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
    • Now Available
    • 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) (Now Available) (ID 11391)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancers invading ipsilateral mediastinal lymph nodes (stage IIIA/N2) account for 30-50% of the locally advanced NSCLC cases [1]. The optimal treatment strategy for potentially resectable stage IIIA/N2 remains challenging and controversial. Interpretation of literature data is complicated by inconsistent evaluation of N2 disease (pathological confirmation vs. imaging-based), heterogeneity of N2 disease spectrum (ranging from single-station microscopic to bulky, multilevel nodal involvement) and pooled analysis of N2 patients with other stage III patients. Results of primary surgery or radiotherapy used as single modality are disappointing. To improve the outcomes combinations of chemotherapy+/-radiotherapy and surgery are being explored.

      Treatment strategies for patients presenting with non-bulky N2 disease include: (1) induction chemotherapy followed by surgery and postoperative radiotherapy if indicated; (2) induction chemoradiotherapy followed by surgery and postoperative chemotherapy if indicated; (3) definitive chemoradiation.

      Preoperative chemotherapy offers the possibility of tumor downstaging, may increase operability and assists in early eradication of micrometastases. Latest meta-analysis of 15 randomized clinical trials showed a significant survival benefit of preoperative chemotherapy (hazard ratio [HR] 0.87, 95% CI 0.78-0.96, p=0.007) [2]. It was consistent with an absolute survival improvement of 5% at 5 years, from 40 to 45%. The tumor downstaging effect is dependent on chemotherapy regimen and number of administered cycles. Cisplatin as compared to carboplatin is found to be more effective in inducing tumor response, that is most pronounced after three cycles of chemotherapy [3].

      Adding radiotherapy to preoperative chemotherapy can increase pathological complete response (pCR) and mediastinal downstaging. Preoperative chemoradiotherapy, as compared to induction chemotherapy alone, is associated with comparable peri-intervention mortality and higher R0 resection [4]. However, based on the negative results of the Intergroup 0139 trial, designed to address the role of surgery after neoadjuvant chemoradiotherapy, level 1 evidence exists for definitive chemoradiation alone [5]. Additionally, in the three published meta-analyses, the use of preoperative chemoradiotherapy did not translate into better overall and progression-free survival of resectable stage IIIA/N2 NSCLC [4, 6, 7]. Furthermore, delivering doses of ≥45Gy in combination with chemotherapy is predictive of postoperative complications [8]. However, in case of a substantial risk of positive resection margins the use of preoperative radiotherapy in combination with chemotherapy, in expert hands, should be considered for carefully selected, fit patients.

      After induction chemo(radio)therapy lobectomy is the preferred surgical approach, as pneumonectomy, especially right-sided, may carry the risk of unacceptable perioperative mortality (14-26%) [5, 9].

      To conclude, neoadjuvant chemoradiotherapy or chemotherapy alone followed by surgery seem both acceptable in selected stage IIIA/N2 NSCLC clinical scenarios. Those approaches present an alternative to definitive chemoradiation strategy for clinically fit patients with potentially resectable N2 NSCLC.

      In the context of the available data a real-life single zone N2 NSCLC case will be presented and discussed. The importance of careful patients' selection and rigorous staging procedures (PET/CT, brain MR, invasive evaluation of mediastinal lymph nodes with pathologic confirmation) will be highlighted. The PET/CT of our 72-year old lung adenocarcinoma patient revealed a primary tumor in the right upper lobe (13x10mm, SUVmax=9,6) accompanied by higher FDG uptake in right hilar lymph nodes (15x13mm, SUVmax=9,5) and lymph nodes located in front of the carina (15x9mm, SUVmax=6,4). To determine the optimal treatment strategy in stage IIIA NSCLC the precise evaluation of the mediastinum is required. As imaging-based evaluation of mediastinal lymph nodes is not sufficient, pathologic confirmation of involvement is obligatory. Our patient underwent EBUS that confirmed the involvement of 4R and 10R lymph node stations. The brain CT ruled out the distant spread into the CNS.

      The optimal treatment strategy of lung cancer patients should be achieved on the basis of multidisciplinary tumor board (MTB) consensus. During the MTB meeting our patient with T1N2 NSCLC was qualified to three cycles of preoperative chemotherapy based on gemcitabine (900mg/m2) and cisplatin (75mg/m2) combination and subsequent upper right lobectomy with mediastinal lymphadenectomy. After the completion of chemotherapy, chest CT and mediastinoscopy were performed, as the adequate post induction re-staging is of paramount importance. The partial response of the primary tumor and the persistent N2 disease were confirmed. The patient underwent right upper lobectomy with mediastinal lymphadenectomy. In the pathological report stage ypT1aN2,R0 was documented. The patient refused the offered adjuvant treatment and is now in watchful follow-up.

      1. Goldstraw P, Crowley J, Chansky K et al: The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007, 2(8):706-714.

      2. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014, 383(9928):1561-1571.

      3. Hotta K, Matsuo K, Ueoka H et al: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2004, 22(19):3852-3859.

      4. Chen Y, Peng X, Zhou Y et al: Comparing the benefits of chemoradiotherapy and chemotherapy for resectable stage III A/N2 non-small cell lung cancer: a meta-analysis. World J Surg Oncol 2018, 16(1):8.

      5. Albain KS, Swann RS, Rusch VW et al: Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009, 374(9687):379-386.

      6. Shah AA, Berry MF, Tzao C: Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac Surg 2012, 93(6):1807-1812.

      7. Guo SX, Jian Y, Chen YL et al: Neoadjuvant Chemoradiotherapy vesus Chemotherapy alone Followed by Surgery for Resectable Stage III Non-Small-Cell Lung Cancer: a Meta-Analysis. Sci Rep 2016, 6:34388.

      8. Fujita S, Katakami N, Takahashi Y et al: Postoperative complications after induction chemoradiotherapy in patients with non-small-cell lung cancer. Eur J Cardiothorac Surg 2006, 29(6):896-901.

      9. Thomas M, Rube C, Hoffknecht P et al: Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol 2008, 9(7):636-648.

      10. Decaluwe H, De Leyn P, Vansteenkiste J et al: Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg 2009, 36(3):433-439.

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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 (Now Available) (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 (Now Available) (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
    • Now Available
    • 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).

      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.

      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.

      Conclusion

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

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

      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.

      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.

      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.

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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.

      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.

      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.

      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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      MA04.04 - Discussant - MA 04.01, MA 04.02, MA 04.03 (Now Available) (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% (Now Available) (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%.

      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.

      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.

      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.

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

      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.

      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.

      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.

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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 (Now Available) (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.

      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.

      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).

      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 (Now Available) (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) (Now Available) (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].

      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.

      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%).

      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 (Now Available) (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).

      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.

      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.

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (ID 14588)

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

      • Abstract
      • Presentation
      • Slides

      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
    • Now Available
    • 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 (Now Available) (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).

      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.

      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

      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 (Now Available) (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).

      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.

      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).

      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 (Now Available) (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.

      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.

      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)

      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 (Now Available) (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 (Now Available) (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.

      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).

      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%).

      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.

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

      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.

      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

      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.

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

      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.

      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.

      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 (Now Available) (ID 14643)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (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).

      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.

      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.

      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.

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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 (Now Available) (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.

      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.

      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.

      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.

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

      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.

      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.

      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 (Now Available) (ID 14644)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS14 - IO in Early Stage NSCLC (ID 793)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 107
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      MS14.01 - Basic Science Rationale of IO in Early Stage NSCLC? (Now Available) (ID 11458)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      The 5-year overall survival (OS) of patients with surgically treated early stage NSCLC ranges from 92% (stage IA) to 36% (stage IIIA). Numerous clinical trials over the last decades tried to improve on these results by either adding adjuvant therapy (i.e. in addition after a radical local therapy) or neoadjuvant therapy (i.e. cytoreductive before a radical local therapy).

      Adjuvant setting

      Adjuvant therapy for resected NSCLC came into place in 2004, when the large International Adjuvant Lung cancer Trial (IALT) demonstrated OS benefit with cisplatin-based chemotherapy. No further progress with other types of adjuvant therapy has been made since then. The progress in patients with advanced NSCLC in stage IV with pemetrexed, bevacizumab and EGFR-directed TKIs was not translated in the adjuvant setting [1].

      As for immunotherapy, the MAGRIT trial assessed antigen-specific immunotherapy directed to the MAGE-A3 antigen in completely resected MAGE-A3 positive NSCLC [2]. The adjuvant setting – where the aim is to eliminate sparse tumor cells remaining after surgery – was judged to be the ideal setting for this approach. Unfortunately, the trial did not improve survival. One of the hypotheses why is that the generated MAGE-A3 directed T-cells with cancer killing properties did not travel nor enter easily in tumors, and even if they did, they encountered checkpoints that blocked their potential benefit.

      Immune checkpoint inhibitor (ICI) immunotherapy, which revolutionized the approach to metastatic NSCLC, is now tested in the post-surgical setting with micrometastatic disease and low tumor burden. In contrast to directly cytotoxic chemotherapy, however, agents blocking the PD-1/PD-L1 axis require an interaction between antigen-presenting cells, CD8+ T cells, and tumor cells. It is far from certain that these intercellular interactions will occur sufficiently in patients with micrometastatic disease, where low tumor (mutation) burden may not sufficiently incite the tumor microenvironment. Because of the adjuvant setting, without detectable disease, no early effectiveness read-outs of efficacy nor translational tissue research is feasible. The results of the different ongoing trials with adjuvant ICI therapy in early stage NSCLC needs to be awaited.

      Neoadjuvant setting

      Because of the aforementioned limitations, the neoadjuvant use of PD-1/PD-L1 blockade is of greater interest for several reasons.

      From a biologic perspective, PD-1/PD-L1 blockade before surgery, when the tumor mass and intact locoregional lymph nodes with ongoing activation of T cells may be present, might be more rational. In a breast cancer model in mice, it has been suggested that neoadjuvant ICI is more effective than adjuvant ICI [3]. In the neoadjuvant setting, there was a stronger systemic antitumor T-cell response with maintenance of tumor specific CD8+ T cells in the blood early after immunotherapy. High levels of CD8+ T cells predicted long-term survival in this mouse model. Moreover, induction of this systemic immune response could lead to immune memory that may prevent metastatic relapse over time.

      From a clinical perspective, the neoadjuvant strategy has advantages, as we learned from the chemotherapy era. The systemic therapy has better distribution because of the intact vascularization, which may reduce the locoregional tumor extension. There is an early attack microscopic metastatic disease and the effectiveness can be evaluated in vivo with pre- and post-imaging.

      From a clinical trial perspective, a big advantage is the possibility to study surrogate endpoints. The crucial outcome in this setting is OS, but this endpoint requires many years of follow-up. Here as well, lessons learnt from neoadjuvant chemotherapy followed by surgical resection are of use. Tumor-free lymph nodes and pathological response in the primary tumor have been associated with significantly better outcome. In a dedicated study on the prognostic impact of morphometric tissue analysis of tumor regression, the latter was graded in I: no regression; II: remaining vital tumor tissue ≥10% (grade IIa) or <10% (grade IIb); and III: no evidence of vital tumor tissue [4]. Patients with tumors of regression grades IIb or III showed significantly longer OS than the others (3-year OS 52% vs 9%, P=0.02). These findings, however, do not help to select patients for surgery, as they are post-hoc analyses on the resection specimen. Ideally, one should have pre-surgical (pre-hoc analysis) predictors, but the standard clinical restaging with repeat CT after neoadjuvant only is a raw tool for this purpose. Our group first demonstrated that morphometric tissue analysis of mediastinal lymph nodes after induction was a strong prognosticator in that setting [5]. This was then validated in a prospective multi-center setting, using the first video-mediastinoscopy after neoadjuvant chemotherapy [6]. Patients with a grade IIA or III regression (<10% viable tumor) had much better outcome than the others: 5-year OS 43% versus 19%.

      A recent pilot study evaluated the clinical, pathological, and immunologic effects of short-term neoadjuvant PD-1 blockade in NSCLC [7]. Here again, major pathological response was defined as ≤10% residual viable tumor on sections of the resected tumor. With this criterion, 45% of the patients had a major pathological response, with clear infiltration of CD8+ T cells in regressing tumors. Moreover, a systemic immune response with T-cells of similar T-cell receptor repertoire as in the tissue were described. Even with its small sample (N=21), this strategy has a strong mechanistic principle, both in the tumor and on distant sites, and has resulted in a promising surrogate endpoint effect. Whether this will translated in better 5-year OS now needs to be defined in larger multi-center phase 3 trials, several of which are currently started.

      References

      1. Deslypere G. et al. Ther Adv Med Oncol 2018; 10: 1-11.

      2. Vansteenkiste J. et al. Lancet Oncol 2016; 17: 822-35.

      3. Liu J et al. Cancer Discov 2016; 6: 1382-99.

      4. Junker K et al. Chest 2001; 120: 1584-91.

      5. Dooms C et al. J Clin Oncol 2008; 26: 1128-34.

      6. Dooms C et al. J.Thorac.Oncol. 12 Suppl 1, 460S. 2017.

      7. Forde P et al. N Engl J Med 2018; 378: 1976-86.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Perioperativ immunotherapy is a relative new field in thoracic oncology. Although several studies are ongoing, there are until now only two publications describing the effect of preoperative immunotherapy and the intraoperative and the postoperative course of patients with thoracic malignancies.

      The first study is a publication by Forde and colleagues (1), dealing with patients with resectable lung cancer who received one or two preoperative doses of PD-1-inhibitior Nivolumab. The immunotherapy was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The authors described an acceptable side-effect profile and no delays in surgery. Treatment-related adverse events of any grade occurred in 5 of 22 patients (23%) an only one event was a 3 grades side effect. This was a patient with a pneumonitis who could be resected thereafter that without any complications. The median interval between the administration of the second dose of Nivolumab and surgery was 18 days (range 11 to 29). Twenty of 21 eligible patients underwent a complete resection. The preoperative imaging showed that the majority of the patients (86 %) had stable disease.

      The other report (2) deals with the safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors. This is a retrospective study on 19 patients treated between 2012 and 2016. The majority of them had lung cancer (47 %) followed by metastatic melanoma. Various types of immunotherapeutic agents were used. Anatomic resections (lobectomy or greater) were performed in 11 patients. Complications occurred in 32 % but the majority of them were again only minor. One patients developed postoperative pneumonitis in the contralateral lung approximately 2 weeks after VATS-resection on the other side.

      In summary, preoperative immunotherapy seems to be applicable with only minor side effects. However, there are only few reports and theoretically other complications might occur. Especially if the side effect spectrum in patients with metastatic disease and immunotherapy is considered (3). Frequent side effects are pneumonitis, hepatitis or even myocarditis. The development of such side effects should be excluded in each patient undergoing surgery after immunotherapy.

      References

      1. Forde PM, Chaft JE, Smithe KN et al. Neoadjuvant PD-1-Blockade in Resectable Lung Cancer. N Engl J MED 2018 378;21.

      2. Matthew JB, Cools-Lartigue J, Tan KS et al. Safety and Feasibility of Lung Resection after Immunotherapy for Metastatic or Unresectable Tumors. Ann Thorac Surg 2018; …..

      3. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med 2018 378;22.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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

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

      • Abstract
      • Presentation
      • Slides

      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
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 107
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      MS32.01 - Genetic Mouse Models (GEMMS) (Now Available) (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
      • Presentation
      • Slides

      Abstract

      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor that has historically been treated as a single disease. Loss of the tumor suppressors RB1 and TP53, and amplifications inMYCfamily members, are frequent events in SCLC. We show that Myc expression cooperates withRb1 andTrp53loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low ‘‘variant’’ subset of SCLC with low ASCL1 and high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival (Mollaoglu et al, Cancer Cell, 2017; Cardnell et al, Oncotarget, 2017). These findings were recently recapitulated in clinical trials where patients with relapsed SCLC exhibited significantly longer survival when treated with an Aurora kinase inhibitor specifically if tumors were high for MYC. More recently, our work and others suggests that MYC-high SCLC is also vulnerable to CHK1 inhibition. These data identify molecular features for patient stratification of SCLC and uncover a potential targeted treatment approach for MYC-driven SCLC.

      More recently, we have performed unbiased metabolic profiling of MYC-driven SCLC cell lines and murine tumors compared to MYCL and MYCN-driven samples. We find that MYC-driven SCLC is metabolically distinct in vitro and in vivo.Our findings reveal that guanosine nucleotides and biosynthetic enzyme Inosine Monophosphate Dehydrogenase-1 and -2 (IMPDH1 and IMPDH2) are elevated in MYC-high/ASCL1-low tumors and cell lines. IMPDH inhibition using Mizoribine selectively impeded the growth of MYC-high/ASCL1-low xenografts, and combined with chemotherapy to improve survival in MYC-driven genetically engineered mouse models (Huang et al, Cell Metabolism, In Press). These data strongly suggest that SCLC is composed of unique molecular subtypes with specific vulnerabilities to targeted therapy that should be considered in basic studies and clinical trial design.

      References:

      Cardnell RJ, Li L, Sen T, Bara R, Tong P, Fujimoto J, Ireland AS, Guthrie MR, Bheddah S, Banerjee U, Kalu NN, Fan YH, Dylla SJ, Johnson FM, Wistuba II, Oliver TG, Heymach JV, Glisson BS, Wang J, Byers LA (2017). Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies. Oncotarget, 8(43), 73419-73432.

      Huang F, Ni M, Chalishazar MD, Huffman KE, Kim J, Cai L, Shi X, Zacharias LG, Cai F, Gu W, Ireland AS, Gazdar AF, Oliver TG, Minna JD, Hu Z, and DeBerardinis RJ (In Press). Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers. Cell Metab, 2018.

      Mollaoglu G, Guthrie MR, Bohm S, Bragelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG (2017). MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell, 31(2), 270-285.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Patient-derived xenograft (PDX) models are a powerful preclinical tool for studying small cell lung cancer (SCLC) biology and therapeutic vulnerabilities. SCLC PDX models can be generated from biopsies or circulating tumor cells (CTCs), though these approaches can be limited by scarcity of tissue and low efficiency of tumor growth. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we have generated over 40 PDX models. In a 24-month period, we initiated 17 biopsy-derived PDXs and 17 CTC-derived PDXs, at 89% and 38% efficiency, respectively (Drapkin et al., Cancer Discovery 2018). Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. We have standardized quantitative measurements of efficacy of in vivo treatments, utilizing both depth of tumor shrinkage (response) and time to tumor volume doubling (time to progression). With these approaches, we have assessed responses to both standard of care and experimental therapies across a large panel of mice. We find that sensitivity to etoposide and platinum (EP) corresponds with the treatment history of patients, and that resistance to EP corresponded to increased expression of a MYC gene signature. Similarly, responses of the PDXs to an experimental combination, olaparib and temozolomide, mirrors the responses seen in patients treated on a clinical trial (Farago et al., ASCO 2018). Biomarker analysis in this panel reveals that basal PARylation is a highly sensitive and specific predictor of response to olaparib and temozolomide. Collectively, this experience highlights the utility of PDX models in SCLC for biomarker discovery and assessment of novel therapeutic strategies.

      References:

      1. Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zong J, Igo P, Hazar-Rethinam MH, Licausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Buttner R, Haas S, Sequist LV, Shaw AT, Wong K-K, Hata A, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, Farago AF. Genomic and functional fidelity of small cell lung cancer patient-derived xenografts. Cancer Discovery 2018 May 8(5):600-615. PMID: 29483136

      2. Farago AF, Drapkin BJ, Charles A, Yeap B, Heist RS, Azzoli CG, Jackman D, Marcoux P, Barbie D, Myers DT, Phat S, Zhong J, Grinnell JB, Sequist LV, Mino-Kenudson M, Maheswaran S, Haber D, Hata A, Dyson N, Shaw AT. Safety and efficacy of combination olaparib (O) and temozolomide (T) in small cell lung cancer (SCLC). American Society of Clinical Oncology Annual Meeting, June 1-5 2018. Poster presentation

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      MS32.03 - Liquid Biopsies for Drug Development in SCLC (Now Available) (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
      • Presentation

      Abstract

      The progress in recent years in understanding SCLC biology and phenotypic heterogeneity has led to a number of rational drug development opportunities being evaluated in early clinical trials. Historically clinical trials in SCLC have not included predictive or pharmacodynamics biomarkers because of a lack of understanding of what to measure and the difficulty of obtaining tumour specimens in which to evaluate them, particularly longitudinally.

      SCLC patients have prevalent circulating tumour cells (CTCs) that express EpCAM and are thus detectable using the CellSearch (CS) platform. CS CTC number is prognostic at baseline, has a wide dynamic range making it useful as a pharmacodynamic biomarker, and also acts as a surrogate of tumour response to chemotherapy (1). The prevalence of CS CTCs also allows CTC-based predictive biomarker assay development. In this regard we showed that a single CTC-based copy number alteration (CNA) signature can predict pre-treatment whether a SCLC patient will be chemorefractory (progress within 90 days of chemotherapy treatment) or initially chemosensitive (2). We have also recently shown using global CNA metrics and a panel of 110 SCLC associated genes that ctDNA was detectable in >90% of a cohort of both limited and extensive stage SCLC patients making it a highly suitable tool for patient monitoring.

      In 2014 we pioneered the development of CTC derived patient explant (CDX) models in immune compromised mice (3) which faithfully recapitulate the donor patients’ tumour morphology and genomic landscape, and mimic their response to cisplatin-based chemotherapy. The models also display patient-relevant metastatic tissue tropism and cell subpopulations are competent for vasculogenic mimicry (4). We are currently interrogating phenotypic heterogeneity in our panel of 45 CDX models and using them to test novel drug combinations including DNA damage repair and cell cycle checkpoint inhibitors (5). CDX cells can be cultured ex vivo for short periods, genetically manipulated and re-implanted in vivo for hypothesis testing studies (6) and most recently we have witnessed progress in culturing CTCs directly from patients' blood samples. These ex vivo approaches allow therapy screening (CDX cultures) or real time viability assays tailored to small cell numbers (CTC cultures) that ultimately may be able to inform patient treatment. All of the aforementioned applications of liquid biopsies in SCLC will be discussed and reviewed.

      References

      1. Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30(5):525-32.

      2. Carter L, Rothwell DG, Mesquita B, Smowton C, Leong HS, Fernandez-Gutierrez F, et al. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat Med. 2017;23(1):114-9.

      3. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014;20(8):897-903.

      4. Williamson SC, Metcalf RL, Trapani F, Mohan S, Antonello J, Abbott B, et al. Vasculogenic mimicry in small cell lung cancer. Nat Commun. 2016;7:13322.

      5. Lallo A, Frese KK, Morrow CJ, Sloane R, Gulati S, Schenk MW, et al. The combination of the PARP inhibitor olaparib and the Wee1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer Clin Cancer Res. in press.

      6. Lallo A, Warpman Berglund U, Frese KK, Potter DS, Helleday T, Dive C. Ex vivo culture of circulating tumour cell derived explants to facilitate rapid therapy testing in small cell lung cancer. European Association for Cancer Research Annual Conference; Manchester, U.K.2016.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Heterogeneity of neuroendocrine (NE) differentiation in small cell lung cancer (SCLC) determines very different molecular phenotypes

      Background and Purpose: SCLC is usually regarded as a homogenous tumor treated in a standard fashion. We have established and validated a 50 gene expression quantitative scoring system for NE lung tumors, consisting of both positive and negative scores [1]. While almost all carcinoid tumors have positive scores, SCLC and large cell neuroendocrine carcinomas have positive and negative subpopulations.

      Methodology: We utilized the NE gene expression score to demonstrate intertumor heterogeneity of gene expression patterns and their relationship to signaling pathways and to immune and inflammatory response. We used cluster analysis to divide the SCLC samples into high and low NE subtypes. We studied two public SCLC tumor data sets (n = 140) as well as 70 cell lines established by us and a pair of high/low sublines established from a single SCLC cell line.

      Results: The NE score cluster analysis indicated that ~10% of cell lines and ~20 of SCLC tumors were of the low NE subtype. The low NE subtype samples had RB1 mutations or low or absent RB1 expression, confirming their SCLC origin. Differences between the high and low subtypes were divided into those common to tumors and cell lines and those largely or entirely limited to tumors.

      Differences common to tumors and cell lines. At least three different lineage specific transcription factors were expressed by SCLC tumors and cell lines. Most NE high cells expressed ASCL1 in conjunction with NKX2-1. NEUROD1, occasionally with ASCL1, was expressed by a smaller subset of NE high and occasionally by NE low cells. POU2F3 was expressed by most of the NE low subtypes, and about half of these also expressed ASCL2. However, about 4% of tumors and cell lines (all belonging to the NE low subtype) lacked an identified lineage specific transcription factor. The NE high subtype expressed all of the classic NE markers, as well as numerous neural markers covering neural and glial differentiation. In addition they selectively expressed markers for DNA damage, the FGFR pathway, calcium signaling and Notch inhibitors. The NE low subtype lacked all or most of the NE cell program, NKX2-1 and DLL3 expression, while MYC and REST expression, the Hippo, TGFb and Notch pathways and EMT were greatly upregulated. These and other findings were predicted to impact on the potential responses of the two subtypes to chemotherapy, radiotherapy, and multiple targeted therapies.

      Differences limited to tumors and absent in cell lines: Despite having a high mutational burden, SCLC is considered to be an “immunological desert”, with few infiltrating immune or inflammatory cells, low or absent PDL-1 expression, and modest responses to PD-1 blockade. While the high NE tumors fitted this description most of the low NE tumors had strands of fibrosis encircling tumor islets, with varying numbers of inflammatory cells in the fibrous strands. Major differences at multiple steps were present in the low NE subtype involving the over 200 genes regulating the Cancer-Immunity Cycle, including the major cytokine families, toll like receptors, the inflammasome pathway, the JAK/STAT pathway, HLA antigens, CD47 antigen, perforin and granzymes. These changes were accompanied by highly significant increases in the relative numbers of multiple types of infiltrating immune and inflammatory cells. In addition, the low NE subtype had increased expression of PDL-1 and the interferon gamma signature, suggesting enhanced responses to immunotherapy.

      Conclusions: SCLC tumors and cell lines can be divided into high and low NE subtypes and these subtypes have major differences in lineage specific transcription factors, expression of the NE program, as well as some oncogenes and pathways, predicting them to respond very differently to conventional and targeted therapies. In addition, very different infiltrating cellular and gene expression patterns of immune responses were present in the low NE tumors, involving multiple aspects of Innate and Adaptive Immunity, and predicting that the low NE subtype tumors are more likely to respond to immunotherapy. In addition, several possibilities of combining cytotoxic, targeted and immunotherapies are suggested from our findings.

      I thank my collaborators for their invaluable contributions: Ling Cai, Tao Wang, Guanghua Xiao, Luc Girard and John Minna.

      1. Zhang W, Girard L, Zhang YA, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 2018;7(1):32-49.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Small cell lung cancer (SCLC) remains one of the most recalcitrant cancer types, with a 5 year survival less than 10% across all stages. At the genomic level, SCLC is characterized by loss of p53 and RB1 function and frequent amplification or overexpression of MYC family members1. These molecular hallmarks of SCLC contribute to high rates of replication stress and genomic instability which, in turn, may make SCLC tumors more susceptible to drugs targeting DNA damage response (DDR).

      Previously, we found that PARP1, Chk1, Wee1, and other proteins regulating DNA repair are highly expressed in SCLC, as compared to other lung cancers2. Based on this finding, several DDR inhibitors have now been tested in SCLC models as single agents or in combination with other DDR inhibitors or chemotherapy. Pharmacologic inhibitors of PARP, Chk1, Wee1, and ATR (alone or in combination) have shown promising activity in SCLC cell lines and mouse models (as reviewed in Sen, Gay, and Byers, TLCR 2018)3.

      Interestingly, in SCLC, response to PARP inhibitors and other DDR inhibitors has not been associated with mutations in BRCA1/2, other gene defects in homologous recombination (HR), or with higher HR deficiency scores. Rather, several novel biomarkers have been identified that define subsets of SCLC with enhanced sensitivity to specific DDR inhibitors. These include high SLFN11 expression as a predictor of PARP inhibitor sensitivity and MYC amplification or overexpression as a predictor for Chk1 and aurora kinase targeting. Many of these biomarkers are associated with pathways that contribute to replication stress (e.g., high MYC activity) or that promote replication arrest following DNA damage (e.g., high SLFN11)4,5. This supports the hypothesis that SCLC tumors under greater replication stress may be more susceptible to DDR inhibitors.

      Several PARP inhibitors (e.g., olaparib, rucaparib, niraparib) are now approved for the treatment of breast and ovarian cancer and inhibitors that hit other DDR targets are in various stages of clinical development. The availability of these agents – together with the preclinical data – has led to several clinical trials investigating DDR inhibitor targeting in SCLC. Results from a recently published randomized Phase 2 trial of temozolomide (TMZ) with either veliparib (PARP inhibitor) or placebo in 104 relapsed SCLC patients did not meet its primary endpoint of 4-month progression free survival (PFS)6. However, response rates were three times as high in the veliparib-treated patients (39% TMZ/veliparib vs. 19% TMZ/placebo, p=0.016). Furthermore, when patients were stratified by biomarker status, those patients with SLFN11-positive tumors (as measured by IHC) who received the PARP inhibitor had significantly higher PFS and overall survival (OS) than biomarker-negative patients (interaction p-value 0.009). For example, SLFN11-positive patients treated with TMZ/veliparib had a median OS of 12.5 months as compared to 7.5 months in SLFN11-negative patients (p=0.014). In contrast, there was no difference in PFS or OS based on biomarker status in patients in the placebo (TMZ only) arm, supporting that the biomarker was in fact predictive of benefit from PARP inhibitor treatment.

      An ongoing study combining the PARP inhibitor olaparib with TMZ is further exploring this combination in relapsed SCLC patients (NCT02446704). In addition, two trials have now been conducted investigating veliparib in combination with frontline platinum-etoposide chemotherapy (NCT01642251 and NCT02289690). SLFN11 biomarker analysis from the first of these studies will be presented at this meeting. Other DDR inhibitors in clinical investigation include the Chk1 inhibitor prexasertib and the Wee1 inhibitor AZD1775 (alone or in combination with other DDR inhibitor or chemotherapy).

      DDR targeting may also potentiate the effect of immunotherapy. In other cancer types, recent reports describe enhanced activity of immune checkpoint inhibitors in cancers with inherent DDR deficiencies such as BRCA1 mutations. Clinical trials in multiple tumor types including lung cancer are underway investigating whether treatment with a DDR inhibitor could enhance response to immunotherapy. Emerging preclinical data suggests activity of DDR-immune targeting in SCLC.

      REFERENCES

      1. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53.

      2. Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov 2012;2:798-811.

      3. Sen T, Gay CM, Byers LA. Targeting DNA damage repair in small cell lung cancer and the biomarker landscape. Transl Lung Cancer Res 2018;7:50-68.

      4. Sen T, Tong P, Stewart CA, et al. CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res 2017;77:3870-84.

      5. Steward, AC, Tong P, Cardnell RJ, et al. Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer. Oncotarget 2017;8:28575-87.

      6. Pietanza MC, Waqar SN, Krug LM, et al. Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer. J Clin Oncol 2018:JCO2018777672.

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      MS32.06 - Epigenetic Targets (Now Available) (ID 11545)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer remains the most common cause of death in men and women, responsible for more deaths than colon, breast and prostate cancer combined. Lung adenocarcinoma (a type of NSCLC) and small cell lung cancer (SCLC) comprise two of the major subgroups within lung cancer and collectively contribute to a high degree of cancer mortality year after year. Despite recent success in developing and implementing targeted therapeutics for several prominent driver oncogenes in NSCLC, SCLC remains a critical unmet medical need in the cancer field, in part due to a relative paucity of actionable mutations and well-defined biomarker-directed therapies. New therapeutic strategies are desperately needed to improve clinical outcomes for patients with SCLC.

      Despite lacking known driver oncogenes, such solid tumors have been shown to have frequent inactivating mutations in epigenetic remodeling enzymes – the “reader” and “writers” of the epigenome – which collectively play a role in the regulation of transcription, cellular plasticity and the ability of cancer to adapt or resist therapeutic interventions. Known to be central to the role in regulation of gene expression are the SWI/SNF family of chromatin remodeling enzymes (also know as “BAF”), the Polycomb Repressive Complexes (PRC1/2), the p300-CBP transcriptional coactivator family, BRD4, LSD1-NuRD, MLL and others. These transcriptional rheostats have a central role in dynamic process of opening and closing chromatin to the access of transcription and elongation factors. It is increasingly appreciated that SCLC is particularly sensitive to perturbations in transcription. Small molecules now exist to target the catalytic function of many of these epigenetic targets and are proceeding to clinical testing for patients with molecularly defined cancers, offering a therapeutic opportunity in an otherwise barren space.

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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
    • Now Available
    • 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. (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (ID 14546)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (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.

      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.

      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

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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.

      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%).

      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 (Now Available) (ID 14547)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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