S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial

Yoon Koo Kang, Keisho Chin, Hyun Cheol Chung, Shigenori Kadowaki, Sang Cheul Oh, Norisuke Nakayama, Keun Wook Lee, Hiroki Hara, Ik Joo Chung, Masahiro Tsuda, Se Hoon Park, Hisashi Hosaka, Shuichi Hironaka, Yoshinori Miyata, Min Hee Ryu, Hideo Baba, Ichinosuke Hyodo, Yung Jue Bang, Narikazu Boku

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22 Citations (Scopus)

Abstract

Background: S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. Methods: We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40–60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40–60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. Findings: Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0–32·8), median overall survival was 16·0 months (95% CI 13·8–18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6–16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69–0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). Interpretation: TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. Funding: Taiho Pharmaceutical and Yakult Honsha.

Original languageEnglish
Pages (from-to)1045-1056
Number of pages12
JournalThe Lancet Oncology
Volume21
Issue number8
DOIs
Publication statusPublished - 2020 Aug

Bibliographical note

Funding Information:
This study was sponsored by Taiho Pharmaceutical and Yakult Honsha. We thank all the patients, their families, and the investigators who participated in this study, our medical adviser Yuh Sakata (Misawa City Hospital, Misawa, Japan), and the independent data and safety monitoring committee composed of Yoshiharu Motoo (Kanazawa Medical University, Kahoku, Japan), Ken Shimada (Showa University Koto Toyosu Hospital, Tokyo, Japan), and Satoshi Morita (Kyoto University, Kyoto, Japan). We also thank Takanori Tanase (Taiho Pharmaceutical, Tokyo, Japan) for statistical analysis, and Atsuki Shinozaki and Taizo Hasegawa (Taiho Pharmaceutical, Tokyo, Japan) for the support in completing this study. We would like to thank Editage for English language editing funded by Taiho Pharmaceutical.

Funding Information:
This study was sponsored by Taiho Pharmaceutical and Yakult Honsha. We thank all the patients, their families, and the investigators who participated in this study, our medical adviser Yuh Sakata (Misawa City Hospital, Misawa, Japan), and the independent data and safety monitoring committee composed of Yoshiharu Motoo (Kanazawa Medical University, Kahoku, Japan), Ken Shimada (Showa University Koto Toyosu Hospital, Tokyo, Japan), and Satoshi Morita (Kyoto University, Kyoto, Japan). We also thank Takanori Tanase (Taiho Pharmaceutical, Tokyo, Japan) for statistical analysis, and Atsuki Shinozaki and Taizo Hasegawa (Taiho Pharmaceutical, Tokyo, Japan) for the support in completing this study. We would like to thank Editage for English language editing funded by Taiho Pharmaceutical.

Publisher Copyright:
© 2020 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Oncology

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