A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†

Abstract

Background: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC.

Patients and methods: Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary.

Results: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia.

Conclusion: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC.

Clinicaltrialsgov registration number: NCT01362296.

Keywords: KRAS; MEK inhibitor; NSCLC; docetaxel; progression-free survival; trametinib.

Figure 1.

CONSORT diagram. AE, adverse event; ITT, intent-to-treat; mITT, modified intent-to-treat; PD, progressive disease; PFS, progression-free survival.

Figure 2.

Investigator-assessed Kaplan–Meier estimated progression-free survival (PFS). Data are for the KRAS-mutant population. The vertical lines indicate censoring of data.

Figure 3.

Best percentage change from baseline in target lesions for the trametinib arm (A) and the docetaxel arm (B). The best tumor response for each patient who had undergone at least one tumor assessment after treatment. Each bar represents data for an individual patient. Colors indicate KRAS mutation status for each patient. The percentage change from baseline in the sum of the diameters of the target lesions is shown on the y-axis. Negative values indicate tumor shrinkage.