The FDA granted regular approvals to dabrafenib and trametinib administered in combination for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.
The FDA also approved the Oncomine Dx Target Test, a next generation sequencing (NGS) 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 NGS oncology panel test approved by the FDA for multiple companion diagnostic indications.
The approvals are based on study BRF113928 (NCT01336634), an international, multi-center, three-cohort, non-randomized, non-comparative, 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 (ORR) for the combination based on independent radiology review committee assessment per RECIST 1.1 was 63 percent (95% CI: 49%, 76%) with a median duration of response (DoR) of 12.6 months (95% CI: 5.8, not estimable [NE]). In the treatment-naive group, the ORR for the combination was 61 percent (95% CI: 44%, 77%) and median DoR was not estimable (95% CI: 6.9, NE); however, 59 percent of responders had response durations greater than 6 months. The ORR for patients who received single-agent dabrafenib was 27 percent (95% CI: 18%, 38%) and the median DoR was 9.9 months.
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 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea. The majority of laboratory abnormalities were grade 1-2. The most common (>=5%) grade 3-4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18 percent and 19 percent 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.
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.