On June 22, 2017, the U.S. Food and Drug Administration (FDA) approved the combination of dabrafenib and trametinib (DABRAFENIB® and TRAMETINIB®, Novartis Pharmaceuticals) for the treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation detected by an FDA-approved test. This is the first time the FDA has approved a drug specifically for the treatment of BRAF V600E mutation-positive metastatic NSCLC.
The FDA also approved the Oncomine™ Dx target assay (Thermo Fisher Scientific), a next-generation sequencing (NGS) technology that can detect multiple gene mutations in lung cancer from a single tissue sample. This trial detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations in tumor tissue from patients with NSCLC. This trial can be used to screen patients with BRAF V600E-mutant NSCLC for combination therapy with dabrafenib and trametinib. This is the first FDA-approved NGS oncology test for diagnosing multiple indications.
The approval is based on the BRF113928 (NCT01336634) study, an international, multicenter, three-arm, non-randomized, non-comparative, open-label trial conducted in patients with locally confirmed BRAF V600E mutation-positive metastatic non-small cell lung cancer. 93 patients received oral dabrafenib (150 mg twice daily) in combination with trametinib (2 mg once daily). Of these 93 patients, 36 had not received prior systemic therapy for metastatic non-small cell lung cancer, and 57 had received at least one platinum-based chemotherapy regimen and demonstrated disease progression. 78 previously treated BRAF V600E mutation-positive NSCLC patients received dabrafenib monotherapy.
In the prior treatment group, the overall response rate (ORR) of combination therapy was 63% (95% CI: 49%, 76%), and the median duration of response (DoR) was 12.6 months (95% CI: 5.8, not estimable [NE]), as assessed by the RECIST 1.1 independent radiological review committee. In the initial treatment group, the ORR of combination therapy was 61% (95% CI: 44%, 77%), while the median DoR was not estimable (95% CI: 6.9, NE); however, 59% of patients with a response had a duration of response longer than 6 months. In the dabrafenib monotherapy group, the ORR was 27% (95% CI: 18%, 38%), and the median DoR was 9.9 months.
The incidence and severity of adverse events in patients with non-small cell lung cancer were similar to those in patients with previously approved melanoma. The most common adverse reactions (≥20%) were fever, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, bleeding, cough, and dyspnea. The most common grade 3-4 adverse reactions were fever, fatigue, dyspnea, vomiting, rash, bleeding, and diarrhea. Laboratory abnormalities were mostly grade 1-2, with the most common (≥5%) grade 3-4 abnormalities being hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and elevated alanine aminotransferase. Dabrafenib and Trametinib were discontinued in 18% and 19% of patients, respectively, due to adverse reactions.
The recommended dose of Dabrafenib is 150 mg orally twice daily, approximately 12 hours apart; the recommended dose of Trametinib is 2 mg orally once daily. The presence of the BRAF V600E mutation in the tumor specimen should be confirmed by an FDA-approved test before initiating treatment.
In 2015, the FDA approved the combination of dabrafenib and trametinib as a breakthrough therapy for advanced metastatic BRAF V600E mutation-positive non-small cell lung cancer in patients who had previously received at least one platinum-based treatment. Dabrafenib was granted orphan drug designation in 2014 as monotherapy for BRAF mutation-positive NSCLC patients, and in 2015, it was approved for use in combination with trametinib.
