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  • WCLC 2018

    19th World Conference on Lung Cancer

    Access to all presentations that occur during the 19th World Conference on Lung Cancer in Toronto, ON

    Presentation Date(s):
    • Sept 23 - 26, 2018
    • Total Presentations: 2384

    To review abstracts of the presentations below, narrow down your search by using the Filter options below, and then select the session listing of your choice. Click the "+" for a presentation to expand & view the corresponding Abstract details.

    Presentations will be available 24 hours after their live presentation time

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    MS06 - Practical Issues in the Management of Oligometastatic NSCLC (ID 785)

    • Type: Mini Symposium
    • Track: Oligometastatic NSCLC
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 BD
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    MS07 - Antibody-Drug Conjugates in Advanced NSCLC (ID 786)

    • Type: Mini Symposium
    • Track: Advanced NSCLC
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 205 BD
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    MS08 - Lung Cancer in the Real World (ID 787)

    • Type: Mini Symposium
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 201 F
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    OA05 - Clinical Trials in IO (ID 899)

    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 8
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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      OA05.01 - Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy (ID 12922)

      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
      • Presentation
      • Slides

      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 (ID 13535)

      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
      • Presentation
      • Slides

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.03 - Safety and Clinical Activity of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes (TIL) Combined with Nivolumab in NSCLC (ID 14388)

      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
      • Presentation
      • Slides

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.04 - Discussant - OA 05.01, OA 05.02, OA 05.03 (ID 14554)

      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 (ID 12930)

      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
      • Presentation
      • Slides

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.06 - CheckMate 227: Patient-Reported Outcomes of First-Line Nivolumab + Ipilimumab in High Tumor Mutational Burden Advanced NSCLC (ID 13450)

      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
      • Presentation
      • Slides

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.07 - IMpower132: PFS and Safety Results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in Stage IV Non-Squamous NSCLC (ID 12389)

      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
      • Presentation
      • Slides

      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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.08 - Discussant - OA 05.05, OA 05.06, OA 05.07 (ID 14555)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA06 - Early Stage Lung Cancer: Outcomes and Interventions (ID 902)

    • Type: Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 8
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 202 BD
      • Abstract
      • Presentation
      • Slides

      Background
      Sex differences in non-small cell lung cancer (NSCLC) susceptibility, tumor biology and survival have been retrospectively reported. We conducted a prospective, case-series intergroup study (SWOG S0424) in 4 cohorts of females (F) and males (M), ever-smokers (ES) and never-smokers (NS) with newly-diagnosed stages I-III NSCLC. This is the first overall survival (OS) report. a9ded1e5ce5d75814730bb4caaf49419 Method
      Patients were accrued at US sites via SWOG/NCI-CTSU. A questionnaire of demographics and exposures (tobacco, environmental, reproductive, hormonal); stage and histology data; treatment; and OS were obtained. Tumor tissue was submitted for EGFR, RAS and p53 mutations. Nuclear and cytoplasmic estrogen receptor (ER) alpha and beta were measured (Cheng, JNCI 2017). Kaplan-Meier (KM) curves and OS modeled using Cox proportional hazards were examined. The NS cohorts remained open longer to maximize accrual. Patients were followed 5 years for OS or until death. 4c3880bb027f159e801041b1021e88e8 Result
      The accrual goal of 981 was achieved from 10/2005-3/2011. Evaluable cases were FES, n=337; MES, 383; FNS, 188; MNS, 49 (MNS under-accrued despite extension). The 4 cohorts differed significantly in demographics, tumor stage, histology, mutational profile (overall, by histology), ER expression, lifestyle factors and exposures. KM curves showed MNS/MES had overlapping OS and FNS/FES had significantly better OS. Five-year estimates were FNS, 73%; FES, 69%; MNS, 58%; MES, 52%. Markedly improved OS for females persisted after adjusting for other factors. Four multivariate OS models were constructed: all patients (model 1) and women only (model 2), each with mutations and ER expression added (models 3, 4). Model 1: better OS for females (HR 0.56, p <.001); higher BMI (continuous, HR 0.98, p=0.045); and adenocarcinoma, BAC, large cell (all vs squamous, HRs 0.84, 0.48, 0.57); worse OS for stages II and III (HRs 1.87, 3.76: each p<.001) and greater age. Model 2: worse OS if ES (HR 1.48, p=0.05), higher stages; histology and hormonal exposure variables were not significant. Model 3: better OS if EGFR mutation (HR 0.53, p=0.013), female, stage I, higher BMI or greater height; worse OS if p53 mutation, higher ER-alpha cytoplasmic or ER-beta nuclear H-scores. Model 4: worse OS if higher stage, p53 mutation or ER-alpha cytoplasmic H-score; EGFR mutation lost significance. 8eea62084ca7e541d918e823422bd82e Conclusion
      Sex, histology, mutations and exposures impacted OS, with dramatically better OS for females regardless of the analysis/model. Hormonal influences (persistent association of ER-expression with OS) were independently significant. Despite adjustments, favorable female survival could not be explained away. Randomized studies should stratify by sex and validation analyses should be conducted in targeted therapy and immunotherapy trials.

      SUPPORT: NIH/NCI grants R01CA106815, U10CA180888, U10CA180819 and UG1CA189974. 6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA06.02 - Video-Assisted Thoracoscopic Surgery vs. Thoracotomy for Non-Small Cell Lung Cancer: Oncologic Outcome of a Randomized Trial (ID 12455)

      13:40 - 13:50  |  Presenting Author(s): Dongrong Situ  |  Author(s): Hao Long, Qunyou Tan, Qingquan Luo, Zheng Wang, Gening Jiang, Tie-Hua Rong

      • Abstract
      • Presentation
      • Slides

      Background

      Video-assisted thoracoscopic surgery (VATS) has been widely used in the treatment of early-stage non–small cell lung cancer (NSCLC). However, there has not been a robust randomized control trial (RCT) to conclude VATS has similar oncologic efficacy to open surgery. Therefore, a large multicenter RCT in China was designed and initialed in order to verify the role of VATS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A non-inferiority phase 3 RCT was undertaken at five thoracic surgical centers in China. Patients aged 18-75 years who were diagnosed of clinically early-stage NSCLCs were randomized in a 1:1 ratio into VATS and thoracotomy groups. Radical lobectomy plus hilar and mediastinal lymph node dissection was the standard surgical intervention as per protocol. The long-term oncologic outcomes including 3-year locoregional recurrence rate, overall survival (OS) and disease-free survival (DFS) would be analyzed and reported here. This study is registered with the ClinicalTrials.gov, number NCT01102517.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 508 patients were recruited in the trial between January 2008 and March 2014. And 433 patients were eligible for final analysis (222 cases in VATS group and 211 cases in thoracotomy group). At 3 years, the locoregional recurrence rates were 4.5% in VATS group and 5.7% in thoracotomy group respectively (P=0.664). Patients who received VATS procedures had a similar DFS rate to those who underwent open surgery (66% versus 69%, P=0.925; Fig 1A). Again, the 3-year OS rates were of no significant difference between VATS and thoracotomy groups (74% versus 73%, P=0.382; Fig 1B).

      fig 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      VATS in the treatment of clinically early-stage NSCLCs was associated with equivalent oncologic efficacy when compared to open surgery.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA06.03 - Sublobar Resection is Equivalent to Lobectomy for Screen Detected Lung Cancer (ID 13968)

      13:50 - 14:00  |  Presenting Author(s): Brendon Stiles  |  Author(s): Mohamed K Hussein, Mohamed Rahouma, Benjamin Lee, Sebron Harrison, Jeffrey L. Port, Nasser Altorki

      • Abstract
      • Presentation

      Background

      Despite the lack of survival data from modern, ongoing randomized clinical trials (CALGB 140503, JCOG 0802), sublobar resection (SLR) is increasingly offered to patients with small, peripheral lung cancers. In particular, SLR may be an attractive surgical strategy for screen detected lung cancers, some of which may be less biologically aggressive than cancers detected by other means. Utilizing prospective data collected from patients undergoing surgery in the National Lung Screening Trial (NLST), we sought to determine whether the extent of resection affected survival for patients with screen detected lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The NLST database was queried for patients who underwent surgical resection for confirmed lung cancer. Numerical variables were compared using Mann-Whitney U test. Categorical variables were compared using Chi-squared test. Propensity score matching analysis (lobectomy versus sublobar resection) controlling for age, gender, race, tumor size, and stage was performed (nearest neighbor, 1:1, matching with no replacement, caliper 0.2). Overall survival (OS) and cancer specific survival (CSS) were compared using log rank test in Kaplan Meier curves.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 1,029 patients who underwent resection for lung cancer, we identified 821 patients (80%) who had lobectomy and 166 patients (16%) who had SLR, among whom the majority (n=114, 69%) had wedge resection. Patients who underwent SLR were older (64 vs. 61, p=0.66), more likely to be female (53% vs. 41%, p=0.004), had smaller tumors (2 cm vs. 4.5 cm, p<0.001), and were more likely to be stage I (80% vs. 75%, p=0.001). At five years, for stage I patients undergoing SLR (n=129) there was no difference in OS (77% vs. 77%, p=0.889) or CSS (83% vs. 83%, p=0.959) compared to patients undergoing lobectomy (n=613). In order to more accurately compare surgical outcomes, we propensity matched 134 patients from each group undergoing SLR and lobectomy. Among these matched groups, there were no differences in age, gender, histology, or stage. Postoperatively, patients undergoing SLR had less total complications (22% vs. 32%, p=0.05) than those undergoing lobectomy (HR 0.59, CI 0.38-0.94). In matched patients at five years, there was no difference in OS (67% vs. 70%, p=0.629) or CSS (74% vs. 74%, p=0.980) for patients undergoing SLR compared to those undergoing lobectomy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      For patients with screen detected lung cancer, SLR confers equivalent survival to lobectomy. By decreasing perioperative complications and potentially preserving lung function, SLR may provide distinct advantages in a screen detected lung cancer patient cohort.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA06.04 - Discussant - OA 06.01, OA 06.02, OA 06.03 (ID 14556)

      14:00 - 14:15  |  Presenting Author(s): Valerie W Rusch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA06.05 - Do SBRT Planning and Delivery Factors Influence Local Control for Early Stage Non-Small Cell Lung Cancer (e-NSCLC)?  (ID 12730)

      14:15 - 14:25  |  Presenting Author(s): Gregory M.M. Videtic  |  Author(s): Chandana A. Reddy, Aditya Juloori, Bindu Manyam, Neil M Woody, Kevin L Stephans

      • Abstract
      • Presentation
      • Slides

      Background

      Stereotactic Body Radiation (SBRT) utilizes a variety of techniques to deliver very high-dose radiation to moving targets in the lung. We investigated the impact of dose-delivery factors on local failure (LF) by surveying our 12 year experience with e-NSCLC from our prospective database.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Curative SBRT was administered to 1,085 patients (pts) between 2005 and 2016 and planned with either pencil beam (PB) or collapsed cone convolution (CCC) dose calculation algorithms (DCA), using open (dynamic arcs) or modulated beams (IMRT or VMAT), immobilized by abdominal compression or automatic breathing control (ABC), and treated with/without available CBCT (aligned to external fiducials and KV x-rays to bone if no CBCT, PTV margins were not altered based on availability of CBCT). We limited our analysis to standard fractionation regimens, [60 Gy/3, 48 Gy/4, 50 Gy/5, & 30-34 Gy/1) chosen per the treating physician in a risk-adapted approach relative to tumor size and location. The intreaction of technical variables with known patient and tumor factors on LF was analyzed using Fine and Gray univariate regression, with significant predictors selected for a forward step-wise multivariate regression model.

      4c3880bb027f159e801041b1021e88e8 Result

      At mean follow-up time of 25.6 months the cumulative incidence of LF at 1, 2, & 5 years was 3.0, 8.3, and 9.8% respectively. Overall survival (1, 2, 5 years) was 83, 62, & 28%. Univariate correlates with LF were PB TPS (HR 2.87, p=0.0004), modulated beam (HR 2.3, p=0.005), lack of CBCT (HR 2.69, p=0.0004), SBRT dose relative to 60 Gy/3 (HR 5.2, p=0.0001 for 4-5 fx; HR 2.7, p=0.051 for 1 fx), tumor size (HR 1.2 per cm, p=0.0009), PET SUV (HR 1.04 per SUV, p=0.0039), and squamous histology (HR 1.8, p=0.0051). Immobilization with ABC (n=96) versus abdominal compression (n=989) did not correlate with LF (p=0.99). On multivariate analysis PET SUV, modulated beam, and use of CBCT were no longer significant correlates with LF, while TPS (HR 2.62, p=0.0019), SBRT dose (HR 4.1, p=0.0009 for 4-5 fx relative to 60 Gy/3) & HR 2.9, p=0.039 for 1 fx versus 60 Gy/3), tumor size (HR 1.2 per cm, p=0.042) and squamous histology (HR 1.7, p=0.027) remained statistically significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      While the use of PB versus CCC DCA was associated with higher rates of LF after SBRT, the use of abdominal compression vs ABC (univariate), open vs modulated beam, and CBCT vs bony alignment (multivariate) were not correlated with higher rates of LF after SBRT in e-NSCLC.

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      OA06.06 - MISSILE-NSCLC: A Phase II Trial Measuring the Integration of Stereotactic Radiotherapy Plus Surgery in Early-Stage Non-Small Cell Lung Cancer (ID 13028)

      14:25 - 14:35  |  Presenting Author(s): David Palma  |  Author(s): Alexander Louie, Richard Malthaner, Dalilah Fortin, George Rodrigues, Brian Yaremko, Joanna M Laba, Keith Kwan, Stewart Gaede, Ting Lee, Aaron Ward, Andrew Warner, Richard Inculet

      • Abstract
      • Presentation
      • Slides

      Background

      Stereotactic Ablative Radiotherapy (SABR) has emerged as a standard treatment option in patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), yet the pathologic complete response (pCR) rate after SABR is unknown. Neoadjuvant SABR in operable patients has been proposed as a mechanism of improving local control and inducing anti-tumor immune activity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This phase II study (NCT02136355) enrolled patients with biopsy-proven clinical T1-2N0M0 NSCLC who were candidates for surgical resection. Patients underwent neoadjuvant SABR using a risk-adapted fractionation of 54 Gy/3 fractions, 55 Gy/5 or 60 Gy/8. Surgical resection took place 10 weeks after SABR. Patients also underwent dynamic FDG-PET and dynamic contrast-enhanced CT prior to SABR and approximately 2 weeks prior to surgery. The primary endpoint was the pCR rate, and secondary endpoints included local, regional, and distant recurrence, quality of life using the FACT Trial Outcome Index (TOI), and toxicity.

      4c3880bb027f159e801041b1021e88e8 Result

      Accrual began in Sept 2014 and completed in August 2017 with 40 patients enrolled. Median age was 69 years (range 44–83 years), and 58% were female. Thirty-one patients (78%) had T1 tumors and 9 (23%) had T2 tumors; histology was adenocarcinoma (n=26; 65%), squamous cell (n=13; 33%) and NSCLC not otherwise specified (n=1; 3%). Baseline FEV1 was median 73% percent predicted (range 50%–117%). Nine patients (23%) received the 3-fraction regimen, 21 (53%) received 5 fractions and 10 (25%) received 8 fractions. Thirty-five patients underwent surgery and were evaluable for the primary endpoint. The pCR rate was 60% (95% CI 44%–76%). 30-day and 90-day post-surgical mortality rates were both 0%. Eighteen percent of patients had grade 3 or 4 toxicities, most commonly pulmonary in nature (Grade 4: atelectasis and respiratory failure [n=1]; Grade 3: pneumonia/pneumonitis [n=2]; bronchopleural fistula [n=1]). In the patients receiving surgery, 2-year outcomes were: overall survival 77%, local control 100%, regional control 53% and distant control 76%. There were no significant changes in FACT-TOI score within the first year of follow-up.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The pCR rate after SABR for T1 and T2 NSCLC was 60%. Toxicity of the combined approach appears favorable, compared to historical series of surgery alone, and there was no perioperative mortality. Larger studies are needed to determine the clinical role of this combined treatment approach.

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      OA06.07 - Predictors and Consequences of Refusing Surgery for Clinical Stage I NSCLC: A National Cancer Database Analysis (ID 13865)

      14:35 - 14:45  |  Presenting Author(s): Brendon Stiles  |  Author(s): Mohamed Rahouma, Mohamed Kamel, Abu Nasar, Sebron Harrison, Benjamin Lee, Jeffrey L. Port, Nasser Altorki

      • Abstract
      • Presentation

      Background

      Given perceived morbidity of lung cancer surgery, patients may instead pursue other treatment options, particularly in the current era of shared decision-making. We sought to determine predictors of refusal of surgery for clinical stage I non-small cell lung cancer (NSCLC) patients and to determine associated outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The NCDB (2004-2014) was queried for clinical stage I NSCLC patients who underwent or were recommended to undergo surgery. A unique field in the NCDB allows identification of those patients who were recommended to have surgery, but refused. We only included cases in which surgery was refused “by the patient, patient’s family member or guardian”. We excluded patients with multiple primary tumors, unknown treatment modality/sequence, those who did not undergo recommended surgery for unknown reasons, and those initially not recommended to have surgery. Survival was compared using log rank test in Kaplan Meier curves. Logistic regression was performed to identify predictors of refusing surgery.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 118,0217 patients undergoing surgery and 3,210 (2.6%) who were recommended, but refused surgery. By multivariate analysis older age (HR=1.09, CI=1.08-1.09), non-white race (HR=2.18, CI=1.97-2.42), low income (HR=1.28,CI=1.16-1.41), lack of insurance (HR=2.62,CI=1.89-3.62), squamous histology (HR=1.40,CI=1.29-1.53), and larger tumor size (HR=1.57,CI=1.42-1.73) predicted refusal of surgery.Patients refusing surgery were treated with chemoradiation (n=249, 7.8%), radiation or chemotherapy alone (n=1,568, 48.8%), or no treatment (n=1393, 43.4%). Median survival was worse for patients who refused any treatment versus those who received other treatment modalities (19.8 vs 42.2 months, P<0.001). Among those patients refusing surgery who were treated with radiation, we identified 758 patients (23.6%) who received stereotactic body radiation therapy (SBRT). The proportion of patients who refused surgery and received SBRT increased over time, from 3.8% in 2004-2006, to 17% in 2007-2009, to 31.1% in 2010-2012, and to 37.9% in 2013-2014. Patients receiving SBRT had improved survival compared to other patients refusing surgery (47.9 vs. 25.2 months, p<0.001), although survival in the SBRT group was inferior to patients undergoing surgery as recommended (47.9 vs. 82.8 months, p<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although patients may be reluctant to undergo surgery for early stage NSCLC, refusal of surgery when recommended comes at the expense of decreased survival. Socioeconomic factors may be associated with refusal of surgery. The use of SBRT is an effective and increasingly used alternative in these patients, which improves survival compared to no treatment but which is still not equivalent to surgery in this unmatched, retrospective cohort.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA06.08 - Discussant - OA 06.05, OA 06.06, OA 06.07 (ID 14557)

      14:45 - 15:00  |  Presenting Author(s): Steven H Lin

      • Abstract
      • Presentation
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      Abstract not provided

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    PC02 - Debate on Local Therapies for Limited Small Cell Lung Cancer? Surgery PRO/CON and BID Radiation PRO/CON (ID 841)

    • Type: Pro-Con Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 203 BD
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    MA08 - Clinical Trials in Brain Metastases (ID 906)

    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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      MA08.01 - Phase 3 Trial of Whole Brain Radiotherapy with Concurrent Erlotinib Versus WBRT Alone for NSCLC with Brain Metastases (ENTER) (ID 12987)

      15:15 - 15:20  |  Presenting Author(s): ZhenZhou Yang  |  Author(s): Yan Zhang, RongQing Li, Abulimiti Yisikandaer, BiYong Ren, JianGuo Sun, JianJun Li, Long Chen, Ren Zhao, JuYing Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      Brain metastasis (BM) is a leading cause of death for non-small cell lung cancer (NSCLC). Whole Brain Radiotherapy (WBRT) is a standard-of-care treatment for NSCLC patients with multiple brain metastases. Elevated EGFR expression and activity are important causes of tumor resistance to radiotherapy. This phase 3 trial sought to determine if concurrent erlotinib with WBRT will benefit patients with multiple BM compared with WBRT alone.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this open-label, randomised, multicenter phase 3 study in China (NCT01887795), we enrolled NSCLC patients with at least two metastatic brain lesions who were naive to brain radiation and free from any EGFR-TKI for at least 4 weeks. Participants were randomly assigned (1:1) to receive either WBRT (2.0 Gy per day, 5 days per week, to 40 Gy) or WBRT plus concurrent oral erlotinib 150 mg daily (Erlotinib was given for 6 days then concurrently with WBRT). Subsequent treatments were maintenance therapy of erlotinib for EGFR-positive patients or standard chemotherapy for EGFR-negative patients until unacceptable adverse events or disease progression. The primary endpoint was intracranial progression-free survival (iPFS), defined as time from randomisation to either intracranial disease progression or death for any cause.

      4c3880bb027f159e801041b1021e88e8 Result

      Between August 7, 2013 and November 25, 2016, in total 222 patients from 11 centers across China were randomized to treatments: 115 with WBRT alone and 107 with WBRT and concurrent erlotinib. Median follow-up was 11.2 months (IQR 4.6-18.2). Median iPFS was 11.2 months (95% CI: 7.2-13.7) with WBRT and concurrent erlotinib versus 9.2 months (95% CI: 6.7-10.9) with WBRT alone (HR 0.926; 95% CI: 0.695-1.234; P=0.601). In the subgroup of 109 patients who were positive for the EGFR mutation, iPFS was not significantly longer among those who received WBRT with concurrent erlotinib than WBRT with sequential erlotinib (14.6 [95% CI 11.8-17.7] vs 12.8 [7.9-14.9] months; HR 0.743; 95% CI: 0.489-1.129; P=0.164). Median PFS of concurrent erlotinib arm was 5.3 months versus 4.0 of WBRT alone (HR 0.969; 95% CI: 0.735-1.277; P=0.825) and median overall survival (OS) was 12.9 versus 10.0 months (HR 0.913; 95% CI: 0.680-1.226; P=0.545).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This multi-institutional study demonstrated WBRT with concurrent erlotinib improved neither iPFS significantly than WBRT alone in the intention-to-treat population and the EGFR-positive subgroup, nor improved PFS or OS in intention-to-treat population, indicating that erlotinib played limited role when concurrently used with WBRT and for EGFR-positive NSCLC patients, WBRT with concurrent erlotinib was not significantly superior to WBRT with sequential erlotinib.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.02 - Prophylactic Cranial Irradiation Reduces the Risk of Brain Metastases in High-Risk Lung Cancer Patients: EGFR and ALK Mutations (ID 13496)

      15:20 - 15:25  |  Presenting Author(s): Oscar Arrieta  |  Author(s): Federico Maldonado, Laura-Alejandra Ramírez-Tirado, Feliciano Barron, Yelitza Esmeralda Campos-Salgado, Monica Blake, Andrés F. Cardona, Jaime G De La Garza

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic Cranial Irradiation (PCI) is considered standard-of-care for small-cell lung cancer, due to consistent findings of a reduced risk of developing brain metastases (BM) and a survival benefit. The role of PCI for patients with Non-small cell lung cancer (NSCLC) is less well established, since a clear survival benefit has not been identified, although high-risk subgroups have been identified, including patients with driver mutations and with elevated carcinoembryonic antigen (CEA) levels.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We assessed the use of PCI compared to observation in patients with stage IV NSCLC (NCT01603849). PCI dose was set 25 Gy/10 f. An amendment to the original record was requested so that patients who received PCI after January 2016 had hippocampal sparing. Primary end point was Intracranial Progression-Free survival (IPFS), secondary was overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      84 patients were included, 43 were randomized to observation and 41 to PCI. 83.3% had a driver mutation (DM). Baseline characteristics were well balanced among groups. Median IPFS was 21.0 months (95%CI 16.2-25.9). Factors which were independently, positively associated with IPFS included ECOG (p=0.012) and therapeutic arm (p=0.006). PCI was associated with lower odds of progression to CNS (OR:0.16 (0.04–0.53), p=0.006).Cumulative incidence of BM at 1-yr was higher among patients without PCI (22% vs. 3%, p<0.001). Relative risk for IPFS in patients with DM was 0.29 (0.10-0.82, p=0.01), HR for OS was 0.48 (0.20-1.16, p=0.098). Median OS was higher in the PCI group compared to control [42.8 (95%CI: 28.1–57.6) vs. 25.9 (95%CI: 17.7 – 34.2)] months. Last, PCI was associated with lower hazards of death, 0.47 (0.24–0.95), p=0.035.rt-prof figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      PCI significantly increases IPFS and decreases risk of death in patients with advanced NSCLC, without neurocognitive impairment or decreased QoL. This intervention appears to be particularly useful for patients with good performance status and driver mutations. PCI increased IPFS without neurocognitive impairment or decreased QoL.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.03 - EGFR-TKI Plus Brain Radiotherapy Versus EGFR-TKI Alone in the Management of EGFR Mutated NSCLC Patients with Brain Metastases: A Meta-Analysis (ID 12990)

      15:25 - 15:30  |  Presenting Author(s): Wenhua Liang  |  Author(s): Xiaojun Xia, Minzhang Guo, Jianxing He

      • Abstract
      • Presentation
      • Slides

      Background

      It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) presented better efficacy than brain radiotherapy (brain RT) in the treatment of brain metastasis (BM) in EGFR mutated NSCLC patients. However, whether the combination of EGFR-TKI and brain RT is better than EGFR-TKI alone remains unclear. We aim to compare the benefit of adding brain RT to EGFR-TKI by a meta-analysis of currently available data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A systematic search for relevant articles was conducted in six databases (PubMed, EMBASE, Cochrane database, Medline, Web of Science, Google scholar). The primary outcome was overall survival (OS) between groups, and the secondary outcome was intra-cranial progression-free survival (icPFS), both being measured as hazard ratios (HRs). The data was synthesized by random-effects model using STATA 13.0.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of four retrospective studies involving 507 EGFR mutated patients with BM at the first diagnosis were included, 209 patients received brain RT (predominantly whole brain RT). Combined therapy of EGFR-TKI and brain RT reduced 19% risk of deaths (OS HR=0.81, 95% CI 0.53-1.26; P=0.36) and 16% risk of intracranial progression (icPFS HR=0.84, 95% CI 0.55-1.27; P=0.40) compared with EGFR-TKI alone, however, no statistically significance was observed. Further subgroup analyses suggested that patients with 21 exon L858R mutation were more inclined to have greater icPFS benefit under combination therapy (HR 0.67, 95% CI 0.19-2.40) in contrast to 19 exon deletion patients (HR 1.35, 95% CI 0.88-2.09). In addition, patients older than 65 (HR 0.74, 95% CI 0.37-1.48) might benefit more from combination than those younger than 65 (HR 4.47, 95%CI 0.29-70.13).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This meta-analysis suggested that the combination of EGFR-TKIs and brain radiotherapy showed similar but potentially better OS and intracrnial control in EGFR-mutated NSCLC patients when compared to EGFR-TKI alone, especially for those with L858R mutations or older than 65. The current results underscore the importance of future randomized control trials and provide information for study design.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.04 - Discussant - MA 08.01, MA 08.02, MA 08.03 (ID 14599)

      15:30 - 15:45  |  Presenting Author(s): Nasser Hanna

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA08.05 - Brain Penetration of Lorlatinib and Cumulative Incidence Rates for CNS and Non CNS Progression from a Phase 1/2 Study (ID 12760)

      15:45 - 15:50  |  Presenting Author(s): Todd M. Bauer  |  Author(s): Alice T. Shaw, Melissa L. Johnson, Alejandro Navarro, Justin F Gainor, Holger Thurm, Yazdi K. Pithavala, Antonello Abbattista, Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Background

      The potent, selective, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib was designed to penetrate the blood-brain barrier (BBB). In a phase 1/2 study, lorlatinib showed robust clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), most of whom had CNS metastases and failed ≥1 ALK TKI. In preclinical studies, lorlatinib demonstrated high BBB permeability with rapid brain uptake in vivo and significant activity against ALK-positive intracranial tumor models.1,2 To assess brain penetration of lorlatinib in a clinical setting, we report exploratory analyses from a phase 1/2 study (NCT01970865), evaluating CSF-to-plasma concentration ratios from a small sample of patients and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and deaths for pretreated patients with ALK-positive NSCLC ± baseline CNS metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Across the ongoing phase 1/2 study, 5 patients at lorlatinib 100 mg QD starting dose underwent CSF sampling. Patients with ALK-positive NSCLC with ≥1 prior ALK TKI were analysed for progressive disease, categorized as either CNS or non-CNS progression, based on independent central review. CIRs for patients in expansion cohorts EXP2–5 from the phase 2 portion of the phase 1/2 study (N=198) were calculated using competing risks methodology.

      4c3880bb027f159e801041b1021e88e8 Result

      In patients (n=5), mean CSF-to-plasma concentration ratio was 0.73 (SD 0.14). The table shows CIRs at 6 and 12 months.

      Months Cumulative Incidence Probability
      Patients with ≥1 prior ALK TKIa CNS Progression

      Non-CNS

      Progression

      Death
      All patients (n=198)

      6 mos

      12 mos

      0.13

      0.18

      0.25

      0.37

      0.05

      NE
      Patients with baseline CNS metastases (n=131)

      6 mos

      12 mos

      0.14

      0.22

      0.21

      0.31

      NE

      NE
      Patients with no baseline CNS metastases (n=67)

      6 mos

      12 mos

      NE

      NE

      0.32

      0.49

      0.05

      NE

      aPatients in expansion cohorts EXP2–5 from the phase 2 study

      NE, not evaluable
      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib showed high BBB permeability as evidenced by a high mean CSF-to-plasma concentration ratio, in line with preclinical rat studies showing CNS penetration. This translated into high activity against CNS metastases as suggested by the numerically higher probability of the first progression event being extracranial rather than intracranial, including in patients with a history of CNS metastases.

      References

      1. Collier, et al. Mol Imaging 2017;16:1–3.

      2. Zou, et al. Cancer Cell 2015;28:70–81.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.07 - Real World Data of Osimertinib in Patients with Central Nervous System (CNS) Metastasis in ASTRIS Korean Subset. (ID 13581)

      15:50 - 15:55  |  Presenting Author(s): Jin-Hyoung Kang  |  Author(s): Byoung Chul Cho, Dong-Wan Kim, Keunchil Park, Jong-Seok Lee, Seung soo Yoo, Sung Yong Lee, Cheol Hyeon Kim, Seung Hun Jang, Young-Chul Kim, Hyoung-Kyu Yoon, Sang-We Kim

      • Abstract
      • Presentation
      • Slides

      Background

      More than 40% of non-small cell lung cancer (NSCLC) patients develop CNS metastasis in their lifetime. Osimertinib is a third-generation EGFR-TKI which selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations. Clinical studies have shown superior efficacy of osimertinib in CNS compared to platinum chemotherapy. Treatment efficacy in patients with or without CNS metastasis were observed within the second interim analysis of ASTRIS (NCT02474355). Data cut-off (DCO) was 20 October 2017.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In ASTRIS, advanced NSCLC patients with a locally confirmed T790M mutation, WHO performance status 0-2, prior EGFR-TKI therapy were enrolled. Patients with stable CNS metastases were allowed. The primary endpoint was overall survival (OS); other endpoints included investigator-assessed response rate (RR), progression-free survival (PFS), time to treatment discontinuation (TTD) and safety. These endpoints were also analyzed according to presence of CNS metastasis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 466 patients received at least one dose of osimertinib 80mg from 31 Korean sites. CNS metastasis was evaluated in 310 patients and was present in 211 (68.1%) patients (CNS-met); 181 brain only, 1 leptomeningeal only, 29 both. 99 (31.9%) patients did not have CNS metastasis (CNS-no), and 155 patients were not evaluated (CNS-ne). At DCO, 236 patients (50.6%) were ongoing and median duration of exposure was 11.2 (0–19) months. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, RR was 71.0% (320/451; 95% CI, 66.5–75.1): Patients with (N=211), without (N=99), and not-evaluated CNS metastasis (N=155) had RR of 68% (134/197; 95% CI, 61.0-74.5), 79.6% (78/98; 95% CI, 70.3-87.1), and 69.7% (108/155; 95% CI, 61.8-76.8), respectively. Median PFS was 12.4 months (95% CI, 11.1-13.6 months); 10.8 months (95% CI, 9.5-11.5) in CNS-met,11.0 months (95% CI, 9.2-14.5) in CNS-no, and 15.1 months (95% CI, 13.6-18.2) in CNS-ne. Median TTD was 16.5 months (95% CI, 14.1-NC); 11.2 months (95% CI, 9.4-14.8) in CNS-met, 14.7 months (95% CI, 12.2-NC) in CNS-no, and NC (95% CI, 15.5-NC) in CNS-ne. OS was not reached (data maturity: 19.7%). Serious adverse event (AE) regardless of causality were reported in 116 patients (24.9%) and AEs leading to death in 13 patients (2.8%). ILD/pneumonitis-like events were reported in 8 patients (1.7%), and QTc prolongation in 7 patients (1.5%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In ASTRIS Korean subset, patients with or without CNS metastasis had comparable efficacy outcome. This data continues to support osimertinib’s clinical benefit on EGFRm T790M NSCLC patients with CNS metastasis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.08 - Discussant - MA 08.05, MA 08.07 (ID 14601)

      15:55 - 16:10  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract
      • Presentation
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      Abstract not provided

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      MA08.09 - Impact of Brain Metastases in Immune Checkpoint Inhibitors (ICI) Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 12575)

      16:10 - 16:15  |  Presenting Author(s): Lizza Hendriks  |  Author(s): Clémence Henon, Eduard Auclin, Laura Mezquita, Roberto Ferrara, Clarisse Audigier-Valette, Julien Mazieres, Corentin Lefebvre, Sylvestre le Moulec, Sophie Cousin, Boris Duchemann, Cecile Le Pechoux, Angela Botticella, Samy Ammari, Anas Gazzah, Caroline Caramella, Julien Adam, David Planchard, Dirk De Ruysscher, Anne-Marie C. Dingemans, Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.10 - Real-Life Intracerebral Efficacy of Nivolumab in Non-Small Cell Lung Cancer Patients with Brain Metastases (ID 14201)

      16:15 - 16:20  |  Presenting Author(s): Margaux Geier  |  Author(s): Renaud Descourt, Romain Corre, Guillaume Léveiller, Regine Lamy, Eric Goarant, Jean-Louis Bizec, Cyril Bernier, Gilles Quéré, Francis Couturaud, Gilles Robinet

      • Abstract
      • Presentation
      • Slides

      Background

      Data regarding intracerebral efficacy of nivolumab in advanced non-small cell lung cancer (NSCLC) are lacking because of routinely exclusion of patients with active brain metastases (BMs) from clinical trials. We aimed at assessing intracranial activity of nivolumab in patients with BMs in a real-life setting and determining the potential role of prior radiotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between 01/09/2015 and 30/09/2016, all consecutive advanced NSCLC patients treated with nivolumab after failure of at least one line of chemotherapy were included. Nivolumab was administered at a dose of 3 mg/kg q2w until progression or unacceptable toxicity. Primary endpoint was intracerebral objective response rate (IORR) assessed by brain magnetic resonance imaging or brain computed-tomography scans. Secondary endpoints were overall response rate (ORR) and median duration of intracerebral response.

      4c3880bb027f159e801041b1021e88e8 Result

      259 patients were treated with nivolumab in 9 centers. Among them, 77 patients who presented BMs before nivolumab initiation were enrolled: 53 (20.5%) at diagnosis and 24 (9.3%) during the course of treatments. Median age at diagnosis was 57 years [29-78]. Most patients were males (72.7%) with smoking history (90.9%) and had adenocarcinoma (72.7%). 23 patients harbored a KRAS mutation. PD-L1 status was unknown. The median of prior lines was 1 [1-6]. BMs were pretreated in 48 (62.3%) patients: 16 received prior SBRT, 32 WBRT. Median time between prior radiotherapy and nivolumab initiation was 4 months [1-;27]. IORR and ORR were 10.4% and 20.8%, respectively. Among the 8 patients with intracerebral response, 5 (6.5%) had pretreated BMs, 3 (3.9%) had radiotherapy-naïve BMs. Median duration of intracerebral response was 11.5 months. No neurological adverse events occurred during nivolumab treatment. Among 259 patients, 36 (13.8%) developed BMs during nivolumab treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab intracerebral response achieved 10.4% in real-life with a satisfactory neurological safety profile. If prior radiotherapy improves IORR must be determined by further investigations.

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      MA08.11 - Early Safety Data of a Phase I/II Combining Nivolumab and Stereotactic Brain Radiosurgery for Treatment of Brain Metastases in Patients with NSCLC (ID 14064)

      16:20 - 16:25  |  Presenting Author(s): Raafat Alameddine  |  Author(s): Philip Wong, Laura Masucci, David Roberge, Cynthia Menard, Bertrand Routy, Mustapha Tehfe, Normand Blais, Marie Florescu

      • Abstract
      • Presentation
      • Slides

      Background

      Radiotherapy can stimulate the immune system through various means. Highly cytotoxic stereotactic radiosurgery (SRS) doses (>10Gy per fraction) may synergize with anti-PD1 to reduce intracranial disease progression or recurrence.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Within a phase I/II trial evaluating the combination of nivolumab with SRS in the treatment of brain metastases from NSCLC and RCC (NCT02978404), 8 patients were enrolled (1 RCC and 7 NSCLC) in the first trial cohort. Herein, only the NSCLC cases are reviewed. Patients were eligible if their KPS ≥70, were minimally symptomatic (RTOG neurological function <2), and had ≤10cc of untreated brain metastases. Prophylactic corticosteroids were not given. Nivolumab (240mg IV q2 weeks) was started 2 weeks prior to SRS, and administered until RECIST progression. SRS (15-20Gy in 1 fraction) was given to each brain metastasis. The aim of the first patient cohort is to estimate the tolerability of the combined treatment strategy.

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up of the three male and four female patients was 2 months. Median age was 63 years (55-84 years). Five NSCLC patients completed ≥1 cycle of nivolumab and SRS, and were evaluated for tolerability of the combination. One patient elected to withdraw before the first nivolumab dose and 1 patient died prior to SRS. Median baseline brain edema and total brain metastases volumes were 0.5cc (0-46.97cc) and 1.25 cc (0.1-3.46cc), respectively. To date, the median number of nivolumab cycles administered is 4.5 (1-15). Intracranial adverse effects were limited to apraxia and paresthesias in the patient who had the largest volume of peri-tumoral brain edema at baseline (46.97cc). Nivolumab was held and dexamethasone was given for 74 days at doses >1mg/day until neurological symptoms resolved. Systemic adverse events included one patient with grade 2 arthritis necessitating a 6-week treatment delay and 51 days of prednisone ≥10mg. At last follow-up, three patients had died of extracranial disease progression, including the two patients who did not receive protocol SRS. Among the three patients evaluable for intracranial response, there was one partial response and two stable diseases. All three patients had stable extracranial disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combining SRS and immunotherapy is safe in regards to acute toxicity with a manageable side effect profile. Close monitoring may be required for patients with significant baseline brain edema. Evaluation for efficacy awaits further follow-up and completion of recruitment in the phase 2 component of the trial.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.12 - Discussant - MA 08.09, MA 08.10, MA 08.11 (ID 14604)

      16:25 - 16:40  |  Presenting Author(s): Arjun Sahgal

      • Abstract
      • Presentation
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      Abstract not provided

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    MA09 - Lung Cancer Surgical and Molecular Pathology (ID 908)

    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 202 BD
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      MA09.01 - Correlation of Pre-Operative Cancer Imaging Techniques with Post-Operative Macro and Microscopic Lung Pathology Images   (ID 13181)

      15:15 - 15:20  |  Presenting Author(s): Stephen James Harrow  |  Author(s): Gabriel Reines-March, Craig Dick, Xiangyang Ju, Stephen Marshall

      • Abstract
      • Presentation
      • Slides

      Background

      This research project aims to investigate the performance of several PET radiotracers in lung cancer by aligning PET-CT and pathology imagery acquired from the same patients at different points in time. The discrimination of tumour substructures is of great importance in therapy planning, as a given treatment may be better adapted depending on the local characteristics of the carcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Due to the high deformability of lung tissue, several intermediate steps must be used for merging pathology and pre-operative PET-CT in a coherent manner. Firstly, the tumour volume is reconstructed from the macroscopic images taken during dissection. For this purpose, an enhanced dissection protocol is used, where the lung specimen is placed in a bespoke slicing rig and embedded in agar to hold it in place. Using a threaded plunger, the specimen is pushed upwards in 5mm steps, sliced and photographed. This procedure allows us to obtain slices of uniform thickness. Secondly, microscopic digital slides of the cancerous tissue are merged with the macroscopic 3D model. Finally, the whole volume is fused with the pre-operative PET-CT scan, using a non-linear deformable model.

      4c3880bb027f159e801041b1021e88e8 Result

      Preliminary results obtained with a synthetic phantom allowed us to analyse the accuracy of the tumour 3D reconstruction algorithm from planar macroscopic slices. Using these findings, we could optimise the interpolation and segmentation routines for building an accurate 3D model of the tumour mass. During our first trial with lung tissue (on-going work), each cross-sectional slice was photographed, the tumour boundary was delineated in each image by a pathologist (CD), and from these contours a high-resolution 3D tumour model was built. Next, the corresponding microscopic digitised slices were merged. To date, ten patients have been identified and consented, therefore allowing us to test our algorithm on different cases and assess its performance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrate a novel set of methods for co-registration of pre-operative PET-CT to macro and microscopically defined lung tumours. This proof of principle now allows interrogation of the raw data from PET-CTs using a range of tracers and the development of algorithms that identify substructure detail within a tumour mass, which could lead to tailored radiotherapy for individual tumours based on tracer patterns and uptake.

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      MA09.02 - Tumor Size and Frozen Section Should Be Considered Jointly to Predict the Final Pathology for Lung Adenocarcinoma (ID 13365)

      15:20 - 15:25  |  Presenting Author(s): Erjia Zhu  |  Author(s): Chang Chen

      • Abstract

      Background

      Invasive adenocarcinoma intraoperatively misdiagnosed as adenocarcinoma in situ or minimally invasive adenocarcinoma is more likely to undergo potentially insufficient resection. The purpose of our study was to evaluate the diagnostic accuracy of frozen section.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed 1,111 lung adenocarcinomas to evaluate the diagnostic performance of frozen section. A derivation cohort consisting of 436 cases of AIS or MIA diagnosed by frozen section in the same period were analyzed to find predictive factors for invasive adenocarcinoma as the final diagnosis. Validation cohorts were included to confirm the results.

      4c3880bb027f159e801041b1021e88e8 Result

      Intraoperatively measured tumor size was the only independent factor for invasive adenocarcinoma as the final diagnosis (P = 0.001) in the derivation cohort, and was confirmed by validation cohorts. Fifty-nine misdiagnosed invasive adenocarcinomas in the three cohorts consisted of 54 lepidic predominant type, 1 papillary and 4 acinar predominant type. There were no positive N1, N2 node, pleural, lymphatic and vascular invasion cases found. Thirty-seven (37/59, 63%) cases of misdiagnosis were attributed to sampling error, which was the main reason.figure1.jpgfigure3.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Adenocarcinoma in situ or minimally invasive adenocarcinoma ≥ 1 cm by frozen section were more likely to be invasive adenocarcinoma because of sampling error.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA09.03 - Multiple Pathological Variables Predict Efficacy of Adjuvant Chemotherapy in Primary Lung Adenocarcinoma (ID 13761)

      15:25 - 15:30  |  Presenting Author(s): John Le Quesne  |  Author(s): Marco Sereno, Claire Smith, Madhumita Das, Robert Hastings, Grace Rake, David Moore

      • Abstract
      • Presentation
      • Slides

      Background

      Adjuvant chemotherapy has become established as a vital complement to surgery over the last decade, and improves survival by targeting micrometastatic disease which is clinically inaparrent at the time of surgery. However, in comparison to other common malignancies, the guidelines for the administration of adjuvant chemotherapy in lung cancer are rudimentary, being based solely upon clinical stage II and above at the time of surgery. We set out to discover pathological factors with the potential to better identify patients who are likely to benefit from this vital therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      662 cases of primary lung adenocarcinoma treated with surgery with curative intent were identified from 2005-2014; 109 received adjuvant chemotherapy. Comprehensive survival/recurrence data, pathological data, and treatment history data were collected. Detailed histopathological data (growth pattern, vascular invasion, pleural stage) were collected by review of scanned histopathological images.

      Multivariate Cox regression survival models were used to identify interactions between clinicopathological variables and adjuvant chemotherapy. A propensity score matching approasch was used to reduce selection biases in the data.

      4c3880bb027f159e801041b1021e88e8 Result

      The existing stage criteria for the recommendation of adjuvant chemotherapy are stage pN1/2 and size>40mm; only nodal invasion interacts with chemotherapy in an OS model (interaction term HR=0.67 P=0.017). However, signficant interactions are seen with predominant growth pattern (HR=0.47 P=0.001 ), pleural stage (HR=0.62 P=0.002 ), and vascular invasion (HR=0.56 P=0.033).

      We reduced selection bias by balancing treated and untreated groups by propensity matching for all prognostic variables. In the matched dataset, patients with predominantly in situ tumours experience no benefit of chemotherapy (HR=1.81 P=0.18), while higher-grade cases show substantial benefit (HR=0.53 P=0.01). Similar benefits were seen for patients with increasing pleural stage and vascular invasion.

      In a multivariate model designed to identify which variable(s) had the most ability to predict treatment efficacy, only tumour growth pattern showed a significant interaction with chemotherapy treatment (HR=0.51 P=0.01 ).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We find that the existing stage-based criteria for adjuvant chemotherapy can be much improved. Low-grade cases experienced only negative effects of chemotherapy, while higher-grade cases showed a benefit. Pleural stage and vascular invasion were also significantly predictive. We suggest that the current criteria may be leading to substantial over- and under-treatment. A nuanced algorithm for the identification of patients likely to benefit from chemotherapy, which includes these additional pathoogical measures, may significantly improve patient outcomes. This would be especially impactful to the majority of surgical patients for whom no personalised therapy is as yet available.

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      MA09.04 - Discussant - MA 09.01, MA 09.02, MA 09.03 (ID 14605)

      15:30 - 15:45  |  Presenting Author(s): Natasha Rekhtman

      • Abstract
      • Presentation
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      Abstract not provided

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      MA09.05 - Can We Predict Radiosensitivity in Non-Small Cell Lung Cancer? (ID 13835)

      15:45 - 15:50  |  Presenting Author(s): Juvenal Baena  |  Author(s): Christopher Talbot, John Le Quesne

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with lung cancer receive different treatments depending on their detailed clinical-pathological context. However, over 70% of patients are treated with radiotherapy, which is of varying efficacy. Rather surprisingly, no biomarkers are currently used to predict tumour response and to aid with radiotherapy dosing or regimen. The aim of this study is to identify histopathological features which may predict tumour radiosensitivity in patients with NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have identified a set of 67 NSCLC cases with a history of radiotherapy for which pre-treatment archival tissue and CT imaging follow-up is available from the period 2009 to 2014. Digital images of archival diagnostic tissue sections were examined to derive morphological measures with the potential to predict radiosensitivity. Quantitative radiological measures of response up to 6 months after radiotherapy were derived. Since radiographic measurements were taken at variable time-points, we standardised by inferring the fractional maximum diameter of the tumour 100 days after radiotherapy (FRT100)

      4c3880bb027f159e801041b1021e88e8 Result

      The density of multipolar mitoses seen microscopically is related to radiosensitivity (regression against FRT100: R2 = 0.14, p=0.005*) and a trend toward a negative relationship with neuroendocrine differentiation (R2 =0.06, p=0.058). The presence of multipolar mitoses was further associated with poor overall survival ( Univariate Cox p= 0.02*). Patients with radiological evidence of good response (ie low FRT100) showed a time-dependent survival benefit (p=0.02*), while after 2 years tendency of both groups was similar. Patients showing squamous differentiation had a poor prognosis, with no overall survival after 4 years, while 21.8% of the ACA were still alive after 4 years (p= 0.04*)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Multipolar mitoses and neuroendocrine differentiation may be predictive histological markers of radiosensitivity in NSCLC. More samples are being gathered, and immhunohistochemical and DNA sequence biomarkers of radiosensitvity are currently being assessed.

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      MA09.06 - The Newly Recognized Filigree Pattern of Micropapillary (MIP) Lung Adenocarcinoma (LADC) is as Clinically Important as the Classical Pattern (ID 11874)

      15:50 - 15:55  |  Presenting Author(s): Katsura Emoto  |  Author(s): Takashi Eguchi, Raj G. Vaghjiani, Yusuke Takahashi, Natasha Rekhtman, Prasad S. Adusumilli, William D Travis

      • Abstract
      • Presentation
      • Slides

      Background

      Filigree pattern is a newly recognized addition to the morphological spectrum of the poor prognostic category of micropapillary (MIP) LADC. However, its morphologic features and clinical importance are not well understood. The aim of this study was to investigate the morphologic spectrum and clinical significance of filigree MIP pattern.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Filigree pattern was defined as tumor cells growing in delicate lace-like narrow stacks of cells (at least 3 piled-up nuclei) without fibrovascular cores, with frequently visible attachments to alveolar walls. This differs from the 2015 WHO description of classical MIP pattern as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores. In order to assess for filigree vs classical MIP, we documented the frequency and extent of both patterns in 1325 Stage I LADC. These were correlated with recurrence free probability (RFP) and lung cancer-specific survival (LCSS) using Kaplan-Meier analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      In addition to 87 MIP predominant ADC previously diagnosed, we identified 57 more cases of MIP predominant LADC due to the new criteria of MIP filigree pattern. Of these 57 cases, 37, 16, and 4 cases were reclassified from papillary, acinar, and solid predominant LADCs, respectively. Survival curves of previously diagnosed MIP and newly diagnosed MIP for RFP showed a similar worse prognosis compared to other LADC histologic subtypes (previously diagnosed MIP vs newly diagnosed MIP, 5-year RFP 66% vs 68% [Figure]) as well as LCSS (previously diagnosed MIP vs newly diagnosed MIP, 5-year LCSS 82% vs 85%). When the MIP cases were divided into filigree or classical predominant MIP, no significant prognostic differences were observed between the two groups.

      figure filigree.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The lack of significant prognostic difference between filigree vs classical predominant MIP LADC supports our proposal that the filigree pattern is an important addition to the morphologic spectrum of the MIP subtype.

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      MA09.07 - Developing a Pathological Grading System in Predicting Prognosis for Invasive Mucinous Adenocarcinomas (ID 12124)

      15:55 - 16:00  |  Presenting Author(s): Wei-Chin Chang  |  Author(s): Yu Zhi Zhang, Eric Lim, Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma with a predominance of mucinous type neoplastic epithelial cells, often showing aerogenous spreading and multifocality. The correlation between histopathological features and prognosis has not been well studied due to its relatively rare incidence compared to non-mucinous adenocarcinoma. Our study aims to evaluate the significance of histopathological features in relation to clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed a series of 101 cases of IMAs resected between 2000 to 2012, comprised of stage I~IV tumours. Five pathological features were scored for each tumour: predominant histological pattern (lepidic: 1, acinar/papillary: 2, solid/micropapillary/cribriform: 3), nuclear atypia (mild:1, moderate: 2, severe: 3), mitotic activity per 2mm2 (<4: 0, ≥4: 1), necrosis (absent: 0, present: 1), lymphovascular invasion (absent: 0, present: 1), and pleural invasion (PL0: 0, PL1: 1, PL2: 2, PL3: 3). Each pathological feature was correlated with disease-free (DFS) and overall survival (OS). Cases were then divided into three grades based on the total pathological score (grade I: 2-4, grade II: 5-7, grade III: 8-11) and correlated with outcome.

      4c3880bb027f159e801041b1021e88e8 Result

      Nuclear atypia, mitotic activity, lymphovascular invasion, and pleural invasion showed significant correlation with OS (p < 0.05). Histological pattern and necrosis showed no significant correlation in relation to OS (p = 0.09). Pleural invasion and lymphovascular invasion were significantly correlated with DFS (p < 0.05), while a trend was noted for nuclear atypia (p = 0.086). No correlation with DFS was seen for histological pattern (p = 0.499), necrosis (p = 0.464), and mitotic activity (p = 0.931). There was an inverse correlation between OS and grade, with grade III tumours showing a significantly worse prognosis (p = 0.001). There was no significant difference in DFS between the three groups (p = 0.201).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our pathological scoring system was able to stratify IMAs into three separate groups with statistically significant differences in overall survival between grade III and grades I/II tumours.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA09.08 - Discussant - MA 09.05, MA 09.06, MA 09.07 (ID 14607)

      16:00 - 16:15  |  Presenting Author(s): Lucian R Chirieac

      • Abstract
      • Presentation
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      Abstract not provided

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      MA09.09 - EBUS-TBNA in Assessing PD-L1 Expression in NSCLC (ID 13471)

      16:15 - 16:20  |  Presenting Author(s): Jason S Agulnik  |  Author(s): Goulnar Kasymjanova, Hangjun Wang, Lama Sakr, David Small, Victor Cohen, Alan Spatz

      • Abstract
      • Presentation
      • Slides

      Background


      Pembrolizumab is the only immunotherapy approved as a first line agent for metastatic NSCLC in patients with high programmed death‐ligand 1 (PD‐L1) expression. The standard samples for PD-L1 testing are considered surgical or core biopsies. In this study, our primary objective is to identify the adequacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) tumor samples in detecting PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between July 2016 and April 2017 a total of 1352 consecutive cases of non-small cell lung cancer (NSCLC) were identified. 29 specimens were deemed inadequate (less than 100 viable tumor cells) and were excluded. 1323 specimens analyzed included surgical samples (N=238), small biopsy (N=744) and cytology cell blocks (N=341). Cytology cell blocks were from EBUS-TBNA (N=190), fine needle aspiration (FNA) (N=61) and pleural/pericardial fluid (N=90). PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1-49% and ≥ 50% tumor cells.

      4c3880bb027f159e801041b1021e88e8 Result

      Most of the 1323 specimens (84%) were non-squamous carcinomas. Overall yield for TPS > 50% was 36%. Rate of PD-L1 positivity was no different in non-squamous (37%) compared to squamous (32%). Diagnostic yield of PD-L1 for different sample types varied substantially (Table 1). The EBUS-TBNA samples had the highest yield for TPS ≥ 50% (p=0.025).

      TPS Surgical resection Small biopsy EBUS-TBNA FNA Fluid cytology Total
      Adequacy 100% 99% 98% 96% 92% 98%
      ≥ 50% 69 (29) 269 (36) 84 (44) 21 (34) 38 (42) 481
      1-49% 87 (37) 274 (37) 57 (30) 22 (36) 22 (24) 462
      <1% 82 (35) 201 (27) 49 (26) 18 (30) 30 (33) 380
      Total 238 744 190 61 90 1323
      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that cytology cell blocks could be considered as a valuable resource for PD-L1 testing in advanced NSCLC. Future studies are warranted to explore clinical correlation of PD-L1 on EBUS-TBNA samples and immunotherapy outcome.

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      MA09.10 - Molecular Profiling and PD-L1 Status in 900 Cases of Surgically Resected Non-Small Cell Lung Cancer with Clinical and Pathological Correlation (ID 11188)

      16:20 - 16:25  |  Presenting Author(s): Zhaolin Xu  |  Author(s): Mathieu Castonguay, Wenda Greer, Akram Alwithenani, Drew Bethune, Arik Drucker, Gordon Flowerdew, Marika Forsythe, Daniel French, Harry Henteleff, Michael Johnston, Mary Macneil, Wojciech Morzycki, Madelaine Plourde, Stephanie Snow, Alexi Surette

      • Abstract
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      Background

      Precision medicine provides efficient treatment options for lung cancer patients as it targets the individual tumor’s genetic makeup. Recent development of immune therapy based on immune checkpoint inhibitor also provides hope for patients. Currently lung cancer mutational data available in the literature are mainly from advanced stage non-small cell lung cancer. There is insufficient information from early stage lung cancer patients. PD-L1 status in relation to clinical and pathological characteristics is also unclear. This study tried to address these issues from 900 cases of surgically resected lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiplexed molecular profiling in 900 surgically resected lung cancer specimens. A panel of gene including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK was tested. PD-L1 was also evaluated by immunohistochemistry using pharmDx22C3. Tumor proportional score (TPS) in a 10% increment was measured. Mutational status and PD-L1 TPS in each cancer subtype in relation to cancer pathological characteristics were investigated. Correlations between gene mutation, PD-L1 status and cancer staging were performed. Gene mutation and PD-L1 status with patients’ demographic information such as gender, age, smoking history, as well as survival data after surgery were also analysed.

      4c3880bb027f159e801041b1021e88e8 Result

      This cohort includes adenocarcinoma (65%), squamous cell carcinoma (24%), large cell carcinoma (6%), other subtypes (5%). Stage I accounts for 56%, stage II, 26%, stage III, 16%, stage IV, <2% with a mean age of 66 years. In adenocarcinoma, KRAS accounts for 36%, EGFR 10%, BRAF 1%, PIK3CA 1%, ALK 0.2%, no mutations 52%. Only 5% squamous cells carcinoma showed mutations.

      PD-L1 TPS <1% accounts for (37%), TPS 1-9% (18%), TPS 10-19% (7%), TPS 20-29% (5%), TPS 30-39% (5%), TPS 40-49% (1%), TPS 50-59% (5%), TPS 60-69% (4%), TPS 70-79% (4%), TPS 80-89% (5%), TPS 90-99% (7%) and unsuccessful (2%). EGFR mutations were significantly associated with female (p<0.001) and never smokers (p<0.001), with well differentiated adenocarcinoma (p<0.001), and with absence of vascular invasion (p<0.01). KRAS mutations were more prevalent in younger age group (p=0.003). Poorly differentiated cancer histology was associated with absence of KRAS or EGFR mutations. There was no significant association between PD-L1 expression and age, sex, pathological stage and smoking status. PD-L1 expression was significantly associated with vascular invasion (p=0.035). EGFR mutations were significant associated with absence of PD-L1 expression (p=0.02), but no association between KRAS mutations and PD-L1 expression (p=0.10).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study provides comprehensive information enhancing our knowledge in depth about driver gene mutations and immune checkpoint PD-L1 status in non-small cell lung cancer patients.

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      MA09.11 - Genomic Landscape and its Correlation with TMB, CD8 TILs and PD-L1 Expression in Chinese Lung Squamous Cell Carcinoma (ID 12370)

      16:25 - 16:30  |  Presenting Author(s): Tao Jiang  |  Author(s): Jinpeng Shi, Chunyan Wu, Henghui Zhang, Caicun Zhou

      • Abstract
      • Presentation
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      Background

      The current study aimed to comprehensively depict the genomic landscape of Chinese lung squamous cell carcinoma (LSCC) and investigate its correlation with tumor mutation burden (TMB), CD8 tumor infiltrating lymphocytes (TILs) density and PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Whole-exome sequencing (WES) were performed on tumor tissue collected from 189 patients with surgically resected LSCC. TMB was defined as total number of nonsynonymous single nucleotide and indel variants. High TMB was defined as greater than 75th percentile. CD8+ TILs and PD-L1 expression were assessed by immunohistochemistry. We determined the 5% of CD8+ TIL or PD-L1 expression as the cut-off point for high/low CD8+ TIL or PD-L1 positive/negative expression.

      4c3880bb027f159e801041b1021e88e8 Result

      We found recurrent mutations (>5%) in 8 genes, including TP53, KMT2C, NFE2L2, KEAP1, CDKN2A, PTEN and FBXW7. FGFR1 and PIK3CA amplifications were found in 19% and 11% of samples. 24.9% of patients had high TMB. Except for expected differences by smoking status, baseline clinical variables were similar between those with high and low TMB. Interestingly, FGFR1, PIK3CA or SOX2 amplification was independently associated with higher TMB (P=0.020, P=0.017, P=0.029; respectively). Patients with copy number variations had significantly higher TMB than those without (P=0.009). Positive PD-L1 and CD8+ TILs expression were identified in 24.3% and 78.8% of all cases. Baseline features were comparable between those with positive and negative CD8+ TIL or PD-L1 expression. NFE2L2 mutation and PIK3CA amplification were independently associated with significantly higher PD-L1 expression (P=0.003, P=0.014; respectively). TP53 mutations were associated with higher CD8+ TILs expression (P=0.008), but FGFR1 amplification was correlated with lower CD8+ TILs expression (P=0.042). Of note, there is no association between TMB and PD-L1 expression (r=0.052, P=0.476), or CD8+ TILs expression (r=0.026, P=0.718). None of TMB, PD-L1 and CD8+ TIL expression could individually predict overall survival (OS). However, combination of TMB and PD-L1 could stratify total populations into two groups with distinct prognosis. Patients with negative PD-L1 expression and high TMB had the worst prognosis (P=0.008). Additionally, combination of TMB and CD8+ TIL expression could also divide total populations into two groups with different prognosis (worst prognosis in negative CD8+ TIL expression and high TMB, P=0.022).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This was the first and most large-scale study to comprehensively portray genomic landscape of Chinese LSCC. The current study provides several meaningful and referential findings for the future design of clinical trials in LSCC, especially immunotherapy based on immune checkpoint inhibitors.

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      MA09.12 - Discussant - MA 09.09, MA 09.10, MA 09.11 (ID 14610)

      16:30 - 16:45  |  Presenting Author(s): Philippe Joubert

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      Abstract not provided

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    MS09 - Tumour Board - Tissue Acquisition and Staging (ID 788)

    • Type: Mini Symposium
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 206 BD
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    MS10 - Part Solid Nodules, GGN and STAS (ID 789)

    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 206 F