V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as an oncogenic driver.1
The BRAF inhibitor dabrafenib 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 patients with metastatic BRAF
V600E–mutant non–small- cell lung cancer [NSCLC; cohort A]).2
The combination of dabrafenib + trametinib has demonstrated significant improvements in efficacy versus BRAF inhibitor monotherapy inBRAF
V600–mutant metastatic melanoma,3
and in preclinical models, this combination was more effective than either agent alone in inhibiting the MAPK pathway and inducing apoptosis in a BRAF
V600E-mutant NSCLC cell line. Planchard and colleagues 4
now present the primary analysis of patients with BRAF
V600E–mutant stage IV NSCLC who experienced failure of ≥1 prior platinum-based therapies for advanced disease and were treated with combination dabrafenib + trametinib (cohort B). This was a multicohort, sequentially enrolled phase 2 trial in patients with metastatic BRAF
V600E–mutant NSCLC. The primary end point was investigator-assessed ORR according to RECIST v1.1 criteria. Secondary efficacy end points included PFS and duration of response (DOR). Dabrafenib was dosed at 150 mg orally twice daily and trametinib at 2 mg orally once daily. A total of 57 patients received dabrafenib + trametinib as ≥second-line treatment and were evaluable for response. Most patients had adenocarcinoma (95%) and were current or former smokers (73%). All patients had nonsquamous histology. In the 52 patients evaluable for efficacy, the ORR was 63% (95% confidence interval [CI], 49%-75%), with a disease control rate (ORR + ≥12 weeks of stable disease) of 79% (95% CI, 66%-89%), compared with an ORR of 33% and a disease control rate of 58% in the 75 patients treated with dabrafenib monotherapy. Of the patients responding to dual therapy, 4% had a complete response, 60% had a partial response, and 16% had stable disease. The median PFS was 9.7 months (95% CI, 6.9-19.6 months) and the median DOR was 9.0 months (95% CI, 6.9-18.3 months). Of the patients with a confirmed response, 50% remained in response at the time of analysis. The most common adverse events (>25%) included pyrexia, nausea, vomiting, diarrhea, asthenia, decreased appetite, and dry skin. The authors concluded that dabrafenib + trametinib was highly efficacious in BRAF
V600E–mutant NSCLC, with a manageable toxicity profile.
- Caparica R, et al. Crit Rev Oncol Hematol. 2016;101:32-39.
- Planchard D, et al. Lancet Oncol. 2016 Apr 11 [Epub ahead of print].
- Spain L, et al. Expert Opin Pharmacother. 2016;17:1031-1038.
- Planchard D, et al. ASCO 2016. Abstract 107.