A phase II study of everolimus in patients with unresectable pancreatic neuroendocrine carcinoma refractory or intolerant to platinum-containing chemotherapy (2018)

Background: Pancreatic neuroendocrine carcinoma (NEC) is rare tumor. If the tumors cannot be resected surgically, systemic chemotherapy is performed. Platinum-containing regimens are widely used as first-line chemotherapy, but there is no established second-line chemotherapy. Everolimus showed longer progressionfree survival (PFS) compared with placebo in the phase III RADIANT-3 trial in patients with pancreatic neuroendocrine tumor. We evaluated the safety and efficacy of everolimus in patients with pancreatic neuroendocrine carcinoma refractory or intolerant to platinum-based chemotherapy. Methods: This study was prospective, multicenter phase II trial in patients with pancreatic NEC refractory or intolerant to platinum-contained chemotherapy. Everolimus treatment was initiated orally at a dose of 10mg once daily and continued until disease progression or intolerable toxicity were observed. Primary endpoint was PFS. Results: Twenty-five patients were enrolled from 12 institutions in Japan. The median age was 63 years, and 65% were male. All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Patients with Ki-67<55% were 61%. The median PFS was 34.5 days [95% confidence interval (CI) 27.0-92.0], and median overall survival was 224 days (95%CI 92.0-406.0). The overall response rate was 0% and disease control rate was 39.1%. Common grade 3/4 adverse events were hyperglycemia (20%), thrombocytopenia (16%), anemia (16%), and hyponatremia (12%). Rhabdomyolysis occurred in one patient. Conclusions: Everolimus monotherapy was tolerable, but the efficacy was limited in patients with unresectable pancreatic NEC patients. It may be necessary to consider multi-drug regimens to improve outcome. Legal entity responsible for the study: NECTOR trial group. Funding: The National Cancer Center Research and Development Fund. Disclosure: M. Ikeda: Reserch funding: Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Zeria Pharmaceutical, Baxter, Chugai Pharmaceutical, Bristol Myers Sqiibb, Merck Serono, Kowa, Nano Carrier, ASLAN Pharmaceuticals; Honoraria: Novartis Pharma, Bayer Yakuhin, Bristol-Myers Squibb, Abbott Japan, Eisai, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi-Sankyo, Yakult, Otsuka Pharmaceutical, Nobelpharma Membership on any entity’s Board of Directors or advisory committees: Nano Carrier, Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, Novartis Pharma, Shire, MSD. T. Okusaka: Honoraria: Novartis Pharma, Taiho Pharmaceutical, Eli Lilly Japan, Dainippon Sumitomo Pharma, Bayer Yakuhin, Yakult Honsha, Nobelpharma, FUJIFILM RI Pharma, AstraZeneca, Ono Pharmaceutical, EA Pharma, Nippon Chemiphar, Celgene, Chugai Pharmaceutical, Bristol-Myers, Eisai, Pfizer Japan, Teijin Pharma, Daiichi Sankyo Consulting or Advisory Role: Dainippon Sumitomo Pharma, Taiho Pharmaceutical, Zeria Pharmaceutical, Daiichi Sankyo Research Funding: Eli Lilly Japan, Eisai, Novartis Pharma, Yakult Honsha, Taiho Pharmaceutical, Nippon Boehringer Inge lheim, Kowa Company, Kyowa Hakko Kirin, Merck Serono, Ono Pharmaceutical, Bayer Yakuhin, Pfizer Japan, AstraZeneca, Dainippon Sumitomo Pharma, Nano Carrier, Baxter, Chugai Pharmaceutical. J. Furuse: Honoraria: Taiho, Chugai, Yakult, Sumitomo Dainippon, Eli Lilly Japan, Astellas, Ono, Pfizer, Bayer, Novartis, Merck Serono, Takeda, Eisai, MSD, Shionogi, J-Pharma, Daiichi Sankyo, Mochida, Nippon Kayaku, EA pharma, Sawai, Teijin pharma Consulting or Advisory Role: Taiho, Chugai, Yakult, Sumitomo Dainippon, Eli Lilly Japan, Astellas, Ono, Pfizer, Bayer, Novartis, Merck Serono, Takeda, Eisai, MSD, Shionogi, J-Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Sanofy, Sandoz, Otsuka, Fujifilm, Astra Zeneca, Shire Research Funding: J-Pharma, Taiho, Sumitomo Dainippon, Janssen, Daiichi Sankyo, MSD, Yakult, Takeda, Chugai, Ono, Astellas, Zeria, Novartis, Nanocarrier, Shionogi, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck Serono, Kyowa Hakko Kirin, Eisai, NanoCarrier, Mochida, Baxalta, Sanofi. M. Furukawa: Grant: Taiho Pharma. S. Ohkawa: Honoraria: FUJIFILM RI Pharma, Yakult Honsha, Otsuka Pharmaceutical, MSD. A. Hosokawa: Honoraria: Taiho Pharmaceutical, Chugai Pharma, Takeda, Ono Pharmaceutical, Novartis, Eisai Research Funding: Taiho Pharmaceutical, Chugai Pharma, Ono Pharmaceutical, Eisai, Yakult Honsha. Y. Kojima: Honoraria: Sanofi. K. Yamaguchi: Grants, Personal fees: Eli Lilly. H. Ishii: Honoraria: Yakult Honsha, Taiho Pharmaceutical, Eisai, Towa Consulting, Advisory Role: Ono Pharmaceutical Research Funding: Taiho Pharmaceutical. N. Mizuno: Research funding: Taiho Pharmaceutical Co. Ltd., Merck Serono, AstraZeneca, Zeria Pharmaceutical, NanoCarrier, Eisai, MSD, Novartis, Dainippon Sumitomo Pharma, ASLAN. Pharmaceuticals, Pharma Valley Center, and Incyte Inc. Honoraria: Taiho Pharmaceutical Co. Ltd., Novartis, Ono Pharmaceutical, and Teijin Pharma Advisory Role: Teijin Pharma. All other authors have declared no conflicts of interest.