Background: BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as an oncogenic driver. The BRAF inhibitor D has demonstrated clinical activity (33% overall response rate [ORR], with a median progression-free survival [PFS] of 5.5 months as monotherapy in 78 previously treated pts with metastatic BRAFV600E–mutant NSCLC (cohort A). The combination of D + T has demonstrated significant improvements in efficacy vs BRAF inhibitor monotherapy in BRAF V600–mutant metastatic melanoma. Here, the primary analysis of pts with NSCLC who experienced failure of ≥ 1 prior platinum-based therapy for advanced disease and were treated with combination D + T is presented (cohort B). Methods: This is a multicohort, sequentially enrolled phase 2 trial in pts with metastatic BRAF V600E–mutant NSCLC. The primary endpoint was investigator-assessed ORR according to RECIST v1.1. Secondary efficacy endpoints included PFS and duration of response [DOR]. D was dosed at 150 mg orally twice daily and T at 2 mg orally once daily. Results: Between December 2013 and January 2015, 57 pts received D + T as ≥ second-line treatment and were evaluable for response. Median age was 64 y (range, 41–88 y). Most pts were female (51%), white (86%), adenocarcinoma (95%), and current or former smokers (73%). All pts had nonsquamous histology. 22 pts (37%) remain on therapy, and 37 have stopped (28 with disease progression, 8 due to adverse events [AEs], 1 due to pt decision). 52 pts were evaluable for efficacy (confirmed response). The ORR was 63% (95% CI, 49%-75%), with a disease control rate (ORR + ≥ 12 weeks of stable disease) of 79% (95% CI, 66%-89%). The median PFS was 9.7 mo (95% CI, 6.9-19.6 mo) and the median DOR was 9.0 mo (95% CI, 6.9-18.3 mo). Of the pts with a confirmed response, 50% remained in response at the time of analysis. The most common AEs (> 25%) included pyrexia, nausea, vomiting, diarrhea, asthenia, decreased appetite, and dry skin. Conclusions: D + T was highly efficacious in BRAF V600E–mutant NSCLC, with a manageable AE profile. This study is the first reported combination trial of a BRAF inhibitor and MEK inhibitor in BRAF V600E–mutant NSCLC. Clinical trial information: NCT01336634