FDA Approves Dabrafenib Plus Trametinib for Unresectable, Metastatic Solid Tumors With BRAF V600E Mutation


In clinical trials, dabrafenib and trametinib showed meaningful efficacy in multiple BRAF-positive tumor types, including in patients with rare cancers who have no other treatment options available.

The FDA has granted an accelerated approval to dabrafenib (Tafinlar) plus trametinib (Mekinist) for the treatment of patients 6 years of age and older with unresectable or metastatic solid tumors harboring a BRAF V600E mutation that progressed after prior treatment and who have no satisfactory alternative treatment options.1

The approval was based on the clinical efficacy and safety data from 3 clinical trials. Results from the phase 2 multi-cohort, multicenter, non-randomized, open-label ROAR basket study (NCT02034110) and arm H of the NCI-MATCH study (NCT02465060) showed the combination produced overall response rates of up to 80% in patients with BRAF V600E–mutated solid tumors, including high- and low-grade glioma, biliary tract cancer and select gynecological and gastrointestinal cancers.2 Study X2101 (NCT02124772), a multicenter, open-label, multiple cohort trial, found a clinical benefit and acceptable toxicity profile for dabrafenib plus trametinib in pediatric patients.2

“The combination of dabrafenib and trametinib demonstrated meaningful efficacy in multiple BRAF-positive tumor types, including in some patients with rare cancers who have no other treatment options available,” said Vivek Subbiah, MD, principal investigator and associate professor of Investigational Cancer Therapeutics and center medical director of the Clinical Center for Targeted Therapy in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in a press release. “Physicians should consider a BRAF test as a routine diagnostic step that could enable a new option for treating patients with many solid tumors.”

The ROAR trial enrolled adult patients with selected tumors harboring a BRAF V600E mutation, including high-grade glioma (n = 45), biliary tract cancer (n = 43), low-grade glioma (n = 13), adenocarcinoma of the small intestine (n = 3), gastrointestinal stromal tumor (n = 1), and anaplastic thyroid cancer. Enrollment was based on local assessments of BRAF V600E mutation status, with a BRAF mutation confirmed via central laboratory in 93 of 105 patients.

In Arm H of the single-arm, open-label NCI-MATCH study, BRAF V600E mutational status for enrollment was evaluated via central or local laboratory test, as patients with melanoma, thyroid cancer, or colorectal cancer were excluded. The study enrolled adult patients with solid tumors, such as gastrointestinal tumors (n = 14), lung cancers (n = 7), gynecologic or peritoneal tumors (n = 6), central nervous system tumors (n = 4), and ameloblastoma of mandible (n = 1).

Among 131 patients enrolled across the trials, the median age at baseline was 51 years and 20% were 65 years of age or older. Further, 56% were female; 85% were White, 9% were Asian, and 3% were Black. Most patients (56%) enrolled had an ECOG performance status of 1, 37% had a status of 0, and 6% had a status of 2. Of the 131 patients, 90% were administered prior systemic therapy.

The study investigators found that the objective response rate (ORR) with dabrafenib plus trametinib in patients with biliary tract cancer (n = 48) was 46% (95% CI, 31%-61%), with a median duration of response (DOR) of 9.8 months (95% CI, 5.3-20.4). In patients with high-grade glioma (n = 48), the ORR was 33% (95% CI, 20%-48%), with a median DOR of 13.6 months (95% CI, 5.5-26.7).

The ORR in patients with low-grade glioma (n = 14) who were administered dabrafenib plus trametinib was 50% (95% CI, 23%-77%), with a DOR ranging from 6 months to 29 months. Tabrafenib plus trametinib produced an ORR of 80% in patients with low-grade serous ovarian cancer (n = 5) and 50% in patients with adenocarcinoma of the small intestine (n = 4). The median DORs ranged from 12 months to 42 months in patients with low-grade serous ovarian cancer and 7 months to 8 months in patients with adenocarcinoma of the small intestine.

Study X2101 enrolled pediatric patients with refractory or recurrent solid tumors. Part C was a dose escalation of dabrafenib plus trametinib in patients whose tumors harbored a BRAF V600E mutation. Part D was a cohort expansion phase of dabrafenib plus trametinib in patients with low-grade glioma and a BRAF V600E mutation.

The efficacy of dabrafenib plus trametinib was analyzed in 48 pediatric patients, 34 of whom had low-grade glioma and 2 with high-grade glioma. In patients with BRAF V600E–mutated low-grade glioma and high-grade glioma in parts C and D, respectively, the median age was 10 years (range, 1-17) and 50% were male. Further, 75% of patients were White, 8% were Asian, and 3% were Black, with 58% of patients having a Karnofsky/Lansky performance status of 100.

Among patients enrolled, 83% previously underwent surgery, 2.8% had prior external beam radiotherapy, and 92% were previously administered systemic therapy. The study showed that dabrafenib plus trametinib produced an ORR of 25% (95% CI, 12%-42%). Among 9 responders, the DOR was 6 months or longer in 78% of patients and 24 months or longer in 44% of patients.

The toxicity profile of dabrafenib plus trametinib in these trials was consistent with the known profile for other approved indications.

“Tackling cancer is complex, which is why it is so important that we continue to follow the science as we pursue meaningful advances and new approaches to treating cancer,” said Reshema Kemps-Polanco, head of Novartis Oncology US, in the press release. “We are grateful to the patients, and to the multitude of individuals and teams working together to make this latest approval possible as we strive to do more for more people living with cancer.”


  1. Novartis Tafinlar + Mekinist receives FDA approval for first tumor-agnostic indication for BRAF V600E solid tumors. News release. Novartis Pharma AG. June 22, 2022. Accessed June 22, 2022. https://bit.ly/3tW25BN
  2. Tafinlar. Prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2022. Accessed June 22, 2022. https://bit.ly/3HM4IMv
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