Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer Toyoaki Hida,1 Makoto Nishio,2 Naoyuki Nogami,3 Yuichiro Ohe,4 Hiroshi Nokihara,4 Hiroshi Sakai,5 Miyako Satouchi,6 Kazuhiko Nakagawa,7 Mitsuhiro Takenoyama,8 Hiroshi Isobe,9 Shiro Fujita,10 Hiroshi Tanaka,11 Koichi Minato,12 Toshiaki Takahashi,13 Makoto Maemondo,14 Koji Takeda,15 Hideo Saka,16 Koichi Goto,17 Shinji Atagi,18 Tomonori Hirashima,19 Naoki Sumiyoshi20 and Tomohide Tamura21 1 Aichi Cancer Center Hospital, Aichi; 2The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo; 3National Hospital Organization Shikoku Cancer Center, Ehime; 4National Cancer Center Hospital, Tokyo; 5Saitama Cancer Center, Saitama; 6Hyogo Cancer Center, Hyogo; 7Kindai University Faculty of Medicine, Osaka; 8National Hospital Organization Kyushu Cancer Center, Fukuoka; 9KKR Sapporo Medical Center, Sapporo; 10Institute of Biomedical Research and Innovation Hospital, Hyogo; 11Niigata Cancer Center Hospital, Niigata; 12Gunma Prefectural Cancer Center, Gunma; 13Shizuoka Cancer Center, Shizuoka; 14Miyagi Cancer Center, Miyagi; 15Osaka City General Hospital, Osaka; 16National Hospital Organization Nagoya Medical Center, Aichi; 17National Cancer Center Hospital East, Chiba; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka; 19Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka; 20Ono Pharmaceutical Co., Ltd, Osaka; 21St. Luke’s International Hospital, Tokyo, Japan
Key words Japanese, Nivolumab, non-small cell lung cancer, programmed cell death-1, squamous cell carcinoma Correspondence Toyoaki Hida, Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Tel: +81-52-762-6111; Fax: +81-52-764-2967; E-mail:
[email protected] Funding Information This medical writing assistance was funded by Ono Pharmaceutical Co., Ltd, Osaka, Japan Received January 11, 2017; Revised February 20, 2017; Accepted February 28, 2017 Cancer Sci 108 (2017) 1000–1006 doi: 10.1111/cas.13225
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Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progressionfree survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4–25.4), 2.7 (range 1.2–5.5) and 4.2 (95% CI 1.4–7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. Clinical trial registration number: JapicCTI-132072
ung cancer is one of the leading causes of cancer-related death worldwide.(1) Non-small cell lung cancer (NSCLC) accounts for up to 85% of lung cancers(2) and is classified based on histology as either squamous or non-squamous cell carcinoma.(3) Squamous NSCLC accounts for approximately 30% of NSCLC cases.(4) Guidelines recommend using combination therapy for the first-line treatment of patients with stage IIIB/IV squamous NSCLC unsuited to radical radiotherapy,(5,6) consisting of a platinum agent plus a third-generation agent such as carboplatin/paclitaxel or cisplatin/ gemcitabine. As for second-line therapy, docetaxel has been a standard treatment in patients with squamous NSCLC for more than a decade, with a median progression-free survival (PFS) of 2.7 months and median overall survival of 7.4 months.(7)
It has been shown that combination chemotherapy as second-line treatment in NSCLC improves the overall response rate (ORR) and PFS compared with single-agent chemotherapy. However, combination chemotherapies have failed to improve overall survival (OS) in these patients and have been associated with more adverse events (AE) than single-agent therapy.(8) Therefore, there is an unmet need for newer agents with better efficacy and safety. Programmed cell death-1 (PD-1) is a receptor present on cytotoxic T cells which binds to its natural ligands PD ligand1 (PD-L1) and PD ligand-2 (PD-L2) and is activated in response to inflammation or infection.(9,10) Binding of PD-L1 to its receptor causes deactivation of T cells leading to immunosuppression. Expression of PD-L1 in NSCLC generates an immunosuppressive tumor microenvironment and promotes
Cancer Sci | April 2017 | vol. 108 | no. 5 | 1000–1006
© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attrib ution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Original Article Hida et al.
www.wileyonlinelibrary.com/journal/cas Table 1. Demographic and baseline included in the present study
characteristics
Characteristic Age, years Median Range 12 doses. The median duration of therapy was 3.6 months (range 0.5–29.3) and the median overall survival was 16.3 months (range 1.7–29.3). After discontinuation of treatment, 68.6% of the patients received subsequent systemic cancer therapy. 48.6% of the patients received subsequent docetaxel (Table S1). Efficacy. Nine patients had IRC-assessed response to treatment, resulting in an ORR of 25.7% (95% CI 14.2, 42.1) and seven patients had study site-assessed response to treatment with an ORR of 20.0% (95% CI 10.0, 35.9; Table 2). IRCassessed BOR was PR for nine patients (25.7%), SD for 10 Cancer Sci | April 2017 | vol. 108 | no. 5 | 1003
Table 4. Subset analysis for independent radiology review committee-assessed overall response rate by baseline characteristics of patients Baseline characteristics
No. responders (n/N)
Age, years
