Pembrolizumab plus chemotherapy-induced pneumonitis in chemo-naïve patients with non-squamous non-small cell lung cancer: A multicentre, retrospective cohort study.

Introduction: Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings.
Methods: We conducted a 36-centre, retrospective cohort study in patients with chemo-naïve advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019.
Results: The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9-16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6-6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4-10.5) and 9 patients (3.0%, 95% CI 1.4-5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0-6.8) and 7.5 (95% CI 6.5-8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07-3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12-8.20, P = 0.03).
Conclusions: Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy.
Trial Registration Number: UMIN000038084.
Competing Interests: Conflict of interest statement Daichi Fujimoto reports personal fees from AstraZeneca K.K.; Ono Pharmaceutical Co., Ltd.; Bristol Myers Squibb Co., Ltd.; Taiho Pharmaceutical Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; MSD K.K.; Boehringer Ingelheim Japan Inc.; Eli Lilly Japan K.K.; and Novartis Pharma K.K., outside the submitted work. Satoru Miura reports personal fees from Boehringer Ingelheim, MSD K.K., Elli Lilly Japan, Ono Pharma, and Chugai Pharmaceutical Co., Ltd., outside the submitted work. Kenichi Yoshimura reports personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ltd., Eizai, Otsuka, Nihon Kayaku, Elli Lilly, Taiho, Novartis, Boehringer Ingelheim, BrightPath Biotherapeutics, and Nihon Shinyaku, outside the submitted work. Kazushige Wakuda reports grants and personal fees from Chugai Pharmaceutical Co., Ltd.; personal fees from Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly K.K., Ono Pharmaceutical, and MSD K.K.; and grants from Novartis and AbbVie, outside the submitted work. Toshihide Yokoyama reports personal fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., and Taiho Pharmaceutical Co., Ltd., outside the submitted work. Takashi Yokoi reports personal fees from MSD K.K. and Eli Lilly Japan K.K. during the conduct of the study and personal fees from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Bristol Myers Squibb, Nippon Boehringer Ingelheim Co., Ltd., and GlaxoSmithKline K.K., outside the submitted work. Tetsuhiko Asao reports personal fees from MSD K.K., Taiho Pharmaceuticals, Chugai Pharmaceutical Co., Ltd., Eli-Lily, and AstraZeneca, outside the submitted work. Motohiro Tamiya reports personal fees from MSD K.K., Chugai Pharmaceutical Co., Ltd., AstraZeneca, Boehringer Ingelheim, Taiho Pharmaceutical, Eli Lilly, and Asahi Kasei Pharmaceutical, as well as grants and personal fees from Ono Pharmaceutical and Bristol Myers Squibb, outside the submitted work. Atsushi Nakamura reports personal fees from MSD K.K., Kyowa Kirin, AstraZeneca, and Boehringer Ingelheim Japan, outside the submitted work. Hiroshige Yoshioka reports personal fees from MSD K.K. during the conduct of the study and personal fees from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Delta Fly Pharma, Otsuka Pharmaceutical Co., Ltd., and Novartis, outside the submitted work. Koji Haratani reports personal fees from AS ONE Corporation, Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., and Pfizer Japan Inc., as well as grants and personal fees from AstraZeneca K.K. and MSD K.K., outside the submitted work. Shunsuke Teraoka reports personal fees from Chugai Pharmaceutical Co., Ltd., AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical Co., Ltd., Novartis, and Boehringer Ingelheim, outside the submitted work. Takaaki Tokito reports personal fees from MSD during the conduct of the study as well as personal fees from Chugai Pharmaceutical Co., Ltd., AstraZeneca, MSD, and Boehringer Ingelheim, outside the submitted work. Shuji Murakami reports grants from Takeda Pharmaceutical and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim, Taiho Pharmaceutical, and Ono Pharmaceutical, outside the submitted work. Akihiro Tamiya reports personal fees from Chugai Pharmaceutical Co., Ltd., Eli Lilly, Boehringer Ingelheim, MSD K.K., Taiho, Pfizer, and Kissei and grants and personal fees from AstraZeneca, Ono Pharmaceutical, and Bristol Myers Squibb, outside the submitted work. Hiroshi Yokouchi reports personal fees from Eli Lilly and Company and AstraZeneca, and grants from AbbVie, Kissei Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical, outside the submitted work. Satoshi Watanabe reports personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical, Bristol Myers, Boehringer Ingelheim, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis, Daiichi Sankyo, and Nippon Kayaku, outside the submitted work. Ou Yamaguchi reports personal fees from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, Taiho Pharmaceutical, MSD, Chugai Pharmaceutical Co., Ltd., AstraZeneca, and Eli Lilly Japan, outside the submitted work. Keisuke Tomii reports personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Kyowa Hakko Kirin, MSD, Novartis, Shionogi, and Taiho, outside the submitted work. Nobuyuki Yamamoto reports grants and personal fees from MSD K.K., AstraZeneca, Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, and Novartis, Pfizer Inc.; personal fees from Thermo Fisher Scientific, Bristol Myers Squibb, Life Technologies Japan Ltd., Nippon Kayaku, and Merk Biopharma; and grants from Astellas Pharma Inc., Tsumura & Co., Shionogi Co., Ltd., AbbVie GK., Amgen Inc., KYORIN Pharmaceutical Co., Ltd., Eisai Co., Ltd., Terumo Corporation, Toppan Printing Co., Ltd., and Tosoh, outside the submitted work. The remaining authors declare no conflicts of interest.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)