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. 2019 Sep;8(11):5183-5193.
doi: 10.1002/cam4.2411. Epub 2019 Jul 29.

Three-year follow-up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non-small cell lung cancer: Pooled analysis of ONO-4538-05 and ONO-4538-06 studies

Hidehito Horinouchi  1 , Makoto Nishio  2 , Toyoaki Hida  3 , Kazuhiko Nakagawa  4 , Hiroshi Sakai  5 , Naoyuki Nogami  6 , Shinji Atagi  7 , Toshiaki Takahashi  8 , Hideo Saka  9 , Mitsuhiro Takenoyama  10 , Nobuyuki Katakami  11 , Hiroshi Tanaka  12 , Koji Takeda  13 , Miyako Satouchi  14 , Hiroshi Isobe  15 , Makoto Maemondo  16   17 , Koichi Goto  18 , Tomonori Hirashima  19 , Koichi Minato  20 , Naoki Sumiyoshi  21 , Tomohide Tamura  22
Affiliations

Three-year follow-up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non-small cell lung cancer: Pooled analysis of ONO-4538-05 and ONO-4538-06 studies

Hidehito Horinouchi et al. Cancer Med. 2019 Sep.

Abstract

Background: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials.

Methods: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed.

Results: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found.

Conclusion: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC.

Trial registration: JapicCTI-132072; JapicCTI-132073.

Keywords: nivolumab; non-small cell lung cancer (NSCLC); phase II study; programmed cell death 1 ligand 1 (PD-L1); programmed cell death 1 receptor (PD-1).

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Conflict of interest statement

Hidehito Horinouchi received a grant from the study sponsor, related to the current research; and grants from Astellas, Merck Serono, and Genomic Health; personal fees from Lilly, and grants and personal fees from BMS, Novartis, Taiho, Chugai, AstraZeneca, and MSD, outside the submitted work. Makoto Nishio received a grant and personal fees from the study sponsor, related to the current research; and grants from F Hoffmann‐La Roche and Astellas; personal fees from Boehringer‐Ingelheim, Sankyo Healthcare, Taiho Pharmaceutical, and Merck Serono; and grants and personal fees from Bristol‐Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, MSD, and Novartis, outside the submitted work. Toyoaki Hida received a grant and personal fees from the study sponsor, related to the current research; and grants from Merck Serono, Eisai, Takeda Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma, AbbVie, Kyowa Hakko Kirin, Daiichi Sankyo, Astellas, and Servier; and grants and personal fees from Ono Pharmaceutical Co., Ltd., Bristol‐Myers Squibb, Chugai Pharmaceutical Co., Ltd., AstraZeneca, Nippon Boehringer Ingelheim, Novartis, Eli Lilly, Taiho Pharmaceutical Co., Ltd., Pfizer, Clovis Oncology, MSD, Kissei, and Ignyta, outside the submitted work. Kazuhiko Nakagawa received a grant from Merck Serono Co., Ltd. and grants and personal fees from the study sponsor, Bristol‐Myers Squibb Company, MSD KK, Chugai Pharmaceutical Co., Ltd. and AstraZeneca, related to the current research; and grants from A2 Healthcare Corp, inVentiv Health Japan, Daiichi Sankyo Co., Ltd., AbbVie Inc, Quintiles Inc, ICON Japan KK, Takeda Pharmaceutical Co., Ltd., EP‐CRSU Co., Ltd., Gritstone Oncology, Inc, Linical Co., Ltd., Eisai Co., Ltd., Parexel International Corp., EPS International Co., Ltd., Yakult Honsha Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AC Medical Inc, Japan Clinical Research Operations, PPD‐SNBL KK, and Covance Inc; personal fees from Clinical Trial Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., SymBio Pharmaceuticals Ltd., Pfizer Japan Inc, EPS Holdings Inc, Showa Yakuhin Kako Co., Ltd., Ayumi Pharmaceutical Corporation and Kissei Pharmaceutical Co., Ltd.; and grants and personal fees from Astellas Pharma Inc, Novartis Pharma KK, Eli Lilly Japan KK, Taiho Pharmaceutical Co., Ltd., and Kyowa Hakko Kirin, outside the submitted work. Hiroshi Sakai received personal fees from the study sponsor, related to the current research; and personal fees from Chugai Pharma, AstraZeneca, and Bristol‐Myers Squibb, outside the submitted work. Naoyuki Nogami received a grant and personal fees from the study sponsor, related to the current research; and personal fees from Pfizer Inc, Kyowa Hakko Kirin, Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan, Boehringer Ingelheim, MSD, AstraZeneca, and Bristol‐Myers Squibb, outside the submitted work. Shinji Atagi received a grant and personal fees from the study sponsor, related to the current research; and personal fees from Hisamitsu and grants and personal fees from MSD, Chugai, AstraZeneca, Taiho, Boehringer Ingelheim, Pfizer, and Bristol‐Myers Squibb, outside the submitted work. Toshiaki Takahashi received a grant and personal fees from the study sponsor, related to the current research; and a grant from Pfizer Japan Inc.; personal fees from Boehringer Ingelheim Japan Inc, and Roche Diagnostics KK; and grants and personal fees from MSD KK, AstraZeneca KK, Chugai Pharmaceutical Co., Ltd., and Eli Lilly Japan KK, outside the submitted work. Hideo Saka received a grant from the study sponsor, related to the current research; and grants from AstraZeneca KK, MSD KK, Bristol‐Myers Squibb KK, Chugai Pharmaceutical Co., Ltd., and Eli Lilly Japan KK, outside the submitted work. Mitsuhiro Takenoyama received a grant from the study sponsor, related to the current research; and grants from Johnson & Johnson, Kaketsuken, Novartis Pharma KK, and Yakult Honsha Co., Ltd., personal fees from MSD KK; and grants and personal fees from AstraZeneca KK, Bristol‐Myers Squibb KK, Chugai Pharmaceutical Co., Ltd., Covidien Japan KK, Eli Lilly Japan, KK, Kyowa Hakko Kirin Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., outside the submitted work. Nobuyuki Katakami received a grant from the study sponsor, related to the current research; and personal fees from Amgen, Boehringer Ingelheim Pharma, Chugai Pharma, Eli Lilly Pharma, Novartis Pharma KK, Ono Pharma, Pfizer, Taiho Pharma, MSD, and Daiichi Sankyo, outside the submitted work. Hiroshi Tanaka received a grant and personal fees from the study sponsor, related to the current research; and a grant from Merck Serono; personal fees from Novartis; and grants and personal fees from Bristol‐Myers Squibb, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Chugai Pharmaceutical, AstraZeneca, and Boehringer Ingelheim, outside the submitted work. Koji Takeda received a grant from the study sponsor, related to the current research; and grants from Merck Serono and MSD; personal fees from Daiichi Sankyo Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and Novartis; and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eli Lilly, Ono Pharmaceutical Co., Ltd., Pfizer, and Taiho Pharmaceutical Co., Ltd., outside the submitted work. Miyako Satouchi received a grant and personal fees from the study sponsor, related to the current research; and grants from Ignyta, AbbVie, and Takeda; personal fees from Taiho Pharmaceutical; and grants and personal fees from Bristol‐Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Pfizer Japan, AstraZeneca, MSD, Boehringer Ingelheim, and Novartis Pharmaceutical, outside the submitted work. Hiroshi Isobe received personal fees from AstraZeneca KK, Bristol‐Myers Squibb Co., Ono Pharmaceutical Co., and Taiho Pharmaceutical Co., outside the submitted work. Makoto Maemondo received personal fees from Ono Pharma, MSD, and AstraZeneca; and a grant and personal fees from Chugai, outside the submitted work. Koichi Goto received grants and personal fees from the study sponsor and Bristol‐Myers Squibb, related to the current research; and grants from Ignyta, OxOnc, Sumitomo Dainippon Pharma, Astellas Pharm, Amgen Astellas BioPharma, Eisai, Kyowa Hakko Kirin, Janssen Pharmaceutical, and RTI Health Solutions; personal fees from F Hoffmann‐La Roche, Otsuka Pharmaceutical, SRL, and Nippon Kayaku; and grants and personal fees from Eli Lilly, AbbVie Stemcentrx, Life Technologies Japan, Riken Genesis, AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, MSD, Merck Serono, Novartis Pharma, Pfizer, Taiho, and Takeda Pharmaceutical, outside the submitted work. Tomonori Hirashima received a grant from the study sponsor, related to the current research; and grants from Chugai, Taiho, MSD, AstraZeneca, Lilly Japan, Merck Serono, Bristol‐Myers Squibb, and Boehringer Ingelheim, outside the submitted work. Koichi Minato received a grant from the study sponsor, related to the current research; and grants from AstraZeneca and Bristol‐Myers Squibb, outside the submitted work. Naoki Sumiyoshi is an employee of the study sponsor. Tomohide Tamura received personal fees from Eli Lilly, Ono, Chugai, Taiho, Boehringer Ingelheim, Bristol‐Myers Squibb, MSD, Kyowa Kirin, and ShiftZero, outside the submitted work.

Figures

Figure 1
Figure 1
Kaplan–Meier curves of overall survival in patients with squamous (A) and non‐squamous (B) NSCLC at 3‐y follow‐up. NSCLC, non‐small cell lung cancer
Figure 2
Figure 2
Duration of response among 3‐y survivors in non‐squamous and squamous NSCLC patients. NSCLC, non‐small cell lung cancer; OS, overall survival; PD, progressive disease; SQ, squamous
Figure 3
Figure 3
Kaplan–Meier curves of progression‐free survival in patients with squamous (A) and non‐squamous (B) NSCLC at 3‐y follow‐up. NSCLC, non‐small cell lung cancer
Figure 4
Figure 4
Reported time to onset of first treatment‐related selected AEs in pooled squamous and non‐squamous NSCLC patients. †Patients with one or more selected AEs in a given category were counted only once in the time interval corresponding to the first event; patients with multiple events from different categories within the same time interval were counted once in each category. AE, adverse event; GI, gastrointestinal; NSCLC, non‐small cell lung cancer
Figure 5
Figure 5
Association between treatment‐related selected AE incidence and (A) overall survival and (B) progression‐free survival in pooled squamous and non‐squamous NSCLC patients. AE, adverse event; NSCLC, non‐small cell lung cancer; HR, hazard ratio; CI, confidence interval
See this image and copyright information in PMC

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