MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC).

Abstract

8029 Background: KRAS mutations are detected in 25% of NSCLC, and there are no approved targeted therapies for this subset of NSCLC. D, an approved second-line treatment for NSCLC, has a response rate of < 10%. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. This phase II trial (NCT01362296) evaluated the efficacy of T vs D in pts with advanced KRAS-mutant NSCLC who had received prior platinum-based chemotherapy. Methods: Pts were randomized 2:1 to T (2 mg QD) or D (75 mg/m2 IV every 3 weeks) and stratified by type of mutational status and gender. Crossover to the other arm after progressive disease was allowed. Primary endpoint was PFS in pts with KRAS-mutant NSCLC (modified ITT; mITT). Secondary endpoints were OS, ORR, duration of response, and safety. PFS and OS were compared using a stratified log-rank test. The trial was stopped early for futility at a planned interim analysis; 92 PFS events were reported at the time of study termination. Results: Between September 2011 and July 2012, 134 pts were randomized to T (89) or D (45); 129 pts had KRAS-mutant NSCLC. Mean age was 61.4 y and 53% were male. In the mITT, 61/86 pts (71%) on T and 31/43 (72%) on D had a PFS event. HR for PFS was 1.14 (95% CI, 0.75-1.75; P = .5197) with a median PFS of 11.7 vs 11.4 wk for T vs D. ORR was 12% for T (10/86) and for D (5/43). With 27 (31%) deaths on T and 15 (35%) on D, HR for OS was 0.97 (95% CI, 0.52-1.83; P= .934). Five fatal SAEs were reported during treatment with T but none with D; 1 unspecified death was considered related to T. Frequent AEs reported with T were rash (59%), diarrhea (47%), nausea (34%), hypertension (34%), and dyspnea (33%). Grade 3/4 AEs with T were hypertension (16%/0), dyspnea (7%/3%), rash (6%/3%), diarrhea (6%/0), and asthenia (6%/0). Rate of treatment related SAEs was 15% with T and 12% with D. Conclusions: T did not improve PFS in pts with KRAS-mutation–positive NSCLC compared with D. However, an ORR of 12% for T in KRAS-mutant NSCLC suggests that an effort to better identify responsive mutations is warranted. The safety profile did not favor T, but is, in general, consistent with the overall T safety profile. Clinical trial information: NCT01362296.