BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Bayer HealthCare Pharmaceuticals Inc 100 Bayer Blvd Whippany NJ 07981 USA

Bayer Pharma AG Müllerstraße 178 13353 Berlin Germany

Bayer S p A Viale Certosa 126 130 20156 Milan Italy

Department of Gastroenterology and Hepatology Medical University Hospital Bochum Alexandrinenstraße 1 Bochum 44791 Germany

Department of Gastroenterology Endocrinology Metabolism and Infectiology University Hospital of Giessen and Marburg Baldingerstraße 35043 Marburg Germany

Department of Gastroenterology Erasme University Hospital CP 572 10 route de Lennik 808 1070 Brussels Belgium

Department of Hematology and Oncology Cancer Center Heilbronn Franken Am Gesundbrunnen 20 26 74078 Heilbronn Germany

Department of Hematology and Oncology University of Munich Medical Center Marchioninistraße 15 81366 Munich Germany

Department of Medical Oncology A O U United Hospitals Polytechnic University of Marche Piazza Roma 22 Ancona Italy

Department of Medical Oncology Guy's and St Thomas' Hospital Westminster Bridge Road London SE1 7EH UK

Department of Medical Oncology Poliambulanza Foundation Hospital Institute Via Bissolati 57 Brescia Italy

Department of Oncological Gastroenterology Maria Skłodowska Curie Memorial Cancer Center ul W K Roentgena 5 02 781 Warsaw Poland

Department of Oncology and Radiotherapy Medical University of Gdansk M Skłodowskiej Curie 3a Street Gdansk 80 210 Poland

Department of Oncology Antwerp University Hospital Wilrijkstraat 10 2650 Edegem Belgium

Department of Oncology Oslo University Radium Hospital Trondheimsveien 235 Bjerke 0514 Oslo Norway

Department of Oncology Palacky University Medical School and University Hospital Olomouc Křížkovského 8 771 47 Olomouc Czech Republic

Department of Oncology UCL Cancer Institute 72 Huntley Street London WC1E 6DD UK

Department of Radiotherapy UZ Brussels Avenue du Laerbeek 101 1090 Brussels Belgium

Division of Medical Oncology University of Colorado Cancer Center 1665 Aurora Ct Aurora CO 80045 USA

Medical Department Division of Hematology Oncology and Tumor Immunology Charity Hospital Virchow Klinikum Campus Augustenburger Platz 1 13353 Berlin Germany

Universitätsklinikum Halle University Hospital Halle Germany

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