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Elisa Gobbini

Moderator of

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    PC03 - Adjuvant Therapy for Resected NSCLC Harboring EGFR Mutation, Chemotherapy or Targeted Therapy (ID 85)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 3
    • Now Available
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      PC03.01 - PROs (Now Available) (ID 3567)

      15:45 - 17:15  |  Presenting Author(s): Wen-Zhao Zhong

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is so far the leading cause of cancer death worldwide. Complete surgical resection remains the most effective approach for patients with early-stage non-small cell lung cancer (NSCLC). Patients with completely resected stage I NSCLC could have a 5-year survival of ~80%, whereas it fails to ~30%. Since 2003, adjuvant chemotherapy became the standard of care showing 4% absolute 5-year survival benefit compared to surgery alone [1]. Following randomized control trials revealed similar results [2-4], yet limited survival benefit, low therapeutic completed rate plus high toxicities rate may somehow hinder its clinical applicability. In the past decade, targeted therapies had achieved tremendous success in oncogene-driven advanced NSCLC showing both high efficacy and low toxicities [5]. As a matter of course, targeted therapy had its baby steps in early-stage NSCLC. However, no positive results were found in these trials which should probably be blame for large proportion of stage IB patients and incorrect detection methods for EGFRmutation. Besides, conservative trial design without head to head comparison could not fully address toxicities issues caused by chemotherapy. Precise target population seemed to be an essential key point to adjuvant targeted therapies and ADJUVANT as well as EVAN trial came into being [6, 7]. Although overall survival (OS) was not mature enough to measure, significantly prolonged disease-free survival (DFS) was observed in both trials along with better tolerability. Indeed, questioning around adjuvant targeted therapy has never been adjourned such as the optimal duration of targeted therapies, study design and lack of OS data. Ross et al brought up with an informative comment for ADJUVANT trial bringing the concept of MRD (molecular residual disease) into adjuvant treatment [8]. Based on the ctDNA testing after standard of care adjuvant chemotherapy, patients of high risk of recurrence will be given further treatments while observation for the others. It highlighted the significant role of discriminating beneficiaries from adjuvant targeted therapies instead of simply providing more efficient treatment modalities. Previous biomarker-based studies regarding adjuvant treatment among different tumor types [9, 10]had provided inspirational examples, and as well shown clinical feasibility and urgent need for personalized adjuvant treatment after complete surgical resection. For ADJUVANT trial, we established a comprehensive signature of genetic-features (MEDUSA) to guide personalized adjuvant treatment in EGFR-mutant stage II-III NSCLC. Results would be unleashed in upcoming ESMO meeting. Through utilizing multi-omics data, we could predict whether additional treatments, adjuvant chemotherapy only or observation would be adequate for each individual and provide optimal sequential treatments. Further translational researches and corresponding trials regarding resectable NSCLC should decipher the issues. Fortunately, several trials regarding dynamic monitoring postoperative ctDNA or genomic profile of primary cancer to guide sequential treatments are ongoing and the results should be expected.

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      Reference:

      1. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351-360.

      2. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597.

      3. Strauss GM, Herndon JE, 2nd, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26: 5043-5051.

      4. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7: 719-727.

      5. Hirsch FR, Scagliotti GV, Mulshine JL et al. Lung cancer: current therapies and new targeted treatments. Lancet 2017; 389: 299-311.

      6. Zhong WZ, Wang Q, Mao WM et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018; 19: 139-148.

      7. Yue D, Xu S, Wang Q et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018; 6: 863-873.

      8. Ng TL, Camidge DR. Lung cancer's real adjuvant EGFR targeted therapy questions. Lancet Oncol 2018; 19: 15-17.

      9. Sparano JA, Gray RJ, Makower DF et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373: 2005-2014.

      10. Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol 2015; 33: 1787-1796.

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      PC03.02 - CONs (Now Available) (ID 3568)

      15:45 - 17:15  |  Presenting Author(s): Jyoti D Patel

      • Abstract
      • Presentation
      • Slides

      Abstract

      Surgery remains the cornerstone of treatment for early-stage non-small cell lung cancer (NSCLC). However, despite undergoing potentially curative surgery, patients with stage I, II, or IIIA NSCLC are at substantial risk for recurrence and death from lung cancer. Adjuvant cisplatin-based systemic therapy has conclusively been proven to decrease the risk of recurrence and improve overall survival outcomes. EGFR tyrosine kinase inhibitors have been proven to be the superior first-line treatment for EGFR-mutant advanced NSCLC. Several trials have shown superior progression-free survival and fewer side effects compared with doublet chemotherapy in advanced disease. Given that EGFR-TKIs are more active than platinum-based doublet chemotherapy in patients with advanced EGFR mutant lung cancer, there has been substantial interest in bringing these agents to earlier disease states.There are several clinical trials evaluating the effect of EGFR-TKIs as adjuvant treatment. Despite improvements in disease free survival, to date, none have demonstrated statistically significant improvements in overall survival. Moreover, multiple questions regarding duration of therapy and appropriate TKI remain unanswered. More survival data are needed before one can recommend adjuvant TKIs for all.

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      PC03.03 - Future Strategies in Early Stage EGFR-mut NSCLC (Now Available) (ID 3569)

      15:45 - 17:15  |  Presenting Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Abstract

      EGFR tyrosine kinase mutations occur in approximately 10% of advanced non-small cell lung cancer (NSCLC) Western patients and in 30% of Asian patients. EGFR tyrosine kinase inhibitors (i.e., gefitinib, erlotinib, afatinib, icotinib, dacomitinib and, recently, osimertinib) are superior to chemotherapy in patients with advanced EGFR+ lung cancers and have become the standard first-line treatment for NSCLC patients harbouring those specific mutations (1-5). Despite this, definitive trials of EGFR-TKIs as adjuvant treatment of EGFR-mutant early stage NSCLC are few and controversial. Improving outcomes with targeted adjuvant therapy and specifically overall survival remains a challenge in the management of radically resected NSCLC. As shown by the addition of the antiangiogenic agent, bevacizumab to adjuvant chemotherapy in the E1505 trial (6).

      The first prospective data to suggest that adjuvant targeted therapy may indeed alter the disease course for early-stage NSCLC were from the SELECT and RADIANT trials (7, 8), in addition retrospective analyses also showed promising results in improving DFS in stage I-III EGFR mut+ NSCLC and a potential OS benefit. The results of the ADJUVANT/CTONG1104 study (9), a randomized open-label phase III trial in completely resected (R0) stage II–IIIA (N1-N2) EGFR-mutant NSCLC (defined as exon 19 deletion or exon 21 Leu858Arg) comparing 4 cycles of standard adjuvant Cisplatin and Vinorelbine or 24 months of the EGFR-tyrosine kinase inhibitor (TKI), gefitinib revealed significantly longer median DFS in the gefitinib arm than in chemotherapy arm, while OS was not mature.

      Several questions remain including: A) the patient subset with early stage disease that may derive the most benefit B) the optimal duration of adjuvant TKI therapy C) the degree of toxicity and associated adherence to therapy over long periods of time and finally D) the cost of therapy. Phase 3 prospective trials remain necessary and several are under way, including the ALCHEMIST study, using erlotinib and the ADAURA study using Osimertinib. Finally use of neoadjuvant targeted therapy (10) and chemotherapy may offer distinct advantages in eliminating micrometastatic disease prior to surgery and clinical trials using this approach are planned or ongoing and will be discussed.

      References

      1.Shi YK, Wang L, Han BH, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol 2017;28:2443-50.

      2.Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830-8.

      3.Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.

      4.Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.

      5.Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:1454-66.

      6.Wakelee HA, Dahlberg SE, Keller SM, et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2017;18:1610-23.

      7.Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-14.

      8.Neal JW, Pennell NA, Govindan R, et al. The SELECT study: a multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). J Clin Oncol 2012;30:abstr 7010.

      9. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II–IIIA (N1–N2) EGFR-mutant NSCLC (ADJUVANT/ CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018;19:139-48.

      10.Zhong WZ et al., Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment for stage IIIA-N2 EGFR.-mutation positive non-small-cell lung cancer (EMERGING-CTONG 1103): multicentre phase 2 randomized study. ESMO 2018, abstract LBA48_PR

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Author of

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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.05 - Immune Checkpoint Inhibitor (ICPi) Re-Challenge: Outcomes Analysis in a French National Cohort of Non-Small-Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 1903)

      13:30 - 15:00  |  Presenting Author(s): Elisa Gobbini

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD1/PDL1 deeply changed the NSCLC therapeutic algorithm in the past few years. Unfortunately, a majority of patients experiences disease progression. ICPis re-challenge could be an attractive option but no data supporting this strategy are available. Here we report outcomes of a large cohort of NSCLC patients treated with anti-PD1/PDL1 re-challenge.

      Method

      We retrospectively collected data about 144 advanced NSCLC patients (diagnosis between 2010 and 2018) from 26 French centers. Patients were re-challenged with ICPis after at least 12 weeks of discontinuation for toxicity, disease progression or clinical decision. Progression Free Survival (PFS) and Overall Survival (OS) were calculated from the start of first or second ICPi to disease progression (PFS1;PFSR) and death or last follow-up (OS1;OS2) respectively.

      Result

      Median age was 63 year [39 –83], most of patients were male (67%), smokers (87%), adenocarcinomas (62%) and stage IV at diagnosis (66%). Most of patients received the first ICPi round in first or second line (66%) and the second ICPi round in third line or later (79%). In both settings patients received preferentially an anti-PD1 (87%) and no differences were detected regarding brain metastasis or ECOG PS (P = 1.10-1 and P = 1.10-1 respectively). The Best Response during the re-challenge was not associated to that one achieved to the first ICPi (P = 1.10-1). The median PFS1 and PFSR were 13 months [95% CI 10-16.5] and 4.4 months [95% CI 3-6.5] respectively. PFSR was longer in patients discontinued because of clinical decision (6.5 months [95% CI 2.5-11.9]) or toxicity (5.8 months [95%CI 3.5-18]) compared to disease progression (2.9 months [95% CI 2.0-4.4]) (P = 2.10-2) and in those not receiving chemotherapy between the two ICPis (5.8 months [95%CI 4.1-10.5]) compared to those who did (3.0 months [95% CI 2.0-4.4])(P = 2.10-3). Median OS1 was 3.3 years [95% CI 2.9-3.9] without differences according to the discontinuation reason (P =2.10-1). Median OS2 was 1.5 y [95%CI 1.0-2.1] and was longer in patients discontinuing the first ICPi due to toxicity (2.1y [95%CI 1.4-NR]) compared to disease progression (1.0y [95%CI 0.4-1.5]) or clinical decision (1.5y [95%CI 0.4-NR]) (P = 3.10-2). Neither OS1 nor OS2 were affected by treatments received between the two ICPis (P = 3.10-1 and P = 1.10-1 respectively).

      Conclusion

      ICPis re-challenge might be a useful option mainly in patients discontinuing the first ICPi because of toxicity or clinical decision and in those able to keep a treatment-free period between the two ICPis.

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    MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      MA08.02 - Durvalumab Impact in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC): An EORTC Young Investigator Lung Cancer Group Survey (Now Available) (ID 608)

      15:15 - 16:45  |  Author(s): Elisa Gobbini

      • Abstract
      • Presentation
      • Slides

      Background

      Stage III NSCLC represents a very heterogeneous population with extremely different treatment modalities including surgery, chemotherapy (CT) and radiotherapy (RT), mostly in combination. The results of the PACIFIC trial have now been reported in full including an overall survival (OS) benefit with durvalumab in addition to concomitant CT-RT. An electronic European survey was circulated to evaluate the impact of durvalumab in the staging and treatment strategy of stage III disease.

      Method

      A Young Investigator EORTC Lung Cancer Group survey containing 31 questions, was distributed between 31/01/18 and 31/03/19 to EORTC LCG and several European thoracic oncology societies’ members

      Result

      206 responses were analyzed (radiation oncologist: 50% [n=103], pulmonologist: 26.7% [n=55], medical oncologist: 22.3% [n=46]; 81.5% with >5 years experience in treating NSCLC). Italy (27.7%, n=57), Netherlands (22.8%, n=47), France (13.6%, n=28), and Spain (11.6%, n=24) contributed most. 83.5% (n=172) confirmed that they had access to durvalumab at the time of the survey. 97.6% (n=201) report that treatment decision is made by a multidisciplinary board. Regarding staging, 76.7% (n=158) support the need of a mediastinal pathological staging in case of suspect lymph-nodes, with a preference for EBUS/EUS (61.2%, n=126). 81.6% (n=168) treated more than half of patients with a concomitant CT-RT with the 1st cycle of chemotherapy in 39.7% (n=81). 95.1% consider durvalumab as practice changing, especially given the OS results (77.9%, n=152/195). 30% (n=119/395) will give patients concomitant CT-RT if PD-L1 >1%, and in borderline resectable cases 17.7% (n=70/395) will propose concomitant CT-RT instead of surgery. Durvalumab administration will be given regardless of PDL1 status in 13.1% (n=27) and 28.6% (n=59) would consider the possibility of a rebiopsy after CT-RT in case of negative PD-L1. 38.8% (n=80) foresee some problems with PD-L1 testing in this population due to availability of cytologic or small histologic samples. About 53.8% (n=105/195) normally will start durvalumab within 6 weeks after CT-RT and 48.5% (n=100) would also use durvalumab after sequential CT-RT

      Conclusion

      Durvalumab results are changing the treatment approach to stage III unresectable (and maybe resectable) NSCLC and planned strict adherence to the patient population as recruited to the PACIFIC study, was not demonstrated. This survey was released after the EMA approval of durvalumab and PD-L1 status seems to play a role in the treatment strategies, but surprisingly almost half of the clinicians will use durvalumab after sequential CT-RT without safety or efficacy data.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-26 - ALK Fusion Variant Detection by Targeted RNA-Seq in TKIs Treated ALK-Positive Lung Adenocarcinoma (ID 1860)

      09:45 - 18:00  |  Author(s): Elisa Gobbini

      • Abstract
      • Slides

      Background

      Clinical outcomes of ALK positive (ALK+) Non-Small-Cell Lung Cancer (NSCLC) and the identification of the most effective anaplastic lymphoma kinase inhibitor (ALKi) according to the specific ALK fusion variants are not well assessed. We retrospectively characterized fusion variant distribution in a cohort of ALK+ lung adenocarcinomas (ADC) with paired clinical data about treatments and outcomes.

      Method

      Diagnostic tumor tissue from advanced ALK+ (by FISH and/or IHC) ADC diagnosed from 2010 to 2018 and treated with single or multiple ALKis were collected (expanded cohort from Gobbini et al. Lung Cancer, 2017). The OncomineTM Solid Tumor Fusion Transcript Kit on an Ion PGM™ system and the Ion Reporter™ software were used to identify targeted ALK fusion gene products (ThermoFisher).

      Result

      Specific fusion variant transcripts were found in 34/55 (62%) of collected samples. As expected, EML4-ALK fusion transcripts were the most common (31/34 samples, 91%), but HIP-ALK transcripts were also detected (3/34 - 9%). Among EML4-ALK fusions the following variants were detected: V1 (n=11); V2 (n=2); V3a/b (n=12 ) V5a/b (n=5 ) and E6A19 (n=1). Patient median age was 60 year [range 36-85], 22 were male and 12 female. Three patients were current, 11 former and 20 never smokers. Crizotinib, alectinib, ceritinib, brigatinib and lorlatinib were the ALKis used. Independently of the therapy line, 12 patients received crizotinib only, while 22 patients received crizotinib followed by one or two other ALKis. Regardless of the type of transcript, those patients who received more than one ALKi had a better median overall survival compared to those receiving crizotinib only, as expected (74 vs 21 months, HR: 5.31; 95%CI: 1.464-19.26, log rank p=0.0006). Furthermore, a significant difference in the mean duration of the different ALKi treatment was found according to the ALK variants (Chi-square p<0.0001), suggesting a private ALKi efficacy profile for specific fusion variants. Finally, the 3 HIP-ALK cases showed a better outcome with respect the EML4-ALK variants (not reached vs 51 months).

      Conclusion

      Our analysis suggests that different ALK fusion variant might affect ALKi treatment duration in ALK+ lung ADC.

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