Scientific Program

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    ES01 - Advances in Lung Cancer Screening Through Imaging

    • Type: Educational Session
    • Track: Screening and Early Detection
    • Moderators:
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      ES01.01 - Image Quality Characteristics and Nodule Growth Measurement, Medical Physics and Machine Parameters

      13:30 - 13:50  |  Presenting Author(s): Ricardo S Avila

      • Abstract

      Abstract not provided

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      ES01.02 - Image Interpretation and Advances from the Perspective of the Radiologist

      13:50 - 14:10  |  Presenting Author(s): David F Yankelevitz

      • Abstract

      Abstract not provided

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      ES01.03 - Deep Machine Learning for Screening LDCT

      14:10 - 14:30  |  Presenting Author(s): Bram Van Ginneken

      • Abstract

      Abstract not provided

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      ES01.04 - Multi-Phasic Screening - Can We Address Competing Causes of Morbidity * Mortality Such as Coronary Artery Disease and COPD

      14:30 - 14:50  |  Presenting Author(s): Rozemarijn Vliegenthart

      • Abstract

      Abstract not provided

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      ES01.05 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

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    MA04 - Novel Approaches with IO

    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Moderators:
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      MA04.01 - Cemiplimab, a Human Monoclonal Anti-PD-1, Alone or in Combination with Radiotherapy: Phase 1 NSCLC Expansion Cohorts

      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

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • Abstract

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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      MA04.04 - Discussant - MA 04.01, MA 04.02, MA 04.03

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

      • Abstract

      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%

      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

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      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

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      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

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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      MA04.08 - Discussant - MA 04.05, MA 04.06, MA 04.07

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

      • Abstract

      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)

      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

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      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

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

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

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

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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

      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

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA04.12 - Discussant - MA 04.09, MA 04.10, MA 04.11

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

      • Abstract

      Abstract not provided

  • +

    MA05 - Improving Outcomes in Locoregional NSCLC II

    • Type: Mini Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Moderators:
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      MA05.01 - E6508: Phase II Study of Immunotherapy with Tecemotide and Bevacizumab after Chemoradiation in Unresectable Stage III NS-NSCLC

      13:30 - 13:35  |  Presenting Author(s): Jyoti Patel  |  Author(s): Ju-Whei Lee, Henry Wagner Jr, David P Carbone, Anil Shanker, Leora Horn, Melissa L. Johnson, David E Gerber, Jane Jijun Liu, Millie S Das, Mohammad Ali Al-Nsour, Christopher S R Dakhil, Suresh S. Ramalingam, Joan Schiller

      • Abstract

      Background

      Chemoradiation (CRT) is standard of care for unresectable stage III NSCLC. Tecemotide is a MUC1 antigen-specific cancer immunotherapy. Bevacizumab is considered to have a significant role in immune modulation. Immunotherapy in combination with VEGF blockade was tested in this phase II trial combining tecemotide and bevacizumab in patients with stage III NS- NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Subjects with stage III NS- NSCLC suitable for definitive CRT received carboplatin(C) AUC 2 + paclitaxel(P) 45 mg/m2 weekly + 66 Gy/33fx/6.5wk and consolidation C AUC 6 + P 225 mg/m2 q21 days x 2. Patients with CR/PR/SD were then registered onto Step 2 (S2). S2 was 6 weekly tecemotide injections followed by q6 weekly injections and bevacizumab 15 mg/kg q3 weeks for up to 34 doses. The primary endpoint was safety of tecemotide and bevacizumab after CRT and consolidation. The proportion of circulating dendritic cells and their expression of CD40, HLA-DR and CD123 (IL-3R) were analyzed by flow cytometry at various time points.

      4c3880bb027f159e801041b1021e88e8 Result

      70 patients were enrolled from Dec 2010 to Oct 2014; 68 started therapy, and 39 completed CRT and consolidation therapy. Reasons for discontinuation included progression (11) and toxicity (10). 33 patients were registered to S2. The median number of S2 cycles was 12 (range 2-34). S2 toxicity: gr 3 N=9 (6 hypertension), gr 4 N=1, gr 5 N=1. Among the treated and eligible patients (n=31), from study entry, the median PFS was 14.3 (95% CI 11.0-22.2), OS was 40.1 (95% CI 21.7-NA) months. A correlative trend of increased expression of CD40 and HLA-DR on CD11c+ cells was observed at cycle 7 (week 21) of S2.

      e6508.patel.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      This cooperative group trial met its endpoint, demonstrating tolerability of tecemotide and bevacizumab after CRT and consolidation in NS-NSCLC pts. In this select group of patients, therapy with tecemotide and bevacizumab was associated with encouraging PFS and OS.

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      MA05.02 - PACIFIC Subgroup Analysis: Pneumonitis in Stage III, Unresectable NSCLC Patients Treated with Durvalumab vs. Placebo After CRT

      13:35 - 13:40  |  Presenting Author(s): Johan F. Vansteenkiste  |  Author(s): Jarushka Naidoo, Corinne Faivre-Finn, Mustafa Özgüroğlu, Augusto Villegas, Davey Daniel, Shuji Murakami, Rina Hui, Ki Hyeong Lee, Byoung Chul Cho, Kaoru Kubota, Lynne Poole, Catherine Wadsworth, Phillip A. Dennis, Scott J Antonia

      • Abstract

      Background

      In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (cCRT), on-treatment pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in both arms with similar rates of grade 3/4 pneumonitis (durvalumab, 3.4%; placebo, 2.6%). We performed exploratory analyses to further characterize time to onset and duration of pneumonitis and examine its relationship with underlying risk factors, including patient characteristics and prior CRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a randomized, double-blind study of patients with WHO PS 0/1 without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after completing cCRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Potential associations between the presence of the AE pneumonitis (investigator assessed with review/adjudication by study sponsor) and baseline characteristics or patient disposition were investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Feb 13, 2017, 709 patients had received treatment; 33.6% on durvalumab and 24.9% on placebo had any-grade pneumonitis. Treatment exposure was similar in patients with or without pneumonitis across both arms. Median time to onset of pneumonitis from treatment start was the same for both durvalumab and placebo, 55.0 days (73.0 and 76.5 days from RT completion). Pneumonitis was self-limited, with median durations of 64.0 and 57.0 days, respectively. Patients with pneumonitis were more likely to be Asian (47.9% vs 17.6%) or have EGFR mutations (11.0% vs 3.8%); however, the proportions of patients with pneumonitis and these risk factors were numerically lower with durvalumab than with placebo (Asian: 44.4% [71/160] vs 57.6% [34/59]; EGFRm: 10.6% [17/160] vs 11.9% [7/59]), suggesting no apparent interaction with treatment. There were no apparent associations of pneumonitis with baseline respiratory disorders, prior RT dose, or prior cisplatin or carboplatin use. Previous induction CT was more commonly associated with the absence of pneumonitis in both treatment arms (durvalumab: 30.1% vs 17.5%; placebo: 31.5% vs 20.3%). The presence of pneumonitis was associated with greater discontinuation due to AEs (durvalumab: 25.6% vs 10.2%; placebo: 18.6% vs 6.8%) regardless of treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Rates of pneumonitis were higher in Asian patients and those with EGFRm, as previously reported. Durvalumab did not increase pneumonitis in patients with these risk factors. There were no differences in treatment exposure in patients based on the presence/absence of pneumonitis. Multivariate analyses may further assist in the discernment of etiologic risks.

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      MA05.03 - Immune Microenvironment and its Association with Adjuvant Chemotherapy Benefit in Locoregionally Advanced Lung Adenocarcinoma

      13:40 - 13:45  |  Presenting Author(s): Raj Ghanshyam Vaghjiani  |  Author(s): Takashi Eguchi, Navin Chintala, Xiaoyu Li, Rania G Aly, Katsura Emoto, Kay See Tan, David R. Jones, Prasad S. Adusumilli

      • Abstract

      Background

      The impact of the tumor immune microenvironment on the effectiveness of platinum-based adjuvant chemotherapy (ACT) in locoregionally advanced (stage II-III) lung adenocarcinoma (ADC) is unknown. We performed an analysis of the cellular components of the tumoral and tumor-associated stromal immune environment in stage II-III lung ADC and examined their association with ACT benefit.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue microarrays (6 tumor and 3 stromal cores from each tumor) were constructed using resected tissue from patients with pT2-T4N1 lung ADC (n=500, 2000-2012) who did (n=225) and did not (n=214) receive ACT. Multiplex immunofluorescence was used to determine the quantity, localization, and colocalization of 21 types of immune cells and markers (including PD-1, PD-L1, CD3, CD20, CD68, CD163, MPO, and PanCK). The association between immune cell infiltration and recurrence free probability (RFP) was compared using Kaplan-Meier methods, and benefit from ACT by unsupervised hierarchical cluster modeling.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, increased tumoral infiltration of CD20+ B-cells and CD3+ and CD4+ T-cells was associated with an improvement in 5-yr RFP (CD20+ low vs high: 37% vs 49%, p=.03; CD3+: 39% vs 48%, p=.003; and CD4+: 39% vs 47%, p=.02, respectively) whereas increased stromal MPO+ neutrophil infiltration was associated with a worse 5-yr RFP (low vs high: 50% vs 38%, p=.003). Among patients who received ACT, cluster modeling revealed 5 risk groups (Groups A-E; Figure) with immune signatures including tumoral B-cells and CD163+PD-1+ macrophages as well as stromal CD57+ NK-cells and CD163+PD-L1+ macrophages that provided a progressive stratification of RFP following adjuvant treatment.

      vaghjiani.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immune infiltration analysis can predict benefit from ACT and thereby provide a rationale to select patients for either chemotherapy, immunotherapy, or combination therapy following surgical resection.

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      MA05.04 - Discussant - MA 05.01, MA 05.02, MA 05.03

      13:45 - 14:00  |  Presenting Author(s): Scott N. Gettinger

      • Abstract

      Abstract not provided

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      MA05.05 - Photon-Based Cardiac Sparing Via Volumetric Modulated Arc Therapy in Thoracic Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

      14:00 - 14:05  |  Presenting Author(s): Matthew J Ferris  |  Author(s): Katherine Sykes, Oluwatosin A Kayode, Jonathan Wolf, Robert H Press, Jeffrey M Switchenko, Walter John Curran, Jr., Kristin A Higgins

      • Abstract

      Background

      Increasing radiation dose to the heart is associated with worse survival in stage III non-small cell lung cancer. Techniques to reduce the dose to the heart, including proton beam therapy (PBT), are being evaluated in ongoing clinical trials. However, advanced technologies such as PBT are not readily accessible for most patients. We therefore sought to evaluate the efficacy of volumetric modulated arc therapy (VMAT), a readily available technology in the United States, to spare cardiac substructures and determine how a cardiac optimization treatment planning algorithm influences dose distribution to other thoracic organs at risk (OARs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We selected stage III non-small cell lung cancer patients who were treated at our institution with VMAT to 60 Gy in 2 Gy fractions. Cardiac substructures were retrospectively contoured, and included: valves, atrioventricular node (AVN), coronary arteries (CA), chambers, and great vessels. New radiation treatment plans were created to spare these structures while preserving planning target volume (PTV) coverage and maintaining standard dose constraints to OARs. Dosimetry variables—maximum dose (Dmax), mean dose (Dmean), and common clinically relevant dose-volume relationships—for the new cardiac-sparing radiation treatment plans were compared via paired t-test to the original radiation treatment plans.

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-six patients, treated from July 2013 to September 2017, were included. Statistically significant improvements were demonstrated for all cardiac structures for the new cardiac-sparing plans compared to the original plans, while maintaining appropriate lung, esophagus, and spinal cord constraints, and PTV coverage goals, as demonstrated in Table 1 (significant P-values in bold).

      Table 1

      Dosimetry variable

      Cardiac-sparing plan (mean)

      Original plan (mean)

      P-value*

      Cardiac parameters

      Heart Dmax

      64.9 Gy

      63.6 Gy

      0.928

      Heart Dmean

      12.3

      16.1

      < 0.001

      Heart V5Gy

      55.4

      64.1

      0.003

      Heart V30Gy

      12.5

      18.7

      < 0.001

      Heart V40Gy

      7.9

      11.5

      < 0.001

      Heart V45Gy

      6.5

      11.5

      < 0.001

      Heart V60Gy

      2.7

      3.4

      0.001

      Aortic valve Dmax

      22.9

      31.7

      < 0.001

      Aortic valve Dmean

      11.4

      31.7

      < 0.001

      Mitral valve Dmax

      24.6

      29.4

      0.002

      Mitral valve Dmean

      11.2

      16.7

      < 0.001

      Pulmonic valve Dmax

      26.8

      35.4

      < 0.001

      Pulmonic valve Dmean

      14.1

      25.1

      < 0.001

      Tricuspid valve Dmax

      9.7

      16.6

      < 0.001

      Tricuspid valve Dmean

      5.6

      10.3

      < 0.001

      AVN Dmax

      13.4

      20.4

      < 0.001

      AVN Dmean

      8.1

      14.0

      < 0.001

      Left main CA Dmax

      26.4

      38.8

      < 0.001

      Left main CA Dmean

      16.4

      30.2

      < 0.001

      Left anterior descending CA Dmax

      27.4

      34.8

      < 0.001

      Left anterior descending CA Dmean

      14.4

      22.6

      < 0.001

      Left circumflex CA Dmean

      32.6

      36.8

      0.001

      Left circumflex CA Dmean

      19.3

      26.9

      < 0.001

      Right CA Dmax

      18.1

      26.1

      < 0.001

      Right CA Dmean

      9.4

      15.7

      < 0.001

      Left atrium Dmax

      51.8

      54.8

      0.091

      Left atrium Dmean

      17.5

      21.0

      < 0.001

      Left ventricle Dmax

      35.7

      40.1

      < 0.001

      Left ventricle Dmean

      8.3

      11.3

      < 0.001

      Right atrium Dmax

      31.4

      36.1

      0.004

      Right atrium Dmean

      11.1

      13.9

      < 0.001

      Right ventricle Dmax

      23.7

      33.2

      < 0.001

      Right ventricle Dmean

      6.9

      12.2

      < 0.001

      Aorta Dmax

      50.8

      55.3

      0.001

      Aorta Dmean

      20.4

      27.9

      < 0.001

      Pulmonary artery Dmax

      65.2

      65.1

      0.895

      Pulmonary artery Dmean

      32.3

      37.9

      < 0.001

      Superior vena cava Dmax

      47.4

      51.7

      0.002

      Superior vena cava Dmean

      29.4

      33.1

      0.006

      Other OAR parameters

      Lungs V5Gy

      56.5

      58.2

      0.121

      Lungs V20

      22.4

      23.3

      0.083

      Lungs Dmean

      13.6

      14.8

      0.012

      Spinal cord Dmax

      28.0

      31.1

      0.013

      Esophagus Dmean

      21.2

      22.1

      0.023

      PTV coverage parameters

      PTV Dmax

      65.5

      67.2

      0.189

      PTV minimum dose

      51.2

      52.7

      0.019

      PTV V100%

      95.2%

      95.4%

      0.195

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dose to the heart and cardiac substructures can be substantially lowered using a cardiac-sparing optimization algorithm with VMAT, without increasing radiation dose other thoracic OARs or compromising PTV coverage. Though time-consuming, delineation of the full complement of cardiac substructures provides an effective means of improving the quality of radiation treatment plans with readily available technologies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.06 - Locally Advanced Lung Cancer Radiotherapy in Deep Inspiration Breath Hold: Dosimetric Benefits from a Prospective Trial

      14:05 - 14:10  |  Presenting Author(s): Mirjana Josipovic  |  Author(s): Marianne C Aznar, Jonas Scherman Rydhög, Jakob Borup Thomsen, Sidsel Marie Skov Damkjaer, Lotte Nygård, Mette Pøhl, Seppo W Langer, Lena Specht, Gitte Fredberg Persson

      • Abstract

      Background

      Radiotherapy for locally advanced non-small cell lung (NSCLC) cancer is often complicated by treatment-related toxicity. A toxicity-reducing technique is deep inspiration breath hold (DIBH), where the lungs inflate and the heart is pushed downwards. DIBH is widely applied in breast radiotherapy, but only sporadically in NSCLC. We initiated the INHALE trial, investigating compliance and benefits of DIBH for NSCLC at a single academic institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients referred for definitive radiotherapy of locally advanced NSCLC (66Gy/33 fractions) were included from May 2015-Dec 2017. All patients underwent respiratory coaching for voluntary visually guided DIBH and were imaged with PET/CT, 4D-CT and DIBH-CT. Target volumes were defined according to national guidelines. PTV margins were patient- and modality-specific. For all patients, FB and DIBH plans were made with volumetric modulated arc therapy, with equal PTV coverage. The plan with the lowest lung and/or heart dose was chosen for treatment. Normal tissue complication probability for pneumonitis was calculated retrospectively based on a logistic dose response model.

      4c3880bb027f159e801041b1021e88e8 Result

      The treatment intent was maintained in 69 of included 88 patients (2 were downstaged, 12 upstaged, 2 withdrew consent, other causes in 3). 62/69 were DIBH compliant and in 61 patients a FB and a DIBH plan were made (in one patient, 4DCT image quality was not sufficient). In 54/61 patients, the DIBH plan was chosen for treatment. 3/54 patients lost DIBH compliance within the first few fractions.

      All data is presented as median (range), with p<0.001 (Wilcoxon signed rank). Lung volume increased in DIBH by 55% (20-168%). Compared to FB, DIBH reduced mean lung dose from 14.4Gy (1.2-25.3Gy) to 11.8Gy (1.0-20.4Gy), and lung V20 from 23.7% (1.5-47.8%) to 20.8% (1.2-39.7%). Reduced lung dose translated to reduced pneumonitis risk: from 8.6% (2.3-23.3%) to 6.5% (2.2-14.4%). Lung dose constraints were violated in 5/62 patients in FB and 1/62 patients in DIBH.

      Mean heart dose was reduced from 3.6Gy (0.1-25.8Gy) in FB to 2.4Gy (0.1-25.3Gy) in DIBH. DIBH reduced mean heart dose in 44/61 patients. The differences between FB and DIBH varied between – 6.6Gy and 8.9Gy, stressing the influence of tumour location on the potential of reducing heart dose with DIBH.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Benefits of changed anatomy with DIBH were reduced dose to lungs and, for most patients, to the heart. Curative treatment intent could be maintained in more patients. Risk of developing radiation pneumonitis was reduced. Continuous follow up of INHALE patients will reveal how the reduced risk is manifested clinically.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.07 - Dose Escalated Chemo-RT to 84 Gy in Stage III NSCLC Appears Excessively Toxic: Results from a Randomized Phase II Trial

      14:10 - 14:15  |  Presenting Author(s): Jan Nyman  |  Author(s): Stefan Bergström, Hedvig Björkestrand, Anna-Maja Svärd, Simon Ekman, Erik Lundin, Erik Holmberg, Mikael Johansson, Signe Friesland, Andreas Hallqvist

      • Abstract

      Background

      Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease, however, with a rather high probability of locoregional and metastatic recurrence further treatment optimization is warranted. Based on previous one-armed trials with dose escalated radiotherapy, showing feasibility, the Swedish Lung Cancer Study Group aimed to investigate whether dose escalation based on individual normal tissue constraints could improve outcome in this randomized phase II trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NSCLC patients with stage III disease, good performance status (0-1), adequate lung function (FEV1 > 1.0 L and CO diff. > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. The radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to a total dose of 68 Gy (standard arm A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week while keeping the total treatment time constant at seven weeks with the same dose to involved nodes and primary tumor.

      4c3880bb027f159e801041b1021e88e8 Result

      A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in the dose escalated group compared to 28 and 45 months in the standard group. The 1-, 3- and 5-year survival rates were 56%, 33% and 17% in the escalated arm and 72%, 61% and 34% in the standard arm. There were four toxicity-related deaths due to esophageal perforations (one in arm A and three in arm B) and three deaths due to pneumonitis (one in arm A and two in arm B).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 5-year survival of 34%. A possible step forward will be to improve systemic therapy, but future approaches with escalated radiotherapy may include boost techniques to remaining PET positive areas or different escalation schedules to the primary tumor and mediastinal nodes.

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      MA05.08 - Discussant - MA 05.05, MA 05.06, MA 05.07

      14:15 - 14:30  |  Presenting Author(s): Benjamin H Lok

      • Abstract

      Abstract not provided

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      MA05.09 - PFS and Cardiac-Toxicity-Adjusted-PFS As Predictors of OS in Locally Advanced NSCLC Treated with Concurrent Chemoradiation

      14:30 - 14:35  |  Presenting Author(s): Chen Hu  |  Author(s): Mitchell Machtay, James Dignam, Rebecca Paulus, Jeffrey Bradley

      • Abstract

      Background

      Overall survival (OS) is the gold standard for LA-NSCLC with chemoradiation (CCRT), while the complex relationships among RT dosimetry, systemic therapies, cardiopulmonary toxicity, progression (PD) and OS are also of increasing scientific and clinical interest.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NRG Oncology RTOG 0617 (NCT00533949) was a randomized phase 3 trial comparing standard (SD, 60 Gy) versus high-dose (HD, 74 Gy) CCRT +/- cetuximab from 11/07-06/11. This secondary analysis includes 469 patients (pts) given ≥50 Gy. A PFS event was defined as the first occurrence of local, regional, distant PD or death w/o documented PD. A CTA-PFS event was the first occurrence of grade 2+ treatment-related cardiac toxicity event or a PFS event. Landmark analyses at 6mo and 12mo were used to minimize the immortal time bias. Cox model with PD or CT/PD as a time-dependent covariate was used to evaluate their predictive roles. Median f/u time for surviving pts was 5.1 years.

      4c3880bb027f159e801041b1021e88e8 Result

      As previously reported, pts treated with HD had significantly lower OS rates (HR=1.28, 95%CI: 1.04-1.58, p=0.018) and CTA-PFS rates (HR=1.24, 95%CI: 1.02-1.51, p=0.035), and marginally lower PFS rates (HR=1.21, 95%CI: 0.99-1.47, p=0.06) than pts treated with SD. Median survival time (MST) among pts having PD within 6mo versus not were 13.4mo (95%CI: 10.0-19.0mo) and 30.7mo (95%CI: 28.0-37.0mo) (p<0.001). MST for pts having PD within 12mo versus not were 20.6mo (95%CI: 18.8-25.0mo) and 60mo (95%CI: 47.6-74.5mo)(p<0.001). Results are similar when using CTA-PFS with 6mo or 12mo cutoff (p<0.001). RT dose was no longer significantly associated with OS (p=0.08 or p=0.15) when PD or CT/PD was included in multivariable analysis (p<0.001), suggesting OS differences in HD/SD may be partially captured by PFS or CTA-PFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Long-term survival results from RTOG 0617 suggest that PFS (or CTA-PFS) status at 6mo or 12mo predicts long-term OS, and may potentially be considered as a surrogate endpoint of OS in clinical trials. Pts who were progression-free at 12mo had a MST of 5 years. Further validation on external datasets and in the modern era of immunotherapy are needed.

      Funding: This project was supported by grants NCORP (UG1CA189867), NRG Operations (U10CA180868), NRG SDMC (U10CA180822), IROC (U24CA180803), and CTEP from the National Cancer Institute (NCI).

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      MA05.10 - The Pathologic Response of Locally Advanced NSCLC Treated with Concomitant Chemoradiation to 60 Gy in Image Guided Radiation Therapy (IGRT)

      14:35 - 14:40  |  Presenting Author(s): Sarit Appel  |  Author(s): Jair Bar, Damien Urban, Amir Onn, Marina Perelman, Yaacov Richard Lawrence, Alon Ben-Nun, Ory Haisraely, Zvi Symon, Tatiana Rabin El Ezra, Edith Marom, Sivan Liberman, Efrat Ofek

      • Abstract

      Background

      Neoadjuvant concomitant chemoradiation (NACCRT) was historically limited to 45 Gy. We recently published data on the safety of a higher radiation dose in this setting. Here we evaluate the pathologic response of locally advanced non small cell lung cancer (LANSCLC) treated with 60Gy NACCRT combined with modern IGRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our cohort comprised patients that underwent NACCRT followed by surgery during August 2012-December 2017 at our institution. We retrospectively collected the demographic, stage, histology, and treatment details. Radiation was planned using eclipse system to deliver 2 Gy per fraction to a total of 60 Gy

      Treatment effect was determined from the pathologic specimen in accordance with College of American Pathologists recommendations, based on the modified tumor regression grading: Favorable pathologic responses included major tumor regression (MTR); we also evaluated the average percent of the residual tumor cells seen in the specimen. Statistical analysis was performed to analyze treatment effect on the pathologic response using spearman correlation and Kruskal-Wallis test with SPSS software v.24.

      4c3880bb027f159e801041b1021e88e8 Result

      Our cohort included 70 patients. Mean age was 63 years (range 45–79.7), men n=49 (70%), smoking status: never smokers n=11 (16.2%), past smokers n=10 (14.7%), current smokers n=47 (69.1%). Histology consisted adenocarcinoma n=42 (60%), squamous n=21 (30%) and other n=7 (10). Stage 2 were n=65 (78.3%) and stage 3 n=15 (21.4%). Chemotherapy consisted of platinum-doublet administered to 69 patients (98.5%). A mean radiation dose of 59 Gy (range 46-72 Gy) was delivered with IGRT prior to each fraction. Five patients received lower radiation doses due to toxicity or dose constraints. Surgery comprised of lobectomy n=50 (71.4%), chest wall resection n=9 (12.9%) or pneumonectomy n=11 (15.7%). Negative surgical margins were achieved in n=63 (90%) and positive margins in n=7 (10%). 30-day mortality was n=2 (2.8%) both cases after Right-sided pneumonectomy.

      MTR was observed in 45 cases (64.3%) including a pathological complete response in 25 (35.7%) and < 10% residual tumor in 20 cases (28.5%). The mean percent of residual tumor cells was 16% and the median 6.5%. Percent of residual tumor cells did not correlate to radiation dose (Rs=0.092), and not to the histology (p= 0.165), and not to type of chemotherapy (p=0.35).

      8eea62084ca7e541d918e823422bd82e Conclusion

      NACCRT delivered to 60 Gy with modern image-guided radiation therapy is safe. Two thirds of such patients achieve major tumor regression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.11 - Radiomics Analysis Using SVM Predicts Mediastinal Lymph Nodes Status of Squamous Cell Lung Cancer by Pre-Treatment Chest CT Scan

      14:40 - 14:45  |  Presenting Author(s): Xing Wang, Wu Nan  |  Author(s): Shi Yan, Quanzheng Li, Ning Guo, Zhe Guo

      • Abstract

      Background

      Assessment of mediastinal lymph nodes (N2 station) is essential in staging patients with Non-small-cell lung cancer (NSCLC), for patients with preoperative confirmed N2 status should follow neoadjuvant therapy before surgery, and occult N2 status should be avoided. There are several invasive and non-invasive exams available for preoperative N staging, like EBUS-TBNA and PET-CT scan. Chest CT scan was the basic examination of every patient, while only the length of minor axis could be used to predict lymph node involvement, and the potential value of CT might be underestimated. In this study we aimed to explore the value of radiomics analysis with machine learning in differentiating N2 from N1/N0 subjects using pre-treatment chest CT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ninety-three patients with squamous cell lung cancer, who underwent pre-treatment CT scans were included in this study. By use of Laplacian of Gaussian (LoG) filter and matrix based radiomics models (e.g. gray-level co-occurrence matrix), comprehensive radiomics features were extracted from the regions of interest which were manually delineated on primary tumors. We performed radiomics analysis using support vector machine (SVM) to test texture and heterogeneity features derived from pre-treatment CT images as indicators for the staging of lymph node metastasis, especially N2. The gold standard of N staging is confirmed pathologically after systematic mediastinal lymphadenectomy (N2 subjects=31).

      4c3880bb027f159e801041b1021e88e8 Result

      For the performance evaluation of single image feature, there are 16 features able to differentiate N2 subjects from others (N0 and N1) with p value <0.05. Furthermore, SVM training and classification were performed using 5-feature combinations as inputs. With feature selection, the best performance of N2 prediction is 83% accuracy with 87% sensitivity and 81% specificity.

      figure.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Radiomics analysis using SVM training can successfully predict N staging by pre-treatment chest CT scan for NSCLC patients, which could diminish the odds of occult N2 status and provide unique information preoperatively for treatment planning.

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      MA05.12 - Discussant - MA 05.09, MA 05.10, MA 05.11

      14:45 - 15:00  |  Presenting Author(s): Matthew Hatton

      • Abstract

      Abstract not provided

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    MA06 - PDL1, TMB and DNA Repair

    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Moderators:
    • +

      MA06.01 - The Intrinsic PD-L1 Promotes Cellular Invasiveness Via their PD-1 Receptor in Lung Adenocarcinoma Cells

      13:30 - 13:35  |  Presenting Author(s): Wen-Pin Su  |  Author(s): Hung-Chang Wu, Shuen-Ru Yang, Jheng-Cheng Huang, Jing-Jou Yan, Wan-Chen Kao, Li-Chan Chang, Wu-Chou Su

      • Abstract

      Background

      Lung cancer is the most frequent cause of cancer death. Programmed death 1 (PD-1) in T cells and its ligand PD-L1 in tumor cells play a key role in immune checkpoint therapy and had applied to advanced stage lung cancer. Migration and invasion of tumor cells is a prerequisite for tumor cell metastasis. Since intrinsic PD-1 receptor functions promote tumor growth was reported, we will investigate the interaction between PD-1 and PD-L1 in lung adenocarcinoma cell lines, the impact on chemosensitivity, and clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In vitro experiments, lung adenocarcinoma CL1-5 cells, derived from CL1-0 cells. We prepared PD-L1-overexpression human lung adenocarcinoma cell line, derived from CL1-0 cells (CL1-0-PD1). Migration and invasion ability were assessed by transwell assay; EMT marker and regulator were evaluated by Western blotting. We also observed the morphology of cells. To explore interaction between PD1 and PD-L1, we added anti-PD-1 antibody into CL1-0, CL1-5, and CL1-0-PDL1 cells, and then test migration, invasion and cellular morphology. We also suppressed PD-1 by siRNA to test whether PD-1/PDL-1 interaction contributed to the EMT change. Further, we evaluated cellular proliferation and chemosensitivity by MTT assay and colony formation assay. We will correlate PD-L1 expression in lung cancer cells with clinical outcome by IHC stain clinically.

      4c3880bb027f159e801041b1021e88e8 Result

      In CL1-5 cells, derived from CL1-0 cells, with high PD-L1 expression possessed higher cellular migration ability than the parental CL1-0 cells with less PD-L1 expression. CL1-0 cells with PD-L1 overexpression had more expression of EMT (epithelial mesenchymal transition) regulator and mesenchymal marker. We also observed that CL1-5 and CL1-0-PDL1, which had more PD-L1 expression, are shaped like spindles; while CL1-0 cells are more rounded. Therefore, PD-L1 up-regulated cell migration and invasiveness in human lung adenocarcinoma cells and promotes EMT.

      After adding anti-PD1 antibody in CL1-5, CL1-0, and CL1-0-PDL1 cells, migration and invasion ability decreased. These result indicated anti-PD-1 antibody block the link between PD-1 and PD-L1 in cancer cells. The phenomenon was confirmed by PD-1 siRNA. Therefore, PD-1/PD-L1 axis regulated cancer cells migration and invasiveness. PD-L1 expression also decreased cellular proliferation and had little influence on chemsensitivity. Finally, we found that higher PD-L1 expression was correlated with lymph node metastasis in clinical specimen.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung adenocarcinoma cells with higher PD-L1 expression promote cell migration, invasiveness, EMT, and little chemoresistance. PD-L1 expression lowers proliferation rate. PD-1 and PD-L1 interaction on lung adenocarcinoma cells contribute cellular migration and invasiveness.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.

      4c3880bb027f159e801041b1021e88e8 Result

      From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.03 - PD-1 and Id-1 Combined Blockade Impacts Tumor Growth and Survival Through PD-L1 Expression and Tumor Infiltration by Immune-Related Cells 

      13:40 - 13:45  |  Presenting Author(s): Ignacio Gil-Bazo  |  Author(s): Iosune Baraibar, Marta Roman Moreno, Ines Lopez, Jesus Corral, Juan Jose Lasarte, Alfonso Calvo, Silve Vicent, Daniel Ajona

      • Abstract

      Background

      PD-1/PDL-1 inhibitors are approved in advanced non-small cell lung cancer (NSCLC). Long-term survival rates associated to PD-1/PDL-1 blockade have changed treatment paradigm. However, many patients do not benefit from PD-1/PDL-1 blockade. New therapeutic combinations are under investigation. Id1 is involved in proliferation, angiogenesis and immunosuppression. We described Id1 as an independent prognostic factor in NSCLC (Ponz-Sarvise, Clin Cancer Res 2011) and more recently showed Id1’s role in lung cancer metastasis (Castanon, Cancer Letters 2017). Here we test a combined therapeutic strategy targeting PD-1 and Id1 in a murine lung cancer model.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Three in vivo studies evaluated the impact of Id1 inhibition in tumor cells, tumor microenvironment and in both, on tumor volumes and mice survival. A syngeneic tumor model using C57BL/6 and Id1-/- Id3+/- mice was created by subcutaneous injection of Lewis Lung Carcinoma (3LL) cells and Id1 silenced 3LL (Id1Sh) cells. After injection, mice were treated with an anti-PD-1 (RMP-1-14) monoclonal antibody or PBS. Tumor volumes according to mice strain, Id1 status in tumor cells and treatment were quantified. Mice's survival was calculated in those groups. Tumor CD8+ and CD3+ TILs and CD68+ cells were quantified by specific immunostainings.

      4c3880bb027f159e801041b1021e88e8 Result

      Id1 inhibition in the tumor environment and the injected tumor cells, combined with anti-PD-1 treatment, induced a significant tumor growth impairment (p < 0.0001) and increased survival (p = 0.0051). CD3+ and CD8+ TILs and tumor CD68 + cells were significantly higher in tumors from mice with the combined Id1-PD-1 blockade treated with the anti-PD-1 inhibitor compared to control animals suggesting that tumor increased immune-related cells infiltration exerts the effector phase of the antitumor immune response. Additionally, PD-L1 expression seemed to be higher when Id1 expression was absent in the immune microenvironment (p = 0.04). Additional data based on multiplexed immunohistochemistry results will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Id1 and PD-1 combined blockade in our syngeneic murine lung cancer model significantly impaired tumor growth and increased survival. Increased tumor PD-L1 expression and CD3+ and CD8+ TILs and CD68+ cells may explain these findings.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.04 - Discussant - MA 06.01, MA 06.02, MA 06.03

      13:45 - 14:00  |  Presenting Author(s): Akihiko Yoshida

      • Abstract

      Abstract not provided

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      MA06.05 - The Micro-Environmental Cross Talk Between Mast Cells and Lung Cancer Cells Through Cell-to-Cell Contact

      14:00 - 14:05  |  Presenting Author(s): Rachel Shemesh  |  Author(s): Yaara Gorzalczany, Smadar Geva, Laila C. Roisman, Ronit Sagi-Eisenberg, Nir Peled

      • Abstract

      Background

      Mast cells (MCs) are key effectors in allergic reactions, but are also involved in tissue remodeling, wound healing and protection against pathogens. MCs infiltrate tumors and their number within the tumor microenvironment in certain cancer types, such as lung cancer, have been correlated with poor prognosis. The nature of crosstalk between lung cancer and MCs remain poorly resolved. In this study, we investigated the activation patterns within the MCs following cell-to-cell contact with lung cancer cells showing CD73 involvement and implying metabolic changes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Human MCs (HMC-1 and LAD-2) were exposed to Human lung cancer cells (H1299), derived membranes to recapitulate cell contact mediated activation. Lysates of MCs were tested for protein expression and posttranslational modifications (i.e. phosphorylation) by targeted western blotting. We unraveled the intracellular signaling molecules that are necessary for this signaling pathway by a pharmacological approach using several inhibitors. Each condition was repeated at least twice.

      4c3880bb027f159e801041b1021e88e8 Result

      H1299 membrane exposure activated the ERK 1/2 MAP kinases in HMC-1 and in LAD-2 cells. AKT signaling was also activated in LAD-2 cells as a result of this contact. CD73 dephosphorylates AMP to adenosine within the MCs. Interestingly enough, this ERK 1/2 activation was inhibited by CD73 inhibitor and A3 receptor antagonists in HMC-1 cells. ERK 1/2 activation was inhibited by A3 receptor antagonists and PI3K in LAD-2 cells. Furthermore, we discovered that protein kinase C (PKC) inhibitor augments the activation of ERK 1/2 in LAD-2 cells. In contrast, PKC inhibitor inhibits the activation of ERK 1/2 in HMC-1 cells. In addition, we discovered that the AKT activation was inhibited by A3 receptor and PI3K inhibitors but not by CD 73 inhibitors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that H1299 membranes activate ERK 1/2 in HMC-1 cells by a mechanism that involves autocrine formation of adenosine and is mediated by CD 73 and A3 receptor. In addition, we discovered that there is an important difference between the ERK 1/2 MAP kinase signal transduction in HMC-1 and LAD-2 cells, PKC is an inhibitor of the H1299 activation of ERK 1/2 in LAD-2 cells. In contrast, the H1299 membrane activation of ERK 1/2 kinase in HMC-1 cells is mediated by PKC. Furthermore, we can conclude that H1299 membranes activate AKT in an A3 receptor dependent mechanism that is mediated by PI3K.

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      MA06.06 - An Ex-Vivo Patient-Derived, Immunocompetent (PDI) Culture System to Evaluate Immunotherapeutic Agents’ Anti-Tumor Efficacy

      14:05 - 14:10  |  Presenting Author(s): Zachary E. Tano  |  Author(s): Stefan Kiesgen, Navin Chintala, Jordan Dozier, John Messinger, Kay See Tan, Prasad S. Adusumilli

      • Abstract

      Background

      Anti-tumor efficacy of human immunotherapeutic agents, such as antibodies, chimeric antigen receptor (CAR) and T-cell receptor transduced T cells, are currently being investigated in immunodeficient mice prior to clinical translation. We developed and optimized an ex-vivo culture system utilizing malignant pleural effusions (MPEs) to compliment these investigations in a human, immunocompetent, tumor-like environment. We hypothesized that CAR T cells’ cytotoxicity will vary by the different immune compositions in each MPE, which are conditions unavailable in current efficacy assays.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Mesothelin-targeted CAR T cells from multiple donors were exposed to MPEs derived from non-small cell lung cancer patients (n=15) and RPMI culture medium. Influence of the MPEs on CAR T-cell efficacy was evaluated by viability and phenotype (flow cytometry), cytotoxicity (chromium release assay), and gene expression (NanoString). Group-based trajectory modeling was used to stratify the inhibitory effect of MPEs. MPE composition (ELISA and Luminex assays) was evaluated to interpret its influence on CAR T cells.

      4c3880bb027f159e801041b1021e88e8 Result

      With the incorporation of our optimized protocols, T cells retain their viability, phenotype (CD4/CD8), and percentage of CAR expression when cultured in MPEs. MPE soluble factor levels remained stable over multiple freeze/thaw cycles. CAR T cells co-cultured in MPE exhibited variable antigen-specific cytotoxicity (Fig. A). MPE-induced T-cell inhibition was stratified into groups of strong, mild, or no inhibition. (Fig. B). Compared to MPEs with either mild or no inhibition, MPEs with strong inhibition had significantly higher levels of TGFβ-2 (average TGFβ-2 level in strong vs. mild inhibition: 402 vs. 50 pg/mL, p<0.05) (Fig. C), IL-6, RANTES, and IL-5.

      pdi culture system.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      We present the first human immunocompetent culture system that can be used to evaluate immunotherapeutic agents’ efficacy prior to their clinical translation. Furthermore, analyses of the culture system’s soluble factors sheds light on their relative influence on T-cell efficacy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.07 - Genetic and Epigenetic Alterations are Associated with Tumor Mutation Burden in Non-Small Cell Lung Cancer

      14:10 - 14:15  |  Presenting Author(s): Liang-Liang Cai  |  Author(s): Hua Bai, Zhi-Jie Wang, Shuhang Wang, Jian-Chun Duan, Shu-Geng Gao, Jie He, Jie Wang

      • Abstract

      Background

      Although several studies have indicated that tumor mutation burden (TMB) is associated with non-small cell lung cancer (NSCLC) development and clinical efficacy of immune checkpoint inhibitors (CPIs), identification of factors associated with TMB is still a major biological issue. It is well-known that DNA transcription can be regulated through methylation and demethylation, gene silencing caused by DNA hypermethylation is associated with cancer development. However, the relationship between DNA methylation and TMB in NSCLCs remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The landscape of DNA sequence in Chinese NSCLCs population were surveyed by using whole-exome sequencing (WES) by profiling 178 lung tissues (89 without any systemic anti-cancer therapy tumors and matched normal lung tissues). According to the 104 median-level of TMB in our cohort, high TMB (n=16, 252-465 range mutations per tumor) and low TMB (n=13, 57-79 range mutations per tumor) groups were divded. The NSCLC methylome between high and low TMB was characterized on a genome-wide scale using Illumina Infinium MethylationEPIC arrays combined with the WES data.

      4c3880bb027f159e801041b1021e88e8 Result

      The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures in high TMB lung cancer. Combining with clinical data, cigarette smoking associated with high TMB were observed in our cohort. Cancer-specific epigenetic alterations were observed in 294,141 CpG sites, comprising both tumor hyper- (769,38) and hypo- (217,203) methylation in high TMB lung cancer while none in low. These different methylations sites cover 1232 genes including 25 HOX genes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Global DNA hypomethylation and TP53 mutation, associated with increased chromosomal instability, were associated with TMB in NSCLCs.The high TMB NSCLCs are characterized by numerous copy number alterations and aberrantly methylated sites and display distinct mutational signatures. 25 hypermethylated HOX genes can be potentially useful as DNA methylation markers for prediction of TMB level. The results provide insights into the epigenetic impact of TMB, which may contribute to improve precison management of NSCLCs.

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      MA06.08 - Discussant - MA 06.05, MA 06.06, MA 06.07

      14:15 - 14:30  |  Presenting Author(s): Jyoti Patel

      • Abstract

      Abstract not provided

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      MA06.09 - XRCC6BP1: A DNA Repair Gene in Cisplatin Resistant Lung Cancer Stem Cells That May Predict Survival Outcomes in Patients

      14:30 - 14:35  |  Presenting Author(s): Martin P Barr  |  Author(s): Robert Farrell, Saravjeet Singh, Emma Foley, Yuexi He, Lauren Brady, Vincent Young, Ronan Ryan, Siobhan Nicholson, Niamh Leonard, Sinead Cuffe, Stephen Finn

      • Abstract

      Background

      Alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating resistance to chemotherapeutic agents.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      DNA Repair Pathway RT2 Profiler Arrays were used to elucidate key DNA repair genes implicated in chemoresistant NSCLC cells using cisplatin resistant (CisR) and corresponding parental (PT) H460 cells. DNA repair genes significantly altered in CisR cells were validated at the mRNA and protein level. The translational relevance of differentially expressed genes was examined in a cohort of chemo-naïve matched normal and tumour lung tissues from NSCLC patients. Loss of function studies were carried out using siRNA technology. The effect of XRCC6BP1 gene knockdown on apoptosis was assessed by FACS. Cellular expression and localisation of XRCC6BP1 protein and γH2AX foci in response to cisplatin were examined by immunofluorescence (Cytell™). To investigate a role for XRCC6BP1 in lung cancer stem cells, Side Population (SP) studies were used to characterise stem-like subpopulations within chemoresistant cells. XRCC6BP1 mRNA analysis was also examined in ALDH1+ and ALDH1- subpopulations. Immunohistochemistry analysis was carried out in resected lung tumour tissues and XRCC6BP1 expression was correlated with survival in addition to a number of clinicopathological parameters such as tumour stage & grade, gender, smoking status and chemotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified a number of critical DNA repair genes that are differentially regulated between PT and CisR NSCLC cells. XRCC6BP1 mRNA and protein expression was significantly increased H460 CisR cells relative to their PT counterparts. Relative to matched normal lung tissues, XRCC6BP1 mRNA was significantly increased in lung adenocarcinoma patients. Gene silencing of XRCC6BP1 induced significant apoptosis of chemoresistant cells and reduced their DNA repair capacity. Immunofluorescence studies showed an increase in XRCC6BP1 protein expression and gH2AX foci in CisR cells. SP analysis revealed a significantly higher stem cell population in resistant cells, while XRCC6BP1 mRNA expression was considerably increased in SKMES-1, H460 and H1299 CisR cells positive for ALDH1 activity (ALDH1+) compared to ALDH1- cells. IHC scoring of XRCC6BP1 demonstrated poor survival outcomes for NSCLC patients with high expression of this DNA repair gene.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data highlight the potential of targeting components of the DNA repair pathway, in particular XRCC6BP1, in chemoresistant lung cancer. Furthermore, XRCC6BP1 may play an important role in subsets of lung cancer stem cells which, at least in part, may be responsible for driving and maintaining the cisplatin resistant phenotype in NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.10 - Germline Mutation in ATM Affect Lung Cancer Risk with High Effect

      14:35 - 14:40  |  Presenting Author(s): Xuemei Ji  |  Author(s): Dakai Zhu, Claudio Pikielny, Olga Gorlova, Maria Teresa Landi, John Kirkpatrick Field, Paul Brennan, Mattias Johansson, Rayjean J. Hung, James D McKay, Christopher Ian Amos

      • Abstract

      Background

      Genome wide association studies have identified several lung cancer susceptibility regions and common variants influencing lung cancer risk. However, few previous studies investigated the association between germline mutations and lung cancer risk.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed data from a case-control study with 19053 lung cancer cases and 15446 healthy controls of European ancestry in a discovery phase and performed a validation analysis using a case-control study comprising 4261 lung cancer cases and 4152 healthy controls of European ancestry for replication. Logistic regression was used to identify germline mutations with high effect within exome regions associated with lung cancer risk.

      4c3880bb027f159e801041b1021e88e8 Result

      We found rs56009889 in ATM was statistically associated with lung cancer risk in the discovery set (OR = 3.05, P = 3.68 × 10−8) and was nonsignificantly associated with lung cancer risk in the validation set (OR = 1.83, P = 0.16). Stratified analyses by gender with adjustment for age and smoking status showed that females carrying at least one mutated allele of rs56009889 (T/C + T/T) had an increased risk of lung cancer with ORs being 7.77 (95% CI 3.45 - 17.47) in discovery and 6.73 (95% CI 1.46–30.98) in replication, compared to C/C homozygotes among females. Individuals carrying at least one T allele showed a significant 6.9-fold increased risk for lung adenocarcinoma in discovery (adjusted OR = 6.85; 95% CI 4.37 – 10.75) and approximately a 4.9-fold increased risk in replication (adjusted OR = 4.89; 95% CI 2.01 – 11.91). Never smokers with combined genotypes (T/C + T/T) had a greater than 8-fold increased risk of lung cancer in discovery (adjusted OR = 8.03, 95% CI 4.00 – 16.13), while smokers only showed a 2.13-fold increased risk (adjusted OR = 2.13, 95% CI 1.25 – 3.65). In replication, however, the risks from this variant were comparable between smokers and nonsmokers, although the sample size is small for nonsmokers (adjusted OR = 2.16; 95% CI 0.48 – 9.79 for never-smokers and adjusted OR = 2.07; 95% CI 0.66 – 6.52 for smokers). All the T/T homozygotes of rs56009889 developed lung adenocarcinoma in discovery (P = 0.036). The association exhibited a dose-response relationship between the number of T allele of rs56009889 and lung cancer risk in discovery (Ptrend = 1.07 x 10 -9).

      8eea62084ca7e541d918e823422bd82e Conclusion

      rs56009889 highly affected the risk of lung cancer, mainly of lung adenocarcinoma, primarily in women and never smokers. These germline mutations provide important insights for the prevention of lung cancer.

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      MA06.11 - Distinct Origins of Lymphatic and Brain Metastasis in Lung Cancer

      14:40 - 14:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Yan Yan, Caicun Zhou

      • Abstract

      Background

      Generally, distant metastases are seeded by lymph node metastases in most solid tumors. This concept provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. However, a recent study found that lymphatic and distant metastases could arise from independent subclones in the primary colorectal cancer. The current study aimed to investigate the origins of lymphatic and brain metastasis in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      39 samples from twelve patients with primary lung cancer and brain metastases were identified. Three of them had the matched lymph node metastases. All tissues and matched peripheral blood samples were collected before any systemic treatment. Whole-exome (>150×) sequencing were conducted on these samples.

      4c3880bb027f159e801041b1021e88e8 Result

      Compared to the primary lesions, both brain and lymph node metastases had the significantly different patterns of somatic genome alterations. The mutational landscape of brain metastases was also distinctly different from matched lymph node metastases. Primary lesions, matched brain and lymph node metastases showed the similar mutation pattern in terms of transition and transversion, and all of samples displayed a higher percentage of C>T transition. Brain metastases had numerically higher tumor mutational burden (TMB) than primary lesions but it did not reach the statistical significance. Notably, we observed the totally distinct origins of lymphatic and brain metastasis in all three matched cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current evidence suggested that brain metastases and matched lymph node metastases had different mutational landscape in patients with lung cancer. Brain metastases had higher TMB than their primary lesions. Lymphatic and brain metastasis had distinct origins in lung cancer. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung cancer and brain metastases.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA06.12 - Discussant - MA 06.09, MA 06.10, MA 06.11

      14:45 - 15:00  |  Presenting Author(s): Rebecca Heist

      • Abstract

      Abstract not provided

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    MA07 - Towards Survivorship: The Landscape, Supports and Barriers

    • Type: Mini Oral Abstract Session
    • Track: Advocacy
    • Moderators:
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      MA07.01 - No Longer Outliers: Understanding the Needs of Long-Term Lung Cancer Survivors

      13:30 - 13:35  |  Presenting Author(s): Maureen Rigney  |  Author(s): Jennifer C King, Andrew Ciupek

      • Abstract

      Background

      Lung cancer is the leading cause of cancer death in most developed and developing countries. But people do survive, sometimes for many years. Those diagnosed with lung cancer experience higher levels of distress and have greater unmet physical and emotional needs compared with other types of cancer. But what of long-term survivors?

      Globally, The Cancer Atlas reported an estimated 1,878,000 people were living with lung cancer in 2012. With the introduction of screening and rapid treatment advancements, that number is only expected to increase. Are we prepared to meet the long term and late effects of lung cancer? First, we must better understand the experiences and identified needs of long-term survivors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      820 people responded to a 120 question online survey that was distributed via social media and targeted outreach. 471 identified as lung cancer patients/survivors and 349 as loved ones. 21% of survivor-respondents indicated they had been diagnosed 5+ years prior.

      Queried on treatment and smoking histories, long-term survivors identified their most prevalent and problematic symptoms and side effects experienced during treatment, shortly after treatment ended and at 5+ years post-diagnosis. They also answered questions regarding treatment decision-making and palliative care discussions and provision of post-treatment survivorship plans.

      4c3880bb027f159e801041b1021e88e8 Result

      74% of long-term survivors had surgery, 43% had experienced a recurrence and 5% had participated in a clinical trial. None were current smokers.

      The most common (and problematic) late and long term symptoms and side effects were shortness of breath (39%), fatigue (28%) and anxiety (24%). Memory problems were also rated as common (27%).

      Long-term survivors indicated that during treatment, physical side effects were most problematic but post-treatment and long-term, emotional effects were more difficult. Financial issues were also more problematic 5+ years after treatment compared with other time periods. Both discussions of palliative care and provision of survivorship care plans were rare.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Long-term lung cancer survivors were once considered ouliers but today those diagnosed are increasingly living five years and longer. How do the late and long-term physical effects of lung cancer and its treatments differ from survivors of other types of cancer? How do long-term survivors manage stigma and survivor guilt? What physical and emotional support and services do they need? This survey provides initial insights into the physical. emotional and financial effects of living longer with lung cancer but more research is needed to allow us to more fully understand how we can support our long-term survivors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.02 - Line of Therapy and Patient Preferences Treating Lung Cancer: A Discrete-Choice Experiment

      13:35 - 13:40  |  Presenting Author(s): Andrea Ferris  |  Author(s): John F.P. Bridges, Upal Basu Roy, Ellen Janssen

      • Abstract

      Background

      Patient preferences now play an important role in cancer research, regulatory science, and value assessment. While there is a growing literature exploring the preference of patients with lung cancer, few studies have explored how preferences vary with patients’ treatment experience. We sought to quantify patient preferences for the benefits and risks of therapy and explore how they vary across line of treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Preferences were estimated using a discrete choice experiment (DCE) developed in partnership with a patient and stakeholder advisory boards. A D-optimal experimental design was used to generate 3 blocks of 9 choice tasks spanning five attributes: progression-free survival (PFS), short-term side effects, long-term side effects, risk of developing late-onset side effects, and mode of administration – each defined across 3 relevant levels. A diverse sample was recruited via email sent to the LUNGevity lung cancer patient database and via social media. A choice mode was estimated use a conditional logistic regression where the dependent variable was the respondents preferred treatment in each profile. The relative attribute importance (conditioned on the chosen attribute levels) was then compared across the respondents’ self-reported line of treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      In total we had 350 eligible respondents, of which 279 (80%) completed as least on DCE task of which 3% did not receive a pharmacotherapy, 39% received first line therapy, and 58% had two or more lines of theory. As with previous studies, PFS was the most important attribute for patients and was similarly valued (P=0.406) among first- and later (second lines and more) lines of treatment (33.4% v 33.8%). Patients on first-line treatment placed great emphasis (P<0.001) on long-term side (18.9% v 14.1%) and late onset side effects (15.3% v 10.3%), but less emphasis (P<0.001) on short-term side effects (27.8% v 29.8 %) and mode of administration (4.6% v 12.0%) than those on later lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Population estimate of patient preference remain important, but more effort is needed to understand how patient preference vary across patient with different backgrounds and treatment experiences. We show that line of treatment does not effect how patients value time, but their experience may have an impact on treatment characteristics. Latent class analysis may allow for the identification of groups with similar preferences that could allow for multivariate analyses to explain preference heterogeneity.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.03 - Attitudes to Lung Cancer in Europe: Findings from a Global Consumer Survey

      13:40 - 13:45  |  Presenting Author(s): Jesme Fox  |  Author(s): Aoife McNamara, Maureen Rigney, Greg Manuel, Sarah Winstone

      • Abstract

      Background

      If lung cancer is diagnosed early, patients’ chances of successful treatment are increased. Stigma
      around lung cancer, as a tobacco-related cancer, can discourage patients from talking to their doctor
      about potential symptoms. In 2017, the GLCC commissioned Populus to undertake an international
      consumer survey in each of the 25 countries of the GLCC members.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      1,000 adults, in 16 European countries, participated via an online survey in July 2017. To assess
      attitudes to lung cancer, they were told that lung cancer is mainly caused by smoking and other
      tobacco products. They were then asked the extent to which they agreed or disagreed with the
      statement: “I have less sympathy for people with lung cancer than for people with other cancers.”

      4c3880bb027f159e801041b1021e88e8 Result

      One in five (20%) people in Europe agreed that they have less sympathy for people with lung cancer
      than other forms of cancer (Chart 1). There was variation between countries with 30% of people in
      Portugal agreeing they have less sympathy in comparison to only 17% agreeing in Denmark, the
      Netherlands, Norway, Russia, Slovenia and Spain. Men in Europe are generally less sympathetic
      than women, and those aged over 55 are most sympathetic. In addition, there was a statistically
      significant correlation between those countries with lower cigarette consumption and people agreeing
      that they have less sympathy for people with lung cancer.

      Chart 1: European attitudes to lung cancer

      glcc - european attitudes - chart 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Everyone - no matter what the cause of their cancer - deserves to have high quality treatment and
      care. The persistent and varied levels of stigma associated with lung cancer across Europe needs to
      be addressed, so that people experiencing symptoms are not discouraged from seeking early
      intervention.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.04 - Discussant - MA 07.01, MA 07.02, MA 07.03

      13:45 - 14:00  |  Presenting Author(s): Kim Norris

      • Abstract

      Abstract not provided

    • +

      MA07.05 - Psychosocial Needs and Programs of Cancer Patients/Survivors and Their Relatives: Unmet Needs from an International Study

      14:00 - 14:05  |  Presenting Author(s): Csaba László Dégi  |  Author(s): Samantha Serpentini, Savita Goswami

      • Abstract

      Background

      In consideration of the dynamic nature of cancer patients’ needs, systematic understanding of their unmet needs from a socio-ecological perspective may be essential as the patients’ needs and available services are likely to vary by different healthcare systems in different countries. To investigate the role of geographical influence in cancer patients’ unmet needs, this study seeks to compare the unmet needs of and available programs for cancer patients/survivors and their family members by different types of healthcare systems across different countries.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The IPOS Survivorship Online Survey is distributed to international and regional Psycho-Oncology organization members, which covers countries in six continents. Survey participants’ countries where they practice/research will be categorized into four groups by the types of healthcare system: Beveridge Model, Bismarck Model, National Health Insurance Model, and Out-of-Pocket Model.

      4c3880bb027f159e801041b1021e88e8 Result

      With estimated survey to be completed by August 30th, 2018, repeated measures ANOVA will be employed to test differences in patients’ unmet needs by the four healthcare system groups, separately for patients’ unmet needs and their family caregivers’. Differences by individual countries will also be explored.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Findings will provide a global overview and a specific knowledge of the geografical differences in the psychosocial unmet needs and psycho-oncological programs for cancer patients/survivors and their family members/caregivers. Findings will also guide how to prioritize areas of cancer care that require improvement in psycho-oncology interventions and practices; and to highlight critical aspects for delivering quality care that vary by healthcare systems.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.06 - Telephonic Communication In Palliative Care For Better Management Of Terminal Cancer Patients In Rural India -  An NGO Based Approach. 

      14:05 - 14:10  |  Presenting Author(s): Nabanita Mandal

      • Abstract

      Background

      Due to financial incapability and absence of manpower poor families often fail to carry their advanced cancer patients to the nodal centres. This pilot study will explore whether communication by mobile phone can lessen this burden.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Initially a plan was generated regarding management of an advanced cancer patient in a nodal centre at District Head Quarter. Subsequently every two week a trained social worker attached to nodal centre will follow up and give necessary advice and emotional support to the patients and their families through their registered mobile phone number. Patient’s family were also encouraged to communicate with the team by phone in case of fresh complain and urgency in between.

      4c3880bb027f159e801041b1021e88e8 Result

      Since initiation in January 2017, 210 cancer patients were contacted by mobile phone every two weeks to enquire about their difficulties. In 76% of the situation trained social workers could give necessary advice by phone regarding management of their physical symptoms. Moreover patient’s family were really overwhelmed by the emotional support offered by the team over phone. Only 24% of cancer patients has to attend the nodal centre for expert advice from Palliative Care specialists.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This novel approach helped
      * In providing regular physical and emotional support to the patients and their families.

      * In significantly reducing the financial and manpower problems of carrying patients to the nodal units.
      * In improve the quality of life of patients by continuous guidance.


      More and more team members can take help of this new strategy for better communication and uninterrupted care.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.07 - Identifying the Severity of Psychosocial Symptoms Among Patients Diagnosed with Lung Cancer. Do We Really Need Emotional Support Groups?

      14:10 - 14:15  |  Presenting Author(s): Arooj Fatima  |  Author(s): Syed Sammar Abbas Zaidi

      • Abstract

      Background

      Lung cancer is the second most common cancer among men and women. Most of the lung cancers are diagnosed at later stages among those patients who are underprivileged. The diagnosis and treatment of lung cancer is a continuous emotional distress for both patient and their family. We aim to identify the severity of depression, emotional distress, stress and mental fatigue among those patients who are diagnosed with lung cancer .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A cross sectional study was conducted in Shaukat Khanum Hospital, Lahore from March 2014 to April 2015. Exclusion and Inclusion criteria were made. 150 were enrolled in the study. Socio demographic characteristics were evaluated using Beck Depression Inventory and socio demographic form. Severity of depression was estimated by using Hamilton D (HAM-D). Various variables were analysed including parent’s age, level of education, socioeconomic status, gender and number of children.

      4c3880bb027f159e801041b1021e88e8 Result

      68% of the participants exhibited severe range of depression. 27% showed moderate depression where as 5% participants were showing the mild range of depression. An inverse co relation was found between educational status, occupational status (paid or unpaid), their marital status, socioeconomic family status and depression. Women 71% were found be more depressed than males.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We concluded that majority of patients from psychosocial symptoms particularly depression and it is mainly associated with some factors. There is need to incorporate patients into the diagnosis and treatment process so that we can over come the effects of depression on the health outcomes of patients diagnosed with lung cancer. This can only be possible through appropriate education and emotional support programmes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.08 - Discussant - MA 07.05, MA 07.06, MA 07.07

      14:15 - 14:30  |  Presenting Author(s): Jennifer C King

      • Abstract

      Abstract not provided

    • +

      MA07.09 - Willingness to Perform Multiple Biopsies to Improve Quality of Lung Cancer Care: Understanding the Oncologists’ Perspective

      14:30 - 14:35  |  Presenting Author(s): Upal Basu Roy  |  Author(s): Margery Jacobson, Andrea Ferris

      • Abstract

      Background

      Biomarker testing of advanced-stage non-small cell lung cancer (NSCLC) at the time of diagnosis is required to determine if a patient will benefit from a targeted therapy or immunotherapy. A patient may, however, need additional biopsies (rebiopsy) if the cancer recurs to determine the next line of therapy or to determine eligibility for a new drug or participation in a clinical trial. A LUNGevity study, conducted with 340 patients, revealed that patients were willing to undergo rebiopsies if that meant access to additional treatment options at the time of recurrence. However, only 36% of patients reported that their doctors recommended repeat biopsies at progression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To understand this patient-physician communications gap, we conducted an IRB-approved semi-structured survey-based study of 130 oncologists from academic research centers, community cancer centers, and private practice.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 130 oncologists surveyed,

      - Ninety percent of oncologists reported recommending a rebiopsy to their patients. However, when stratified by advanced-stage patient volume, oncologists with higher advanced-stage patient volumes reported higher rebiopsy and testing rates than those with low volumes (95% vs. 78%, p<0.05). Only 29% of the oncologists prescribed a rebiopsy in the past one year.

      - Major barriers to rebiopsy reported by oncologists included cost/reimbursement of a rebiopsy and treatment delay for 2nd- or subsequent lines of therapy

      - Among the types of biomarker testing performed at the time of progression, oncologists were more likely to prescribe testing for biomarkers with approved treatments (driver mutations – 94%, PD-L1 – 85%) unlike biomarkers for treatments in clinical development (43%) (p<0.05).

      - A forward linear regression analysis revealed that positive predictors of rebiopsy included treatment at a NCI Designated Cancer Center, while treatment at a community cancer center or private practice, presence of driver mutations at the time of diagnosis, and performance status of patient were negative predictors of rebiopsy

      - When presented with specific treatment scenarios for biomarkers (EGFR and ALK) that have 2nd-line treatment options, oncologists differed in their approach, suggesting a need for oncologist education about rebiopsying and subsequent biomarker testing

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study demonstrates that rebiopsy practices vary by practice settings and volume of advanced-stage lung cancer patients. Even when rebiopsies are prescribed, a comprehensive biomarker profile of the tumor may not be obtained, due to variations in tests requested. A major implication is the need for appropriate oncologists’ education to ensure practice change for delivery of optimal care to lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.10 - Utilizing a Personalized Navigation Program to Identify Barriers and Increase Clinical Trial Participation Among Lung Cancer Patients

      14:35 - 14:40  |  Presenting Author(s): Andrew Ciupek  |  Author(s): Tara Perloff, Achintya Jaitly, Jennifer C King

      • Abstract

      Background

      Only about 5% of cancer patients participate in clinical trials. We previously conducted a survey of U.S. lung cancer patients and found that only 22% reported discussing clinical trials with their oncologist at the time of making treatment decisions. We hypothesized that a personalized navigation program could both increase rates of trial discussion and identify barriers to participation among lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We asked callers to Lung Cancer Alliance's 1-800 support line if they had considered clinical trial participation and referred willing callers to a navigator for further discussion. Navigators provided basic clinical trial education and a personalized list of trial matches. Patients were encouraged to discuss these trials with their treating oncologist. Navigators then regularly followed up with participants, via email or phone, at two to four-week intervals, to offer further support and collect outcomes information.

      4c3880bb027f159e801041b1021e88e8 Result

      We referred sixty callers to a navigator. Only 43% of callers reported a prior clinical trials conversation with their provider. Patients who had not started treatment or were on first-line treatment reported lower discussion rates (30%) than those on later treatment lines (60%). Among patients with follow up, 13 of 20 patients who had not discussed trials with their provider reported doing so after navigation. Ten of eleven patients that had a previous trial conversation initiated an additional one. Primary reasons given for not talking discussing after navigation were having stable disease on a current treatment or waiting for a clinical result. Ten patients reported contacting a trial. Primary reasons for not contacting a trial after discussion were disease progression, choosing a standard of care alternative, or waiting for a clinical result. Four patients have enrolled on a trial. Two patients were determined ineligible for a trial they approached for not meeting listed eligibility criteria and two for reasons not appearing in public trial information.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified barriers throughout the clinical trials consideration and enrollment process. One set of barriers was related to care coordination, as exemplified by low rates of trial discussion during early stages of treatment and patient reports of delayed trial consideration when currently receiving treatment or waiting on a clinical result. Communication of trial information was another area presenting barriers, as exemplified by exclusion of patients from trials for reasons not readily apparent from public trial information. Improving integration of trial discussion during care and ensuring availability of accurate, updated trial information may be essential to increase trial participation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.11 - Drug Price Comparison in Advanced Lung Cancer – High Cost Prices is Accompanied by Patient Benefits?

      14:40 - 14:45  |  Presenting Author(s): Luciene Bonan

      • Abstract

      Background

      In our recent decade we are seen new drugs coming up with high speed development to attend personalized conditions in lung cancer treatment. After the first TKI for EGFR mutation, many other target drugs such as TKI for ALK/ROS1 alteration, third-generation EGFR TKI, anti-PD-1/PD-L1 immunotherapies bring together an improvement in survival with better quality of life than chemotherapies. But this new specialty drugs are also testing the affordability of the market with new launched ceiling prices. Frequently, their prices have been settled down in a context of an unmet condition appeal rather than the truly health benefits. In pricing it is a common practice to use the external reference price between countries to align the prices based on international market. But if the first price is launched (frequently in USA) in countries that don’t use metrics based on evidence or clinical benefits, the price plateau could be replicated even without necessarily deserving this price. The objective of this presentation is to show the price comparison of drugs included in TKI class and immunotherapy class between high and middle-income countries. Then to compare the cost-treatment of therapies commonly used in advanced lung cancer and their magnitude of clinical benefit.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All local currencies were converted to US dollars using PPP factor. The magnitude of effect was evaluated based on the ESMO Magnitude of Clinical Benefit Score.

      4c3880bb027f159e801041b1021e88e8 Result

      USA has the highest drug price followed by Brazil, especially in recent launched drugs. Costs of advanced lung cancer treatment significantly increase 5 times more when compared first-generated TKI and new generation TKI. Immunotherapy for second line costs 6 times more than first line with EGFR TKI and could cost more than 7 to 130 times the chemotherapy with docetaxel. Clinical benefits do not reach the same scale.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The market of anticancer drug increasing 10% annually, but clinical benefits don’t advance in the same compass. Specialized drugs come into the market with pricing warrant of unmeet conditions, but if we think in precision medicine all new drug-target biomarker could be priced higher because it will cover a rare or unmet condition. In the context of precision medicine, is it fear a patient pays more because he has a different biomarker for the same clinical condition? If countries do not start to evaluate and pricing drugs based on value, market strategists will continue to test the ceiling price that health systems can(not) afford.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA07.12 - Discussant - MA 07.09, MA 07.10, MA 07.11

      14:45 - 15:00  |  Presenting Author(s): Govind Babu Kanakasetty

      • Abstract

      Abstract not provided

  • +

    MS05 - Diagnostic Dilemma in Lung Cancer

    • Type: Mini Symposium
    • Track: Pathology
    • Moderators:
    • +

      MS05.01 - Staging and Pathology of Multiple Lung Nodules

      13:30 - 13:50  |  Presenting Author(s): Alain C. Borczuk

      • Abstract

      Abstract not provided

    • +

      MS05.02 - Defining Invasion in Minimally Invasive Adenocarcinoma

      13:50 - 14:10  |  Presenting Author(s): Masayuki Noguchi

      • Abstract

      Abstract not provided

    • +

      MS05.03 - Tumor Heterogeneity in Lung Cancer

      14:10 - 14:30  |  Presenting Author(s): Elisabeth Brambilla

      • Abstract

      Abstract not provided

    • +

      MS05.04 - Diagnosis and Classification in Biopsies

      14:30 - 14:50  |  Presenting Author(s): Andre Moreira

      • Abstract

      Abstract not provided

    • +

      MS05.05 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

  • +

    MS06 - Practical Issues in the Management of Oligometastatic NSCLC

    • Type: Mini Symposium
    • Track: Oligometastatic NSCLC
    • Moderators:
    • +

      MS06.01 - The Role of Radiation in Treating the Mets

      13:30 - 13:45  |  Presenting Author(s): Hak Choy

      • Abstract

      Abstract not provided

    • +

      MS06.02 - The Role of Interventional Pulmonology and Radiology

      13:45 - 14:00  |  Presenting Author(s): Kwun M Fong

      • Abstract

      Abstract not provided

    • +

      MS06.03 - The Role of Surgical Resection

      14:00 - 14:15  |  Presenting Author(s): Boris Sepesi

      • Abstract

      Abstract not provided

    • +

      MS06.04 - Systemic Therapy for Oligomets: Before, During, or After Local Therapies?

      14:15 - 14:30  |  Presenting Author(s): Ross Camidge

      • Abstract

      Abstract not provided

    • +

      MS06.05 - The Special Case of Brain Metastases: Systemic Therapy, Radiation or Both?

      14:30 - 14:45  |  Presenting Author(s): Laurie Gaspar

      • Abstract

      Abstract not provided

    • +

      MS06.06 - Q&A

      14:45 - 15:00

      • Abstract

      Abstract not provided

  • +

    MS07 - Antibody-Drug Conjugates in Advanced NSCLC

    • Type: Mini Symposium
    • Track: Advanced NSCLC
    • Moderators:
    • +

      MS07.01 - Basic Science

      13:30 - 13:50  |  Presenting Author(s): David E Gerber

      • Abstract

      Abstract not provided

    • +

      MS07.02 - Pharmacology

      13:50 - 14:10  |  Presenting Author(s): Christian Rolfo

      • Abstract

      Abstract not provided

    • +

      MS07.03 - Clinical Data

      14:10 - 14:30  |  Presenting Author(s): Thomas E. Stinchcombe

      • Abstract

      Abstract not provided

    • +

      MS07.04 - Future Directions

      14:30 - 14:50  |  Presenting Author(s): Silvia Novello  |  Author(s): Annapaola Mariniello

      • Abstract

      Abstract not provided

    • +

      MS07.05 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

  • +

    MS08 - Lung Cancer in the Real World

    • Type: Mini Symposium
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Moderators:
    • +

      MS08.01 - How Can Real World Data Improve Clinical Evidence Generation and Impact Regulatory Bodies - European Perspective

      13:30 - 13:45  |  Presenting Author(s): Yolande Lievens

      • Abstract

      Abstract not provided

    • +

      MS08.02 - How Can Real World Data Improve Clinical Evidence Generation and Impact Regulatory Bodies – US Perspective

      13:45 - 14:00  |  Presenting Author(s): Gideon Blumenthal

      • Abstract

      Abstract not provided

    • +

      MS08.03 - Sources of Real World Data: Research Designs, Statistical Modelling and Quality Assurance Requirements

      14:00 - 14:15  |  Presenting Author(s): Mary W. Redman

      • Abstract

      Abstract not provided

    • +

      MS08.04 - The ASCO Perspective

      14:15 - 14:30  |  Presenting Author(s): Bruce E Johnson

      • Abstract

      Abstract not provided

    • +

      MS08.05 - The ESTRO Perspective

      14:30 - 14:45  |  Presenting Author(s): Umberto Ricardi

      • Abstract

      Abstract not provided

    • +

      MS08.06 - Discussion

      14:45 - 15:00

      • Abstract

      Abstract not provided

  • +

    OA05 - Clinical Trials in IO

    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Moderators:
    • +

      OA05.01 - Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy

      13:30 - 13:40  |  Presenting Author(s): Matthew D. Hellmann  |  Author(s): Pasi A Jänne, Mateusz Opyrchal, Navid Hafez, Luis E Raez, Dmitry Gabrilovich, Fang Wang, Peter Ordentlich, Susan Brouwer, Serap Sankoh, Emmett Schmidt, Michael L Meyers, Suresh S. Ramalingam

      • Abstract

      Background

      Treatment options are limited for lung cancer patients whose disease has progressed on anti-PD-(L)1 therapy. HDAC inhibitors may synergize with PD-(L)1 inhibition to overcome resistance. We report the interim results of a Phase 2 trial of entinostat (ENT), a class I selective histone deacetylase (HDAC) inhibitor, plus pembrolizumab (PEMBRO) in patients with NSCLC previously treated with anti-PD-(L)1 therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ENCORE-601 is an open-label study evaluating the combination of ENT + PEMBRO in patients with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy. Patients were eligible irrespective of histology or baseline PD-L1 expression. Patients were treated with ENT 5 mg PO weekly and PEMBRO 200 mg IV Q3W. The primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were taken prior to and during treatment in a subset of patients. A total of 70 patients will be enrolled.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 57 patients with anti-PD-(L)1 resistant/refractory NSCLC, the confirmed objective response rate with ENT + PEMBRO was 11% (6 of 57, 95% CI: 4-21%). Of 49 patients with post-baseline tumor measurements, 47% had at least some reduction in tumor. Anti-PD-(L)1 therapy was the most recent line of therapy in 38 of 57 patients, and the median time from last dose of prior anti-PD-(L)1 to study entry was 67 days. The median duration of response with ENT + PEMBRO was 5 months, with the longest over 14 months. Of the 6 responders, four were PD-L1 negative at study entry. Response was associated with a higher median baseline level of peripheral classical monocytes (CD14+CD16-HLA-DRhi) with 16.9% of total live PBMCs in responders (n=6) compared to 8.2% in non-responders (n=45). 5 patients (8.8%) experienced Grade 3/4 related irAEs (2 events each of pneumonitis and colitis, 1 event of hyperthyroidism). In addition, 19 patients (33.3%) experienced other Grade 3/4 related AEs with only fatigue, anemia, hypophosphatemia, and hyponatremia occurring in more than 1 patient. Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress.

      8eea62084ca7e541d918e823422bd82e Conclusion

      ENT + PEMBRO demonstrated anti-tumor activity and acceptable safety in patients with NSCLC who have progressed on prior PD-(L)1 blockade. Ongoing analysis of immune correlates may identify strategies for effective patient selection.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.02 - Epacadostat Plus Pembrolizumab in Patients with Non-Small Cell Lung Cancer: Phase 1/2 Results from ECHO-202/KEYNOTE-037

      13:40 - 13:50  |  Presenting Author(s): Liza Villaruz  |  Author(s): Bryan J Schneider, Todd M. Bauer, Alexander Spira, Gina D'Amato, Jeffery Wasser, Ani Balmanoukian, Primo Lara, Anthony Olszanski, Thomas Gajewski, Sandip Patel, Ahmad Tarhini, Joshua Michael Bauml, Emmett Schmidt, Jill Bowman, Jeannie Daniel, Sherry Owens, Tara C Mitchell

      • Abstract

      Background

      Epacadostat (E) is a potent, highly selective inhibitor of the indoleamine 2, 3-dioxygenase 1 (IDO1) enzyme. ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of E + pembrolizumab (P) in patients (pts) with advanced tumors (NCT02178722). We report updated efficacy and safety data for the phase 1 and 2 non-small cell lung cancer (NSCLC) cohort as of 8 Jan 2018 data cutoff.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Adult pts with prior platinum-based therapy (tx), no prior immune checkpoint inhibitors, and those intolerant to EGFR-targeted therapy were eligible. Pts could receive E (25, 50, 100, or 300 mg twice daily [BID]) + P (2 mg/kg or 200 mg every 3 weeks [Q3W]) during phase 1; maximum tolerated dose was not achieved. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 evaluation. Efficacy was assessed by RECIST v1.1 criteria. Programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) was evaluated using the 22C3 pharmDx assay. IDO1 status was measured by RNAScope. Safety was assessed in pts receiving ≥1 E + P dose.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 70 pts (phase 1, n=12; phase 2, n=58) were evaluated. Median age was 63 years and 57% of pts were female. EGFR mutation status (+/-/not available) was 10%/71%/19%; KRAS status was 19%/26%/56%, respectively. Most pts had adenocarcinoma (70%), a history of smoking (76%), and 0–1 prior lines of tx (64%). PD-L1 TPS results were available in 55/70 pts; IDO1 status (+/-) in 41/70 pts. Overall, the objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (CR + PR + stable disease [SD]) were 29% (20/70; 17 PR) and 50% (35/70; 15 SD), respectively. ORR was 22% (2/9) in pts with TPS ≥50% and 0–1 prior tx; for pts with TPS <50% and 0–1 prior tx, ORR was 22% (5/23). ORR for pts with IDO1+ and IDO1- tumors were 24% (6/25) and 19% (3/16), respectively. At data cutoff, 10/20 responses were ongoing. Median progression-free survival (PFS) was 4.0 mo (90% confidence interval, 2.1–6.2 mo); PFS rates at 6, 12, and 18 mo were 43% (33%–53%), 31% (22%–40%), and 17% (10%–26%), respectively. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 27% of pts; 3 pts discontinued due to TRAEs; and no TRAEs led to death.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The E + P combination was generally well tolerated and associated with promising responses in pts with NSCLC.

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      OA05.03 - Safety and Clinical Activity of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes (TIL) Combined with Nivolumab in NSCLC

      13:50 - 14:00  |  Presenting Author(s): Ben C. Creelan  |  Author(s): Jamie K Teer, Eric M Toloza, John E Mullinax, Ana M Landin, Jhanelle Elaine Gray, Tawee T Tanvetyanon, Matthew C Taddeo, David R Noyes, Linda L Kelley, Bin Fang, John M Koomen, Amod A Sarnaik, Sungjune Kim, Eric B. Haura, Scott J Antonia

      • Abstract

      Background

      Adoptive transfer of tumor infiltrating lymphocytes (TIL) can cause durable regression by recognition of neoantigens unique to the patient. NSCLC TIL has synergistic preclinical activity with nivolumab, and we hypothesized it may induce remissions in anti-PD1-refractory patients. We initiated a phase I trial with the primary objective to characterize the safety and preliminary activity of the combination.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Metastases from patients with Stage 4 NSCLC were resected, morselized, cultured, and tested for autologous reactivity. Reactive TIL fragments were pooled and cryopreserved. Patients received nivolumab over 8 weeks. Patients with progressive disease (PD) proceeded to lymphodepletion cyclophosphamide/fludarabine (Cy/Flu), TIL, and IL-2. Tumor whole exome sequencing, transcriptomics, and LC-MS/MS peptide sequencing was performed. TCR-Vß rearrangements were analyzed from tumor, TIL, and pre-/post-infusion peripheral lymphocytes.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 14 patients enrolled to date, 13 had successful ex vivo TIL expansion from resected metastases. TIL had high proliferative capacity, expanding to median 81 billion CD3+ cells infused per patient (range 27–138 billion) and median 27% of fragments were autologously reactive (range 0-67%). Demographics: median age 54 (range 44-74), median TMB 4 mutations/MB (range 0.9–25), median PD-L1 proportion-score 0% (range 0–100%), and 4 had LKB1 allelic inactivation. Predicted neoantigens correlated with variants on proteomic sequencing. Outcomes: 9 patients had confirmed PD on nivolumab, and proceeded to receive Cy/Flu/TIL/IL-2. No unexpected serious adverse reactions (SUSARs) were identified. Of these 9 patients, 7 had reduction in sum of target lesions at Day+28 CT scan (Figure 1). Peripheral lymphocytes expanded at Days 2-7 in the majority of patients. In patients tested to date, TIL clonotypes persisted through Day+100, and CCR7+CD95+CD45RA+ stem cell-like memory (TSCM) cells were increased at post-infusion timepoints.

      abstract figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Adoptive cell transfer with TIL and nivolumab for NSCLC had acceptable toxicity and preliminary activity in this ongoing trial.

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      OA05.04 - Discussant - OA 05.01, OA 05.02, OA 05.03

      14:00 - 14:15  |  Presenting Author(s): Scott Owen  |  Author(s): Martin J. Edelman

      • Abstract

      Abstract not provided

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      OA05.05 - Avelumab vs Docetaxel for Previously Treated Advanced NSCLC: Primary Analysis of the Phase 3 JAVELIN Lung 200 Trial

      14:15 - 14:25  |  Presenting Author(s): Fabrice Barlesi  |  Author(s): Johan F. Vansteenkiste, David R. Spigel, Hidenobu Ishii, Marina Chiara Garassino, Filippo De Marinis, Mustafa Özgüroğlu, Aleksandra Szczesna, Andreas Polychronis, Ruchan Uslu, Maciej Krzakowski, Jong-Seok Lee, Luana Calabro, Osvaldo Arén Frontera, Barbara Ellers-Lenz, Marcis Bajars, Mary Ruisi, Keunchil Park

      • Abstract

      Background

      Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is an approved treatment for metastatic Merkel cell carcinoma (various regions) and platinum-treated advanced urothelial carcinoma (US). We report findings from a global, open-label, phase 3 trial of avelumab vs docetaxel in patients with advanced NSCLC after platinum failure (NCT02395172).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with stage IIIB/IV or recurrent NSCLC with disease progression after platinum doublet therapy were randomized 1:1 to avelumab 10 mg/kg Q2W or docetaxel 75 mg/m2 Q3W, stratified by PD-L1 status (PD-L1+/PD-L1−) and histology (squamous/nonsquamous). The primary endpoint was overall survival (OS) in the PD-L1+ population (expression on ≥1% of tumor cells, assessed using the PD-L1 IHC 73-10 assay).

      4c3880bb027f159e801041b1021e88e8 Result

      Between April 2015 and February 2017, 792 patients were randomized to receive avelumab or docetaxel, including 264 and 265 with PD-L1+ tumors, respectively; 0.8% vs 7.5% did not receive study treatment. Median follow-up in the avelumab and docetaxel arms was 18.9 and 17.8 months; 15.5% vs 1.5% remained on treatment at data cutoff (November 22, 2017). In the avelumab and docetaxel arms, 39.8% vs 47.5% received subsequent anticancer therapy after discontinuation, including checkpoint inhibitors in 5.7% vs 26.4%, respectively. In the PD-L1+ population, median OS in the avelumab and docetaxel arms was 11.4 vs 10.3 months (hazard ratio [HR], 0.90 [96% CI, 0.72-1.12]; P=0.1627, 1-sided). Pre-planned exploratory analyses based on higher PD-L1 cutoffs showed increased OS with avelumab vs docetaxel, including PD-L1-high (≥80% cutoff, 29% of patients; 17.1 vs 9.3 months; HR, 0.59 [95% CI, 0.42-0.83]; P=.0022, 2-sided) and PD-L1-medium/high (≥50% cutoff, 40% of patients; 13.6 vs 9.2 months; HR, 0.67 [95% CI, 0.51-0.89]; P=0.0052, 2-sided) subgroups. In the PD-L1+ population (≥1% cutoff), ORR was 18.9% vs 11.7% (odds ratio, 1.76 [95% CI, 1.08-2.86]; P=0.0105, 1-sided); median duration of response was not reached with avelumab (95% CI, 9.9-not estimable [NE]) vs 6.9 months with docetaxel (95% CI, 3.5-NE). Overall rates of treatment-related adverse events (AEs) were lower with avelumab than docetaxel, including all grades (63.9% vs 85.8%) and grade ≥3 (9.9% vs 49.3%). Immune-related AEs occurred in 16.5% of avelumab-treated patients (grade ≥3 in 2.8%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Avelumab showed increasing clinical activity in patients who had platinum-treated NSCLC with higher tumor PD-L1 expression; however, the trial did not meet its primary objective of improving OS vs docetaxel in PD-L1+ tumors (≥1% cutoff). OS findings may have been confounded by subsequent checkpoint inhibitor therapy in the docetaxel arm.

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      OA05.06 - CheckMate 227: Patient-Reported Outcomes of First-Line Nivolumab + Ipilimumab in High Tumor Mutational Burden Advanced NSCLC

      14:25 - 14:35  |  Presenting Author(s): Julie R. Brahmer  |  Author(s): Michael Schenker, Ki Hyeong Lee, Mariano Provencio, Makoto Nishio, Krzysztof Lesniewski-Kmak, Randeep Sangha, Samreen Ahmed, Judith Raimbourg, Kynan Feeney, Romain Corre, Fabio Andre Franke, Eduardo Richardet, John R. Penrod, Yong Yuan, Faith Nathan, Prabhu Bhagavatheeswaran, Michael De Rosa, Fiona Taylor, Rachael Lawrance, Martin Reck

      • Abstract

      Background

      The randomized, open-label, multipart phase 3 study CheckMate 227 (NCT02477826) demonstrated a significant progression-free survival benefit (co-primary endpoint) with first-line nivolumab+ipilimumab versus histology-based, platinum-doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and high tumor mutational burden (TMB; ≥10 mutations/Mb). Patient-reported outcomes (PROs) for this population within CheckMate 227 are presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible chemotherapy-naïve patients had stage IV or recurrent NSCLC, ECOG performance status 0−1, and no known sensitizing EGFR/ALK alterations. PROs were assessed as an exploratory endpoint; this analysis included patients with high TMB randomized to nivolumab+ipilimumab or chemotherapy; specific outcomes included proportion of patients with disease-related symptom deterioration by 12 weeks and time to deterioration in symptoms (by Lung Cancer Symptom Scale [LCSS] Average Symptom Burden Index [ASBI]), and assessment of quality of life and overall health status (by EuroQoL-5 Dimension [EQ-5D] utility index [UI] and visual analog scale [VAS]). PROs were evaluated each cycle (Q2W, nivolumab+ipilimumab; Q3W, chemotherapy) for the first 6 months, every 6 weeks thereafter during treatment, and at follow-up visits 1/2. EQ-5D was also assessed during survival follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      PRO completion rates were ~90% at baseline and >80% for nearly all on-treatment assessments. Among patients with high TMB, fewer patients in the nivolumab+ipilimumab (n=139) versus chemotherapy (n=160) groups reported symptom deterioration by week 12, irrespective of whether they were still on therapy or had discontinued (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% CI: 2.4–22.5]). Time to first deterioration (TTD) using common assessment time points (on/off treatment) was delayed with nivolumab+ipilimumab versus chemotherapy for the LCSS ASBI (hazard ratio [HR]: 0.40; 95% CI: 0.26–0.63) and 3-Item Global Index (3-IGI; HR: 0.56; 95% CI: 0.38–0.82). The estimated benefit in TTD generally favored nivolumab+ipilimumab for individual symptoms in the ASBI and each item in the 3-IGI (HRs: 0.48–0.74), except for hemoptysis (HR: 1.20), which exhibited very low burden; an advantage for nivolumab+ipilimumab was also seen in the EQ-5D VAS (HR: 0.62; 95% CI: 0.42–0.92) and UI (HR: 0.50; 95% CI: 0.34–0.73). Mean changes from baseline with nivolumab+ipilimumab showed early and clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; for patients treated with chemotherapy, symptoms and quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following completion of chemotherapy (EQ-5D VAS).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab+ipilimumab demonstrated early and sustained improvements in health-related quality of life versus chemotherapy in patients with advanced NSCLC and high TMB.

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      OA05.07 - IMpower132: PFS and Safety Results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in Stage IV Non-Squamous NSCLC

      14:35 - 14:45  |  Presenting Author(s): Vassiliki A Papadimitrakopoulou  |  Author(s): Manuel Cobo, Rodolfo Bordoni, Pascale Dubray-Longeras, Zsuzsanna Szalai, Grigoriy Ursol, Silvia Novello, Francisco Orlandi, Simon Ball, Jerome Goldschmidt Jr., Rachel E Sanborn, Tien Hoang, Diana Mendus, Yu Deng, Marcin Kowanetz, Xiaohui Wen, Wei Lin, Alan Sandler, Makoto Nishio

      • Abstract

      Background

      In addition to the combination of atezolizumab (anti–PD-L1)+platinum+taxane±bevacizumab, non-squamous NSCLC patients may derive benefit from adding atezolizumab to platinum+pemetrexed. The randomized Phase III IMpower132 study (NCT02657434) evaluated first-line pemetrexed+carboplatin or cisplatin±atezolizumab in patients with stage IV non-squamous NSCLC without EGFR or ALK driver mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were randomized 1:1 to receive 4 or 6 cycles of carboplatin AUC 6 mg/mL/min or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W alone (arm PP) or in combination with atezolizumab 1200 mg Q3W (arm APP), followed by pemetrexed (arm PP) or atezolizumab + pemetrexed (arm APP) maintenance. Atezolizumab could be continued beyond disease progression per protocol guidelines. PFS and OS were co-primary endpoints. Efficacy by PD-L1 expression was an exploratory endpoint. Here, we present investigator-assessed PFS per RECIST v1.1 (final analysis), OS (interim analysis) and safety data.

      4c3880bb027f159e801041b1021e88e8 Result

      292 pts were enrolled in arm APP and 286 pts in arm PP. 43% and 40% in arms APP and PP, respectively, had ECOG PS 0. At the data cutoff (22 May 2018), median follow-up was 14.8 mo overall. PFS analysis showed a statistically significant improvement between arm APP vs PP (median PFS 7.6 vs 5.2 mo; HR=0.596; 95% CI: 0.494, 0.719; P<0.0001). Interim analysis showed a numerical but non-statistically significant OS improvement (Table). Efficacy results were consistent across all key clinical subgroups. Grade 3-4 TRAEs occurred in 53.6% of patients (APP) vs 39.1% (PP). 7.2% of patients (APP) vs 5.1% (PP) had a Grade 5 AE, 3.8% (APP) vs 2.6% (PP) were treatment related. 48.5% of patients (APP) vs 38.0% (PP) experienced AEs of special interest specific to atezolizumab.

      8eea62084ca7e541d918e823422bd82e Conclusion

      IMpower132 met its co-primary endpoint of investigator-assessed PFS in the ITT. Interim OS data (not fully mature) showed numerical improvement. Atezolizumab+pemetrexed+carboplatin or cisplatin was well tolerated, and no new safety signals were identified.

      Table. IMpower132 Efficacy Analyses

      APP Arm
      (atezolizumab+pemetrexed+ carboplatin or cisplatin)
      PP Arm
      (pemetrexed+carboplatin or cisplatin)
      ITT n=292 n=286
      Median PFS (95% CI), mo 7.6 (6.6, 8.5) 5.2 (4.3, 5.6)
      HRa (95% CI; P value) 0.596 (0.494, 0.719; P < 0.0001)
      12-Month PFS (95% CI), % 33.7% (28.2, 39.2) 17.0% (12.6, 21.4)
      Median OS (95% CI), mo 18.1 (13.0, NE) 13.6 (11.4, 15.5)
      HRa (95% CI; P value) 0.813 (0.644, 1.025; P = 0.0797)
      12-Month OS (95% CI), % 59.6% (53.9, 65.3) 55.4% (49.5, 61.2)
      ORR (confirmed, inv-assessed), % 46.9% 32.2%
      DOR (95% CI), mo 10.1 (7.2, 13.3) 7.2 (5.7, 9.0)
      PD-L1–highb n=25 n=20
      Median PFS (95% CI), mo 10.8 (7.9, NE) 6.5 (2.4, 10.6)
      HR (95% CI; P value) 0.464 (0.224, 0.960; P = 0.0339)
      PD-L1–lowb n=63 n=73
      Median PFS (95% CI), mo 6.2 (4.4, 8.4) 5.7 (4.2, 7.9)
      HR (95% CI; P value) 0.804 (0.556, 1.163; P = 0.2462)
      PD-L1–negativeb n=88 n=75
      Median PFS (95% CI), mo 8.5 (6.1, 11.2) 4.9 (4.2, 5.8)
      HR (95% CI; P value) 0.448 (0.313, 0.642; P < 0.0001)

      DOR, duration of response; HR, hazard ratio; inv, investigator; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

      a Stratified. b Baseline tissue available in 60% of patients. PD-L1high (TC3/IC3): patients with PD-L1 expression in ≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells; PD-L1low (TC12/IC12): patients with PD-L1 expression in ≥1% and <50% of tumor cells or ≥1% and <10% of tumor-infiltrating immune cells; and PD-L1negative (TC0/IC0): patients with PD-L1 expression in <1% of tumor cells and <1% of tumor-infiltrating immune cells.

      NCT02657434

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      OA05.08 - Discussant - OA 05.05, OA 05.06, OA 05.07

      14:45 - 15:00  |  Presenting Author(s): Hossein Borghaei

      • Abstract

      Abstract not provided