Oral Mek1/Mek2 Inhibitor Trametinib (Gsk1120212) In Combination With Docetaxel In Kras-Mutant And Wild-Type (Wt) Advanced Non-Small Cell Lung Cancer (Nsclc): A Phase I/Ib Trial.

8028 Background: KRAS-mutant NSCLC, usually reflecting tobacco-related carcinogenesis, represents an unmet medical need in lung cancer therapy. Trametinib plus docetaxel (doc) enhances growth inhibition and apoptosis of NSCLC cell lines in vitro with and without RAS/RAF mutations when compared with either agent alone. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib+doc in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib + doc at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 46 NSCLC pts (24 WT [67% had ≥ 2 prior therapies] and 22 KRAS [41% had ≥ 2 prior therapies]) have been treated at the trametinib + doc RP2D (2.0 mg + 75 mg/m 2 + growth factors). Diarrhea, fatigue, asthenia, and nausea were the 4 most frequent toxicities. Dose reduction occurred in 10 pts (22%), mostly for diarrhea, fatigue, mucositis, neutropenia, and skin fissures (all 4%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed + unconfirmed) was 3 partial response (PR; RR = 17%) and 8 stable disease (SD; 44%); additionally, 4 pts had > 20% tumor shrinkage. The current disease control rate (DCR) is 61%; 4 pts have not had postbaseline scans. In WT pts, 5 PR (RR=21%) and 11 SD (46%) were observed (67% DCR). Final response and progression-free survival data will be reported upon maturity. Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib + doc (+ growth factors) demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.