KEYNOTE-025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1-positive advanced non-small-cell lung cancer

Makoto Nishio, Toshiaki Takahashi, Hiroshige Yoshioka, Kazuhiko Nakagawa, Tatsuro Fukuhara, Kazuhiko Yamada, Masao Ichiki, Hiroshi Tanaka, Takashi Seto, Hiroshi Sakai, Kazuo Kasahara, Miyako Satouchi, Shi Rong Han, Kazuo Noguchi, Takashi Shimamoto, Terufumi Kato, Makoto Nishio, Toshiaki Takahashi, Hiroshige Yoshioka, Kazuhiko Nakagawa, Tatsuro Fukuhara, Kazuhiko Yamada, Masao Ichiki, Hiroshi Tanaka, Takashi Seto, Hiroshi Sakai, Kazuo Kasahara, Miyako Satouchi, Shi Rong Han, Kazuo Noguchi, Takashi Shimamoto, Terufumi Kato

Abstract

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been shown to improve overall survival (OS) in patients with previously treated advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE-025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD-L1 TPS ≥1% and had received ≥1 platinum-doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD-L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD-L1 TPS ≥50%. Thirty-eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41-78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3-5 treatment-related adverse events (AE); 9 patients (24%) experienced immune-mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD-L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6-61). Among evaluable patients with PD-L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10-38). Median (95% CI) progression-free survival and OS were 3.9 (2.0-6.2) months and 19.2 (8.0-26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD-L1-expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE-010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.).

Keywords: PD-L1; immunotherapy; non-small-cell lung cancer; pembrolizumab; phase 1.

Conflict of interest statement

Makoto Nishio: Honoraria from Ono Pharmaceutical, Bristol‐Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Daiichi Sankyo, Merck Serono; grants from MSD, Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol‐Myers Squibb, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, Pfizer, Astellas. Toshiaki Takahashi: Honoraria from AstraZeneca K.K., Chugai Pharmaceutical, Eli Lilly Japan K.K.; grants from AstraZeneca K.K., Chugai Pharmaceutical, Eli Lilly Japan K.K., Ono Pharmaceutical, Pfizer Japan Inc., MSD K.K. Hiroshige Yoshioka: Honoraria from MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol‐Myers Squibb, AstraZeneca, Taiho Pharmaceutical, Pfizer, Eli Lilly, Boehringer Ingelheim. Kazuhiko Nakagawa: Honoraria from Eli Lilly Japan K.K., Novartis Pharma K.K., AstraZeneca, Pfizer Japan Inc., Astellas, Ono Pharmaceutical, Nippon Boehringer Ingelheim, MSD K.K.; grants from Chugai Pharmaceutical, Ono Pharmaceutical, Bristol‐Myers Squibb, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, MSD K.K., EPS Associates, JCRO, Quintiles, PPD‐SNBL K.K., Pfizer Japan Inc., Kyowa Hakko Kirin, Astellas, PAREXEL International Corp., inVentiv Health Japan, ICON Japan K.K., A2 Healthcare Corp., AC Medical Inc. Tatsuro Fukuhara: Grants from MSD, Ono Pharmaceutical and Bristol‐Myers Squibb. Kazuhiko Yamada: No relevant disclosures. Masao Ichiki: No relevant disclosures. Hiroshi Tanaka: Honoraria from Boehringer Ingelheim, Bristol‐Myers Squibb, AstraZeneca, Chugai Pharmaceutical; grants from Taiho Pharmaceutical, AstraZeneca, Chugai Pharmaceutical, Astellas, Bristol‐Myers Squibb, Eli Lilly, MSD. Takashi Seto: Honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Merck Sharp & Dohme Corp.; grants from Astellas, AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Eisai, Kissei Pharmaceutical, Merck Serono, Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim, Novartis, Pfizer, Verastem and Yakult Honsha. Hiroshi Sakai: Honoraria from Bristol‐Myers Squibb, Ono Pharmaceutical, MSD, Chugai Pharmaceutical, AstraZeneca; grants from Bristol‐Myers Squibb, Ono Pharmaceutical, MSD, Chugai Pharmaceutical, AstraZeneca, Merck Serono. Kazuo Kasahara: Grant from MSD. Miyako Satouchi: Honoraria from MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol‐Myers Squibb, AstraZeneca, Taiho Pharmaceutical, Pfizer, Novartis, Eli Lilly, Boehringer Ingelheim; grants from MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol‐Myers Squibb, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, AbbVie, Takeda, Eli Lilly. Shi Rong Han: Employee of MSD K.K. Kazuo Noguchi: Employee of MSD K.K. Takashi Shimamoto: Employee of MSD K.K. Terufumi Kato: Advisory role for MSD, AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical and Sumimoto Dainippon; honoraria from MSD, AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa Kirin, Novartis, Ono Pharmaceutical, Pfizer, Quintiles, Taiho Pharmaceutical, Roche and Merck Serono; grants from AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa Kirin, Novartis, Ono Pharmaceutical, Parexel, Quintiles, Taiho Pharmaceutical and Merck Serono.

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1
Figure 1
Treatment exposure, duration of response (as assessed per RECIST version 1.1 per central review), and overall survival time in individual patients. Bar lengths indicate time from start of first treatment to death or last follow‐up. ALK, anaplastic lymphoma kinase translocation; EGFRm, epidermal growth factor receptor mutant; PD, progressive disease; PD‐L1, programmed death ligand 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; TPS, tumor proportion score
Figure 2
Figure 2
Best response change from baseline in tumor size for each patient as assessed per RECIST version 1.1 per central review. ALK, anaplastic lymphoma kinase translocation; EGFRm, epidermal growth factor receptor mutant; PD‐L1, programmed death ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors; TPS, tumor proportion score
Figure 3
Figure 3
Longitudinal changes in the sum of the longest target lesion diameters for each patient as assessed per RECIST version 1.1 per central review. PD‐L1, programmed death ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors; TPS, tumor proportion score
Figure 4
Figure 4
Survival estimates in patients who received pembrolizumab. (A) Progression‐free survival per RECIST version 1.1 per central review. (B) Overall survival. NR, not reached; OS, overall survival; PD‐L1, programmed death ligand 1; PFS, progression‐free survival; RECIST, Response Evaluation Criteria in Solid Tumors, version 1.1; TPS, tumor proportion score

References

    1. Center for Cancer Control and Information Services, National Cancer Center . Cancer statistics in Japan – 2015. 2016. . Accessed 3 March 2018.
    1. Leighl NB. Treatment paradigms for patients with metastatic non‐small‐cell lung cancer: first‐, second‐, and third‐line. Curr Oncol. 2012;19:S52‐S58.
    1. Reck M. Pembrolizumab as first‐line therapy for metastatic non‐small‐cell lung cancer. Immunotherapy. 2018;10:93‐105.
    1. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD‐L1‐positive, advanced non–small‐cell lung cancer (KEYNOTE‐010): a randomised controlled trial. Lancet. 2016;387:1540‐1550.
    1. Reck M, Rodriguez‐Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD‐L1‐positive non–small‐cell lung cancer. N Engl J Med. 2016;375:1823‐1833.
    1. Gandhi L, Rodgríguez‐Abreu D, Gadgeel S, et al. KEYNOTE‐189: randomized, double‐blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first‐line therapy for metastatic NSCLC. American Association for Cancer Research Annual Meeting; 2018 April 14‐18; Chicago, IL, USA.
    1. Soo RA, Kawaguchi T, Loh M, et al. Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy. Future Oncol. 2012;8:451‐462.
    1. Nakanishi Y. Implementation of modern therapy approaches and research for non‐small cell lung cancer in Japan. Respirology. 2015;20:199‐208.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228‐247.
    1. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non–small‐cell lung cancer. N Engl J Med. 2015;372:2018‐2028.
    1. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18:e143‐e152.
    1. Roach C, Zhang N, Corigliano E, et al. Development of a companion diagnostic PD‐L1 immunohistochemistry assay for pembrolizumab therapy in non‐small‐cell lung cancer. Appl Immunohistochem Mol Morphol. 2016;24:392‐397.
    1. Yamazaki N, Takenouchi T, Fujimoto M, et al. Phase 1b study of pembrolizumab (MK‐3475; anti‐PD‐1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE‐041). Cancer Chemother Pharmacol. 2017;79:651‐660.
    1. Saka H, Sugawara S, Hida T, et al. Japan subset analysis of phase III study of pembrolizumab for PD‐L1 positive, pretreated non‐small cell lung cancer (KEYNOTE‐010). Japan Lung Cancer Society; 2016.
    1. Nishino M, Giobbie‐Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor‐related pneumonitis in patients with advanced cancer: a systematic review and meta‐analysis. JAMA Oncol. 2016;2:1607‐1616.
    1. Sekine I, Yamamoto N, Nishio K, Saijo N. Emerging ethnic differences in lung cancer therapy. Br J Cancer. 2008;99:1757‐1762.
    1. Delaunay M, Cadranel J, Lusque A, et al. Immune‐checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J. 2017;50 10.1183/13993003.00050-2017.
    1. Lee CK, Man J, Lord S, et al. Checkpoint inhibitors in metastatic EGFR‐mutated non‐small cell lung cancer–a meta‐analysis. J Thorac Oncol. 2017;12:403‐407.
    1. Chatterjee M, Turner DC, Felip E, et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non‐small‐cell lung cancer. Ann Oncol. 2016;27:1291‐1298.
    1. Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer. 2017;5:43.
    1. Patnaik A, Kang SP, Rasco D, et al. Phase I study of pembrolizumab (MK‐3475; anti‐PD‐1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21:4286‐4293.
    1. Elassaiss‐Schaap J, Rossenu S, Lindauer A, et al. Using model‐based “Learn and Confirm” to reveal the pharmacokinetics‐pharmacodynamics relationship of pembrolizumab in the KEYNOTE‐001 trial. CPT Pharmacometrics Syst Pharmacol. 2017;6:21‐28.

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