Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer.

Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Session Type and Session Title: 
General Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Abstract Number: 


Poster Board Number: 
General Poster Session B (Board #C13)
J Clin Oncol 33, 2015 (suppl 3; abstr 344)
Eric Van Cutsem, Manuel Hidalgo, Igor Bazin, Jean-Luc Canon, Elena Poddubskaya, Nebojsa Manojlovic, Michele Milella, Dejan Radenkovic, Chris Verslype, Wei Guo, Lars Damstrup, Pascal Hammel; University Hospitals Gasthuisberg/Leuven, Leuven, Belgium; Hospital Madrid Norte Sanchinarro, Madrid, Spain; N.N. Blokhin Russian Cancer Research Center, Moscow, Russia; Grand Hôpital de Charleroi, Charleroi, Belgium; Clinic for Gastroenterology and Hepatology of Military Medical Academy of Serbia, Belgrade, Serbia; Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy; First Surgical Clinic, Clinical Center of Serbia and School of Medicine, University of Belgrade, Belgrade, Serbia; University Hospitals Gasthuisberg, KU Leuven, Leuven, Belgium; EMD Serono Research and Development Institute, Billerica, MA; Merck KGaA, Darmstadt, Germany; Hôpital Beaujon, Clichy, France

Abstract Disclosures


Background: In metastatic pancreatic cancer (mPaCa), KRAS mutations lead to constitutive activation of the MAPK pathway in the vast majority of cases. Pimasertib (Pim) is a selective, non-competitive MEK 1/2 inhibitor with potent antitumor activity in preclinical models with constitutive MAPK activation. Methods: Following a phase I, dose-finding part to the trial, 88 patients (pts) with mPaCa were randomized 1:1 to receive Pim 60 mg BID (A, 44 pts) or placebo (B, 44 pts) in combination with weekly gemcitabine (Gem) 1000 mg/m2(7 of 8 wks in cycle 1, then 3 of 4 wks in subsequent cycles), in a phase II setting (NCT01016483). The primary endpoint was progression-free survival (PFS). Response rate (RR), overall survival (OS) and safety were secondary endpoints. Biomarker analysis was an exploratory endpoint. Results: Pt characteristics were balanced (median age 63.5 yrs, males 56%, stage IV at initial diagnosis 75%) except for PS 0, which was more frequent in arm A (59 vs 41%). Time on treatment was longer in arm B (10.6 vs 8.0 wks). A higher proportion of pts in arm A discontinued treatment during the first 4 wks (31 vs 19%), predominantly due to adverse events (AEs) and PD. Median PFS was 3.7 mo in arm A and 2.8 mo in arm B (HR=0.883, 95% CI: 0.549–1.42; p=0.608). No statistically significant differences were observed between arms for OS (median 7.3 mo in arm A vs 8.3 mo in arm B) and RECIST 1.0 RR (9.1% in both arms). Grade ≥3 thrombocytopenia (20.0 vs 0%), vomiting (15.6 vs 4.8%), fatigue (15.6 vs 7.1%), stomatitis (13.3 vs 0%) and diarrhea (11.1 vs 2.4%) were more common in arm A. Typical allosteric MEK inhibitor-related AEs, such as all grade retinal detachment (24.4%) and creatine phosphokinase elevation (20.0%), were observed almost exclusively in arm A. KRAS mutational status did not influence PFS or OS. Conclusions: The primary study endpoint was not met; secondary endpoints did not suggest clinically meaningful differences between arms, except for selected toxicities observed more frequently with the combination of Gem and Pim. The outcome does not support further development of this combination in the first-line setting in mPaCa. Pim is currently in development in other solid tumors. Clinical trial information: NCT01016483