FDA Grants Regular Approval to Dabrafenib and Trametinib Combination for Metastatic NSCLC With BRAF V600E Mutation

On June 22, 2017, the U.S. Food and Drug Administration granted regular approvals to dabrafenib (Tafinlar) and trametinib (Mekinist) administered in combination for patients with metastatic non–small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.

These are the first FDA approvals specifically for treatment of patients with BRAF V600E mutation–positive metastatic NSCLC.

The FDA today also approved the Oncomine Dx Target Test, a next-generation sequencing test to detect multiple gene mutations for lung cancer in a single test from a single tissue specimen. This test detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations in tumor tissue of patients with NSCLC. This test can be used to select patients with NSCLC with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib. This is the first next-generation sequencing oncology panel test approved by the FDA for multiple companion diagnostic indications.

Clinical Trial Results

The approvals are based on Study BRF113928 (NCT01336634), an international, multicenter, three-cohort, nonrandomized, noncomparative, open-label, trial in patients with locally confirmed BRAF V600E mutation–positive metastatic NSCLC. Ninety-three patients were treated with the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily). Of these 93 patients, 36 had received no prior systemic therapy for metastatic NSCLC and 57 received at least one platinum-based chemotherapy regimen with demonstrated disease progression. Seventy-eight patients with previously treated BRAF V600E mutation­–positive NSCLC received single-agent dabrafenib.

In the previously treated group, the overall response rate for the combination based on independent radiology review committee assessment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was 63% (95% confidence interval [CI] = 49%–76%) with a median duration of response of 12.6 months (95% CI = 5.8 to not estimable). In the treatment-naive group, the overall response rate for the combination was 61% (95% CI = 44%–77%) and median duration of response was not estimable (95% CI = 6.9 to not estimable); however, 59% of responders had response durations greater than 6 months. The overall response rate for patients who received single-agent dabrafenib was 27% (95% CI = 18%–38%) and the median duration of response was 9.9 months.

Adverse Reactions

The incidence and severity of adverse reactions occurring in patients with NSCLC were generally similar to those reported in prior approvals for patients with melanoma. The most common adverse reactions (≥ 20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. The most common grade 3 to 4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea.

The majority of laboratory abnormalities were grade 1 to 2. The most common (≥ 5%) grade 3 to 4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18% and 19% of patients, respectively.

The recommended doses are dabrafenib 150 mg orally twice daily, approximately 12 hours apart, with trametinib 2 mg orally once daily. The presence of BRAF V600E mutation in tumor specimen should be confirmed by an FDA-approved test prior to initiation of therapy.

The FDA granted Breakthrough Therapy designation in 2015 for the combination of dabrafenib and trametinib for the treatment of patients with advanced and metastatic BRAF V600E mutation–positive NSCLC who received at least one prior line of platinum-containing therapy. Orphan Drug designation was granted in 2014 to dabrafenib as a single agent for the treatment of patients with BRAF mutation–positive NSCLC and in 2015, in combination with trametinib for the same indication.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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