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Benjamin Besse



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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.03 - Immunotherapy for Non-Small Cell Lung Cancers (NSCLC) with Oncogenic Driver Mutations: New Results from the Global IMMUNOTARGET Registry (ID 13187)

      13:40 - 13:45  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Prospective data on immunotherapy for NSCLC with oncogenic driver mutations are limited. We recently reported first results from the global IMMUNOTARGET registry (Mazières, ASCO 2018). Here, we present new data for PD-L1 and mutation subgroups.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In 2017, we started an international retrospective registry study ("IMMUNOTARGET") for patients with advanced NSCLC, known driver mutations (KRAS, EGFR, ALK, ROS1, BRAF, HER2, MET and RET) and PD-L1 immune checkpoint inhibitor therapy. The registry is approved by University of Toulouse and Swissethics, and funded by University of Toulouse and Cantonal Hospital of Lucerne. Anonymized real-world data submitted to the coordinating center include: patient and tumor characteristics, mutation test methods and results, systemic therapy lines, immune related adverse events, best response by RECIST, survival, and tumor PD-L1 expression (optional). Statistical calculations including best response, median PFS and OS are done at University of Toulouse.

      4c3880bb027f159e801041b1021e88e8 Result

      In April 2018, the registry included 551 pts from Europe, USA, Israel and Australia. Patients were 50% male/female, 28% current smokers, median age 60 years (range 28-83), 85% had PS0/1. Most (73%) tumors were stage IV at diagnosis, almost all (96%) were adenocarcinomas. Molecular classification by dominant driver mutation: KRAS=271 (49%), EGFR=125 (23%), BRAF=43 (8%), MET=36 (7%), HER2=29 (5%), ALK=23 (4%), RET=16 (3%), ROS1=7 (1%), 1 (0.2%) not classified (ALK+RET+MET). Most pts received nivolumab (466) or pembrolizumab (48) and were treated with immunotherapy in second or third line (67%). The median number of cycles was 5 (range 1-68). Fifty (11%) pts had grade 3-5 toxicity. Median OS from start of immunotherapy was 13.3 months, median PFS was 2.8 months. Best response was PR/CR in: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. Percentage of PD-L1 positive cells was available for 177 pts: 0%=71 (40%), 1-49%=46 (26%), 50-100%=60 (34%). Median % of positive cells was highest for ROS1 (90%), BRAF (50%), MET (30%) and RET (26%) mutant tumors. PD-L1 positivity was predictive for improved PFS in KRAS and EGFR mutant tumors. PD-L1 status was known in 18 tumors with ALK, ROS1 or RET rearrangements: 5 had 0%, 4 had 1-49% and 9 had 50%-100%. No tumor remissions were observed in this subgroup. The registry remains open, updated results will be presented at the conference.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although response rates were lower than in KRAS mutant NSCLC, individual tumors with other driver mutations responded to immunotherapy. PD-L1 expression may not accurately predict clinical benefit from immunotherapy in some molecular subgroups, better markers are needed.

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    MA08 - Clinical Trials in Brain Metastases (ID 906)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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      MA08.09 - Impact of Brain Metastases in Immune Checkpoint Inhibitors (ICI) Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 12575)

      16:10 - 16:15  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Brain metastases (BM) are frequent in NSCLC. Unfortunately, patients with (untreated) BM are often excluded from ICI trials so that their outcome on ICI is largely unknown..

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective data collection of all consecutive advanced ICI treated NSCLC patients in 6 centers (5 French, 1 Dutch) (nov 2012 – march 2018). Active BM was defined as non-irradiated new and/or growing lesions on brain imaging < 6 weeks before ICI start. Progression free survival (PFS), overall survival (OS) and site of progression on ICI was collected.

      4c3880bb027f159e801041b1021e88e8 Result

      945 patients included: 63% male, 83% WHO PS 0-1, median age 64 years, 73% non-squamous, 4% targetable driver mutations, 33% known PD-L1 (65% ≥1% expression). ICI treatment was median 2nd line (range 1-12), 94% had monotherapy PD-(L)1 inhibition. 241 patients (26%) had BM, 68% had previous cranial irradiation, 40% had active BM. BM patients were significantly younger than others (61 vs 66 years), had more adenocarcinoma (78 vs 62%), more organs involved (median 3 vs 2), a poorer PS (0-1: 76 vs 85%) and more steroids at baseline (26 vs 9%). Median follow-up: 15 months. Median (95% CI) PFS and OS without and with BM were 2 (2-3) vs 2 (1-2) months and 13 (9-16) vs 9 (7-13) months, respectively. In multivariate analysis, > 2 metastatic sites, PS ≥2 and steroids use were associated with worse PFS and OS, BM were not (table 1). In univariate analysis of BM patients, active BM were not associated with worse outcome compared to stable BM (HR PFS 0.98 (p=0.66), HR OS 0.93 (p=0.92)). Progressing BM patients had more often brain PD and a dissociated response (not specifically brain dissociated) on ICI (40 vs 12% and 13 vs 7%, respectively).

      Factor PFS HR (95% CI) p-value OS HR (95% CI) p-value
      Age > 65 vs ≤ 65 1.02 (0.87-1.20) 0.79 1.11 (0.92-1.34) 0.29
      Smoking yes vs no 0.53 (0.41-0.69) <0.001 0.81 (0.59-1.12) 0.20
      Histology squamous vs adeno 1.07 (0.89-1.28) 0.78 1.24 (0.99-1.55) 0.12
      Nr of organs with metastases > 2 vs ≤ 2 1.28 (1.09-1.50) 0.003 1.48 (1.22-1.80) <0.001
      Immuno line > 2 vs ≤ 2 1.11 (0.94-1.30) 0.22 1.10 (0.91-1.33) 0.34
      WHO PS 0-1 vs ≥2 2.14 (1.75-2.62) <0.001 3.48 (2.78-4.36) <0.001
      Use of corticosteroids yes vs no 1.36 (1.10-1.69) 0.005 1.31 (1.03-1.68) 0.03
      BM yes vs no 1.05 (0.88-1.26) 0.58 0.96 (0.77-1.19) 0.70

      8eea62084ca7e541d918e823422bd82e Conclusion

      BM, treated or active, do not negatively impact outcome on ICI although BM failure is more common in these patients.

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    MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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      MA15.02 - Long-Term Safety and Clinical Activity Results from a Phase Ib Study of Erlotinib Plus Atezolizumab in Advanced NSCLC (ID 12095)

      13:35 - 13:40  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with EGFR mutation–positive non-small cell lung cancer (NSCLC) achieve favorable outcomes with EGFR tyrosine kinase inhibitors (TKIs); however, the long-term efficacy of these agents is limited by development of acquired resistance. Atezolizumab (anti–PD-L1 mAb) monotherapy has shown tolerability and durable clinical activity in NSCLC. By selectively targeting PD-L1 to block its interaction with receptors PD-1 and B7.1, atezolizumab can reinvigorate anti-cancer T-cell activity. Thus, combining atezolizumab and erlotinib could result in improved anti-tumor immunity and durable anti-tumor effects. Safety and preliminary clinical activity from a Phase Ib study of erlotinib plus atezolizumab in locally advanced or metastatic NSCLC have been previously reported (Rudin, et al. WCLC 2016). Here we describe updated findings from this study (NCT02013219).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFR TKI-naive patients with NSCLC were enrolled into a safety-evaluation stage (Stage 1) regardless of EGFR status, and an expansion stage (Stage 2) enrolled patients with EGFR-mutant NSCLC who were previously untreated or treated with 1 prior non–EGFR TKI therapy. A 7-day run-in period with erlotinib 150 mg PO QD was followed by addition of atezolizumab 1200 mg IV q3w. The primary endpoint was safety/tolerability of the combination; secondary endpoints included clinical activity per RECIST v1.1.

      4c3880bb027f159e801041b1021e88e8 Result

      At data cutoff (August 18, 2017), 28 patients (Stage 1, n = 8; Stage 2, n = 20) were evaluable for safety, and the median survival follow-up was 26.0 months (range, 7.8-32.9; Stage 2). The median age was 61 years (range, 47-84), and the most common EGFR mutation was exon 19 deletion (44%). Grade 3 treatment-related AEs (TRAEs) were reported in 43% of patients; no Grade 4 or 5 TRAEs occurred. The most common TRAEs were increased ALT, pyrexia, rash and diarrhea (2 patients each). Serious AEs occurred in 54% of patients; treatment-emergent AEs led to atezolizumab discontinuation in 18% and erlotinib discontinuation in 11%. Clinical activity was evaluated in Stage 2 patients. ORR was 75% (95% CI: 50.9, 91.3), with a median DOR of 16.7 months (range, 4.2-26.0+). Median PFS was 15.4 months (95% CI: 8.4, not estimable [NE]), and median OS was 32.7 months (95% CI: 32.7, NE).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Atezolizumab plus erlotinib demonstrated a tolerable safety profile and compared favorably with prior reports of efficacy with erlotinib monotherapy. OS data are expected to mature and improve with longer follow-up; updated clinical and biomarker data will be presented. Further investigation of the combination is warranted to assess its full potential.

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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.09 - Feasibility, Clinical Relevance of ALK/ROS1 Fusion Variant Detection by Liquid Biopsy in Advanced Non-Small Cell Lung Cancer (ID 13492)

      14:30 - 14:35  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Liquid biopsy offers an alternative non-invasive approach to reflect the tumor genomic landscape of NSCLC patients; however, the potential of liquid biopsies for ALK/ROS1 fusion detection is poorly described. Herein, we evaluated an amplicon-based NGS assay for ctDNA detection of ALK and ROS1 fusions in a large cohort of ALK and ROS1 NSCLC patients and correlation of variants with clinical data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ALK- and ROS1-translocated advanced NSCLC patients, were prospectively enrolled from October 2015 to April 2018 in 9 French institutions. ALK or ROS1 positivity was as confirmed by immunochemistry and FISH or RNAseq. ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and mutations in a panel of 36 NSCLC-associated genes were investigated in ctDNA using InVisionFirst™ (Plagnol V PLoS ONE, 2018).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 120 patients were included: 96 ALK and 24 ROS1. 30 samples were collected from patients who were TKI-treatment-naive, 257 during follow-up and 73 at progressive disease (PD) under TKI. The median age was 55 years-old (range 23-75); most patients were female (57%) and had a non-smoking history (59%). At diagnosis, 20% of patients presented with brain metastasis. All patients received at least 1 ALK-TKI (median: 1.6; range:1-6).

      Preliminary results are available for the first 54 patients: 21 at diagnosis and 33 at PD under TKI. ALK/ROS1 fusions were detected in 13/21 patients (62%) at diagnosis: 12/20 ALK-fusions (7 v1, 2 v2 and 3 v3) and in 1/1 ROS1-fusion (CD74-ROS1). No fusion was detected in 8 patients, which may be due to partner genes or variants not covered by this panel. However, 5 of these 8 patients had exclusive thoracic or brain PD.

      Liquid biopsies collected at the radiographic evaluation under therapy revealed complete ctDNA clearance of the fusion when patients experienced PR (n=4). In samples at PD, fusion was detected in 44% of patients (24/55) with evidence of acquired resistance in patients both positive and negative for fusion.

      Results for the remaining samples, correlation between fusion variant and survival, fusion variant and mechanism of resistance will be presented at the Congress.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that ctDNA profiling is a promising non-invasive tool for identification of ALK/ROS1 fusions and monitoring of response in advanced NSCLC patients. Systematic identification of the fusion partner may help to better understand the heterogeneity and evolution (sensitivity profile to targeted inhibitors and associated-mechanisms of resistance) of NSCLC driven by ALK and ROS1 rearrangement.

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    MA25 - Oligometastasis: Defining, Treating, and Evaluating (ID 929)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 203 BD
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      MA25.01 - EORTC Lung Cancer Group Survey to Define Synchronous Oligometastatic Disease in NSCLC (ID 13770)

      13:30 - 13:35  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Synchronous oligometastasic disease (sOMD) has been described as a separate disease entity; however there is no consensus on what specific criteria constitutes sOMD in NSCLC. A consensus group (CG) was formed aiming to agree on a common sOMD definition (sOMD-d) that could be used in future clinical trials. A European survey was circulated to inform the discussion on sOMD-d.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      An EORTC Lung Cancer Group (LCG) / sOMD-d CG survey containing 31 questions on sOMD-d was distributed between 14/12/17 and 19/02/18 to EORTC LCG, sOMD-d CG, and several European thoracic oncology societies’ members.

      4c3880bb027f159e801041b1021e88e8 Result

      444 responses were analyzed (radiation oncologist: 55% [n=242], pulmonologist: 15% [n=66], medical oncologist: 14% [n=64]; 78% with >5 years’ experience in treating NSCLC). Belgium (14%, n=62), Italy (12%, n=55), Germany (11%, n=47), and Netherlands (10%, n=44) contributed most. 81% (n=361) physicians aimed to cure sOMD NSCLC patients and 82% (n=361) included the possibility to treat the patient with radical intent in their sOMD-d. The maximum number of metastases considered in sOMD-d varied: 19%, 42%, 4%, and 17% replied <2, 3, 4, and >5 metastases, respectively. 79% (n=353) stated that the number of organs involved was important for sOMD-d, and most (80%, n=355) considered that only <3 involved organs (excluding primary) should be included in the definition. 317 (71.7%) allowed mediastinal lymph node involvement (MLN) in the sOMD-d, and 22.1% of them counted MLN as a metastatic site. For 195/327 (60%), when N2/N3 disease is included in the sOMD-d, there is no specific issue regarding the MLN volume/location as long as radical treatment is possible. 384 (86%) considered pulmonary metastasis (outside primary tumor: M1a) as metastatic site. Most physicians confirmed sOMD patients with brain MRI (91%, n=403) and PET-CT (98%, n=437). For mediastinum staging, most (64%, n=285) respondents stated that histology/cytology should be obtained when PET-CT shows suspected lymph nodes or in case of a central primary tumor. Pathology proof of metastatic disease was necessary in sOMD for 315 (71%) physicians, and 37% (n=163) acknowledged that histology should be obtained from at least from one metastatic site. Preferred primary outcome parameter in clinical trials of sOMD was overall survival (73%, n=325).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although certain consensual answers were obtained (81% aimed to cure and >90% mandated baseline imaging with PET-CT and brain MRI), a number of issues remain unresolved and will require further discussion by a panel of experts to agree on a sOMD-d.

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      MA25.02 - Searching for a Definition of Synchronous Oligometastatic (sOMD)-NSCLC: A Consensus from Thoracic Oncology Experts (ID 13452)

      13:40 - 13:45  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Recent prospective single centre studies reported improved outcomes in patients with sOMD-NSCLC who were treated with radical intent. Since then sOMD has been perceived as a separate disease entity. However, a clear definition of sOMD-NSCLC is lacking. We aimed to develop a definition and diagnostic criteria of sOMD-NSCLC following a consensus process.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A European multidisciplinary consensus group was established with representatives from different scientific societies. Consensus questions were extracted from a survey, case series and a systematic review. The questions were discussed, and the statement formulated during a consensus meeting in Dublin (23.01.18).

      4c3880bb027f159e801041b1021e88e8 Result

      Summary of consensus statement

      Defining sOMD-NSCLC

      Definition of sOMD is relevant for patients in whom a radical treatment is technically feasible with acceptable toxicity, taking into account all sites, that may modify the course of the disease leading to a long-term disease control.

      All sites must be technically and safely treatable.

      The maximum number of metastases/organs meeting the criteria involved will depend on the possibility of offering a treatment strategy with radical intent, taking into account local control and toxicity. Based on the systematic review, a maximum of 5 metastases and 3 organs is proposed.

      Diffuse serosal metastases and bone marrow involvement are excluded.

      Mediastinal lymph node (MLN) involvement should be considered as locoregional disease in the definition of sOMD-NSCLC.

      MLN involvement is of importance in determining if a radical local treatment of the primary tumour may be applied and the MLN will not be counted as a metastatic site.

      Staging of sOMD-NSCLC

      PET-CT and brain imaging are considered mandatory.

      In case of a solitary liver metastasis a dedicated MRI of the liver and for a solitary pleural metastasis, thoracoscopy and biopsies of distant ipsilateral pleural sites are advised.

      Staging of the mediastinum requires a minimum of a FDG-PET scan, with pathological confirmation preferred if this influences the treatment strategy.

      Pathological proof is required unless the MDT decides that the risk outweighs the benefit. Pathology proof is advised for single metastatic location and if it may change the therapeutic strategy, confirmation of the MLN involvement is recommended.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A multidisciplinary consensus statement on the definition and staging of sOMD-NSCLC was formulated taking into account results of a European survey, a systematic review and case discussion. This statement might be helpful to standardise inclusion criteria in future clinical trials. However, the definition of sOMD may change over time when more prospective data will become available.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.03 - Defining Oligometastatic Non-Small Cell Lung Cancer (NSCLC): An Evolving Multidisciplinary Expert Opinion (ID 12573)

      13:35 - 13:40  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Synchronous oligometastatic NSCLC definition varies between: 1 metastasis in 1 organ (TNM8), 1-3 metastases (ESMO), ≤3 metastases after systemic treatment with mediastinal nodes (MLN) counting as 1 site (Gomez, Lancet Oncol 2016) to 3-≥5 metastases in ongoing trials. A single definition is however needed to design and compare trials. To assess synchronous oligometastatic NSCLC definitions used by clinical experts in daily practice and its evolution, we redistributed a 2012-case based survey (Dooms et al, presented at WCLC 2013).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In December 2017, 10 real-life multidisciplinary team (MDT) discussed patients (all good condition, no significant comorbidities, 18FFDG-PET and brain MRI staged, all < 5 metastases, 9/10 ≤ 3 metastases, oncogene-addicted or wildtype NSCLC) were distributed to 33 international NSCLC experts involved in the EORTC oligometastatic NSCLC consensus group, questioning: 1) can you discuss these cases in your MDT?, 2) do these patients have oligometastatic disease? and 3) what is your treatment proposal for the oligometastatic disease patients? Current answers were compared to the previous ones, and the real-life treatment and survival of the patients was added.

      4c3880bb027f159e801041b1021e88e8 Result

      26/33 experts (24 centers) replied: 8 medical oncologists, 7 pulmonologists, 7 radiation oncologists, 4 thoracic surgeons. 62% discussed the cases in their MDT. 1 case had 100% oligometastatic disease consensus, 3 cases had > 90% consensus, the number of treatment proposals varied between 3 to 8 (Table). Radical treatment was more often offered in case of a single metastasis or N0 status. Compared to 2012 there was a trend towards a more conservative oligometastatic definition and chemotherapy was more often included in the treatment proposal.

      table 1
      Case TNM8

      oligometastatic

      yes answer %

      2012 / 2017

      Number of tx

      proposals

      2012 / 2017

      Radical tx

      answers %

      2012/2017

      Real life radical

      tx intent

      real life survival

      (months) /

      5Y survival

      EGFR+ T2aN3M1c (3 brain mets) 55 / 38 2 / 5 27 / 23 - 40.1 / -
      EGFR+ T4N0M1a (ground glass) 36 / 35 4 / 3 45 / 35 + 65.2 / +
      T2aN1M1b (solitary renal) 91 / 96 5 / 5 100 / 92 + 8.3 / -
      T1bN3M1b (solitary adrenal) 73 / 58 4 / 5 36 / 54 + 66.1 / +
      T2bN1M1c (adrenal + pelvic node) 55 / 50 2 / 5 36 / 46 - 18.6 / -
      T2aN0M1c (3 liver mets) 64 / 69 4/ 5 27 / 62 - 51.5 / -
      T2aN2M1b (solitary bone) 91 / 92 4 / 5 73 / 85 + 13.4 / -
      T3N1M1c (2 brain mets) 91 / 96 3 / 8 73 / 85 + 39.6 / -
      T2aN0M1c (1 lung, 1 pancreas) 82 / 69 5 / 4 64 / 50 + 74.0 / +
      T1bN0M1b (solitary bone) 100 / 100 3 / 5 82 / 92 + 11.6 / -

      8eea62084ca7e541d918e823422bd82e Conclusion

      Synchronous oligometastatic NSCLC definition was more conservative than in 2012 and linked to radical intent of treatment. Number of organs, MLN status and possibility for radical treatment seem to be components of daily practice synchronous oligometastatic definition.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MS23 - What's New in Targeted Therapy? (ID 801)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 106
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      MS23.05 - Role of Immunotherapy in Patients with Molecular Driven NSCLC (ID 11500)

      11:30 - 11:45  |  Presenting Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA09 - Prevention and Cessation (ID 909)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Prevention and Tobacco Control
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 205 BD
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      OA09.06 - Molecular Alterations and Estimated Indoor Radon in NSCLC Patients from the French National Cancer Institute Registry: Radon France Study (ID 14168)

      16:10 - 16:20  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation

      Background

      Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. We assessed the correlation between the radon exposure areas in France and the molecular alterations nationally registered in non-small cell lung cancer (NSCLC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected all NSCLC tested for EGFR, BRAF, HER2 and KRAS mutations (m) and ALK and ROS1 rearrangements (r) on the 28 French Plateform led by INCa (French National Cancer Institute). The prevalence of molecular alterations by region was correlated to the indoor radon risk area based on the official French (Institut de Radioprotection et de Sûreté Nucléaire, INSN, France). Paris and its region Ile-de-France were not included in this analysis due to its high rate of patients that are native from other regions.

      4c3880bb027f159e801041b1021e88e8 Result

      116.424 NSCLC were included. Overall, KRAS was positive in 27,7% (27.314/98.522), EGFR in 11,27% (13.125/116.424), ALK in 3,2% (2.928/91.291), BRAF in 2,3% (2.419/105.919), ROS1 in 1,12% (373/33.222) and HER2 in 0,8% (816/97.749) of all cases.

      We stratified the French regions in 3 areas based on their exposure to radon: high (Auvergne-Rhône-Alpes, Bretagne, Normandie, Pays de la Loire), intermediate (Bourgogne-Franche-Comté, Nouvelle Aquitaine, Occitanie, Provence-Alpes-Cote-d'Azur) and low explosure (Centre Val-de-Loire, Grand Est, Hauts de France). The prevalence of driver alterations (EGFR, BRAF, HER2 and ROS1 were significantly higher in high exposure area. The prevalence of KRAS mutations was significantly higher in low exposure area.

      Low risk

      Intermediate

      High

      P

      EGFR mutation

      1962 (10%)

      4338 (11%)

      4176 (11.4%)

      <0.0001

      ALK rearrangement

      577 (3.3%)

      1019 (3%)

      896 (3%)

      0.35

      BRAF mutation

      327 (1.8%)

      830 (2.4%)

      692 (2.4%)

      0.0001

      HER2 mutation

      109 (0.6%)

      266 (0.9%)

      252 (0.8%)

      0.01

      ROS1 rearrangement

      61 (0.9%)

      133 (0.9%)

      126 (1.3%)

      0.005

      KRAS mutation

      4717 (29.8%)

      9215 (28.2%)

      7895 (27%)

      <0.0001

      Molecular drivers*

      3037 (3.9%)

      6587 (4.4%)

      6142 (4.4%)

      <0.0001

      * EGFR, BRAF & HER2 mutations, ALK & ROS1 rearrangements; KRAS mutation excluded.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC molecular alterations that are linked to low tobacco consumption were higher in the French region with high radon exposure. Role of the radon in lung cancer carcinogenesis of specific molecular subtypes should be further explored.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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    OA12 - Novel Therapies in MET, RET and BRAF (ID 921)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
    • +

      OA12.07 - Clinical Activity of LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell Lung Cancer (ID 13922)

      16:20 - 16:30  |  Author(s): Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P1.01-07 - Immune-Related Pneumonitis in NSCLC Patients Treated with Immune Checkpoint Inhibitors (ICI): Impact of Previous Thoracic Radiotherapy (ID 12805)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract

      Background

      Pneumonitis is a potentially lethal side effect of immune checkpoint inhibitors (ICI), occurring in 1–5% of patients enrolled in clinical trials. Little is known about the interactions between ICI and previous thoracic radiation. This is the aim of the present study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between December 2012 and November 2017, 318 consecutive non-small cell lung cancer (NSCLC) patients received ICI in our Institution and their charts were retrospectively analyzed. Primary endpoint was to determine whether previous radiotherapy had an effect on pulmonary toxicity. Pulmonary toxicity was retrospectively assessed by Common Terminology Criteria for Adverse Events version 4.0.

      4c3880bb027f159e801041b1021e88e8 Result

      Median follow-up was 32.8 months [95%CI: 5-190]. Median age at the start of ICI was 63 years. 205 patients (64,5%) were males, 103 (32,4%) smokers and 250 (78,6%) with PS ≤1; 206 (64,8%) had adenocarcinoma and 76 (23,9%) squamous; 79 (24,8%) were KRAS mutated, 18 (5,5%) EGFR mutated and 5 (1,6%) ALK positive. PDL1 was ≥ 1% by immunohistochemistry in 86 (27%), negative in 37 (11,6%) and unknown in 196 (61,3%) patients. ICI treatment was median 3rd line (range: 1-12), 89,4% monotherapy PD-(L)1 inhibition.

      72 patients (22,6%) received a thoracic RT: 62 out of the 72 RT patients (87,5%) were irradiated with a curative intent. 53 patients (73,6% of the RT patients) received thoracic 3D-conformal RT or intensity modulated RT (normo- or mildly hypofractionated), whereas 9 received SBRT.

      16,7% of the RT patients (12/72) showed a G1-4 immune-related pneumonitis (with a G=>3 of 11,1%), whereas for never-irradiated patients the G1-3 rate of immune-related pneumonitis was 2,4% (6/246), with only 1 G3 toxicity observed and no G>4 (t-test, p 0,001).

      Median interval between the onset of the immune-related pneumonitis and the end of the RT was 22,4 months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC patients treated with ICI may be at higher risk of developing immune-related pneumonitis when previously treated with curative-intent thoracic RT.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-18 - Immunosenescence Correlates with Progression upon PD-(L)-1 Blockade (IO) in Advanced Non-Small Cell Lung Cancer (aNSCLC) Patients. (ID 14074)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract

      Background

      Immunosenescence is a progressive remodeling of immune functions with a multifactorial etiology (i.e. aging, chronic inflammation, cancer). Although a CD28-CD57+KLRG1+ phenotype on peripheral T-lymphocytes is a potential hallmark of immunosenescence, the characterization of such phenotype in IO-treated NSCLC patients and the correlation with clinical characteristics and benefit from immunotherapy are unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A senescent immune phenotype (SIP) defined as a percentage of circulating CD8+CD28-CD57+KLRG1+ T-lymphocytes was assessed by flow cytometry (FC) on fresh blood samples from IO-treated aNSCLC patients (03/2017–04/2018). A log-rank maximization method was used to identify a SIP cut-off level and dichotomize patients accordingly. The objective was to correlate SIP with clinical characteristics and RECIST response by univariate logistic regression analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      39 aNSCLC patients were evaluable for SIP before IO: 38% ≥ 65 years, 87% non-squamous, 38% KRAS mutated, 54% with PD-L1 expression ≥1%, 13% chemotherapy naïve. Among 30 patients evaluable for IO response, 53% had progression (PD), 27% stability (SD), 20% partial response (PR). Median PFS was 1.9 months (95% CI 1.5; 2.5). OS was not calculated due to the short follow-up [6 months (95% CI 4-11)]. SIP (% CD28-CD57+KLRG1+) median value on circulating CD8+ lymphocytes was 15.26% (min 1.87%, max 56.28%). Overall, 13 (33%) of 39 patients had >22.25% CD8+ lymphocytes with a CD28-CD57+KLRG1+ phenotype, being classified as SIP+. SIP status did not correlate with age, IO-baseline patients’ characteristics or chemotherapy exposure. Among patients evaluable for IO response, only 1 (10%) of 10 SIP+ experienced disease control (PR/SD), compared to 13 (65%) of 20 SIP- patients; similarly, PD rate was significantly higher in SIP+ compared to SIP- patients (90% vs 35%, p=0.007) (Figure).

      plot-pd.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immunosenescence, monitored by FC measurement of 3 surface molecules on circulating CD8 + lymphocytes, is observed in 33% of aNSCLC patients, is independent of age and correlates with lower IO disease control rate.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-19 - Efficacy of Tyrosine Kinase Inhibitors in EGFR Mutated Non-Small Cell Lung Cancer with Leptomeningeal Metastases. (ID 13820)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Background

      Leptomeningeal dissemination (LM) in patients with non-small cell lung carcinoma (NSCLC) is usually associated with dismal prognosis. However, survival data and optimal management of tyrosine kinase inhibitors (TKI) in EGFR-mutated (EGFRm) patients (pts) are unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pts with EGFRm NSCLC with LM treated in 2 institutions were included. Clinical, pathological and radiological data were retrospectively collected. We performed overall survival (OS) analysis from LM diagnosis. We assessed survival, clinical response rate (CRR) and disease control rate (DCR; stable disease > 2 months or clinical response) in patients who received a subsequent TKI after experiencing LM progression with first-line TKI.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy pts were included between Apr. 2003 and Feb. 2018. Median age was 54 [26-79], 60 (85%) were non-smokers, 51 (73%) female and median number of prior systemic treatments before LM diagnosis was 2 [1-7].

      Median OS from LM diagnosis was 7 months (m) [95% CI 6-9], with a 1 year-OS of 29%. Pts received a median of 2 [1-6] lines of subsequent systemic therapy and 19 had additional intrathecal treatment.

      At first LM progression, 40 pts received subsequent TKI treatment with a median PFS of 3m [95% CI 2-not reached]. DCR and CRR were 73% and 38%, respectively. In patients without T790M mutation (N=36), median OS was 7 months [95% CI 4-7] with 2nd-line erlotinib (N=21) and 3 months [2-17] with 2nd-line afatinib or gefitinib (N=5). Eight patients received high-dose erlotinib as 2nd-line treatment after prior erlotinib with a median OS of 3 months [1-3] and a DCR of 75%. Four patients with T790M mutation received 2nd-line osimertinib with a median OS of 10 months [6-10] and a DCR of 100%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pts with LM from EGFRm NSCLC have prolonged survival with 1st generation TKI. Second-line erlotinib after LM progression is an efficient approach in T790M-negative pts. Erlotinib dose increase is a suitable strategy in erlotinib-refractory T790M-negative pts.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-66 - Randomized Phase II Evaluating EGFR-TKI Associated with Anti-Estrogen in Women with Non-Squamous Advanced Stage NSCLC: IFCT-1003 LADIE Trial. (ID 13740)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract

      Background

      The incidence of lung cancer is increasing dramatically in women with recent findings as the preferential involvement of the EGFR pathway and the potential impact of hormonal factors in women. Preclinical data have shown that the combination of an EGFR-TKI with an anti-estrogen could overcome resistance to EGFR-TKI.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      IFCT-1003 LADIE Trial was a 2x2 arms parallel open-label randomized phase II trial. PS 0-2 post-menopausal women with advanced stage lung adenocarcinoma were treated with gefitinib (G 250 mg/day) vs. G + fulvestrant 500 mg / month with a supplementary dose at day 15 (G+F) in the EGFR mutated group (EGFR+) in 1st or 2nd line setting or with erlotinib (E 150 mg/day) vs. E + fulvestrant (E+F) in the EGFR wild-type group (EGFR WT) in 2nd or 3rd line setting until progression or unacceptable toxicity. Primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR WT and EGFR+ patients, respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      From 02/2012 to 03/2017, 204 pts (G 104, G+F 100) and 175 (E 87, E+F 88) were enrolled in the EGFR+ and EGFR WT cohorts respectively. The median number of fulvestrant injections was 10 in the G+F group and 3 in the E+F group. The tolerance was correct (grade 3/4: 24.2% in the G+F group vs 21.3% in the G group, 16.0% in the E+F group vs 13.8% in the E group) and no treatment-related death. In the EGFR+ cohort, the primary endpoint was reached as 54 pts in the G+F group were non-progressive at 9 months. Nevertheless, addition of F to G was not associated with significant better PFS (9.9 vs 10.1 months) or OS (22.1 vs 29.9 months). In the EGFR WT cohort, the primary endpoint was not reached as 29 patients were non-progressive at 3 months. Here also, addition of F to E was not associated with better outcome (PFS 1.8 vs 2.0 and OS 10.0 vs 7.3 months). No PFS difference was observed in the subgroup of patients with positive staining for REα.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Addition of fulvestrant to EGFR-TKI is feasible and is associated with good PFS in the EGFR mutated group. Nevertheless, the lack of benefit associated with the combination of fulvestrant to EGFR-TKI does not support its future development in a phase 3 trial in women with NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-67 - Clinical Relevance of ALK/ROS1 Resistance Mutations and Other Acquired Mutations Detected by Liquid Biopsy in Advanced NSCLC Patients (ID 14279)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract

      Background

      Liquid biopsies (LB) for circulating tumor DNA (ctDNA) can be a tool for somatic mutation detectionin NSCLC patients. However, the applicability and clinical relevance of ALK/ROS1 and other acquired mutation detected by LB is poorly described. We evaluated ALK/ROS1 and other acquired mutations detected by ctDNA in a large cohort of ALK/ROS1+ NSCLC patients described to date.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced ALK/ROS1+ NSCLC patients were prospectively enrolled from October 15 to April 2018 in 9 French institutions. ctDNA anlaysis was performed using ctDNA using InVisionFirst™ (36-gene panel) for ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and other somatic mutations.

      4c3880bb027f159e801041b1021e88e8 Result

      120 patients were included: 96 ALK, 24 ROS1. The median prior tyrosine kinase inhibitors (TKI) received was 2 (0-4). Blood samples (n=402) were collected: tyrosine kinase inhibitors (TKI)-naive (n=30), during (n=257) or at progression (PD) under TKI (n=73. Prior treated patients received at least 1 TKI (1-6). Preliminary results are available for the first 54 patients; ALK/ROS1 status was confirmed by ALK IHC (39), FISH (56) and RNAseq (2).

      ALK mutations were detected in 36% of blood samples at PD to TKI (12/33): 8% (1/13) post-crizotinib and 55% (11/20) post next-generation TKI (F1174/F1174V/D1203N/R1192P/G1202R (6)/F1174L+G1202/G1202R+F1174L+C1156Y). Complex ALK mutations were observed in 2/12 samples (17%) post next-generation TKI (G1202R+F1174L+C1156Y/F1174L+G1202R). Other acquired mutations were found in 36% (12/33) of samples at PD: TP53 (10), NFE2L2 (4), PTEN (2), PI3KCA (1), CDKN2A (1). Complex ALK mut.+ non-ALK mut. were found in 6/33 (18%) samples, 1 post crizotinib (G1269A+R1264K+L1196Q+F1164L+C1156Y+NFE2L2(4)), and 5 samples post next-gen TKI (G1202R+PTEN/G1202R+TP53/F1174L+G1202R+TP53/TP53(2)+D1203N/TP53+R1192P). Non-ALK mut. were exclusive and could explain TKI resistance in 6/33 (18%) samples.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Routine liquid biopsies can assess the heterogeneity of the TKI resistance, detecting ALK resistance and other acquired mutations in pretreated advanced ALK & ROS1 NSCLC patients. This could have an impact on clinical outcomes. The association of ALK mut. and complex ALK mut. +/- other acquired mut. with clinical outcomes will be presented at the congress.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-68 - Correlation of the Lung Immune Prognostic Index (LIPI) and PDL1 Status with Outcomes for Immune Checkpoint Inhibitors in Advanced NSCLC Patients (ID 14256)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract

      Background

      Baseline LIPI, based on derived NLR (neutrophils/[leucocytes-neutrophils]) and lactate dehydrogenase (LDH) was associated with outcomes for immune checkpoint inhibitors in advanced NSCLC patients. We assessed the correlation between LIPI and PDL1 for ICI outcomes in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Baseline dNLR and LDH and clinical data were retrospectively collected in advanced NSCLC patients, treated with PD1/PDL1 +/- CTLA4 inhibitors from Nov. 2012 to Mar. 2018, in a multicentric cohort (N=794) from 11 centers. LIPI stratified 3 groups: good (dNLR<3+LDH<upper limit of normal (ULN), intermediate (dNLR>3 or LDH>ULN), poor risk (dNLR>3+LDH>ULN). PDL1 positivity was defined as ≥ 1% tumor cells expression by immunohistochemistry.

      4c3880bb027f159e801041b1021e88e8 Result

      476 patients (60%) were male, 693 (87%) smokers, 695 (88%) had PS ≤1, with median age 65; 576 (73%) had nonsquamous histology. PDL1 was ≥ 1% in 195 (70%) patients, negative in 82 (30%), and unknown in 517. The median of prior lines was 1 (0-11). The median PFS and OS were 4 months (m) [95% CI 4-5] and 12 m [10-15]. dNLR was>3 in 276 (35%) and LDH>ULN in 290 (37%) patients. LIPI stratified 349 patients as good (44%), 323 (41%) as intermediate and 121 (15%) as poor LIPI risk groups. LIPI was an independent factor for OS (table) and PFS (HR 2.58; CI 1.3-5.2, P=0.02). ≥ 1% PDL1 and ≥ 50% PDL1 were not correlated with OS and PFS. Median OS for good, intermediate, and poor LIPI risk groups were 21 m [17-23], 11 m [9-14] and 4 m [2-6], respectively (P=<0.0001). Median PFS for good, intermediate, and poor risk was 5 m [5-7], 4 m [3-5], and 2 m [1-3], respectively (P=0.0005). No differences were observed in LIPI groups according to the PDL1 expression.

      Multivariate analysis for OS

      HR

      95% CI

      P value

      Immunotherapy line

      >2

      2.117

      0.641

      6.992

      0.219

      N# Metastasis sites

      ≥2

      1.242

      0.727

      2.121

      0.428

      Performance status

      ≥2

      2.141

      1.059

      4.332

      0.034

      Albumin

      >35 g/dL

      0.867

      0.507

      1.48

      0.6

      LIPI

      Intermediate

      Poor

      1.697

      4.178

      0.917

      1.956

      3.142

      8.925

      0.001

      PDL1 IHC

      ≥1%

      0.713

      0.406

      1.252

      0.239

      8eea62084ca7e541d918e823422bd82e Conclusion

      Baseline LIPI is associated with ICI outcomes in advanced NSCLC, regardless the PDL1 expression. LIPI should be evaluated in prospective clinical trials.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.09 - Pathology (Not CME Accredited Session) (ID 941)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P1.09-17 - CTNNB1 (Beta-Catenin) Mutations in Non-Small Cell Lung Carcinoma: A Clinicopathological Study of 18 Cases (ID 12163)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Background

      Beta-catenin, encoded by the CTNNB1 gene, plays an important role in a signaling pathway of progenitor cell proliferation and differentiation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Otherwise, beta-catenin expression by immuno-histochemistry has been described as a prognostic factor in non-small cell lung carcinomas.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our study was conducted on 18 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Fifteen cases (2.6%) were from a series of 568 consecutive and contributive analyses performed between January 2017 and March 2018, on 417 adenocarcinomas, 60 squamous cell carcinomas and 91 large cell carcinomas. The 3 other cases dated from before this series. The hospital files of the 18 patients and pathological data from surgical samples (n=11), small biopsies (n=3) and trans-bronchial fine needle aspirations (n=4) were reviewed. Immuno-histochemistry was performed with an anti-beta-catenin antibody.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 6 female and 12 male patients aged 54 to 83 (mean = 66). Six of the 18 patients were non-smokers (< 5 pack-years). There were 17 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas were TTF1-positive (16/17) and had a papillary component accounting for more than 30% of their volume (n=11). Eight cases (44%) with CTNNB1 mutations showed associated EGFR mutations including exon 19 deletion (n=5) and L858R (n=2). Oncogenic KRAS mutations were only found in 3 cases (17%). The frequency of CTNNB1 mutations among EGFR mutated adenocarcinomas was 9% (7/79). The most frequent CTNNB1 mutations were S37F (n=7) and S45P (n=4). Immuno-histochemistry showed normal membrane expression with no nuclear or cytoplasmic abnormal expression in all cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study shows that CTNNB1 mutations are rare in non-small cell lung carcinomas and mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are similar to those observed in other tumor types but they probably do not play the same oncogenic role. Furthermore, in lung carcinomas, CTNNB1 mutations were often associated with EGFR mutations and may interfere in the mechanism of resistance to tyrosine kinase inhibitors. This should be thoroughly investigated in larges series evaluating the degree of response to EGFR tyrosine kinase inhibitors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P2.01-33 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1 Containing Therapy (HUDSON) (ID 13743)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line NSCLC. However, the majority of patients do not respond or have non-durable responses to anti-programmed cell death-1/programmed cell death-ligand 1 (anti-PD-1/PD-L1) containing therapy (primary resistance) or progress during anti-PD-1/PD-L1 containing therapy (acquired resistance). HUDSON addresses the urgent need to identify treatments and understand ICI resistance for this emerging ICI-resistant population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      HUDSON is a multi-centre, international multi-arm umbrella study that will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in NSCLC patients who have progressed following standard-of-care platinum and ICI-based therapies. HUDSON is a platform study that consists of two groups; a biomarker matched and a biomarker non-matched group. Within the biomarker matched group, different cohorts will test 1) homologous recombination repair (HRR) defects and 2) LKB1 aberration for response to durvalumab and olaparib (PARP inhibitor), 3) ATM deficiency for response to durvalumab and AZD6738 (ATR inhibitor) and 4) RICTOR amplification for response to durvalumab and vistusertib (mTORC1/2 inhibitor). In the biomarker non-matched group, cohorts will test durvalumab in combination with either i) olaparib, ii) AZD9150 (STAT3 inhibitor) or iii) AZD6738, in patients with primary and acquired resistance to a prior ICI. Allocation to a cohort is informed by the tumour molecular profile according to a pre-specified assignment algorithm. New cohorts will be added as new translational hypotheses are established. Translational research will be performed on serial peripheral blood samples (including ctDNA) and tumour biopsies. HUDSON enrols ICI-resistant patients in a signal searching manner. Biomarker matched and non-matched groups will be opened simultaneously, and all eligible patients can be allocated a treatment option irrespective of their tumour profile. Enrolment is ongoing, clinical trial information: NCT03334617.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-24 - Prospective Efficacy of Osimertinib in Circulating Tumour DNA (ctDNA) T790M-Mutant NSCLC Patients (ID 14031)

      16:45 - 18:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Background

      Liquid biopsy circulating tumor DNA (ctDNA) analysis in advanced EGFR-mutant NSCLC patients is an approved tool for molecular profiling and disease surveillance when tissue is not available. Long-term efficacy of osimertinib in patients with the T790M resistance mutation positive detected only by ctDNA (without tissue information) has not been fully validated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In a prospective study, EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKI, in whom a repeat tissue biopsy was not feasible, were assessed for ctDNA T790M mutational status using InVisionSeqTM. T790M-positive NSCLC patients received osimertinib (80 mg daily; extended access program or approval) at RECIST progression. The objectives were to assess: proportion of patients with acquired ctDNA-T790M positive; overall survival (OS) of the overall EGFR-mutant population as well as OS comparison for T790M +ve/-ve. Also, for those T790M-positive NSCLC patients who received osimertinib in a real world data we assessed: response rate (RR) according to RECIST 1.1 by investigator and progression free survival (PFS), calculated from the date of osimertinib initiation until the date of progression or death (whichever came first), or the date of last follow-up are also reported.

      4c3880bb027f159e801041b1021e88e8 Result

      We recruited 82 patients (71% female, median age 64 years, 72% Del19 EGFR mutation, 71% never-smokers). The ctDNA T790M mutation was detected in 55% (N=45) of NSCLC patients. Median OS of EGFR-mutant population was 38.2 months (mo.). According to T790M status, median OS was 41.2 months and 30.4 mo. for T790M-positive and T790M-negative NSCLC patients, respectively. Both cohorts had already received a median of 3 previous treatment lines. In 40 T790M-positive NSCLC patients who receive osimertinib, RR was 55% (PR: 55%, SD 27.5% and PD: 12.5%) and median PFS of 8.5 mo. Median OS on osimertinib among 10 patients with brain and/or leptomeningeal metastases at baseline was of 13.4 months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In patients with acquired resistance to first- or second-generation EGFR TKIs, ctDNA T790M detection by InVisionSeq™ is equivalent to what has been reported in tissue biopsy. Osimertinib has clinical benefit in patients for which the T790M resistance mutation is detected only through a liquid biopsy procedure.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.03 - Biology (Not CME Accredited Session) (ID 969)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.03-27 - Somatic BRCA1/2 Mutations in Advanced NSCLC Patients: Description of a Sub-Population from the Ongoing Unicancer SAFIR02-Lung / IFCT-1301 Trial (ID 13332)

      12:00 - 13:30  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Background

      Molecular profiling is considered standard of care in advanced NSCLC. Identification of druggable molecular alterations may enhance the percentage of patients suitable for personalized treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 04/2014 to 03/2017, 602 newly diagnosed,advanced NSCLC patients (pts) were enrolled in SAFIR02-Lung trial (NCT02117167). Molecular profile provided information on copy number alterations and mutations on 71 oncogenes and tumor suppressor genes. The profile was performed for 420 pts (70%) on archival tissue or frozen tissue collected from a new biopsy performed before the 3rd cycle (tissue or liquid) of chemotherapy. The frequency of BRCA mutation (mut) was assessed and clinicopathologic data collected. A homologous recombinant deficiency (HRD) score was performed on the copy number variations (CNV) data and the germline status was based on blood analysis. The BRCAshare database was the reference for the variants classification.

      4c3880bb027f159e801041b1021e88e8 Result

      18 pts were identified with BRCA alterations. BRCA variants of unknown significance were detected in 11 pts (2.6%). Response to chemotherapy according to RECIST 1.1 by investigator was: 6 stable disease (SD), 1 partial response, and 4 progressive disease (PD). CNV profile was evaluable for HRD in 6 out of 11 pts, with 50% positive.

      Seven pts (1.7%) were identified with deleterious BRCA-mut. 2 pts (0.5%) harboured germline BRCA2-mut (1 with breast cancer familiar history). Both pts had SD to chemotherapy. Somatic BRCA-mut was identified in 5 pts (1.2%, 2 BRCA1- and 3 BRCA2-mut). All were male, 100% adenocarcinoma, 75% smokers of 40 pack/year, 1 pt with familial cancer history, and 80% of pts had bone metastases. Response to chemotherapy was: 4 SD, and 1 PD. Three of 7 corresponding CNV profiles were evaluable for HRD score analysis with 100% positive.

      N=420

      BRCA alterations (N=18)

      BRCA VUS

      N=11

      BRCA deleterious

      N=7

      Somatic

      6

      5

      Germline

      5

      2

      HRD positive- Somatic

      Germline

      3/6*

      2

      1

      3/3*

      3

      0

      VUS: variants of unknown significance

      *Amongst patients with available samples for analysis

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pathogenic BRCA1/2 mutations occur in 1.7% of advanced NSCLC with 71% of somatic mutations suggesting its value for exploring new therapeutic strategies in this population

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-11 - Association of the Lung Immune Prognostic Index (LIPI) with Outcomes for Immune Checkpoint Inhibitors in Diffuse SCLC Patients (ID 14200)

      12:00 - 13:30  |  Author(s): Benjamin Besse

      • Abstract

      Background

      Pretreatment LIPI (Lung Immune Prognostic Index), based on derived NLR (neutrophils/[leucocytes-neutrophils] ratio) and lactate dehydrogenase (LDH) has been associated with outcomes for immune checkpoint inhibitors (ICI) in advanced NSCLC patients. We tested whether LIPI has the same role in diffuse small cell lung cancer (SCLC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Baseline dNLR and LDH and clinical data were retrospectively collected in SCLC patients, treated with ICI (PD1 inhibitor, PDL1 inhibitors +/- CTLA4 inhibitor) from April 2014 to Jan. 2018 (N=66) from 6 European centers. LIPI was calculated combining dNLR and LDH, stratifying 3 risk groups: good (dNLR<3+LDH<upper limit of normal (ULN), intermediate (dNLR>3 or LDH>ULN), poor (dNLR>3+LDH>ULN). The primary endpoint was overall survival (OS), and secondary endpoint was progression-free survival (PFS).

      4c3880bb027f159e801041b1021e88e8 Result

      Fifty-three patients (80%) were males, 58 (88%) smokers and all patients had PS ≤1, with median age 63 years (41-82). PDL1 was ≥ 1% by immunohistochemistry in 6 patients, and unknown in 60 patients. The median of prior lines was 1 (0-6). Platinum-based therapy was the prior line in 63 (95%) patients, with ORR of 88%. The median PFS and OS with ICI were 2.7 months (m) [95% CI 1.87-4.43] and 10.3 m [95% CI 5.8-12.6]. dNLR was greater than 3 in 16 (25%) and LDH> Upper Limit of Normal (ULN) in 33 (50%) patients. Based on both, LIPI stratified the population in 3 groups: 26 patients as good (40%), 29 (45%) as intermediate and 10 (15%) as poor LIPI risk groups. LIPI was an independent factor for OS (HR 2.77, 95% CI 1.07-7.14, P=0.03) and PFS (HR 3.13, 1.37-7.16, P=0.01). Median OS for good, intermediate, and poor risk groups were 11.4 m [95% CI 5.5-27.3], 11 m [95% CI 6.8-not-reached (NR)] and 2.3 m [95% CI 0.7-NR], respectively (P=0.004). Median PFS for good, intermediate, and poor risk groups were 3 m [95% CI 1.9-12.6], 2.8 m [95% CI 1.6-6.0 and 1.2 m [95% CI 0.47-NR], respectively (P=0.004).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Baseline LIPI poor risk group is associated with poor outcomes for ICI in diffuse SCLC patients. LIPI effect in a validation cohort is currently evaluated.

      6f8b794f3246b0c1e1780bb4d4d5dc53