On June 22, 2022, the FDA accelerated the approval of dabrafenib (Tafinlar; Novartis), a mutation inhibitor, in combination with trametinib (Mekinist; GlaxoSmithKline), a MEK inhibitor, for the treatment of unresectable or metastatic solid tumors and BRAF V600E mutation in adults and pediatric patients aged ≥6 years who have had disease progression after receiving previous treatment.
The combination of dabrafenib and trametinib is currently approved for unresectable or metastatic melanoma and BRAF V600E or V600K mutations, melanoma with BRAF V600E or V600K mutations involving lymph node(s), metastatic non–small-cell lung cancer with BRAF V600E mutation, and locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation.
This approval was based on the results of 3 clinical trials that included 131 adults in the first 2 studies, 36 patients in the pediatric study, and a total of 24 types of solid tumors.
The phase 2 Rare Oncology Agnostic Research (ROAR) study was an open-label, single-arm, multicenter study of patients with BRAF V600E–positive solid tumors, including low- or high-grade gliomas, biliary tract cancer, adenocarcinoma of the small intestine, gastrointestinal stromal tumor, and anaplastic thyroid cancer. The patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily.
The phase 2 National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) was a precision medicine clinical trial that included adults with BRAF V600E–positive solid tumors, excluding melanoma, thyroid cancer, and colorectal cancer.
The third study, Study X2101, included pediatric patients with BRAF V600 refractory or recurrent low- or high-grade glioma to evaluate the clinical benefit and safety of dabrafenib plus trametinib in pediatric patients.
The major efficacy end point of these 3 studies was overall response rate (ORR), which was up to 80% in patients with BRAF V600E solid tumors. The highest overall responses were seen in biliary tract cancer (46%) and low- and high-grade gliomas (50% and 33%, respectively). In the 2 studies with 131 adults, 54 (41%) patients had an objective response. In the 36 pediatric patients, the ORR was 25%, with a duration of response of ≥6 months in 78% of patients, and of ≥24 months in 44% of patients.
The most common (≥20%) adverse reactions with the combination seen in adults were pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema. In the pediatric patients the most common (≥20%) adverse reactions were pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.