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A multicenter phase II study of mFOLFOX6 in advanced gastric cancer patients with severe peritoneal metastases: WJOG10517G
Background
Advanced gastric cancer (AGC) patients with severe peritoneal metastases, defined as massive ascites and/or inadequate oral intake, have been excluded from pivotal clinical trials due to poor prognosis and tumor-related complications. JCOG1108/WJOG7312G comparing 5-fluorouracil/l-leucovorin with 5-fluorouracil/l-leucovorin plus paclitaxel for AGC patients with severe peritoneal metastases showed median overall survival (OS) of around 6–7 months, remaining extremely poor (Nakajima TE, et al. Gastric Cancer. 2020;23:677-688). Retrospective studies of mFOLFOX6 showed median OS of 8.8–13.2 months and efficacy in improving ascites and oral intake because of severe peritoneal metastases of AGC.
Methods
This multicenter, open-label, single-arm phase II study of mFOLFOX6 enrolled HER2-negative or untested AGC patients with severe peritoneal metastases (massive ascites throughout the abdominal cavity and/or inadequate oral intake requiring daily intravenous infusion), those between 20 and 75 years old, ECOG performance status (PS) of 0–2, no prior chemotherapy, and preserved organ function. The primary endpoint was OS, and secondary endpoints were response rate, progression-free survival (PFS), ascites response rate defined as ascites disappearance or decrease in at least one ascites level (classified; massive as throughout the abdominal cavity, moderate as not either mild or massive, mild as limited in the upper or lower abdominal cavity, and no ascites), oral intake improvement (defined as no intravenous infusion for >7days) rate, and safety. This study included safety lead-in part for safety evaluation in the first cycle (two weeks) of mFOLFOX6 for the initial six patients. The sample size was 50, including 6 patients enrolled in safety lead-in part, expecting a median OS of 9 months with a threshold of 6 months (one-sided α, 0.05; β, 0.2).
Results
Between October 2018 and April 2020, we enrolled 51 patients with a median age of 65 (range, 26–74) years; ECOG PS (0/1/2) of 3/40/8; histological type (diffuse/intestinal/unknown) of 38/12/1; and severe peritoneal metastases factors (massive ascites/inadequate oral intake/both) of 18/26/7. In safety lead-in part, no dose-limiting toxicity was observed. With a median follow-up of 18.1 months as of April 15, 2021, median OS was and median PFS was 7.4 months (lower limit of one-sided 95% confidence interval, 6.5) and 3.8 months, respectively. Among 17 patients with measurable lesions, the response rate was 41%. Among 25 patients with massive ascites, the ascites response rate was 36%. Among 33 patients with inadequate oral intake, the oral intake improvement rate was 46% with median time to improvement from mFOLFOX6 initiation of 17 days (range, 4–416), and median duration of adequate oral intake of 174 days (range, 14–330). Common grade 3–4 adverse events were neutropenia (51%), anemia (24%), nausea (16%), and anorexia (16%). Febrile neutropenia was observed in one patient. No treatment-related deaths occurred. The most common reason for treatment discontinuation was disease progression (84%). Second- and third-line chemotherapy was administered in 73% and 35% of patients, respectively.
Conclusions
mFOLFOX6 can be one of the treatment options for AGC patients with severe peritoneal metastases. However, further development is needed in this setting because their prognosis remains poor.
Clinical trial identification
jRCTs041180007.
Editorial acknowledgement
The authors wish to thank Dr. Narikazu Boku, Dr. Kentaro Yamazaki, Dr. Shuichi Hironaka, and Dr. Toshikazu Moriwaki for reviewing this abstract. The authors wish to thank the member of the West Japan Oncology Group Data Center and Support Office for managing this study.
Legal entity responsible for the study
WJOG (West Japan Oncology Group).
Funding
Yakult Honsha.
Disclosures
H. Hara: Honoraria (self): Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Sanofi, Taiho, Takeda and Yakult; Advisory / Consultancy: Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Lilly, MSD and Ono; Research grant / Funding (institution): Amgen, Astellas, AstraZeneca, Bayel, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Elevar Therapeutics, GSK, Incyte, Merck Biopharma, MSD, Ono, Pfizer, and Taiho. T. Masuishi: Honoraria (self): Taiho, Lilly, Chugai, Yakult Honsha. T. Kawakami: Honoraria (self): Taiho Pharmaceutical, Ono pharmaceutical, Bristol-Myers Squibb, Bayer. Y. Yamamoto: Honoraria (self): Yakult; Speaker Bureau / Expert testimony: Yakult. T. Esaki: Honoraria (self): Chugai, Taiho, MSD; Research grant / Funding (institution): Astellas Amgen Biopharma, Ono, MSD. M. Nakamura: Honoraria (self): Bayer Yakuhin, Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd.. H. Kawakami: Honoraria (self): Taiho Pharmaceutical Co. Ltd, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Daiichi-Sankyo Co. Ltd.; Advisory / Consultancy: Daiichi-Sankyo Co. Ltd.; Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd, Bristol-Myers Squibb Co. Ltd, Eisai Co. Ltd., Kobayashi Pharmaceutical. Co., Ltd.. T. Nakajima: Honoraria (self): Taiho Pharm; Research grant / Funding (self): Chugai Pharm, Taiho Pharm. K. Muro: Honoraria (self): Eli Lilly, Chugai, Takeda, Ono, Taiho, Sanofi, Bristol-Myers Squibb, and Bayer ; Advisory / Consultancy: Amgen, AstraZeneca, Ono, and Chugai; Research grant / Funding (institution): Astellas, Amgen, Solasia Pharma, Sanofi, Daiichi Sankyo, Parexel International, Taiho, MSD, Merck Biopharma, Pfizer, Eisai, Novartis, and Ono . All other authors have declared no conflicts of interest.
