A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas

Abstract

Background: Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.

Methods: Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups.

Results: Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia.

Conclusions: The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.

Trial registration: ClinicalTrials.gov NCT01231581.

Keywords: Gemcitabine; MEK inhibitor; Pancreas; Randomised; Trametinib.