation Testing (ID 1965)

      10:15 - 18:15  |  Author(s): Manuel Cobo

      • Abstract
      • Slides

      Background

      Tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients progressed within 1 to 2 years. The EGFR p.T790M mutation is the most common resistance mechanism to first and second generation EGFR TKIs. The identification of p.T790M mutation is of considerable clinical relevance as osimertinib has demonstrated clinical efficacy in this setting. Guidelines recommend testing for the p.T790M mutation in blood at relapse to TKIs, and re-biopsy only in case of a negative result. Several blood based methodologies for detection of EGFR mutations have been developed in the recent years. However, the number of comparison studies between platforms is very limited.

      Method

      This is a multicenter, cross-sectional study (ClinicalTrials.gov Identifier: NCT03363139) performed by the Spanish Lung Cancer Group. Samples from 75 consecutive EGFR mutant NSCLC patients were collected at disease progression to first line TKI treatment. The presence of EGFR mutations in the cfDNA was evaluated in 39 samples by 7 methodologies, namely: Cobas® EGFR Mutation Test v2 (Roche Diagnostics), Therascreen EGFR Plasma RGQ PCR Kit (Qiagen), QuantStudio® 3D Digital PCR System (Thermofisher), a 5′-nuclease real-time PCR (TaqMan®) assay in presence of PNA, OncoBEAM EGFR (Sysmex Inostics), NGS with two different gene panels: Oncomine® (Thermofisher) and Lung Cancer Panel (Qiagen). The agreement between methodologies was assessed using the kappa coefficient (K) and its corresponding 95% confidence intervals (95% CI). For quantitative variables the concordance correlation coefficient (ccc) was used.

      Result

      Complete results are available for 39 patients. Overall, the agreement between all methodologies for the detection of p.T790M mutation as well as the original EGFR sensitizing mutation was good (K=0.669; 95CI: 0.504-0.835 and K=0.750 95CI: 0.599-0.899 respectively). Remarkably, the agreement between FDA-approved methodologies for p.T790M detection was almost perfect (K=0.926; 95CI: 0.712-1) and good for the EGFR sensitizing mutations (K=0.657; 95CI: 0.417-0.902). Similarly, the agreement between NGS-based methodologies for the detection of p.T790M and the EGFR activating mutations was very high (K=0.843; 95CI: 0.567-1 and K=0.872 95CI: 0.595-1 respectively). Moreover, concordance between both technologies for p.T790M and EGFR sensitizing mutation mutant allele frequency was excellent (ccc=0.956; 95CI: 0.906-1 and ccc=0.980 95CI: 0.950-1 respectively). The proportion of samples that were positive for p.T790M detection varied from 28% (PCR based technologies) to 37% depending on the methodology.

      Conclusion

      NGS and PCR-based methodologies show a good to excellent agreement for the detection of EGFR mutations, including the p.T790M. Our results support the use of liquid biopsies for non-invasive testing of clinically relevant mutations (Data from the whole cohort will be presented at the meeting).

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-10 - Biomarkers of Pathological Response on Neo-Adjuvant Chemo-Immunotherapy Treatment for Resectable Stage IIIA NSCLC Patients (ID 1466)

      10:15 - 18:15  |  Author(s): Manuel Cobo

      • Abstract
      • Slides

      Background

      PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described peripheral blood immune cells parameters as biomarkers of response to immunotherapy. In our study, we described the effect of neo-adjuvant chemo-immunotherapy treatment in Complete Blood Count (CBC) and Peripheral Blood Mononuclear Cells (PBMCs) phenotype, as well as, the association of these parameters with the degree of pathological response.

      Method

      Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), major response (<10% viable tumour) and incomplete response (>10% viable tumour, pIR). Wilcoxon and Mann-Whitney U statistic test were used to evaluate differences between pre and post treatment and between pathological responses groups respectively.

      Result

      From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers of Leucocytes, Eosinophil, Monocytes, Neutrophils, Haemoglobin and Platelets from hemograms were significantly reduced after neo-adjuvant treatment. However, no changes were observed for Lymphocytes, Basophils, LDH levels or the Lung Immune Prognostic Index (LIPI). Additionally, post-treatment Neutrophil-to-Lymphocyte (NLR), Myeloid-to-Lymphoid lineage (M:L) and Platelets-to-Lymphocytes (PLR) ratios were decreased. Remarkably, from all the CBC absolute numbers and ratios, only PLR variation showed differences between pCR and pIR.

      On the other hand, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neo-adjuvant treatment, however activation of CD4 T cells and NK cells as well as PD-1 receptor expression on immune cells were downregulated after neo-adjuvant chemo-immunotherapy. Interestingly, these variations correlate with pCR.

      Conclusion

      In our study, PLR, PD-1 expression, CD4 T cells and NK cells activation are predictive biomarkers of response to treatment. Thus, a higher decrease on PLR post neo-adjuvant treatment is associated to pCR. Moreover, a decrease of PD-1 expression in CD4, CD8 and NK cells, as well as, a reduction of CD4 T cells and NK cells activation after neo-adjuvant treatment, are associated to pCR.

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