Mutations in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF), which occur in 2% to 4% of patients with non–small-cell lung cancer (NSCLC), lead to activation of the BRAF protein and the mitogen‐activated protein kinase (MEK) signaling pathway. The most common BRAF mutation is characterized by a glutamate substitution for valine at codon 600 (V600E).1
Although the profile of patients with BRAF-mutated NSCLC is not fully defined, it appears to be different compared with patients with NSCLC who have other actionable mutations (eg, EGFR, ALK, and ROS1). Data show that patients with BRAF-mutated NSCLC are typically former or current smokers with adenocarcinoma histology and that the incidence of BRAF-mutated NSCLC may be lower in Asian patients compared with white patients. Neither age nor sex has been associated with BRAF mutation in NSCLC.1
On June 22, 2017, the FDA granted approval to the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test.2 Oncomine™ Dx Target Test, a next-generation sequencing test, was also approved on the same date. The test detects the presence of multiple gene mutations for lung cancer in a single test using a single tissue specimen. Because Oncomine Dx Target Test detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations, it can be used to select patients with BRAF V600E mutation–positive metastatic NSCLC for treatment with dabrafenib plus trametinib.2
Data supporting the approval of dabrafenib plus trametinib for BRAF V600E mutation–positive metastatic NSCLC are from a phase 2 trial known as BRF113928, a multicenter, 3-cohort, nonrandomized, open-label study. Of 93 patients who received the combination of dabrafenib (150 mg orally twice daily) plus trametinib (2 mg orally once daily) in this trial, 36 were previously untreated (cohort C), and 57 had received at least 1 platinum-based chemotherapy regimen and progressed (cohort B). Seventy-eight patients with previously treated BRAF V600E mutation‒positive NSCLC received single-agent dabrafenib (cohort A).3
The primary end point of the trial was investigator-assessed objective response rate (ORR), and secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. At a median follow-up of 15.9 months, 11 of the 36 (31%) patients in cohort C were still receiving treatment. The median age of these patients was 67 years (range, 44-91 years), and most were women (61%), white (83%), and current or former smokers (72%).3
The investigator-assessed ORR associated with dabrafenib plus trametinib in BRAF V600E mutation–positive NSCLC was 64% (95% confidence interval [CI], 46%-79%); 21 partial responses (58%) and 2 complete responses (6%). Four (11%) additional patients had stable disease that lasted at least 12 weeks, such that the disease control rate was 75% (95% CI, 58%-88%). Median DOR was 10.4 months (95% CI, 8.3-17.9 months), median PFS was 10.9 months (95% CI, 7.0-16.6 months), and median OS was 24.6 months (95% CI, 12.3 months-not estimable).3
All patients who received dabrafenib plus trametinib experienced ≥1 adverse events (AEs), and 69% had ≥1 grade 3/4 AEs. Serious AEs that occurred in ≥2 patients included alanine aminotransferase increase (14%), pyrexia (11%), aspartate aminotransferase increase (8%), and ejection fraction decrease (8%).3
The researchers concluded that the combination of dabrafenib and trametinib shows clinically meaningful antitumor activity and a manageable safety profile in patients with previously untreated BRAF V600E‒mutated metastatic NSCLC, thus validating the recent approval of this combination by the FDA.
1. Baik CS, Myall NJ, Wakelee HA. Targeting BRAF-mutant non-small cell lung cancer: from molecular profiling to rationally designed therapy. Oncologist. 2017;22:1-11.
2. US Food and Drug Administration. FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation. June 22, 2017. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm. Accessed January 26, 2018.
3. Planchard D, Smit EF, Groen HJM, et al. Phase 2 trial (BRF113928) of dabrafenib (D) plus trametinib (T) in patients (pts) with previously untreated BRAF V600E–mutant metastatic non-small cell lung cancer. Ann Oncol. 2017;28(suppl 5):v605-v649.