Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non-small-cell lung cancer: KEYNOTE-189 Japan Study

Hidehito Horinouchi, Naoyuki Nogami, Hideo Saka, Makoto Nishio, Takaaki Tokito, Toshiaki Takahashi, Kazuo Kasahara, Yoshihiro Hattori, Eiki Ichihara, Noriaki Adachi, Kazuo Noguchi, Fabricio Souza, Takayasu Kurata, Hidehito Horinouchi, Naoyuki Nogami, Hideo Saka, Makoto Nishio, Takaaki Tokito, Toshiaki Takahashi, Kazuo Kasahara, Yoshihiro Hattori, Eiki Ichihara, Noriaki Adachi, Kazuo Noguchi, Fabricio Souza, Takayasu Kurata

Abstract

Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator's choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co-primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7-38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9-29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07-1.15). The median (95% CI) PFS was 16.5 (8.8-21.1) compared with 7.1 (4.7-21.4) months (HR, .62; 95% CI, .27-1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.

Keywords: Japan; PD-L1 protein; non-small-cell lung carcinoma; pembrolizumab; treatment outcome.

Conflict of interest statement

Hidehito Horinouchi: Lecture fees, honoraria, or other fees from Eli Lilly, AstraZeneca, Kyowa Kirin, MSD, Ono Pharmaceutical, and Bristol‐Myers Squibb; Research funds from Chugai Pharmaceutical, Daiichi Sankyo, AstraZeneca, MSD, Ono Pharmaceutical, Bristol‐Myers Squibb, and Genomic Health. Naoyuki Nogami: Honoraria from AstraZeneca, Chugai Pharmaceutical, Pfizer Japan Inc, Eli Lilly Japan KK, Ono Pharmaceutical, Taiho Pharmaceutical, MSD KK, Kyowa Kirin, Bristol‐Myers Squibb KK, and Nippon Boehringer Ingelheim. Hideo Saka: Nothing to disclose. Makoto Nishio: Honoraria for lectures and consulting from Ono Pharmaceutical, Bristol‐Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, and Novartis; Research support from MSD, Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol‐Myers Squibb, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer. Takaaki Tokito: Personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, and Boehringer Ingelheim. Toshiaki Takahashi: Grants and personal fees from AstraZeneca KK, Chugai Pharmaceutical, Eli Lilly Japan KK, Ono Pharmaceutical, and MSD KK; Grants from Pfizer Japan Inc; Personal fees from Boehringer Ingelheim Japan, Inc and Roche Diagnostics KK. Kazuo Kasahara: Grants from Boehringer Ingelheim. Yoshihiro Hattori: Lecture fees from Taiho Pharmaceutical; Grants from Ono Pharmaceutical and MSD. Eiki Ichihara: Honoraria from Boehringer Ingelheim; Research support from MSD. Noriaki Adachi: Employee of MSD KK. Kazuo Noguchi: Employee of MSD KK. Fabricio Souza: Employee of Merck & Co., Inc. Takayasu Kurata: Personal fees from AstraZeneca, MSD, Eli Lilly, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol‐Myers Squibb, Boehringer Ingelheim, and Pfizer; Grants from AstraZeneca, MSD, Chugai Pharmaceutical, Takeda, and Bristol‐Myers Squibb.

© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

FIGURE 1
FIGURE 1
Disposition of patients in the study. PD‐1, programmed death 1; PD‐L1, programmed death ligand 1. aIncludes patients with clinical progression or progressive disease. bIncludes patients who received subsequent antineoplastic therapy. It excludes 1 patient in the pembrolizumab combination arm who received radiation (see Table S1 for further details)
FIGURE 2
FIGURE 2
Kaplan‐Meier analysis of (A) OS and (B) PFS in the intent‐to‐treat population. HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression‐free survival
FIGURE 3
FIGURE 3
Treatment duration and time to response among patients in the pembrolizumab plus pemetrexed‐platinum group. Light green bars indicate the months of follow up. AE, adverse event; CR, complete response; PD, progressive disease; PR, partial response
FIGURE 4
FIGURE 4
Kaplan‐Meier analysis of progression‐free survival‐2 (PFS2) in the intent‐to‐treat population. PFS2 was defined as the time from randomization to objective tumor progression on next‐line treatment (including subsequent anti–PD‐[L]1 therapy) or death from any cause, whichever occurred first. HR, hazard ratio; NR, not reached; PD‐(L)1, programmed death 1 or programmed death ligand 1

References

    1. Global Burden of Disease Cancer Collaboration , Fitzmaurice C, Abate D, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability‐adjusted life‐years for 29 cancer groups, 1990 to 2017: a systematic analysis for the Global Burden of Disease study. JAMA Oncol. 2019;5:1749‐1768.
    1. Editorial Board of Cancer Statistics in Japan . Cancer Statistics in Japan ‐ 2017. 2018. . Accessed August 26, 2020.
    1. Zappa C, Mousa SA. Non‐small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5:288‐300.
    1. Akamatsu H, Ninomiya K, Kenmotsu H, et al. The Japanese Lung Cancer Society guideline for non‐small cell lung cancer, stage IV. Int J Clin Oncol. 2019;24:731‐770.
    1. Novello S, Barlesi F, Califano R, et al. Metastatic non‐small‐cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow‐up. Ann Oncol. 2016;27:v1‐v27.
    1. Peters S, Reck M, Smit EF, Mok T, Hellmann MD. How to make the best use of immunotherapy as first‐line treatment for advanced/metastatic non‐small‐cell lung cancer. Ann Oncol. 2019;30:884‐896.
    1. Hendriks L, Besse B. New windows open for immunotherapy in lung cancer. Nature. 2018;558:376‐377.
    1. Reck M. Pembrolizumab as first‐line therapy for metastatic non‐small‐cell lung cancer. Immunotherapy. 2018;10:93‐105.
    1. Silvinato A, Floriano I, Bernardo WM. Advanced non‐small cell lung cancer ‐ treatment with pembrolizumab. Rev Assoc Med Bras (1992). 2019;65:1423‐1432.
    1. Merck’s KEYTRUDA® (pembrolizumab) receives five new approvals in Japan, including in advanced non‐small cell lung cancer, as adjuvant therapy for melanoma, and in advanced microsatellite instability‐high tumors. 2019. . Accessed August 27, 2020.
    1. Agency PaMD . Report on the Deliberation Results. 2018. . Accessed September 15, 2020.
    1. Paz‐Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non‐small‐cell lung cancer. N Engl J Med. 2018;379:2040‐2051.
    1. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non‐squamous non‐small‐cell lung cancer: a randomised, phase 2 cohort of the open‐label KEYNOTE‐021 study. Lancet Oncol. 2016;17:1497‐1508.
    1. Gandhi L, Rodriguez‐Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non‐small‐cell lung cancer. N Engl J Med. 2018;378:2078‐2092.
    1. Gadgeel S, Rodriguez‐Abreu D, Speranza G, et al. Updated analysis from KEYNOTE‐189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non‐small‐cell lung cancer. J Clin Oncol. 2020;38:1505‐1517.
    1. Peng L, Wu YL. Immunotherapy in the Asiatic population: any differences from Caucasian population? J Thorac Dis. 2018;10:S1482‐S1493.
    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. Soo RA, Loh M, Mok TS, et al. Ethnic differences in survival outcome in patients with advanced stage non‐small cell lung cancer: results of a meta‐analysis of randomized controlled trials. J Thorac Oncol. 2011;6:1030‐1038.
    1. European Medicines Agency . Guideline on the evaluation of anticancer medicinal products in man. 2017. . Accessed August 26, 2020.
    1. Rodriguez Abreu D, Powell SF, Hochmair MJ, et al. Protocol‐specified final analysis of KEYNOTE‐189: Pemetrexed‐platinum chemotherapy with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC.American Society of Clincal Oncology (ASCO); 2020 May 29‐31; Virtual Scientific Program.
    1. Kurata T, Nakagawa K, Satouchi M, et al. Primary results from Japanese phase I study of pembrolizumab plus chemotherapy as front‐line therapy for advanced NSCLC. Ann Oncol. 2019;30:vi114.
    1. Okamoto I, Kato T, Imamura F, et al. Pembrolizumab plus chemotherapy in 1st line metastatic squamous NSCLC: KEYNOTE‐407 Japanese subgroup. Japan Lung Cancer Society; 2019 December 6‐8; Osaka, Japan.
    1. Wu YL, Planchard D, Lu S, et al. Pan‐Asian adapted clinical practice guidelines for the management of patients with metastatic non‐small‐cell lung cancer: a CSCO‐ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS. Ann Oncol. 2019;30:171‐210.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться