Predictive Correlates of Response to Nivolumab in Japanese Patients with Esophageal Cancer

Background: Identification of biomarkers for immunotherapy can help in predicting response to treatment in cancer patients. This longterm follow-up of an open-label, single-arm, multicenter, phase 2 study of nivolumab in Japanese patients with treatment-refractory advanced esophageal cancer investigated the long-term efficacy of nivolumab, and the association between nivolumab activity and programmed death-L1 (PDL1), CD8 tumor-infiltrating lymphocytes (TILs), and human leukocyte antigen (HLA) class 1 status. This was the first clinical study for esophageal cancer in which patients were followed up for more than two years. Methods: Patients received nivolumab 3 mg/kg, intravenously every 2 weeks in 6 weekly cycles until disease progression or unacceptable toxicity. Tumor biopsies were collected during screening and at day 28, and analyzed for PD-L1, CD8 and HLA class 1. Efficacy endpoints included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to response and duration of response. Findings: Between Feb 25 and Nov 14, 2014, 65 patients (83% male) were enrolled. At 2 years, nivolumab had an ORR of 17·2%, PFS of 1·51 months and OS of 10·78 months. The time to response and duration of response were 1·45 months and 11·17 months. 41 patients had tissue samples available for biomarker analysis. Tumor PD-L1 positive patients tended to have a numerically longer PFS (2·04 vs 1·41 months, cut-off 1%) and OS (11·33 vs 6·24 months, cut-off 1%), compared with negative patients. Median OS was prolonged in patients with a median number of TILs >63·75% versus ≤63·75% (11·33 vs 7·85 months). Interpretation: Nivolumab had continued long-term efficacy, as shown by the stability of PFS and OS, in the treatment of esophageal squamous cell carcinoma in Japanese patients, in whom PD-L1 tumor expression and TILs may help in identifying patients likely to benefit from nivolumab therapy. Clinical Trial Number: This study is registered with clinicaltrials.jp, number ONO-4538-07 (ATTRACTION-1)/JapicCTI-No.142422. Funding Statement: This study was funded by Ono Pharmaceuticals and Bristol–Myers Squibb. Declaration of Interests: KK reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from MSD and BeiGene, grants from Shionogi, nonfinancial support from Eli Lilly, personal fees from Taiho Pharmaceutical, outside the submitted work. YD reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants from CSL Behring, EA Pharma, Astellas Pharma Eisai, Kaken Pharmaceutical, Tsumura, Yakult Honsha, Kyowa Hakko Kirin, Shionogi, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, Nestle Japan, grants and personal fees from Pfizer, outside the submitted work. TU reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from Chugai Pharmaceutical and Ono Pharmaceutical, personal fees from Merck Serono, Taiho Phamaceutical, Bayer Yakuhin and Takeda Pharmaceutical, grants from Yakult Honsha, Ayumi Pharmaceutical, Showa Yakuhin Kako, Shionogi, Terumo and Nippon Zoki Pharmaceutical, outside the submitted work. YH reports research support from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study. TK reports grants support from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants from MSD, Shionogi, Oncolys BioPharma and Astellas Amgen BioPharama, outside the submitted work. TT reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study. SH reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Yakult Honsha, Daiichi Sankyo and Chugai Pharmaceutical, outside the submitted work. HH reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants from AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Merck Serono, MSD, Taiho, Chugai Pharmaceutical, Eisai, LSK BioPharma, Incyte, Pfizer, Boehringer-ingelheim and BeiGene, outside the submitted work. TK reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants from Ono Pharmaceutical, outside the submitted work. SI reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants from Ono Pharmaceutical, Bristol-Myers Squibb, Eisai, Bayer Yakuhin, Otsuka Pharmaceutical, Novartis Pharma and Merck Serono, grants and personal fees from Chugai Pharmaceutical, Eli Lilly, and Taiho Phamaceutical, outside the submitted work. KM reports grants from Ono Pharmaceutical and Bristol-Myers Squibb, during the conduct of the study; grants from Geliad Sciences, Merck Serono, MSD, Daiichi Sankyo, S ...