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Yuichiro Ohe
Moderator of
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 9
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.01 - Pemetrexed-Carboplatin Plus Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC: KEYNOTE-021 Cohort G Update (ID 9059)
14:30 - 14:40 | Presenting Author(s): Hossein Borghaei | Author(s): Corey J Langer, Shirish M Gadgeel, Vassiliki A Papadimitrakopoulou, A. Patnaik, S.F. Powell, R.D. Gentzler, R.G. Martins, J.P. Stevenson, S.I. Jalal, A. Panwalkar, James Chih-Hsin Yang, Matthew A Gubens, Lecia V Sequist, M.M. Awad, J. Fiore, S. Saraf, H. Raftopoulos, L. Gandhi
- Abstract
- Presentation
Background:
Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.
Method:
Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).
Result:
123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.
Conclusion:
Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).
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OA 17.02 - Updated Efficacy Results From the BIRCH Study: First-Line Atezolizumab Therapy in PD-L1–Selected Patients With Advanced NSCLC (ID 8006)
14:40 - 14:50 | Presenting Author(s): Enric Carcereny | Author(s): Enriqueta Felip, Martin Reck, J. Patel, R. Heist, A. Balmanoukian, Laura Q Chow, Luis Paz-Ares, J. Qiu, S. Coleman, S. Mocci, A. Sandler, T. Kurata, Frances A Shepherd
- Abstract
- Presentation
Background:
The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.
Method:
Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.
Result:
With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.
Conclusion:
With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.Endpoint (95% CI) TC3 or IC3[a ](n = 65) TC2 or IC2[b] (n = 73) All Treated Patients (N = 138) INV-assessed ORR, % 35% (23.9, 48.2) 18% (9.8, 28.5) 26% (19.0, 34.2) EGFR mutant/wild-type, % 25%/33% 33%/15% 31%/23% KRAS mutant/wild-type, % 38%/33% 25%/15% 31%/24% mDOR, mo 16.5 (8.5, NE) 12.5 (8.3, 17.9) 13.1 (9.9, NE) mOS, mo 26.9 (12.0. NE) 23.5 (18.1, NE) 24.0 (18.1, 31.9) 12-mo OS rate, % 61% (49.0, 74.0) 71% (59.8, 81.5) 66% (58.1, 74.6) 24-mo OS rate, % 52% (39.3, 65.2) 49% (37.0, 61.1) 50% (41.5, 59.2) 30-mo OS rate, % 48% (35.3, 61.5) 39% (27.2, 51.2) 43% (34.3, 52.1) mPFS, mo 7.3 (4.9, 12.0) 7.6 (4.0, 9.7) 7.6 (5.7, 9.7) 12-mo PFS rate, % 38% (25.1, 49.9) 30% (19.2, 41.2) 34% (25.3, 41.9) 24-mo PFS rate, % 28% (16.5, 40.0) 13% (4.5, 21.5) 20% (12.9, 27.5) 30-mo PFS rate, % 19% (5.4, 33.5) 9% (1.4, 16.4) 14% (6.5, 21.9) NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.
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OA 17.03 - First-Line Nivolumab plus Platinum-Based Doublet Chemotherapy for Advanced NSCLC: CheckMate 012 3-Year Update (ID 9043)
14:50 - 15:00 | Presenting Author(s): Rosalyn J. Juergens | Author(s): M.D. Hellmann, Julie R Brahmer, Hossein Borghaei, Scott N. Gettinger, Laura Q Chow, David E Gerber, S.A. Laurie, J. Goldman, Frances A Shepherd, W.J. Geese, T.C. Young, X. Li, S. Antonia
- Abstract
- Presentation
Background:
Platinum-based doublet chemotherapy is the standard-of-care first-line treatment for most patients with advanced NSCLC, but responses are not durable (~4.5–6 mo). Chemotherapy may sensitize NSCLC tumors to immune checkpoint inhibitors. Nivolumab, a fully human programmed death (PD)-1 antibody, demonstrated long-term survival benefit in patients with previously treated advanced NSCLC. Here we report the 3-year update of safety and efficacy of first-line nivolumab combined with chemotherapy in the phase 1 CheckMate 012 study (NCT01454102).
Method:
Chemotherapy-naïve patients with stage IIIB/IV NSCLC were randomly assigned based on histology in 3 cohorts combining nivolumab Q3W with 3 platinum-based doublet chemotherapy regimens: nivolumab 10 mg/kg + gemcitabine-cisplatin (all squamous histology), nivolumab 10 mg/kg + pemetrexed-cisplatin (all non-squamous), and nivolumab 10 mg/kg or 5 mg/kg + paclitaxel-carboplatin (any histology). After 4 cycles of nivolumab plus chemotherapy, patients received nivolumab monotherapy until progression or unacceptable toxicity. The primary objective was safety. ORR, PFS, and OS were secondary/exploratory endpoints.
Result:
56 patients were treated. Median age was 63.5 years, 46% were male, and 14% were never-smokers; 29% of tumors had squamous histology. At database lock (September 19, 2016) the minimum follow-up was 45.5 mo. Median duration of chemotherapy treatment was ~12 weeks (4 cycles; range: 3–18 weeks) and median duration of nivolumab treatment was 17–22 weeks across cohorts (range: 3–204). No new safety signals were observed in patients receiving nivolumab maintenance compared with the September 2014 database lock. ORR was 46%. Median duration of response was 10.4 mo (95% CI: 5.1, 26.3). Median PFS was 6.0 mo (95% CI: 4.8, 8.3). Median OS was 19.2 mo (95% CI: 14.1, 23.8), and the 3-year OS rate was 25%. ORR and OS were similar in patients with tumor PD-L1 expression <1% (n=23) vs ≥1% (n=23): ORR 48% vs 52%; median OS 19.2 mo (95% CI: 12.2, 23.8) vs 20.2 mo (95% CI: 10.9, 27.2). The 3-year OS rate was 22% in both PD-L1 expression subgroups.
Conclusion:
Nivolumab plus chemotherapy resulted in prolonged survival in a subset of patients, with a 3-year OS rate of 25%. In all patients, ORR and OS were similar irrespective of tumor PD-L1 expression. These results support further evaluation of nivolumab-chemotherapy combinations as first-line treatment for advanced NSCLC, which are being explored in CheckMate 227 (NCT02477826).
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OA 17.04 - Discussant - OA 17.01, OA 17.02, OA 17.03 (ID 10802)
15:00 - 15:15 | Presenting Author(s): Martin Schuler
- Abstract
- Presentation
Abstract not provided
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OA 17.05 - IFCT-1502 CLINIVO: Real-Life Experience with Nivolumab in 600 Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 9371)
15:15 - 15:25 | Presenting Author(s): Nicolas Girard | Author(s): O. Molinier, C. Audigier-Valette, J. Cadranel, I. Monnet, J. Hureaux, W. Hilgers, E. Fauchon, E. Fabre, Benjamin Besse, P. Brun, D. Coëtmeur, E. Quoix, P. Mourlanette, Fabrice Barlesi, S. Bordenave-Caffre, T. Egenod, P. Missy, F. Morin, D. Moro-Sibilot
- Abstract
- Presentation
Background:
Nivolumab is a standard option for second‐line treatment in pts with advanced NSCLC. Real‐life data are lacking regarding the efficacy of nivolumab and post‐nivolumab treatment.
Method:
This analysis included the first 600 consecutive pts with stage IIIB/IV NSCLC who received ≥1 dose of nivolumab 3mg/kg q2w through the French EAP from 01/2015 for Squamous ﴾Sq﴿ and 06/2015 for Non‐Sq NSCLC, until 08/2015.
Result:
Median age was 64 yo, there were 409 ﴾68%﴿ men, 521 ﴾87%﴿ smokers, 478 ﴾80%﴿ PS0/1 pts, 230 ﴾38%﴿ Sq and 370 ﴾62%﴿ Non‐Sq NSCLC, 130 ﴾22%﴿ pts with brain metastases. Nivolumab was administered as 2nd/3rd/≥4th‐line for 26%/33%/41% pts, respectively. Best response was PR/SD/PD for 17%/30%/37% of patients, respectively, with 16% not assessable. Toxicities occurred in 187 ﴾31%﴿ pts, including 10% grade ≥3 events. After a median follow‐up of 22.1 ﴾95% CI 21.6‐22.6﴿ months, median PFS and OS from the initiation of nivolumab were 2.1 ﴾95%CI 1.9‐2.3﴿ and 9.5 ﴾95%CI 8.4‐10.8﴿ months, respectively. In the 92 pts with PS2 at initiation of nivolumab, PR/SD rates were 7%/28%; median OS was 3.6 (95%CI 2.7-5.2) months. A total of 130 pts had brain metastases at initiation of nivolumab: PR/SD rates were 12%/25%; median OS was 6.6 (95%CI 3.8-8.3) months. Post‐nivolumab treatment was administered to 262 ﴾44%﴿ pts, and mostly consisted of gemcitabine ﴾19%﴿, docetaxel ﴾18%﴿, paclitaxel ﴾14%﴿, erlotinib ﴾12%﴿, vinorelbine ﴾9%﴿, platin‐based doublet ﴾8%﴿, or pemetrexed ﴾8%﴿. Access to post‐nivolumab treatment was higher in PS0/1 vs. PS2 pts ﴾48% vs. 23%, p<0.001﴿, but was not different according to histology or treatment line or disease control with nivolumab. Best response to post‐nivolumab treatment was PR/SD/PD for 15%/42%/42% of pts, respectively. In the whole cohort, median post‐nivolumab OS was 4.0 ﴾95%CI 2.8‐4.6﴿ months, and was significantly higher in case of PR to nivolumab ﴾HR=0.38; 95%CI 0.23‐0.64; p<0.001﴿, and if subsequent treatment was delivered ﴾HR=0.30; 95%CI 0.24‐0.38; p<0.001﴿; median post‐nivolumab OS in pts receiving post‐nivolumab treatment was 7.5 ﴾95%CI 6.8‐8.7﴿ months, and did not differ based on histology or treatment line.
Conclusion:
Efficacy and safety of nivolumab was in line with available data. Post‐nivolumab treatment may be delivered in many pts, including pts with PS2 and brain metastases, with favorable impact on response and OS. Data on the whole cohort of 900 pts enrolled in the EAP will be presented.
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OA 17.06 - Updated Analysis of KEYNOTE-024: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC With PD-L1 TPS ≥50% (ID 9582)
15:25 - 15:35 | Presenting Author(s): Julie R Brahmer | Author(s): D. Rodríguez-Abreu, A.G. Robinson, R. Hui, T. Csőszi, A. Fülöp, Maya Gottfried, Nir Peled, A. Tafreshi, S. Cuffe, M. O'Brien, S. Rao, K. Hotta, A. Riccio, J. Yang, M..C. Pietanza, Martin Reck
- Abstract
- Presentation
Background:
KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy.
Method:
Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.
Result:
305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%).
Conclusion:
With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.
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OA 17.07 - Long-Term Survival in Atezolizumab-Treated Patients with 2L+ NSCLC from Ph III Randomized OAK Study (ID 8663)
15:35 - 15:45 | Presenting Author(s): Miyako Satouchi | Author(s): L. Fehrenbacher, Manuel Cobo Dols, Ji-Youn Han, J. Von Pawel, R. Bordoni, T. Hida, Keunchil Park, D. Moro-Sibilot, P. Conkling, C. Matheny, W. Yu, P. He, Marcin Kowanetz, M. Gandhi, M. Ballinger, A. Sandler, David R. Gandara
- Abstract
- Presentation
Background:
Atezolizumab (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. OAK, a Phase III study of atezolizumab vs docetaxel demonstrated superior OS of atezolizumab. The characteristics of the long-term survivors (LTS) in the OAK primary population (n = 850) are evaluated and describe the largest cohort of cancer immunotherapy-treated NSCLC LTS yet reported.
Method:
Patients received IV q3w atezolizumab (1200 mg) until PD / loss of clinical benefit or docetaxel (75 mg/m[2]) until PD / unacceptable toxicity. No crossover was allowed. LTS were defined as patients with OS ≥ 24 months and non-LTS as those who died within 24 months of randomization. Patients with OS censored prior to 24 months were not included. Data cutoff, January 23, 2017.
Result:
A higher 2-year survival rate was observed for the atezolizumab-arm (31%) vs docetaxel-arm (21%). After a minimum follow-up of 26 months, there were 119 LTS vs 279 non-LTS in the atezolizumab-arm and 77 LTS vs 299 non-LTS in the docetaxel-arm. Characteristics of atezolizumab-arm LTS and non-LTS are shown (Table). Atezolizumab-arm LTS were enriched for non-squamous histology and high PD-L1–expressing tumors, but also included low/no PD-L1–expressing tumors (40.3%). Atezolizumab-arm LTS had higher ORR (39.5%) than non-LTS (5.0%) but included LTS subjects with PD. 52.9% atezolizumab-arm vs 71.4% docetaxel-arm LTS received anti-cancer non-protocol therapy (NPT) after discontinuation of protocol-defined therapy. 51.9% of docetaxel-arm LTS vs 12.7% non-LTS received non-protocol immunotherapy. Median treatment exposure in atezolizumab-arm LTS was 18.0 months. Atezolizumab-arm LTS had a comparable safety profile to all atezolizumab-treated population.
Conclusion:
Atezolizumab provides superior 2-year OS benefit vs docetaxel and is well tolerated. The majority of docetaxel-arm LTS received a checkpoint inhibitor as NPT. Atezolizumab LTS appeared to have favorable prognostic factors, including non-squamous histology, but notably were not limited to patients with RECIST v1.1 response or with PD-L1 expression.Table. Characteristics of Atezolizumab-Arm Long-Term Survivors (LTS) vs Non-Long Term Survivors (Non-LTS) Atezolizumab LTS (n = 119) n (%) Atezolizumab Non-LTS (n = 279) n (%) Sex Male 61 (51.3) 183 (65.6) Female 58 (48.7) 96 (34.4) Tobacco use history Never smoker 29 (24.4) 47 (16.8) Current/previous smoker 90 (75.6) 232 (83.2) Histology Non-squamous 101 (84.9) 195 (69.9) Squamous 18 (15.1) 84 (30.1) No. of prior therapies, 1 89 (74.8) 209 (74.9) ECOG performance status at baseline 0 60 (50.4) 89 (31.9) 1 59 (49.6) 190 (68.1) EGFR mutation status, positive 11 (9.2) 26 (9.3) PD-L1 IHC subgroup TC3 or IC3 28 (23.5) 39 (14.0) TC1/2/3 or IC1/2/3 71 (59.7) 156 (55.9) TC0 and IC0 48 (40.3) 119 (42.7) Best overall response Complete response 5 (4.2) 0 (0) Partial response 42 (35.3) 14 (5.0) Stable disease 47 (39.5) 97 (34.8) Progressive disease 25 (21.0) 142 (50.9) IC, tumor-infiltrating immune cell; TC, tumor cell. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT02008227.
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OA 17.08 - Phase II Study of Pembrolizumab for Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT) (ID 9449)
15:45 - 15:55 | Presenting Author(s): Joshua Michael Bauml | Author(s): R. Mick, C. Ciunci, C. Aggarwal, T. Evans, L. Miller, N. Muhammad, E. Alley, C. Knepley, F. Mutale, R.B. Cohen, Corey J Langer
- Abstract
- Presentation
Background:
Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide additional benefit after LAT. We are running a Phase II study to evaluate the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy will be effective in the setting of a minimal disease burden.
Method:
Eligibility stipulates oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts begin pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for a full year in the absence of progression or toxicity. Progression free survival (PFS) and overall survival (OS) are measured from the start of LAT. A sample size of 42 pts provides 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.
Result:
Since January 2015, 39 pts have been enrolled. The median age is 64 years; 54% are male; 90% Caucasian. Current and former smokers comprise 90% of the cohort, with a median of 32 pack yrs. Most common metastatic sites are lung (15 pts), brain (13), and bone (8). LAT has included surgery (24 pts), SRT (23), and concurrent chemoradiotherapy (17). Attributable adverse events (AEs) have been mostly mild and self-limited. There has been one episode of Grade 3 pneumonitis and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 16 mos. To date, 11 pts have had progression or death. The median PFS has not yet been reached. The PFS rates (+ SE) at 6, 12 and 18 mos are 92%+5%, 64%+9% and 64%+9%, with 16 and 5 pts at risk beyond 12 and 24 mos, respectively. To date, 8 pts (21%) have died. The median OS has not yet been reached. The OS rates (+ SE) at 6, 12 and 18 mos are 100%, 90%+6% and 75%+9%, with 22 and 5 pts at risk beyond 12 and 24 mos, respectively.
Conclusion:
Use of pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. In a preliminary analysis, PFS appears favorable. Continued follow-up is necessary to confirm these findings. It is expected that accrual will be complete as of September 2017. Updated survival estimates will be presented.
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OA 17.09 - Discussant - OA 17.05, OA 17.06, OA 17.07, OA 17.08 (ID 10803)
15:55 - 16:10 | Presenting Author(s): Penelope Bradbury
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:K. Shibuya, Francoise Mornex
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 313 + 314
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MA 16.04 - Phase II Trial of S-1 Treatment as Palliative-Intent Chemotherapy for Previously Treated Advanced Thymic Carcinoma (ID 8627)
16:00 - 16:05 | Author(s): Yuichiro Ohe
- Abstract
- Presentation
Background:
Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival with palliative-intent chemotherapy. Sunitinib and everolimus monotherapies have been proposed as active molecular-targeted approaches based on phase II (Ph II) trials, and S-1, an oral fluoropyrimidine, has been described in the NCCN guideline as an active cytotoxic agent for refractory TC based on a case series. Therefore, we conducted a Ph II trial to study the result of S-1 treatment in patients with refractory TC.
Method:
In this Ph II study performed at three cancer centers in Tokyo, we aimed to enroll 26 TC patients previously treated with platinum-based chemotherapy. The patients received S-1 orally twice daily at a dose of 40–60 mg/m2 for 4 weeks, followed by 2 weeks off until progressive disease or unacceptable toxicities. S-1 was used off-label. The primary end-point was determining the objective response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicities.
Result:
Twenty-six patients (10 males) were recruited between November 2013 and May 2016. The median age was 63 (27–74) years. Among the 26 patients, 23 had squamous cell carcinoma histology and 10 had an ECOG performance status of 0. Additionally, one patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (95% confidence interval [CI], 16.5–50.0) and a 65.4% disease control rate (95% CI, 46.2–80.6). After a median follow-up of 13.4 months, the median PFS was 4.3 months (95% CI, 2.3–7.6 months) and median OS was 23.4 months (95% CI, 12.8–not reached). Treatment-related adverse events (AEs) of grade ≥3 included neutropenia (12%), skin rash (8%), elevated ALT, decreased WBC count, and fatigue (4%). No treatment-related death was observed. However, treatment was discontinued in three patients (12%) because of AEs.
Conclusion:
S-1 for refractory TC confirmed clinical activity with good tolerability. Clinical trial identification: UMIN000010736
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MA 17 - Locally Advanced NSCLC (ID 671)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:S. Jheon, Georgios Stamatis
- Coordinates: 10/17/2017, 15:45 - 17:30, F203 + F204 (Annex Hall)
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MA 17.06 - Safety Data from Randomized Phase II Study of CDDP+S-1 vs CDDP+PEM Combined with TRT for Locally Advanced Non-Squamous NSCLC (ID 8296)
16:20 - 16:25 | Author(s): Yuichiro Ohe
- Abstract
- Presentation
Background:
Both cisplatin (CDDP)+S-1 and CDDP+pemetrexed (PEM) can be given at full systemic doses with thoracic radiotherapy (TRT) in locally advanced non-small cell lung cancer (NSCLC), and CDDP+PEM is one of the standard chemotherapy regimens in patients with advanced non-squamous (non-sq) NSCLC. This multicenter, randomized, open-label, phase II study (SPECTRA) compared the efficacy and safety of the two above-mentioned promising regimens combined with TRT in patients with unresectable locally advanced non-sq NSCLC.
Method:
Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. If the 2-year PFS rate is assumed to be 25% in the inferior therapy group and 15% higher in the superior therapy group of this study, the sample size needed for selection of the optimum treatment group at a probability of approximately 95% will be 51 cases/group with the Simon’s selection design. The sample size was set at 100 patients.
Result:
Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n=17 (33%)/n=17 (34%); stage IIIB, n=21 (40%)/n=20 (40%); ECOG PS of 1, n=14 (27%)/n=14 (28%); never smoker, n=12 (23%)/n=12 (24%); and adenocarcinoma, n=47(90%)/n=45(90%). Completion rate of TRT (60Gy) and chemotherapy (4 cycles) was 92%/98% and 73%/86%, respectively. Response rate was 60%/64%. Grade 3 or higher toxicities included febrile neutropenia (12%/2%), anorexia (8%/16%), diarrhea (8%/0%), esophagitis (6%/8%), pneumonia (4%/4%), neutropenia (38%/52%), anemia (8%/12%), thrombocytopenia (4%/6%), and hyponatremia (12%/12%). Grade 1 radiation pneumonitis was observed in 8 (15%)/2 (4%) patients on the basis of the data collected 30 days or less after the discontinuation of protocol treatment. No treatment-related death was observed. The data on PFS and overall survival are immature.
Conclusion:
Response rate was similar between the two arms. Toxicities were tolerable and manageable in both arms; however febrile neutropenia was more frequently observed in the CDDP+S-1 arm. We will present the updated safety data of this study at the conference. Survival data will be analyzed in late 2018.
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.01 - A Phase II Study of Nivolumab: A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT) (ID 9111)
11:00 - 11:05 | Author(s): Yuichiro Ohe
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and limited treatment options beyond progression after platinum-based combination with pemetrexed chemotherapy. Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a humanized monoclonal antibody, PD-1 immune-checkpoint inhibitor, has demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Here, we report the preliminary results of a phase II study to evaluate the efficacy and safety of Nivolumab in previously treated Japanese MPM patients (pts): ONO-4538-41/JapicCTI-No.163247.
Method:
This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including platinum-based combination therapy with pemetrexed. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable disease and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS).
Result:
From July to October 2016, 34 pts were enrolled in 15 centers. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6%. Median follow-up was 6.7 months. Independent review committee-assessed 6-month ORR was 29.4% (n=10, 95%CI: 16.8-46.2) and objective responses were observed across tissue types, epithelioid 7/27 (25.9%), sarcomatoid 2/3 (66.7%), biphasic 1/4 (25.0%). 13 pts (38.2%) had stable disease, resulting in a 6-month DCR of 67.6%. Median PFS was 6.1 months (95%IC: 2.9-NR). Median OS has not been reached. 6-month PFS and OS rates are 50.9% (95%CI: 32.7-66.5) and 85.3% (95%IC: 68.2-93.6). 23 (67.6%) pts experienced drug-related adverse event (DRAE), and 7 (20.6%) experienced grade 3/4 DRAEs. 2 pts required dose discontinuation because of pneumonitis (Grade2 and 3).
Conclusion:
Single-agent Nivolumab has significant activity in 2[nd]/3[rd] line MPM pts and met the primary endpoint, suggesting that Nivolumab has a potential to be a new therapeutic option for MPM.
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MS 05 - Clinical Issues of Immune Checkpoint Inhibitors (ID 527)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Luis E Raez, Nico Van Zandwijk
- Coordinates: 10/16/2017, 15:45 - 17:30, Main Hall
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MS 05.04 - Practical Approach to Combination of Chemotherapy with IO (ID 7660)
16:30 - 16:45 | Presenting Author(s): Yuichiro Ohe
- Abstract
- Presentation
Abstract:
Combination of chemotherapy with immune-check point inhibitor is considered to be one of the most promising strategy to improve efficacy of immune-check point inhibitors. Several clinical trials of chemotherapy with immune-check point inhibitor are conducted and the results have been reported. KEYNOTE-021 cohort G is a randomised, open-label, phase 2 cohort of a multicohort study assessed whether the addition of pembrolizumab to carboplatin and pemetrexed improves efficacy in patients with advanced non-squamous NSCLC. Thirty-three (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (p=0·0016). Progression-free survival (PFS) was significantly longer with pembrolizumab plus chemotherapy compared with chemotherapy alone (HR 0·53 [95% CI 0·31–0·91]; p=0·010). Median PFS was 13·0 months for pembrolizumab plus chemotherapy and 8·9 months for chemotherapy alone. The FDA has granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression. Antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab that are currently approved for use in the treatment of NSCLC. Bevacizumab, in addition to platinum-based chemotherapy is widely used for the first-line treatment of advanced, metastatic, or recurrent NSCLC, excluding squamous cell carcinoma. VEGF influences lymphocyte trafficking across endothelia to the tumor by inhibiting lymphocyte adhesion and VEGF has a systemic effect on immune-regulatory cell function through multiple mechanisms, such as Tregulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs); suppression of dendritic cell maturation; and inhibition of T-cell development from hematopoietic progenitor cells. Thus, combination of antiangiogenic monoclonal antibody and immune-check point inhibitor is potentially synergistic. National Cancer Center Hospital conducted a single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced NSCLC. In this trial, nivolumab with gemcitabine/cisplatin, pemetrexed/cisplatin, paclitaxel/carboplatin/bevacizumab, or docetaxel were evaluated for six patients each arm. Combination of nivolumab and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Although small number of patients, nivolumab with paclitaxel/carboplatin/bevacizumab seems to be most promising with higher response rate and longer PFS. Based on these data, phase III study of paclitaxel/carboplatin/bevacizumab with/without nivolumab for advanced non-squamous NSCLC is ongoing.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.08 - Final Result of Phase I/II Study (AF-001JP) of Alectinib, a Selective CNS-Active ALK Inhibitor, in ALK+ NSCLC Patients (Pts) (ID 9732)
17:00 - 17:10 | Author(s): Yuichiro Ohe
- Abstract
- Presentation
Background:
Alectinib (ALC) is a selective, CNS-active ALK tyrosine kinase inhibitor. In two Phase 3 studies (J-ALEX and ALEX), ALC proved superior efficacy and tolerability compared to crizotinib (CRZ). Here we report the final efficacy and safety results of the 46 pts enrolled in the phase II part of study AF-001JP with a longer follow-up period than that observed in J-ALEX and ALEX studies.
Method:
ALC 300 mg b.i.d was given to ALK+ NSCLC pts who were ALK inhibitor-naive and had disease progression after at least one line of chemotherapy to investigate the efficacy and safety until the investigator confirmed no further clinical benefits.
Result:
This study was completed in December 2016. The median treatment duration was 46.1 months (range: 1-62). 20 of 46 pts were on treatment with alectinib at the study termination. Progressive disease (PD) was confirmed in 20 pts (43%). Median PFS was not reached and 4-year PFS rate was 52% (95% CI: 36-66). 14 of 46 pts had CNS metastasis at baseline. Median PFS was 38 months (95% CI: 9-NE) in pts with CNS metastases and was not reached in pts without CNS metastases. Four pts had CNS progression and the 4-year cumulative incidence rate of CNS progression was 9.5%. Median OS was not reached and the 4-year OS rate was 70% (95% CI: 54-81). Safety profile was similar to that reported previously and there were no treatment-related Grade 4 or 5 adverse events for this long administration period.
Conclusion:
Regardless of CNS metastases at baseline, ALC have demonstrated excellent efficacy in ALK+ NSCLC pts without prior ALK inhibitor treatment. ALC was well tolerated over a prolonged administration period.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-035 - PD-L1 IHC Test on Cytological Cell Block Specimen; Potential Utility and Practical Issues (ID 9018)
09:30 - 09:30 | Author(s): Yuichiro Ohe
- Abstract
Background:
PD-L1 IHC test is an important biomarker for predicting the response of the immune checkpoint inhibitor against the PD1/PD-L1 axis. The FFPE tissue sample is an only validated specimen used in the clinical study, although it is sometimes difficult to obtain an enough tissue sample in advanced stage patients. Cytology specimen is an expected candidate. In this study, we evaluated the PD-L1 IHC expression on cytology cell block specimen (CB) and compared to the corresponding formalin-fixed-paraffin-embedded tumor tissue sample (FFPE-T).
Method:
Nine primary lung cancer patients who have both surgical resected FFPE-T and pleural effusion CB were recruited. CB was prepared as following; pleural fluid was centrifuged to collect the cell pellet, then fixed in formalin and embedded in paraffin. PD-L1 expression was evaluated using two clones (DAKO PharmDx kit, 22C3 and 28-8). Three pathologists (two certified, one path-trainee) and one cytotechnologist reviewed the slides independently. The proportion score of tumor cell (TPS) was evaluated and divided into 2-tier (positive, negative for 28-8) and 3-tier (no, low, high expression for 22C3) categories, according to the manufactural protocols. The correlation between CB and FFPE-T and the inter-observer agreement (kappa value) were calculated.
Result:
All samples were acceptable for PD-L1 evaluation. FFPE-T resulted in 2 positive, 7 negative (28-8); 3 low and 6 no expression (22C3), respectively. CB resulted in 5 positive, 2 negative (28-8); 3 low and 6 no expression (22C3), respectively. The TPS and tiered-category of CB did not correlate to those of FFPE-T, statistically. The concordant rate of tiered-category between FFPE-T and CB resulted in 4/9 (45.4%) for both clones. It can be explained by the heterogeneity of PD-L1 expression. The TPS and category judgment of two tests (28-8 and 22C3) within each observer were statistically correlated (R=0.588-0.951, p-value <0.001). The kappa value of the inter-observer agreement varied from 0.18 to 1.0, depending on the experience and education. Two certified pathologists reached moderate (kappa=0.59 for 28-8) to high (1.0 for 22C3) agreement on CB, but low (0.05 and 0.14) on FFPE-T. The kappa value between certified pathologist and path-trainee/ cytotechnologist was 0.6/ <0.01 for FFPE-T, and 0.18/0.57 for CB, respectively. These results seem to be influenced by the recognition of appropriate target tumor cells.
Conclusion:
Our study suggested that the properly processed cytology sample has a potential clinical utility for PD-L1 evaluation. The difficulty of target cell recognition on cytology specimen seems to be one of the critical issues of standardization.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-036 - Comparing the Efficacy/Toxicity of Osimertinib and First Line EGFR-TKI by Individual Patient Analysis (ID 9380)
09:30 - 09:30 | Author(s): Yuichiro Ohe
- Abstract
Background:
Osimertinib is a third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which showed its efficacy for T790M resistant mutation in patients with advanced and recurrent non small cell lung cancer (NSCLC). The efficacy and toxicity of osimertinib comparing to previous EGFR-TKIs are not fully elucidated. Since every patient receiving osimertinib has received previous EGFR-TKI therapy, we compared the efficacy and toxicity of those agents in the same patients.
Method:
We retrospectively reviewed medical records of patients with T790M mutation positive advanced and recurrent NSCLC, who had disease progression after previous EGFR-TKI, the standard first line therapy, and started osimertinib between April 2016 and March 2017 at National Caner Center Hospital. Progression free survival (PFS) of osimertinib, and 1st line EGFR-TKI PFS of the same patients were calculated by Kaplan-Meier method. Objective response rate (ORR) was assessed according to RECIST version 1,1. Adverse events (AEs) were also reviewed to evaluate the difference of safety profiles between osimertinib and previous EGFR-TKIs.
Result:
A total of 46 patients with T790M positive NSCLC received osimertinib after the failure of first line EGFR-TKI treatment. At May 2017, the median follow-up time since the start of osimertinib was 7.8months. The median age was 65 (range 36-82), the median number of treatment received before osimertinib was 3 (range 1-9), and the median wash out time of 1st line EGFR-TKI till the start of osimertinib was 14.0 months. The median PFS of osimertinib is not reached. The median PFS of first line EGFR-TKI was 15.2 months. ORR of osimertinib and first line EGFR-TKI was 56.0% and 65.2%, respectively. The most frequent AEs of any grade of osimertinib were rash, dry skin, paronychia, and diarrhea (39.4%, 35.8%, 32.1%, and 30.2%, respectively). Rash, paronychia, and diarrhea over grade 2 was 6.5%, 6.5%, and 0% with osimertinib, compared to 0%, 12.5%, and 4.1% with gefitinib, and 41.7%, 8.3%, and 0% with erlotinib. The incidence of pneumonitis with osimertinib treatment was 10.9% (5 cases) in any grade, and 6.5% (3 cases) in grade 3 to 4, though 2 of them (1 case in grade 1 and 1 in grade 3) had received nivolumab as the prior chemotherapy. Except for pneumonitis, there was no AE leading to permanent discontinuation related to osimertinib.
Conclusion:
Osimertinib showed the efficacy and feasibility even in practical use. Adverse effect of osimertinib was generally better tolerated than previous EGFR-TKIs, except for pneumonitis.
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P2.03-048 - Mixed Response of Non-Small Cell Lung Cancer Harboring the EGFR T790M Mutation to Osimertinib (ID 9807)
09:30 - 09:30 | Author(s): Yuichiro Ohe
- Abstract
Background:
Although patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), most progress after approximately 1 year. At the time of progression, the EGFR T790M mutation is detected in more than half of these tumors. NSCLC harboring the T790M mutation shows a high response rate to osimertinib. However, the heterogeneous nature of NSCLC may limit the efficacy of osimertinib to those lesions with the T790M mutation, and a subset of patients may show a mixed response (MR), whereby some lesions shrink while others progress at the first evaluation. Previous study showed that about 20% of NSCLC patients exhibit MR to systemic therapies including EGFR-TKI. However, little is known about characteristics of MR to osimertinib.
Method:
To determine the frequency of a MR, we retrospectively reviewed patients treated with osimertinib for NSCLC harboring the EGFR T790M mutation at the National Cancer Center Hospital.
Result:
Between April and December 2016, 45 patients (median age 65 [36‒82] years, 19 [42%] males) who had NSCLC with the T790M mutation received osimertinib. The median numbers of previous chemotherapies and EGFR-TKI therapies received by the patients were 1 and 2, respectively. All measurable tumor lesions showed a response to therapy in 35 (77%) patients and progression in three (7%) patients. A MR was seen in seven (16%) patients. Of these seven patients, the re-biopsy specimens in which T790M was detected were derived from the primary lesion in six and a metastatic lymph node in one patient. Two types of MRs were seen among these seven patients: (1) the tumor including the re-biopsy site responded, while the other lesions progressed (five patients), and (2) the tumor including the re-biopsy site progressed (two patients). The most frequent progressive sites were liver and lung metastasis (four patients, respectively). Three patients continued to receive osimertinib after the MR, one of whom underwent drug-eluting bead transarterial chemoembolization (DEB-TACE) for progressive liver metastasis and achieved disease control on osimertinib for an additional 4 months after the MR.
Conclusion:
A MR to osimertinib was seen in 16% of patients with NSCLC harboring the EGFR T790M mutation. This suggests that resistance mechanism of 1st line EGFR-TKI may differ by the site in same patient. Since benefit of osimertinib is mainly seen in T790M mutation, addition of local therapy may be beneficial for patients who develop a MR to osimertinib.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-011 - Long Follow up from Phase I Study of Nivolumab and Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer (ID 8156)
09:30 - 09:30 | Author(s): Yuichiro Ohe
- Abstract
Background:
This phase I study investigated the tolerability, safety and pharmacokinetics of nivolumab in combination with chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC).
Method:
Patients who have stage IIIB without indication for definitive radiotherapy, stage IV，or recurrent NSCLC were eligible. nivolumab (10 mg/kg，day 1) and chemotherapy [arm A: cisplatin (80 mg/m[2], day 1) / gemcitabine (1250 mg/m[2], day 1 and 8), arm B: cisplatin (75 mg/m[2], day 1) / pemetrexed (500 mg/m[2], day 1), arm C: carboplatin (AUC 6, day 1) / paclitaxel (200 mg/m[2], day 1) / bevacizumab (15 mg/kg, day 1), arm D: docetaxel (75 mg/m[2], day 1)] were administered every three weeks. Arm A and B were administrated for four cycles and arm C was for four to six cycles as first-line chemotherapy. After that, nivolumab in arm A, nivolumab / pemetrexed in arm B, and nivolumab / bevacizumab in arm C were continued every three weeks as maintenance therapy until disease progression. Arm D were administrated until disease progression as second-line chemotherapy.
Result:
Six patients each in four arms, total 24 patients were enrolled. Median follow-up time was 20.4 months. Progression free survival [median (range)] were 6.3 (0.7-42.2+) months in arm A, 11.8 (1.4-47.4+) months in arm B, 40.7 (5.3-43.5+) months in arm C, and 3.2 (1.9-10.9) months in arm D. Three-year progression-free survival rates were 20% in arm A, 16,7% in arm B, 62.5% in arm C, and 0% in arm D.
Conclusion:
nivolumab 10 mg/kg showed acceptable toxicity profile and encouraging antitumor activity in combination with chemotherapies in Japanese patients with advanced NSCLC. Especially, arm C showed favorable response rate and long progression free survival in this study.
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-004 - Underrepresentation of Elderly Patients with ED-SCLC as Clinical Trial Candidates (JCOG1201/TORG1528) (ID 8837)
09:30 - 09:30 | Author(s): Yuichiro Ohe
- Abstract
Background:
Since December 2013, we initiated a phase II/III trial [Japan Clinical Oncology Group (JCOG) 1201/Thoracic Oncology Research Group (TORG) 1528: UMIN000012605] for elderly patients with extensive-disease small-cell lung cancer (ED-SCLC). Aim of the study is to demonstrate that a carboplatin plus irinotecan regimen is superior to carboplatin plus etoposide in elderly patients with ED-SCLC. However, the patient accrual rate did not satisfactorily match our expectations a year from the time of initiation of our study. To define factors related to low accrual, we searched institutional records and analyzed.
Method:
We collected data of elderly patients with ED-SCLC from each institution and investigated the total number of elderly patients with ED-SCLC, number of patients eligible/ineligible for the study, numbers of patients registered for the study, and the reasons for non-registration of even eligible patients. Doctor-reported questionnaires concerning elderly (≥71 years old) ED-SCLC patients diagnosed in their institutions were sent to chief or coordinate doctors at each institution in December 2014.
Result:
We received a response from 32 (84%) of 38 institutions. Approximately 260 patients were diagnosed as elderly patients with ED-SCLC in the last year. Only 100 patients (38%) were eligible for the JCOG 1201/TORG1528 trial. Reasons for ineligibility primarily included poor performance status (PS) (25%), low organ functions (25%), interstitial pneumonitis (19%) and double cancer (18%). Only 23 patients among the 100 eligible candidates accrued to the study. The primary reasons for non-accrual were delayed approval from the Institutional Review Board (IRB) of the individual institution (24%), physician preferences (23%), patient refusal (18%), and registration for other trials (12%).
Conclusion:
Our data demonstrated that 62% of ED-SCLC patients were ineligible for the protocol due to frailty with the most frequent reason being comorbidities such as poor PS and low organ functions. However, inactive institutions need to increase their efforts to register a greater number of eligible patients in addition to obtaining quicker IRB approval of protocol. Based on responses to questionnaires sent out as part of our investigation, in January 2016, the protocol was revised in terms of eligibility criteria to enhance patient accrual. Eligibility criteria for participation of elderly patients with ED-SCLC need to be formulated prudently so that patients are benefitted in routine clinical practice.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-041 - EGFR Amplification Mediates Resistance to TAS121, A Third-Generation EGFR-TKI, in EGFR T790M-Positive Non-Small Cell Lung Cancer (ID 9168)
09:30 - 09:30 | Author(s): Yuichiro Ohe
- Abstract
Background:
Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown promising efficacy in EGFR T790M-mutation-positive non-small cell lung cancer (NSCLC). However, acquired resistance to third-generation EGFR-TKIs has been reported in EGFR T790M-positive NSCLC. The mechanism of resistance to these third-generation EGFR-TKIs has not been fully elucidated. We report a case of metastatic NSCLC harboring an EGFR T790M mutation in which EGFR amplification mediated acquired resistance to TAS121, a novel third-generation EGFR-TKI.
Method:
A 68-year-old woman with metastatic lung adenocarcinoma, harboring an EGFR L858R mutation, received gefitinib in September 2013. Although the patient achieved a partial response, the tumor progressed and she was treated with 4 cycles of chemotherapy using cisplatin and pemetrexed followed by pemetrexed maintenance therapy. In April 2015, computed tomography (CT) showed disease progression (PD) with liver metastases, and re-biopsy of hepatic lesions was performed. Tumor genotyping with the PNA LNA PCR-Clamp method revealed an original mutation of EGFR L858R in exon 21 and a secondary mutation of EGFR T790M in exon 20. Tumor progression was noted after completion of one cycle of docetaxel, and she was enrolled into a phase 1 trial of TAS121 in June 2015. Although she showed a partial response to TAS121, PD was confirmed on CT, which indicated progression of liver metastases. She discontinued TAS121 and received supportive care. She died in October 2015, and an autopsy was performed. To determine the mechanism of resistance to TAS121, we performed next-generation sequencing (NGS) (NCC OncoPanel, Agilent) with post-TAS121 samples obtained from progressing liver lesions during TAS121 treatment. We also conducted fluorescence in situ hybridization (FISH) analysis for EGFR in pre-TAS121 liver lesions, post-TAS121 liver lesions, and autopsy samples from the lung and liver. The study protocol was approved by the Ethical Review Committee of the National Cancer Center Hospital.
Result:
NGS with the post-TAS121 liver samples showed EGFR amplification in the tumor cells (log2 ratio 2.2). On FISH analysis, EGFR amplification was not detected in the pre-TAS121 liver lesions (the ratio of EGFR signals to CEP signals 1.7), but was detected in the post-TAS121 liver lesions (2.1) and those obtained at autopsy (3.0). EGFR amplification was not detected in the autopsy samples of the lung lesions (1.0), which remained stable during TAS121 treatment.
Conclusion:
Our case revealed that genomic instability of the EGFR domain contributed to the development of resistance to TAS121. Further molecular analysis is warranted to understand the role of EGFR amplification in acquired resistance to third-generation EGFR-TKIs.
