Virtual Library

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    GR02 - Management of N2 NSCLC - A Case Based Discussion (ID 778)

    • Event: WCLC 2018
    • Type: Grand Rounds Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 107
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      GR02.01 - Case 1: Single Zone N2 (No Pneumonectomy Necessary) (ID 11391)

      15:15 - 15:25  |  Presenting Author(s): Anna Wrona

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      GR02.02 - Panel Discussion (ID 11394)

      15:25 - 15:45  |  Presenting Author(s): David Harpole, Hiroshi Date, Alexander Sun, Joop de Langen, Mary Duffy, Kathy S. Albain

      • Abstract

      Abstract not provided

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      GR02.03 - Case 2: Multiple N2 Bulky Primary (ID 11392)

      15:45 - 15:55  |  Presenting Author(s): Megan Eileen Daly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      GR02.04 - Panel Discussion (ID 14533)

      15:55 - 16:15  |  Presenting Author(s): David Harpole, Hiroshi Date, Alexander Sun, Joop de Langen, Mary Duffy, Kathy S. Albain

      • Abstract

      Abstract not provided

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      GR02.05 - Case 3: Post Operative Management of Incidentally Found N2 Disease (ID 11393)

      16:15 - 16:25  |  Presenting Author(s): Masaya Yotsukura

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      GR02.06 - Panel Discussion (ID 14534)

      16:25 - 16:45  |  Presenting Author(s): David Harpole, Hiroshi Date, Alexander Sun, Joop de Langen, Mary Duffy, Kathy S. Albain

      • Abstract

      Abstract not provided

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    ISS02 - Symposium Supported by Incyte: Novel Immunotherapy Strategies in Lung Cancer (Not IASLC CME Accredited) (ID 855)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/23/2018, 11:30 - 13:00, Room 107
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    ISS05 - Symposium provided by Oakstone Publishing, LLC and PeerVoice, supported by an educational grant from AstraZeneca: EGFR-Mutant NSCLC: Evolving Treatment Paradigms and Game Changers for Current and Future Front-Line Care (Not IASLC CME Accredited) (ID 858)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/23/2018, 16:00 - 17:30, Room 107
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      Welcome and Introduction (ID 12159)

      16:00 - 16:05  |  Presenting Author(s): Pasi A Jänne

      • Abstract

      Abstract not provided

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      Exploring Our Therapeutic Options in the First-Line: What’s New? (ID 14836)

      16:05 - 16:20  |  Presenting Author(s): Pasi A Jänne

      • Abstract

      Abstract not provided

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      Assessing the Impact of the Latest Data on Practice (ID 14837)

      16:20 - 16:35  |  Presenting Author(s): Pasi A Jänne, David Planchard, Howard West

      • Abstract

      Abstract not provided

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      Controversies in First-Line Management of EGFR-Mutant NSCLC (ID 14838)

      16:35 - 17:00  |  Presenting Author(s): Pasi A Jänne, David Planchard, Howard West

      • Abstract

      Abstract not provided

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      Current and Evolving Treatments: Cases in Point (ID 14839)

      17:00 - 17:25  |  Presenting Author(s): Pasi A Jänne, David Planchard, Howard West

      • Abstract

      Abstract not provided

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      Concluding Remarks and Ask the Faculty (ID 14840)

      17:25 - 17:30  |  Presenting Author(s): Pasi A Jänne

      • Abstract

      Abstract not provided

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    ISS07 - Symposium Supported by Clinical Care Options, LLC: Strategies to Maximize the Clinical Benefit of EGFR TKIs in Advanced NSCLC (Not IASLC CME Accredited) (ID 991)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 107
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      Welcome and Overview (ID 14719)

      07:00 - 07:05  |  Presenting Author(s): Shirish Gadgeel

      • Abstract

      Abstract not provided

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      Selecting First-line Therapy in the Setting of EGFR-Mutated NSCLC (ID 14848)

      07:05 - 07:20  |  Presenting Author(s): Shirish Gadgeel

      • Abstract

      Abstract not provided

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      Selecting Second-line Therapy and Beyond in the Setting of EGFR-Mutated NSCLC (ID 14849)

      07:20 - 07:35  |  Presenting Author(s): Heather A Wakelee

      • Abstract

      Abstract not provided

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      Future Directions in Treatment Strategies for EGFR-Mutated NSCLC (ID 14850)

      07:35 - 07:50  |  Presenting Author(s): Helena Yu

      • Abstract

      Abstract not provided

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      Conclusions and Audience Question and Answer Session (ID 14851)

      07:50 - 08:00  |  Presenting Author(s): Shirish Gadgeel, Heather A Wakelee, Helena Yu

      • Abstract

      Abstract not provided

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    ISS13 - Symposium Supported by Medscape: Progress of the NSCLC Revolution: Questioning the Experts (Not IASLC CME Accredited) (ID 864)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 107
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      Welcome and Introductions (ID 12167)

      07:00 - 07:05  |  Presenting Author(s): Tony S. Mok

      • Abstract

      Abstract not provided

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      Molecular Testing in NSCLC: Where Are We Going? (ID 14804)

      07:05 - 07:20  |  Presenting Author(s): Fabrice Barlesi

      • Abstract

      Abstract not provided

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      Treating New Molecular Targets in NSCLC: How Are We Progressing? (ID 14805)

      07:20 - 07:35  |  Presenting Author(s): Sanjay Popat

      • Abstract

      Abstract not provided

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      Immunotherapy in NSCLC: Where Have We Got to? (ID 14806)

      07:35 - 07:45  |  Presenting Author(s): Edward B Garon

      • Abstract

      Abstract not provided

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      How Are We Doing in the Delivery of the NSCLC Revolution? (ID 14807)

      07:45 - 07:57  |  Presenting Author(s): Tony S. Mok, Fabrice Barlesi, Edward B Garon, Sanjay Popat

      • Abstract

      Abstract not provided

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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.01 - Cemiplimab, a Human Monoclonal Anti-PD-1, Alone or in Combination with Radiotherapy: Phase 1 NSCLC Expansion Cohorts (ID 13177)

      13:30 - 13:35  |  Presenting Author(s): Victor Moreno  |  Author(s): Marta Gil-Martin, Melissa L. Johnson, Raid Aljumaily, Maria Pilar Lopez-Criado, Donald W Northfelt, Marka Crittenden, Salma Jabbour, Lee Rosen, Emiliano Calvo, Kyriakos P Papadopoulos, Pilar Garrido, Asuncion Hervás Morón, Petra Rietschel, Kosalai Mohan, Jingjin Li, Elizabeth Stankevich, Minjie Feng, Israel Lowy, Matthew Fury

      • Abstract
      • Slides

      Background

      Cemiplimab (REGN2810), a human monoclonal anti-PD-1, has exhibited substantial antitumor activities in patients with advanced malignancies in a first-in-human study. We report interim results of the Phase 1 expansion cohorts (ECs 1 and 2) of cemiplimab, alone or plus radiotherapy, in advanced NSCLC (NCT02383212).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced NSCLC who had relapsed after, or were refractory to, at least, first-line therapy received cemiplimab 200 mg Q2W in EC 1, or cemiplimab 3 mg/kg Q2W plus radiotherapy (9 Gy × 3 times/week 1 week after first dose of cemiplimab) to a single lesion in EC 2. For EC 2, patients were required to have NSCLC for which palliative radiation therapy was indicated. Planned treatment duration was up to 48 weeks in both ECs. The co-primary objectives were to evaluate the safety, tolerability, and efficacy of cemiplimab, alone or plus radiotherapy. Tumor measurements (of non-irradiated lesions) were performed by RECIST 1.1 Q8W.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Sept 1, 2017, 20 patients (13 M/ 7 F; median age 64.0 years [range, 50–82]) and 33 patients (22 M/ 11 F; median age 67.0 years [range, 47–82]) were enrolled in EC 1 and EC 2, respectively. ECOG performance status 1 versus 0 was 80.0% versus 20.0% and 66.7% versus 30.3%, respectively, for ECs 1 and 2, and missing in one in EC 2; 75.0% (EC 1) and 48.5% (EC 2) had received prior radiotherapy. Investigator-assessed overall response rate (ORR; complete response [CR] + partial response [PR]) was 40.0% (1 CR and 7 PRs) and 18.2% (6 PRs) in EC 1 and EC 2, respectively. Disease control rate (ORR + stable disease [SD]) was 60.0% (1 CR + 7 PRs + 4 SDs) and 72.7% (6 PRs + 18 SDs) in EC 1 and EC 2, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade were arthralgia, asthenia, cough, and dyspnea (each 20.0%) in EC 1, and decreased appetite (30.3%), fatigue (27.3%), cough (24.2%), asthenia and back pain (each 21.2%) in EC 2. Grade ≥3 TEAEs occurring in ≥2 patients were pneumonia (10.0%) in EC 1; and anemia (12.1%), hypophosphatemia and urinary tract infection (each 6.1%) in EC 2. One patient in EC 2 experienced TEAE of pneumonitis with an outcome of death, considered related to study drug.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Cemiplimab monotherapy demonstrated substantial antitumor activity in pretreated NSCLC patients. The safety profiles were comparable with other anti-PD-1 agents and radiotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.02 - Responses and Durability in NSCLC Treated With Pegilodecakin and Anti-PD-1 (ID 13986)

      13:35 - 13:40  |  Presenting Author(s): Edward B Garon  |  Author(s): Deborah J. Wong, Jeffrey G. Schneider, Raid Aljumaily, W. Michael Korn, Jeffrey R. Infante, Manish Patel, Karen A. Autio, Kyriakos P Papadopoulos, Aung Naing, Nashat Y. Gabrail, Pamela N. Munster, Jonathan W. Goldman, Annie Hung, Peter Van Vlasselaer, Joseph Leveque, Martin Oft, David R. Spigel

      • Abstract
      • Presentation
      • Slides

      Background

      Responses in NSCLC to agents targeting the PD-1/PD-L1 axis are correlated with PD-L1 expression by immunohistochemistry (IHC), tumor mutational burden (TMB), interferon-associated mRNA expression profile (GEP), and the absence of liver metastases. Anti-PD-1 impedes the inhibition of T cells while pegilodecakin (AM0010) stimulates the survival and expansion of intratumoral, antigen-activated CD8+ T cells (Mumm et al, 2010). This provides a rationale for combining anti-PD-1 agents with pegilodecakin.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pretreated NSCLC subjects (N = 34) received pegilodecakin (10-20 µg/kg QD, SC) with pembrolizumab (2 mg/kg, Q3W, IV; n = 5) or nivolumab (3 mg/kg, Q2W, IV; n = 29). Median follow-up is 31.2 months (range, 28.3-33+ months) and 17.5 months (range, 8.3- 25.9+ months), respectively. Responses were assessed by irRC. Twenty subjects had sufficient tissue for PD-L1 testing with the 22C3 IHC assay (CLIA) and 10 subjects had sufficient tissue for TMB evaluation by whole exome sequencing (WES) and pretreatment GEP by NanoString.

      4c3880bb027f159e801041b1021e88e8 Result

      In 26 subjects evaluable for response, the ORR was 41% (11 PRs). Another 12 subjects (46%) had SD as best response. As investigators were asked to preferentially enroll PD-L1–negative patients, PD-L1 expression was <1% in 12 of 20 PD-L1–evaluable subjects with 4 achieving a PR. Ten subjects had sufficient tissue for TMB and GEP, including 6 PRs. Five of the 8 who tested low to intermediate for TMB (<243 mut) had a PR as did 2 of 6 GEP-negative subjects. In addition, 5 of 8 subjects with liver metastasis had a PR. The mPFS and mOS of the 5 NSCLC subjects (4/4 tested PD-L1 <1%) treated with pegilodecakin + pembrolizumab was 10.9 and 32.2 months, respectively. The mPFS and mOS for the pegilodecakin + nivolumab cohort (8/16 tested PD-L1 <1%) has not been reached.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pegilodecakin, when added to anti-PD-1 therapy in advanced NSCLC patients, was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB, and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.04 - Discussant - MA 04.01, MA 04.02, MA 04.03 (ID 14585)

      13:45 - 14:00  |  Presenting Author(s): Jose Pacheco

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA04.05 - Outcomes in NSCLC Patients Treated with First-Line Pembrolizumab and a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100% (ID 14358)

      14:00 - 14:05  |  Presenting Author(s): Mark M. Awad  |  Author(s): Elizabeth Jimenez Alguilar, Justin F Gainor, Sasha Kravets, Sara Khosrowjerdi, Christine A Lydon, Anika Adeni, Safiya Subegdjo, Hira Rizvi, Matthew D. Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      Among patients with NSCLC and a PD-L1 tumor proportion score (TPS) ≥50%, the response rate to the PD-1 inhibitor pembrolizumab is ~45%. Whether certain subsets of patients with a PD-L1 TPS ≥50% are more likely to benefit from treatment with a PD-1 inhibitor is currently unknown. We compared outcomes among NSCLC patients treated with first-line pembrolizumab and different PD-L1 TPS groupings: 50-74% vs 75-100% or 50-89% vs 90-100%.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed patients who received commercial pembrolizumab as first-line treatment for NSCLC with a PD-L1 TPS of ≥50% from the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Massachusetts General Hospital. Clinicopathologic characteristics and clinical outcomes were compared among patients with a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100%. Event-time distributions were estimated using Kaplan-Meier and compared with the log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      172 patients were identified for inclusion in this study. In the entire cohort, the overall response rate (ORR) to pembrolizumab was 33.9%, median progression-free survival (mPFS) was 4.8 months, and median overall survival (mOS) was 20.6 months. Compared to patients with TPS 50-74% (N=68, 39.5%), patients with TPS 75-100% (N=104, 60.5%) had a significantly higher ORR (45.2% vs 20.6%, P=0.001), a significantly longer mPFS (5.3 vs 2.5 mo, HR=0.61 [95% CI: 0.41-0.90], P=0.008), and a trend towards improved mOS (33.6 vs 20.6 mo, HR=0.60 [95% CI: 0.34-1.04], P=0.056). Compared to patients with TPS 50-89% (N=99, 57.6%), patients with TPS 90-100% (N=73, 42.4%) had a significantly higher ORR (50.7% vs 24.2%, P<0.001), a significantly longer mPFS (6.4 vs 2.8 mo, HR=0.52 [95% CI: 0.36-0.76], P<0.001), and a significantly longer mOS (33.6 vs 18.0 mo, HR=0.46 [95% CI: 0.27-0.79], P=0.008). There were no significant differences in smoking history, histology, sex, and age between patients in each TPS cutoff group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among NSCLCs with a PD-L1 TPS ≥50% treated with first-line pembrolizumab, higher PD-L1 TPS levels above 75% and 90% are associated with improved clinical outcomes compared to NSCLCs with lower PD-L1 levels.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.06 - PD-1 Blockade Promotes Hyperprogressive Disease in NSCLC Through Macrophages Activation via Antibody-Fc/FcR Interaction (ID 12334)

      14:05 - 14:10  |  Presenting Author(s): Gabriella Sozzi  |  Author(s): Michele Sommariva, Massimo Moro, Claudia Proto, Diego Signorelli, Monica Ganzinelli, Sabina Sangaletti, Mattia Boeri, Giuseppe Lo Russo, Simona Ferro, Elena Tassi, Veronica Huber, Lucia Sfondrini, Massimo Milione, Claudio Tripodo, Mario Colombo, Andrea Anichini, Andrea Balsari, Licia Rivoltini, Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      In a subset of patients, named hyperprogressors (HPs), immunotherapy seems to paradoxically boost tumor growth. However, neither pathological and clinical features nor the underlying biological mechanism have been identified. We dissected the role of tumor-myeloid cells crosstalk as possible players.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      HPs were defined on the basis of clinical and radiological features. Baseline histological samples from patients treated with immune checkpoints inhibitors (ICI) were evaluated by immunohistochemistry for myeloid and lymphoid markers. We tested the effect on tumor growth of murine and human ICI in T-cell deficient mice injected with human lung cancer cell lines and PDXs bearing different genotypes (EGFR+, KRAS+, STK11+ and wt). Innate immune microenvironment was evaluated by FACS analysis and immunohistochemistry. In vitro studies of ICI binding functional modulation were performed in human myeloid cells from patients and healthy donors.

      4c3880bb027f159e801041b1021e88e8 Result

      In a clinical series of 187 patients treated with ICI, hyperprogression was observed in 40 (26.3%) cases. All available HP pre-treatment tissue samples (11 cases) showed CD163+CD33+PD-L1+Arginase-A1+ clustered epithelioid macrophages infiltrating the tumor foci also expressing FcRs including CD32b. No differences in T cell compartment were observed. Murine and human PD1 blocking mAbs induced a boost of tumor growth in H460 xenografs in imunocompromised mice. A similar effect was observed in EGFR+ but not in KRAS+ and wt PDXs treated with human anti-PD1. Notably, no hyperprogression was observed after treatment with murine and human anti PD-1 F(ab)2. Hyperprogressive tumors were enriched in arginase+ myeloid-macrophage cells and fibrotic features. ICI bind in vitro to human macrophages and monocytes via Fc/FcR interactions, likely involving CD32b (FcgRIIb) and triggering functional polarization.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results provide evidence that FcR triggering on macrophages by ICI delivers a signaling cascade promoting a functional reprogramming of these cells toward a more aggressive pro-tumorigenic behavior eventually inducing hyperprogression in a subset of patients with distinctive immune and genetic profile. A validation prospective study in ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.07 - MicroRNA-Based Liquid Biopsy Combines with PD-L1 Tumor Expression to Predict Response to Immunotherapy in Advance NSCLC Patients (ID 12566)

      14:10 - 14:15  |  Presenting Author(s): Mattia Boeri  |  Author(s): Massimo Milione, Diego Signorelli, Claudia Proto, Giuseppe Lo Russo, Carlotta Galeone, Giovanni Centonze, Ugo Pastorino, Marina Chiara Garassino, Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      The advent of the new immune checkpoint inhibitors (ICIs) targeting the PD-1/L1 axis drastically improves survival of advance non-small-cell lung cancer (NSCLC) patients. However, only a limited subset of patients actually benefits of ICIs treatment and PD-L1 as predictive biomarker has a limited efficacy. We have previously identified a plasma microRNA-signature classifier (MSC) reflecting a circulating tumor-host interaction with diagnostic and prognostic value in low-dose computed tomography (LDCT) lung cancer screening trials.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The tumor immune contexture of 40 LDCT-screening detected lung tumors was characterized by the “cell-type identification by estimating relative subsets of RNA transcripts” (CIBERSORT) software. In a consecutive series of 84 advanced lung cancer patients treated with ICIs, both plasma and tissue samples were collected and prospectively analyzed. Both 2-years progression free (PFS) and overall survival (OS) in strata of plasma MSC risk level alone or combined with tumor PD-L1 expression were evaluated in univariate and multivariate analysis by log-rank test and Cox proportional hazards models.

      4c3880bb027f159e801041b1021e88e8 Result

      A pro-tumorigenic immune contexture was identified in tumors of MSC high risk patients. Lower levels of cytotoxic CD8+ and CD4+ T cells and increased levels of Tregs, γδ T Cells, M2 macrophages characterized these tumors. In addition, genes differentially expressed according to MSC risk level (high vs. intermediate and low) were associated with 5-years OS in the screening series (p-values=0.02), as well as in additional 1000 cases from The Cancer Genome Atlas database (p-values<0.01). In the 84 advanced NSCLC patients treated with ICIs, the PFS hazard ratio ranged from 0.44 (95%CI: 0.25-0.75) of PD-L1 (adjusted p-value=0.005) and 0.38 (95%CI:0.2-0.73) of MSC (adjusted p-value=0.004) alone, to 0.25 (95%CI: 0.14-0.45) if combined (adjusted p-value<0.0001). In the subgroup of 45 patients with both plasma and tumor tissue available, the combination of MSC and PD-L1 stratified patients in three groups with 2-years PFS ranging from 25%to 10% and 0% (p-value=0.01) according to the presence of 2, 1 or 0 favorable markers, respectively. Similar results were obtained when considering OS, where the median survival time for patients with no favorable markers was 5.6 months (p-value<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Overall, these findings suggest that a circulating microRNA-based risk level, reflecting an altered tumor immune contexture, could implement PD-L1 tumor tissue expression as predictive biomarkers of response to immunotherapy.

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      MA04.08 - Discussant - MA 04.05, MA 04.06, MA 04.07 (ID 14589)

      14:15 - 14:30  |  Presenting Author(s): Patrick M Forde

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA04.09 - Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Updated Results from a Multicenter Study (LCMC3) (ID 12941)

      14:30 - 14:35  |  Presenting Author(s): Valerie W Rusch  |  Author(s): Jamie E Chaft, Bruce E Johnson, Ignacio I. Wistuba, Mark G Kris, Jay M Lee, Paul A. Bunn, Jr., David J Kwiatkowski, Karen L. Reckamp, David J. Finley, Eric B. Haura, Saiama N. Waqar, Robert C. Doebele, Edward B Garon, Justin Blasberg, Alan Nicholas, Katja Schulze, See Phan, Mayank Gandhi, David P Carbone

      • Abstract
      • Presentation
      • Slides

      Background

      Cisplatin-based chemotherapy, before or after surgery, provides only a 5% benefit in 5yr. OS in resectable NSCLC. A 20 patient study (NEJM April 2018) showed that preoperative immune checkpoint inhibitor therapy yielded a clinically meaningful major pathologic response rate (MPR ≤10% residual viable tumor cells) and did not delay or complicate surgery. This large multicenter trial measures MPR and biomarkers of benefit using neoadjuvant atezolizumab (atezo) [NCT02927301].

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We planned 2 cycles of atezo (1200mg, days 1, 22) in patients with stages IB -selected IIIB resectable NSCLC prior to surgical resection (day 40 +/- 10). Chest CT, PET were planned pre-atezo and presurgery to assess response. Primary tumor +/- node biopsies and blood samples were obtained before atezo and presurgery for biomarker studies. The primary endpoint was MPR. Secondary endpoints included safety, response by PD-L1, OS, and DFS.

      4c3880bb027f159e801041b1021e88e8 Result

      For this updated efficacy and safety analysis (Feb’18 datacut), we report first 54 of 180 planned pts: 29 males, median age 65 yr, all ECOG 0-1; 17 current, 33 former smokers; 35 non-squamous NSCLC; clinical stages Ib/IIa/IIb/IIIa/IIIb = 5/11/13/20/5. Two pts received one dose of atezo due to treatment related AE (Gr 1 pyrexia, Gr 2 dyspnea) but underwent uncomplicated resection with MPR assessment. There was 1 unrelated Gr 5 AE (sudden cardiac death post surgical resection), 16 Gr 3-4 AEs (3 treatment related). Surgery was delayed in 1 pt due to Gr3 pneumonitis. By RECIST, 3 pts had PR, and 49 had SD. 50 pts underwent surgery and 47 pts had MPR assessment: 2 pts discontinued study preop due to radiographic PD and 2 discontinued due to other reasons; 3 pts had unresectable disease. MPR rate was 10/50 (20%, 95% CI 10-34%) including 3 pts who had pCR (no viable tumor cells) in the primary tumor. Excluding 5 pts who had known driver mutations (4 EGFR+, 1 ALK+), MPR rate was 10/45 (22%, 95% CI 11-37%). PD-L1 status was evaluable in 44/54 pts; 8/10 pts with MPR had PD-L1+ status and 2 had unknown PD-L1 status; 8/28 PDL-1 (+) patients had MPR (29%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a multicenter study, neoadjuvant atezo was well tolerated. MPR rate is encouraging. Clinical and pathological responses are often discordant. Correlative analyses on pre- and post atezo tissues are ongoing. Preliminary correlative analyses in blood samples are included in a separate abstract.

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      MA04.10 - Comprehensive Peripheral Blood Immunophenotyping and T-Cell Clonal Analysis During Neoadjuvant Immunotherapy with Atezolizumab in NSCLC (ID 13118)

      14:35 - 14:40  |  Presenting Author(s): Filiz Oezkan  |  Author(s): Kai He, Dwight Hall Owen, Maciej Pietrzak, Rhonda Kitzler, Rebecca Pearson, Alan Nicholas, Paul A. Bunn, Jr., Mark G Kris, David J. Kwiatkowski, Bruce E Johnson, Fred R. Hirsch, Ignacio I. Wistuba, Valerie W Rusch, Jay M. Lee, Mayank Gandhi, Katja Schulze, David S. Shames, Gerard Lozanski, David P Carbone

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint blockade targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response rates and survival compared to chemotherapy in selected metastatic NSCLC patients. Evaluation of the pre-therapeutic immune profile and its treatment-related evolution associated with clinical benefit will guide future immunotherapy development and support clinical decision-making. Here, we present an analysis of peripheral blood (PB) immunophenotyping and T-cell-receptor (TCR) clonality before and after immunotherapy from an ongoing 180-patient phase II study of atezolizumab as neoadjuvant therapy with stage IB-IIIB resectable NSCLC (NCT02927301; LCMC3).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      As of February 5th datacut, the first 54 enrolled and dosed patients are presented. The biomarker evaluable population (BEP) further subset to patients with paired PB samples analyzed within 72 hours after collection and a major pathological response (MPR) assessment. Comprehensive immune cell phenotyping (10-color flow cytometry, IMMUNOME) and TCR-Vß-analysis by flow cytometry were performed. Immunoprofile analyses were correlated with atezolizumab treatment, pathological response and PD-L1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      In this ongoing analysis, BEP included 31 patients. 5 patients (16%, 95% CI (5%, 34%)) had a MPR; all of which stained positive for PD-L1 by IHC using 22C3 (TPS≥1%) and SP142 (PD-L1 expression on ≥1% tumor cells (TC) and/or tumor infiltrating immune cells (IC)) at baseline. We observed significant increases in natural killer (NK) cells (p=0.005) and CD8+ T-cells (p=0.031) and a Th1-response related dendritic cell (DC) subpopulation (p=0.031) and significant decreases in B-cells (p=0.015) after treatment.

      Patients who achieved MPR show lower baseline levels of degranulated CD8+ T-cells (p=0.015), late-activated NK-cells (p=0.043), memory CD4+ (p=0.048) and memory CD8+ T-cells (p=0.032); changes in PB NK-cells (p=0.041), a decrease in M-MDSCs and a Th-2 and Th-17-response related DC subpopulation (p=0.043) in response to treatment were noted in patients with MPR versus non-MPR.

      Among the 16 patients with TC/IC 1/2/3 (> 1% PD-L1 expression) the following significant differences were observed compared to TC0/IC0 (7 patients): higher levels of late-activated CD4+ T-cells (p=0.025) and mid-activated CD8+ T-cells (p=0.044) at baseline, decrease of senescent T-cells (p=0.041), monocytic myeloid-suppressor cell subpopulations (M-MDSCs) and an increase in a Th1-response related DC subpopulation (p=0.026) after treatment.

      TCR clonality analysis showed expansions in Vß-subtypes after atezolizumab treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immunophenotyping and TCR-Vß-repertoire analysis in peripheral blood samples from NSCLC patients treated with neoadjuvant atezolizumab show differences in immune cell subsets in baseline samples and changes after treatment.

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      MA04.11 - Neoantigen Targeting and T Cell Reshaping in Resectable NSCLC Patients Treated with Neoadjuvant PD-1 Blockade (ID 12605)

      14:40 - 14:45  |  Presenting Author(s): Kellie Nicole Smith  |  Author(s): Margueritta El Asmar, Jiajia Zhang, Justina X Caushi, Zhicheng Ji, Valsamo Anagnostou, Tricia R Cottrell, Hok Yee Chan, Prerna Suri, Haidan Guo, Kristen A. Marrone, Jarushka Naidoo, Taha Merghoub, Jamie E Chaft, Matthew D. Hellmann, Janis M Taube, Julie R. Brahmer, Patrick M Forde, Victor Velculescu, Drew M Pardoll, Hongkai Ji

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1 blockade is now standard treatment for advanced non-small cell lung cancer (NSCLC) and has recently shown impressive efficacy in promoting major pathologic response (MPR) and delaying relapse in the neoadjuvant setting. The role of tumor mutational burden, and specifically T cells targeting neoantigens derived from these mutations, in facilitating tumor clearance has been demonstrated in advanced NSCLC. However, it is unknown how neoadjuvant PD-1 blockade impacts the frequency and function of tumor specific T cells and their ability to promote major pathologic response, or how these factors may synergize to prevent or delay relapse after surgical resection.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Whole exome sequencing and neoantigen prediction was performed on pre-treatment tumor biopsies and matched normal tissue from 11 patients with resectable NSCLC treated with neoadjuvant nivolumab as part of a clinical trial (NCT02259621). T cell recognition of peptides representing candidate neoantigens was evaluated using the MANAFEST assay, which identifies T cell receptor clonotypes corresponding to antigen specificities. T cell receptor sequencing was additionally performed on serial peripheral blood T cells, pre-treatment tumor biopsies, and resected post-treatment tissues. A bioinformatic platform was developed to evaluate the dynamics of intratumoral T cell clonotypes, and more specifically neoantigen-specific clonotypes detected before, during, and after treatment and during long-term follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      High-magnitude, polyclonal neoantigen-specific T cell responses were detected in the peripheral blood and persisted for many months after surgical resection and cessation of treatment. Binding to and stability with cognate HLA I molecules was validated for reactive neoantigens. Significant treatment-induced systemic perturbations in the tumor-specific T cell repertoire and an influx of peripheral T cell clonotypes into tumor tissue and lymph nodes was observed in patients regardless of pathologic response, whereas peripheral clonotypic reshaping of the anti-tumor repertoire and intratumoral T cell clonality were associated with MPR status.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We show significant and systemic alterations in the peripheral anti-tumor T cell repertoire in NSCLC patients treated with neoadjuvant anti-PD-1 regardless of MPR status. Notwithstanding, the impaired restructuring of the anti-tumor T cell repertoire in patients without MPR highlights a potential immunological deficiency to overcome in future therapeutic approaches aiming to increase the MPR rate in NSCLC patients treated with neoadjuvant PD-1 blockade.

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      MA04.12 - Discussant - MA 04.09, MA 04.10, MA 04.11 (ID 14588)

      14:45 - 15:00  |  Presenting Author(s): Alex Adjei

      • Abstract
      • Presentation
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      Abstract not provided

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

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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      MA15.01 - Strong PD-L1 Expression Predicts Poor Response and de Novo Resistance to EGFR TKIs Among Non-Small Cell Lung Cancer Patients with EGFR Mutation (ID 12920)

      13:30 - 13:35  |  Presenting Author(s): Shan Su  |  Author(s): Zhong-Yi Dong, Xie Zhi, Jian Su, Zhi-Hong Chen, Jin-Ji Yang, Hai-Yan Tu, Qing Zhou, Wen Zhao Zhong, Xu-Chao Zhang, Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      This study evaluated whether tumor expression of programmed death-ligand 1 (PD-L1) predicted the response of EGFR-mutated non-small cell lung cancer (NSCLC) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC between April 2016 and September 2017 at the Guangdong Lung Cancer Institute. None of them were enrolled in clinical studies, and their EGFR and PD-L1 statuses were simultaneously evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 101 eligible patients, strong PD-L1 expression significantly decreased the objective response rate (ORR) compared with those with weak or negative PD-L1 expression (35.7% vs 63.2% vs 67.3%, P=0.002) as well as shortened progression-free survival (PFS, 3.8months vs 6.0months vs 9.5months, P<0.001), regardless of EGFR mutation types (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% vs 30.2%, P=0.009). Notably, patients with de novo resistance had a high proportion of dual positive for PD-L1 and CD8 (46.7%, 7/15). Finally, one patient with de novo resistance to EGFR-TKIs and dual positivity for PD-L1 and CD8 experienced a favorable response to anti-PD-1 therapy.1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study uncovered the adverse impact of PD-L1 expression on the efficacy of EGFR- TKIs, especially in those with de novo resistance NSCLC, which inclined to reshape an inflamed immune phenotype of dual positive for PD-L1 and CD8 and showed potential therapeutic sensitivity to PD-1 blockade.

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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  |  Presenting Author(s): Charles M. Rudin  |  Author(s): Andres Cervantes, Afshin Dowlati, Benjamin Besse, Brigette Ma, Daniel B Costa, Peter Schmid, Rebecca Heist, Victoria M. Villaflor, Indrani Sarkar, Genevive Hernandez, Paul Foster, Jessica Spahn, Carol O'Hear, Scott N. Gettinger

      • 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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      MA15.03 - PD-L1 Expression in Untreated EGFRm Advanced NSCLC and Response to Osimertinib and SoC EGFR-TKIs in the FLAURA Trial (ID 12989)

      13:40 - 13:45  |  Presenting Author(s): Suresh S. Ramalingam  |  Author(s): Helen Brown, Johan F. Vansteenkiste, Kazuhiko Nakagawa, Manuel Cobo Dols, Thomas John, Craig Barker, Alexander Kohlmann, Alexander Todd, Matilde Saggese, Juliann Chmielecki, Aleksandra Markovets

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase III FLAURA trial (NCT02296125), osimertinib significantly improved PFS relative to SoC EGFR-TKIs (gefitinib/erlotinib) in patients with untreated Ex19del/L858R positive (EGFRm) NSCLC. EGFRm NSCLC tumors can exhibit high PD-L1 expression, an important biomarker for immunotherapy treatment decisions. The frequency and clinical relevance of exhibiting both biomarkers prior to treatment are unclear. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following EGFR-TKI treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue samples from 994 patients with advanced NSCLC were screened for EGFR Ex19del/L858R mutations for enrolment in FLAURA; 556 were randomized to treatment. 197 tissue-blocks from the screened population (including EGFR mutation-positive and -negative samples) were tested for PD-L1 using the SP263 (Ventana) immunohistochemical assay; positive tumour cell (TC) staining PD-L1 TC≥25% and TC≥1% thresholds were applied. PFS was investigator-assessed, per RECIST 1.1, according to PD-L1-expressers (TC≥1%) or -negatives (TC<1%) in randomized patients.

      4c3880bb027f159e801041b1021e88e8 Result

      193/197 blocks had sufficient tumor tissue for staining. 65/193 patients were EGFR mutation-negative. 128/193 patients were EGFR mutation-positive: 106/128 were randomized to treatment (osimertinib: 54; SoC: 52). The table presents PD-L1 expression according to EGFR mutation status. For PD-L1-expressers (TC≥1%), median PFS was 18.4 months for osimertinib and 6.9 months for SoC (HR 0.30 [95% CI 0.15, 0.60]). For PD-L1-negative patients (TC<1%), median PFS was 18.9 months for osimertinib and 10.9 months for SoC (HR 0.37 [95% CI 0.17, 0.74]).

      PD-L1 TC≥1%, n (%)

      PD-L1 TC≥25%, n (%)

      EGFR mutation-negative (n=65)

      Screened population (n=65)

      44 (68)

      23 (35)

      EGFR mutation-positive (n=128)

      Screened population (n=128)

      65 (51)

      10 (8)

      Randomized to treatment (n=106)

      52 (49)

      8 (8)

      Randomized to osimertinib (n=54)

      28 (52)

      3 (6)

      Randomized to SoC EGFR-TKI (n=52)

      24 (46)

      5 (10)

      8eea62084ca7e541d918e823422bd82e Conclusion

      There was PFS benefit with osimertinib versus SoC regardless of whether tumors were PD-L1-expressers (TC≥1%) or -negatives (TC<1%). Using the TC≥25% threshold, PD-L1 prevalence was lower in EGFR mutation-positive than mutation-negative samples; there were insufficient patients with TC≥25% tumors for PFS assessment.

      These results support the efficacy of EGFR-TKIs, including osimertinib, as first-line treatment of EGFRm advanced NSCLC, irrespective of PD-L1 expression.

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      MA15.04 - Discussant - MA 15.01, MA 15.02, MA 15.03 (ID 14641)

      13:45 - 14:00  |  Presenting Author(s): Adrian Sacher

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA15.05 - The Mutational Profiles of EGFR 19 Exon Deletion and 21 Exon L858R Mutation and Their Association with Primary Response to EGFR-TKIs (ID 12671)

      14:00 - 14:05  |  Presenting Author(s): Wenhua Liang  |  Author(s): Caichen Li, Yi Zhao, Jianxing He

      • Abstract
      • Presentation
      • Slides

      Background

      In addition to the known resistant genetic alterations, such as de novo T790M and TP53 mutations, some recent studies suggested that other concomitant mutations might also compromise the efficacy of EGFR-TKIs. Meanwhile, it has been widely observed that EGFR 19 exon deletion (19del) was associated with better outcomes in treatments with EGFR-TKIs than L858R mutation (L858R). It is of interest to explore whether the respective mutational profiles of 19del and L858R may explain their different sensitivity to EGFR-TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We obtained individual patient data from 7 studies (including 1 from our center) using next generation sequencing to comprehensively determine the mutational profile of EGFR mutated patients. As different panels were used by different studies, we analyzed T790M, TP53 and the loci that were reported by at least 4 studies (half of the included ones).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 250 19del and 279 L858R patients were included. We found similar prevalence of all co-mutations (19del 65.2% vs. L858R 64.2%), TP53 (19del 36.8% vs. L858R 40.9%), APC, BRAF, PIK3CA, STK11, PDGFRA, PTEN, AKT1 and KIT between the two types, except for de novo T790M (19del 34.4% vs. L858R 50%, P=0.07), CDKN2A (19del 10.5% vs. L858R 3.4%, P=0.03) and KRAS (19del 0.5% vs. L858R 4.0%, P=0.01). In addition, the number of co-mutations was equivalent between the two types (19del 0.95±0.95 vs. L858R 0.93±0.90, P=1.00). Through multivariate logistic regression, we found that EGFR mutation type, de novo T790M, TP53 and other co-mutations, all had independent adverse effects on primary response rate. Consistently, we found that in those without co-mutations, 19del still showed better outcomes compared with L858R (pure EGFR mutations: 19del 88.0% vs. L858R 68.4%), and that the response rates in both mutation types decreased in the same extent when contaminated with other mutations (EGFR mutations with co-mutations: 19del 53.1% vs. L858R 30.0%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study demonstrated that the presence of T790M, TP53 and other concomitant mutations indicated poor response to EGFR-TKIs, but most of them showed similar prevalence between 19del and L858R. Patients with L858R showed significantly less response than those with 19del regardless of the co-mutation status, indicating that some intrinsic factors and potentially de novo T790M, rather than other co-mutations, might underlie the different sensitivity of 19del and L858R to EGFR-TKIs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.06 - Circulating Tumor DNA Portrays the Resistance Landscape to a Novel Third Generation EGFR Inhibitor, AC0010 (ID 13641)

      14:05 - 14:10  |  Presenting Author(s): Yi-Chen Zhang  |  Author(s): Qing Zhou, Zhi-Hong Chen, Chong-Rui Xu, Jin -Ji Yang, Xu-Chao Zhang, Xiao-Yan Bai, Hong-Hong Yan, Zhi Xie, Wen -Feng Li, Shannon Chuai, Jun-Yi Ye, Han Zhang-Han, Zhou Zhang, Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      In a Phase I/II dose-escalation and expansion study conducted at Guangdong Lung Cancer Institute, AC0010 demonstrated promising efficacy and good tolerability in advanced NSCLC patients with EGFR T790M-mediated resistance to previous EGFR TKIs, (NCT02330367). As disease progression (PD) with EGFR T790M-directed therapy also emerges over time, we investigated the resistance mechanisms to AC0010 in this study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Serial ctDNA samples obtained from patients who developed PD with AC0010 were analyzed using ultra-deep sequencing capturing 295 cancer-related genes. Alterations that were absent before treatment and acquired at PD or that increased in abundance during treatment were identified as putative resistance mechanisms.

      4c3880bb027f159e801041b1021e88e8 Result

      Longitudinal plasma samples were obtained from 23 patients who progressed on AC0010 (data cut-off October 14, 2016; figure1). Putative resistance mechanisms to AC0010 were identified in 19/23 patients (>1 putative resistance mechanism was detected in some patients). EGFR amplification was the predominant resistance mechanism (21.1% [4/19 patients]), followed by TP53 loss of heterozygosity (15.8% [3/19]). EGFR C797S mutation, Met amplification and mutations in the PI3KCA pathway each occurred in 10.5% of patients (2/19). SCLC transformation, ERBB2 amplification, CD79A_A32G mutation, CDKN2A_R80 mutation, CRLF2 amplification, MLH1 amplification, Rb1 loss, and concurrent rise in the allelic fraction of tumor suppressor gene TP53 and Rb1 were each detected in 5.3% of patients (1/19). In a patient with PD following single-agent AC0010 and EGFR amplification as the putative resistance mechanism to AC0010, subsequent treatment with AC0010 plus nimotuzumab (EGFR monoclonal antibody) successfully overcame resistance, resulting in a response that lasted for 7.7 months.

      fig 1_study profile.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The resistance landscape to AC0010 appears to differ from that described previously with osimertinib. In this cohort of patients in China, EGFR amplification was the predominant resistance mechanism to AC0010 and could be potentially overcome by EGFR dual inhibition.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.07 - Different Responses to Osimertinib in Primary and Acquired EGFR T790M-Mutant NSCLC Patients (ID 12766)

      14:10 - 14:15  |  Presenting Author(s): Shuyuan Wang  |  Author(s): Bo Zhang, Baohui Han

      • Abstract
      • Presentation
      • Slides

      Background

      Primary EGFR T790M could be occasionally identified by routine molecular testing in tyrosine kinase inhibitor TKI-naive non-small cell lung cancer (NSCLC) patients. This study was aimed to compare clinical characteristics of primary and acquired T790M mutations and their responses to Osimertinib in NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We collected clinical characteristics of patients diagnosed with epidermal growth factor receptor (EGFR) mutation from 2012 to 2017 in Shanghai Chest Hospital. For patients with primary and acquired T790M mutations, the responses to Osimertinib were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      Primary T790M was identified in 1.03% (61/5900) of TKI-naive patients. Acquired T790M was detected in 45.50% (96/211) of TKI-treated patients. T790M always coexisted with sensitizing EGFR mutations. Primary T790M was always coexisted with 21L858R (45/61) whereas acquired T790M was coexisted with 19del (61/96). Among them, 18 patients with primary T790M mutation acquired Osimertinib and 75 patients with acquired T790M mutation received Osimertinib. The median progression-free survival (mPFS) of Osimertinib in primary T790M group was greatly longer than that in acquired T790M group (18.0 months:95% CI:15.0-21.0 VS 10.0months:95% CI:8.3-11.7, P=0.016). The DCR of both groups were 89.3% and 100%. In primary T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 15.7m and 24.0 m, respectively. In acquired T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 11.0m and 10.0m, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Primary and acquired T790M-mutation patients showed different molecular characteristics. Both of them may respond to Osimertinib. However, primary T790M patients showed greater survival benefits from Osimertinib than acquired T790M patients.

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      MA15.08 - Discussant - MA 15.05, MA 15.06, MA 15.07 (ID 14643)

      14:15 - 14:30  |  Presenting Author(s): Charu Aggarwal

      • Abstract
      • Presentation
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      Abstract not provided

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      MA15.09 - Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR Mutant Advanced NSCLC Patients Treated with First-Line EGFR-TKIs (ID 13236)

      14:30 - 14:35  |  Presenting Author(s): Chunxia Su  |  Author(s): Tao Jiang, Jing Zhao, Xuefei Li, Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      We proposed a non-invasive, folate receptor (FR)-based circulating tumor cell (CTC) assay counts to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutant non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients were enrolled and three milliliter (mL) of blood were obtained prior to initial treatment, after one month, and follow-up every two months hereafter. CTCs were isolated based on negative enrichment by immunomagnetic beads and detected by a ligand-targeted polymerase chain reaction (LT-PCR) method.

      4c3880bb027f159e801041b1021e88e8 Result

      232 patients with EGFR mutations treated with first-line EGFR-TKIs were included. The objective response rate (ORR) of patients with low baseline CTC level (<20.5 FU/3 mL) were significantly higher than those with high baseline CTC level (≥20.5 FU/3 mL) (55.8% vs 38.5%, P = 0.030). Moreover, patients with low baseline CTC level had a markedly longer progression-free survival (PFS) than those with high baseline CTC level (HR = 0.50, P < 0.001). This difference remained significant after multivariate analysis (P = 0.003). Dynamic change of CTC value was significantly associated with partial response (PR) (P = 0.042) and stable disease (SD)/progression disease (PD) (P = 0.032). Of note, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before CT scanning, median: 113 days; range: 45 to 169 days.

      Table 1. Clinical and molecular characteristics of included patients.

       

      CTC < 20.5 (n = 165)

      %

      CTC > 20.5 (n = 52)

      %

      P value

      Age, years

       

       

       

       

       

      Median

      61

       

      63

       

       

      Range

      27-85

       

      40-83

       

       

      Sex

       

       

       

       

       

      Male

      79

      47.88

      28

      53.85

      0.453

      Female

      86

      52.12

      24

      46.15

       

      Smoking status

       

       

       

       

       

      Never-smoker

      122

      73.94

      35

      67.31

      0.351

      Current/ever Smoker

      43

      26.06

      17

      32.69

       

      Pathological type

       

       

       

       

       

      ADC

      150

      90.91

      47

      90.38

      0.909

      ADS

      4

      2.42

      1

      1.92

       

      NOS

      13

      7.88

      4

      7.69

       

      Clinical stage

       

       

       

       

       

      Ⅲb

      9

      5.45

      3

      5.77

      0.794

      156

      94.55

      49

      94.23

       

      Distant metastases

       

       

       

       

       

      Brain

      43

      26.06

      15

      28.85

      0.953

      Bone

      78

      47.27

      21

      40.38

       

      Liver

      10

      6.06

      1

      1.92

       

      Other sites

      109

      66.06

      34

      65.38

       

      No metastases

      12

      7.27

      3

      5.77

       

      Mutation type

       

       

       

       

       

      19DEL

      76

      46.06

      24

      46.15

      0.012

      L858R

      79

      47.88

      19

      36.54

       

      Rare mutations

      10

      6.06

      9

      17.31

       

      Response rate

       

       

       

       

       

      Complete response

      0

      0.00

      0

      0.00

       

      Partial response

      92

      55.76

      20

      38.46

       

      Stable disease

      48

      29.09

      21

      40.38

       

      Progressive disease

      25

      151.50

      11

      21.15

       

      Disease control rate

      140

      84.85

      41

      78.85

      0.310

      Objective response rate

      92

      55.76

      20

      38.46

      0.030

      ADC, adenocarcinoma; ADS, adenosquamous carcinoma; CTC, circulating tumor cell.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current evidences suggest that FR-positive CTCs can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutant NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to CT scanning.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.10 - Loss of T790M Mutation is Associated with Early Progression to Osimertinib in Chinese Advanced NSCLC Patients Harboring EGFR T790M (ID 13645)

      14:35 - 14:40  |  Presenting Author(s): Sha Zhao  |  Author(s): Tao Jiang, Xuefei Li, Chao Zhao, Chunxia Su, Shengxiang Ren, Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib has demonstrated striking superior efficacy in non-small cell lung cancer (NSCLC) patients detected acuqired T790M mutation as resistant mechanism to upfront early-generation EGFR-TKIs. However, not all the T790M positive tumors are homogeneously sensitive to osimertinib, and the duration of response often varies. Previous studies suggest that loss of T790M mutation upon progression is related to decreased therapeutic benefit from osimertinib. The aim of this study is to investigate the association of T790M-mutant status and clinical outcomes after osimertinib treatment in Chinese NSCLC patients harboring acquired EGFR T790M mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed the electric medical records of all patients receiving osimertinib monotherapy after detected acquired T790M mutation in rebiopsy after resistant to prior EGFR-TKIs, and underwent re-rebiopsy again upon progression to osimertinib at our hospital. Detailed clinicopathologic characteristics and response data were collected for all patients.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 2014 to December 2016, 230 patients were confirmed T790M mutation positive for acquired resistance to early-generation EGFR-TKIs (gefitinib, erlotinib, afatinib and icotinib). Among them, 90 patients received osimertinib monotherapy as subsequent treatment. Out of the patients, 84 (93.3%) were eligible for osimertinib-resistance analysis, and 31 (34.4%) patients underwent T790M detection in biopsy after disease progression to osimertinib. The most commonly used biopsy sample were tumor tissue, peripheral blood and hydrothorax. 16 patients remained T790M positive, while 15 patients lost T790M mutation in their re-rebiopsy samples. Loss of T790M upon progression was significantly associated with shorter duration of response to osimertinib (median time 5.93 vs 11.87 m, HR:0.325, 95%CI: 0.087 to 0.45, p=0.0005), while overall survival (OS) was not statistically different between T790M-loss and -remain groups. The objective response rates were also similar in two groups (85% and 100%, respectively). In multivariate analysis, T790M mutation loss remained significantly associated with early progression to osimertinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Loss of T790M mutation was associated early progression to osimertinib in Chinese NSCLC patients harboring acquired T790M mutation. Dynamic detection during osimertinib treatment may be a potential strategy to timely reveal disease progression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.11 - Real World Biomarker Testing and Treatment Patterns in Patients with Advanced NSCLC Receiving EGFR-TKIs (ID 12705)

      14:40 - 14:45  |  Presenting Author(s): Anne Chiang  |  Author(s): Ancilla W. Fernandes, Melissa Pavilack, Jennifer W. Wu, Francois Laliberté, Mei Sheng Duh, Nabil Chehab, Janakiraman Subramanian

      • Abstract
      • Presentation
      • Slides

      Background

      In patients who progress on treatment with first- or second-generation EGFR-TKIs, 50–60% will have an EGFR T790M resistance mutation. Osimertinib, a third-generation EGFR-TKI, is FDA approved for use in patients with metastatic EGFR T790M-positive NSCLC and disease progression on or after prior EGFR-TKI therapy, and recently gained additional approval for first-line treatment for patients with EGFR Ex19del/L858R positive advanced NSCLC. We sought to observe how many patients in the real world underwent biomarker testing on progression and subsequently received osimertinib, when T790M positive.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Flatiron Health EHR-derived database was used to identify adult patients with NSCLC treated with a first- or second-generation EGFR-TKI from 11/2015–09/2017, with the start of first EGFR-TKI defined as the index date. Patients were stratified by EGFR-TKI use as a first (1L) or later line (2L+) treatment. EGFRm status, including T790M testing and subsequent treatments received after initiating first- or second-generation EGFR-TKI, were described. Chart review was conducted on patients who received a subsequent therapy to confirm disease progression.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients in this study (n=782; 1L: n=435; 2L+: n=347) had a median age of 69 years, 64% were female, 56% were white, 87% were seen in the community, with a median follow-up of 307 days. During the study period, 30% (235/782; 1L: 96/435 [22%]; 2L+: 139/347 [40%]) of patients died without receiving a subsequent therapy, and 38% (294/782; 1L: 160/435 [37%]; 2L+: 134/347 [39%]) received subsequent therapies. From post-index date to initiation of subsequent therapies, 30% (88/294; 1L 63/160 [39%]; 2L+ 25/134 [19%]) of patients were tested for EGFR mutations including T790M. Among patients who received subsequent therapies, treatments included chemotherapies (1L=23%; 2L+=37%), immunotherapies (1L=16%; 2L+=43%), and targeted therapies (1L=64%; 2L+=30%). On progression, 25% (1L 40/160) and 5% (2L+ 7/134) of the patients received osimertinib. Of those tested for EGFR mutation post-index date (n=88), 28% (n=25) were positive for T790M and 96% of these (n=24) received osimertinib. Most patients (251/294 [85%]; 1L: 136/160 [85%]; 2L+: 115/134 [86%]) on subsequent therapies were confirmed to have disease progression at chart review.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, a third of patients were tested for subsequent EGFR mutations including EGFR T790M following treatment with first- or second-generation EGFR-TKI. Of these, a third were positive for T790M and nearly all of the T790M positive patients received osimertinib. These findings highlight low rates of biomarker testing at progression, and the need for optimal treatments that maximize benefits for patients with EGFRm NSCLC.

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      MA15.12 - Discussant - MA 15.09, MA 15.10, MA 15.11 (ID 14644)

      14:45 - 15:00  |  Presenting Author(s): Joel W. Neal

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    MS14 - IO in Early Stage NSCLC (ID 793)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 107
    • +

      MS14.01 - Basic Science Rationale of IO in Early Stage NSCLC? (ID 11458)

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

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      Abstract not provided

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

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

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      Abstract not provided

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

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

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      Abstract not provided

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

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

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      Abstract not provided

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

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

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      Abstract not provided

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    MS32 - SCLC - From Benchside to Bedside - Clinical Science Session (ID 810)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 107
    • +

      MS32.01 - Genetic Mouse Models (GEMMS) (ID 11540)

      13:30 - 13:45  |  Presenting Author(s): Trudy G Oliver  |  Author(s): Gurkan Mollaoglu, Milind Chalishazar, Fang Huang, Matthew Guthrie, Stefanie Bohm, Johannes Breagelmann, Triparna Sen, Lauren Byers, Jane Johnson, Robert Wechsler-Reya, Adi Gazdar, Ralph Deberardinis, Martin L Sos

      • Abstract
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      Abstract not provided

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      MS32.02 - Patient Derived Models (PDX &amp; CTC-Derived) (ID 11541)

      13:45 - 14:00  |  Presenting Author(s): Anna F. Farago

      • Abstract
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      Abstract not provided

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      MS32.03 - Liquid Biopsies for Drug Development in SCLC (ID 11542)

      14:00 - 14:15  |  Presenting Author(s): Caroline Dive  |  Author(s): Ged Brady, Dominic Rothwell, Kristopher Frese, Kathryn Simpson, Jacqueline Pierce, Elaine Kilgour, Fiona Blackhall

      • Abstract
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      Abstract not provided

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      MS32.04 - Molecular Phenotypes of SCLC (ID 11543)

      14:15 - 14:30  |  Presenting Author(s): Adi Gazdar

      • Abstract
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      Abstract not provided

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      MS32.05 - Targeting DNA Damage and Repair (ID 11544)

      14:30 - 14:45  |  Presenting Author(s): Lauren Byers

      • Abstract
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      Abstract not provided

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      MS32.06 - Epigenetic Targets (ID 11545)

      14:45 - 15:00  |  Presenting Author(s): John Poirier

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      Abstract not provided

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    OA01 - Improving Outcomes in Locoregional NSCLC I (ID 892)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 8
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 107
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      OA01.01 - 10-Year Updated Analysis of NRG Oncology/RTOG 0214: A Phase III Comparison of PCI vs. Observation in Patients with LA-NSCLC. (ID 14189)

      10:30 - 10:40  |  Presenting Author(s): Alexander Sun  |  Author(s): Chen Hu, Elizabeth Gore, Stuart Wong, Gregory M.M. Videtic, Swati Dutta, Mohan Suntharalingam, Yuhchyau Chen, Laurie Gaspar, Hak Choy

      • Abstract
      • Presentation
      • Slides

      Background

      To determine if prophylactic cranial irradiation (PCI) improves survival in locally advanced non–small-cell lung cancer (LA-NSCLC), we conducted a prospective randomized phase III trial. Previously we reported that compared to observation, PCI significantly increased disease-free survival and reduced brain metastases. With extended follow-up, we sought to determine whether PCI conferred an overall survival benefit.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with stage III NSCLC without disease progression after treatment with surgery and/or radiation therapy (RT) with or without chemotherapy were eligible. Participants were stratified by stage (IIIA v IIIB), histology (nonsquamous v squamous), and therapy (surgery v none) and were randomly assigned to PCI or observation. PCI was delivered to 30 Gy in 15 fractions. The primary end point of the study was overall survival (OS). Secondary end points were disease-free survival (DFS), neurocognitive function (NCF), and quality of life. Kaplan-Meier and log-rank analyses were used for OS and DFS. The incidence of brain metastasis (BM) was evaluated with the logistic regression model.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 356 patients entered to this study, 340 are eligible for analysis. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The survival estimates and hazard ratio indicate that there appears to be no improvement in survival with the use of PCI (p=0.12, HR=1.23, 95% CI: 0.95-1.59). Of note, with the current data there is only 45% power to detect the hypothesized difference HR=1.25 at 1-sided significance level of 0.025. The DFS estimates are better in the PCI arm (p=0.03, HR=1.32, 95% CI: 1.03-1.69). Patients in the observation arm were 2.33 times more likely to develop BM than those in the PCI arm (p= 0.004). On multivariate analysis PCI was significantly associated with decreased BM and improved DFS, but not OS. However, among the 225 non-surgical patients, use of PCI was associated with higher OS (p=0.026, HR=1.42, 95% CI: 1.04-1.94) and DFS (p=0.014), and lower BM (p=0.003). NCF was previously published (Sun, JCO 2011 and Gondi, IJROBP 2013), however, with longer follow-up, there is insufficient data for further analysis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this 10-year updated analysis, use of PCI continued to significantly improve DFS and reduce brain metastases. However, the early accrual closure failed to provide adequate power to detect the hypothesized difference in OS and the survival rates were not significantly different between PCI and observation. Subgroup analyses based on stratification factors suggest that PCI may improve survival among non-surgical patients.

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      OA01.02 - The Estimate of Shrinking Field and SIB Radiotherapy Guided by 18F-FDG PET/CT in Locally Advanced NSCLC Patients: A Phase 2 Randomized Clinical (ID 14474)

      10:40 - 10:50  |  Presenting Author(s): Yaping Xu  |  Author(s): Yaoyao Zhu, Chenxue Jiang, Feiying Gu, Qingren Lin, Xiaojiang Sun

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor control remains suboptimal in locally advanced lung cancer. Radiation dose acceleration has a positive effect to local tumor control, but is limited by radiation-induced lung injury (RILI). The aim of this study was to evaluate the safety and efficacy of adaptive radiation therapy guided by functional imaging 18F-FDG PET/CT in patients with locally advanced non-small lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total number of 72 patients with locally advanced NSCLC were enrolled between November 2012 and June 2017. After signing the inform consent form, 36 patients were randomized into the shrinking field and simultaneous integrated boost radiotherapy group, others were in the conventional radiotherapy group. The Objective Response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared, as well as the safety of shrinking field and simultaneous integrated boost radiotherapy (radiological dosimetry parameters and the incidence of grade 2 or higher radiotherapy-related toxicity). T-test was utilized to compare the differences between the quantitative data of two groups, while chi-square test or Fisher exact test were utilized to compare the differences between the count data of two groups. Kaplan-Meier curve was utilized to show PFS and OS, and the log-rank test analysis was utilized to compare the survival difference between two groups. P value less than 0.05 was considered statistical difference.

      4c3880bb027f159e801041b1021e88e8 Result

      All the patients in both two groups had completed their treatment according to the study protocol. The shrinking field and simultaneous integrated boost radiotherapy group was significantly greater than the conventional radiotherapy group in ORR (77.8% vs. 52.8%, P=0.026). The median OS and PFS in shrinking field and simultaneous integrated boost radiotherapy group was 22.0 months (95%CI:18.1~25.9) and 12.4 months (95%CI:10.4~14.3), which is significantly longer than 18.1 months (95%CI:12.4~23.8) and 8.2 months (95%CI:5.2~11.2) in the conventional radiotherapy group (P=0.045 and P=0.013). There was no significant difference between the two groups in radiological metrological parameters and organ at risk (OAR). The incidence of grade 2 or higher RILI, radiation-induced esophagitis, radiation-related myocardial damage and myelosuppression between two groups has no statistically significant difference.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Shrinking field and simultaneous integrated boost radiotherapy guided by function imaging 18F-FDG PET/CT is a safe and operable technique in practice. It can improve ORR, OS and PFS without increasing the risk of radiotherapy-related toxicity in patients with locally advanced NSCLC.

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      OA01.03 - Interaction Between Dose and Calcifications Is a Predictor for Overall Survival in Lung Cancer Patients Receiving Radiotherapy (ID 13920)

      10:50 - 11:00  |  Presenting Author(s): Alan McWilliam  |  Author(s): Eliana Vasquez Osorio, Frank Brewster, David Catharina Petrus Cobben, Corinne Faivre-Finn, Anna Scaife, Marcel Van Herk

      • Abstract
      • Presentation
      • Slides

      Background

      Recently, incidental dose to the heart was found to be predictive for overall survival in lung cancer patients receiving radiotherapy [McWilliam et al EJC 2017, Johnson et al Radiother Oncol 2018]. These patients often present with multiple comorbidities that should be incorporated in survival analysis. However, such data is often missing. We investigated whether calcifications, identified on the radiotherapy planning CT, can be used as a surrogate for cardiac health. In particular, we investigated the interaction between calcifications, dose and survival.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data from 814 unselected non-small cell lung cancer patients was used, all treated with 55Gy in 20 fractions. Methodology was developed to automatically segment calcifications within the heart, the aortic arch and their surroundings. The 3D planning CT scans, and the associated lung and spinal cord delineations were processed using well-established image processing algorithms, e.g., convex hull, thresholding, morphological operations, connected pixel analysis and flood filling to detect calcifications. Moreover, shape analysis was included to enhance regions that presented tubular or plate-like appearance. The detection algorithm was validated in a small subset of 10 patients, and this group was used to determine the success and error rate of the automatic segmentation. Finally, a Cox-proportional hazards multivariate analysis was performed for overall survival of all patients accounting for tumour size, total calcification volume, mean dose across all identified calcifications, and interaction between calcification volume and dose.

      4c3880bb027f159e801041b1021e88e8 Result

      The success rate of the algorithm for identifying calcifications was 81.8%, its error rate was 8.8%. The multivariate survival analysis identified tumour size (continuous, p<<0.0001) and the interaction of calcification volume and their mean dose (continuous, p=0.029) as significant. Calcification volume (p=0.57) or mean calcification radiation dose alone (p=0.269) were not found to be significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Multivariate analysis shows a significant interaction between volume of the identified calcifications and their mean radiotherapy dose predicting survival. Further improvements to identify calcifications in the descending thoracic aorta and validation of our methodology are required. Further work linking our results with the established Agatston or Coronary Artery Calcium score is in progress.

      * EVO-FB share first authorship

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      OA01.04 - Discussant - OA 01.01, OA 01.02, OA 01.03 (ID 14546)

      11:00 - 11:15  |  Presenting Author(s): John Armstrong

      • Abstract
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      Abstract not provided

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      OA01.05 - Phase II Study of Neo-Adjuvant Chemo/Immunotherapy for Resectable Stages IIIA Non-Small Cell Lung Cancer- Nadim Study-SLCG (ID 12907)

      11:15 - 11:25  |  Presenting Author(s): Mariano Provencio  |  Author(s): Ernest Nadal, Amelia Insa, Rosario García Campelo, Gerardo Huidobro, Manuel Domine, Margarita Majem, Delvys Rodríguez-Abreu, Virginia Calvo, Alex Martinez-Marti, Javier De Castro, Manuel Cobo Dols, Guillermo Lopez-Vivanco, Elvira Del Barco, Reyes Bernabé, Nuria Vinolas, Isidoro Barneto, Bartomeu Massuti

      • Abstract
      • Presentation
      • Slides

      Background

      The combination of chemotherapy and immunotherapy (CT-IO) has a high response rate and longer survival in unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). There are no data about this combination in the neoadjuvant setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Phase II, single-arm, open-label multicenter study of local-advanced resectable stage IIIA N2-NSCLC adult patients with CT plus IO (nivolumab (NV)) followed by adjuvant treatment for 1 year. Neoadjuvant treatment: Three cycles of NV 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W. After completing neoadjuvant therapy, tumor assessment is performed in patients prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. Adjuvant treatment: NV 240mg IV Q2W for 4 months and NV 480mg IV Q4W for 8 months (total one year) after surgical resection. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present preliminary data on patients that completed 3 cycles and underwent surgical resection.

      4c3880bb027f159e801041b1021e88e8 Result

      At the time of submission, 46 pts had been included and 20 underwent surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts was withdrawn from the study preoperatively due to progression or toxicity.

      Twenty surgeries had been performed and all tumors were deemed resectable. The overall clinical response rate was 5% complete (CR) and 65% PR. The pathological response evaluated after surgery: 13 cases (65.0%) achieved CR (CPR) (95% CI 40.8-84.6%), and 3 (15.0%) had a major pathologic response (MPR), defined as <10% viable tumor cells in the resection specimen. Considering both CPR and MPR, the overall response rate was 80.0% (95% CI 56.3-94.3%) and 60% of complete responses were unsuspected

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first multicentric study testing CT-IO in the neoadjuvant setting with promising antitumor activity in locally advanced, potentially resectable NSCLC yields an unprecedented complete pathologic response rate. The data will be updated at the time of the congress. EudraCT Number: 2016-003732-20

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      OA01.06 - DETERRED:  Phase II Trial Combining Atezolizumab Concurrently with Chemoradiation Therapy in Locally Advanced Non-Small Cell Lung Cancer (ID 12842)

      11:25 - 11:35  |  Presenting Author(s): Steven H Lin  |  Author(s): Xiuyan Lin, Debora Clay, Luyang Yao, Isabel Mok, Daniel Gomez, Jonathan M Kurie, George R. Simon, George R Blumenschein, Jenean Young, See Phan, Alan Sandler, Vassiliki A Papadimitrakopoulou, John V Heymach, Anne S. Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      While consolidation immunotherapy after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC (LA-NSCLC), the effectiveness of immunotherapies may be enhanced when combined concurrently with CRT. We report on the safety and preliminary efficacy of combining PD-L1 blockade using atezolizumab (atezo) and concurrent CRT followed by consolidation full dose carboplatin/paclitaxel (CP) with atezo and maintenance atezo up to 1 year for LA-NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single institution phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N=10) with CP after completing CRT, or II) concurrently (N=30) with CRT followed by consolidation atezo with CP. Atezo was given at 1200 mg IV Q3 weeks for up to one year from the first dose. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Severe adverse events (AEs) ≥ grade 3 are defined within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Evaluable patients (pts) have received at least one dose of atezo.

      4c3880bb027f159e801041b1021e88e8 Result

      From February 2016 to April 2018, we accrued 40 evaluable pts. For part 1, any grade 3+ AEs was seen in 6 pts (60%), with most common being pneumonia (2 of 10, 20%). Three grade 3+ AEs (30%) were attributed to atezo, including dyspnea, arthralgia and a grade 5 TE fistula. Grade 2 radiation pneumonitis (RP) was seen in 3 pts. Four progressed with disease during atezo maintenance and have died, ranging from 0.93 to 1.86 years. Four pts completed atezo and are in follow up without recurrence. For part 2, 17 of 30 pts had any grade 3+ AEs (57%), with pneumonia being the most common (6 of 30, 20%). Three (10%) were attributed to atezo (dyspnea, fatigue and heart failure). RP was seen in 3 pts, with 2 grade 2 and 1 grade 3, which led to atezo discontinuation. So far, 4 pts have progressed and 4 have died, 2 due to disease and 2 due to treatment (neutropenic sepsis and gastric hemorrhage). All others have completed CRT and are on maintenance atezo, ranging from 5 to 19 doses. Updated efficacy results will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Concurrent atezo with CRT followed by consolidation and maintenance atezo appears safe without increased toxicities compared to CRT alone followed by consolidation and maintenance atezo.

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      OA01.07 - Updated Results of a Phase II Trial of Concurrent Chemoradiation with Consolidation Pembrolizumab in Patients with Unresectable Stage III NSCLC (ID 13961)

      11:35 - 11:45  |  Presenting Author(s): Greg Durm  |  Author(s): Sandra Althouse, Ahad Sadiq, Shadia Jalal, Salma Jabbour, Robin Zon, Goetz H Kloecker, William Fisher, Karen L. Reckamp, Ebenezer Kio, Robert Langdon, Bamidele Adesunloye, Ryan Gentzler, Nasser Hanna

      • Abstract
      • Presentation
      • Slides

      Background

      Concurrent chemoradiation (CRT) has been the standard Rx for pts with unresectable stage III NSCLC. A recent phase III trial (PACIFIC) of consolidation durvalumab [PDL-1 inhibitor] demonstrated improved median PFS vs. placebo (16.8 vs. 5.6 mo, HR 0.52, p<0.001). 12-mo (55.9% vs. 35.3%) and 18-mo (44.2% vs. 27%) PFS were also improved. Toxicity was manageable with a grade 3-4 pneumonitis rate of 3.4%, and 4 patients experienced grade 5 pneumonitis. We report updated results of a phase 2 trial of consolidation pembrolizumab [PD-1 inhibitor] following concurrent CRT in patients with unresectable stage III NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      After completion of CRT with carboplatin/paclitaxel, cisplatin/etoposide, or cisplatin/pemetrexed + 59-66.6 Gy XRT, those pts w/o PD after 4-8 weeks off CRT received pembro 200 mg IV q3wk for up to 1 yr. The primary endpoint was time to metastatic disease or death [TMDD]. Key secondary endpoints included PFS, OS, and toxicity.

      4c3880bb027f159e801041b1021e88e8 Result

      93 pts enrolled [92 eligible for efficacy analysis]. Median f/u was 18.6 mo and median age 66 (45-84). 64.1% male and 35.9% female. Stages were 59.8% IIIA and 40.2% IIIB. 55.4% non-SqCC and 43.5% SqCC with 1 mixed histology. 94.6% were current/former smokers. Chemo regimens included carbo/pac (71.7%), cis/etop (26.1%), cis/pemetrexed (2.2%). Median number of cycles of pembro was 13.5 [1-19]. 16% received < 4 cycles; 84% received > 4 cycles; 37% completed 1 yr pembro. Median TMDD was 22.4 months (95% CI 17.9-NR). Median OS was NR (95% CI 22.4-NR), and the estimates of 1-yr and 2-yr OS were 81% and 61.9% respectively. Median PFS was 17 months (95% CI 11.9-NR). 12, 18, and 24-month PFS were 60.2%, 49.9%, and 44.6% respectively. 16 (17.2%) pts developed G2 pneumonitis, 5 (5.4%) had G3-4 pneumonitis. There was 1 pneumonitis-related death. In those developing G2 pneumonitis, the median time was 8.4 wks [1.1-48.3]. No other G 3/4 toxicities exceeded 5% except dyspnea (5.4%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Consolidation pembrolizumab following CRT substantially improves TMDD and PFS compared with historical controls. Prelim OS data is promising and suggests a substantial gain in outcomes of patients with stage III NSCLC is possible with consolidation pembrolizumab. These data will be updated further prior to the World Conference on Lung Cancer Meeting.

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      OA01.08 - Discussant - OA 01.05, OA 01.06, OA 01.07 (ID 14547)

      11:45 - 12:00  |  Presenting Author(s): Corey J Langer

      • Abstract
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      Abstract not provided

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