Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer
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Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.
Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.
Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively).
Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.
KeywordsGemcitabine Objective Response Rate KRAS Mutation Disease Control Rate Advanced Pancreatic Cancer
The authors would like to thank Tanja Torbica, PhD, at Complete HealthVizion for assistance in the preparation and revision of the draft manuscript, based on detailed discussion and feedback from all the authors.
Compliance with Ethical Standards
This study was supported by Bayer HealthCare Pharmaceuticals, Inc. John Bridgewater is partly supported by the UCLH/UCL Biomedical Research Centre.
Conflict of Interest
HR has performed a consulting or advisory role for Boehringer Ingelheim, Bayer, GlaxoSmithKline, Bristol-Myers Squibb, Roche, and Sanofi-Aventis. JJ has performed a consulting or advisory role for Eli Lilly, Pfizer, AstraZeneca, and Celgene; participated in a speaker bureau for Roche; received research funding from GlaxoSmithKline, Roche, and Novartis; and received travel, accommodation, and other expenses from Boehringer Ingelheim. MH has received honoraria from Celgene, research funding from Roche and Boehringer Ingelheim, and travel, accommodation, and other expenses from Celgene and Boehringer Ingelheim. MP has received honoraria and research funding from Bayer. PR has received honoraria from Roche, Sirtex, Bayer, and Celgene; performed a consulting or advisory role for Roche, Sirtex, Sanofi-Aventis, Celgene, Baxter, Merck Serono, and Daiichi Sankyo; received research funding from Sanofi-Aventis, Bayer, Roche, and Merrimack; and received travel, accommodation, and other expenses from Roche, Merck Serono, Celgene, and Sanofi-Aventis. JB is partly supported by the UCLH/UCL Biomedical Research Centre. He has performed a consulting or advisory role for Roche, Merck Serono, and AstraZeneca, and has received travel, accommodation, and other expenses from Merck Serono and the European Society for Medical Oncology. BM has received honoraria from, and has performed a consulting or advisory role for, Bayer. SC has performed a consulting or advisory role for Roche, Sanofi-Aventis, and Celgene. PM has received honoraria from Ipsen, Bayer, and Celgene, and has received research funding from Ipsen. DVB has received travel, accommodation, and other expenses from Amgen. MG, KR, AS, and HS are employees of Bayer Pharma AG. VLG is an employee of Bayer S.p.A. PRa is an employee of Bayer HealthCare Pharmaceuticals, Inc. and has stock or other ownership interests in Bayer HealthCare Pharmaceuticals, Inc. MT and BHC are employees of Bayer HealthCare Pharmaceuticals, Inc. J-LVL, UMM, CW, PS, AZ, WS, and SD have no conflicts of interest to declare.
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