FDA Grants Accelerated Approval to Dabrafenib Plus Trametinib for BRAF V600E–Mutated Solid Tumors


The FDA approval of dabrafenib plus trametinib for BRAF V600E–mutated unresectable or metastatic solid tumors highlights a potential need for routine BRAF testing in clinical practice, experts say.

The combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) has secured accelerated approval from the FDA for the treatment of adult and pediatric patients aged 6 years and older who have BRAF V600E–mutated, unresectable or metastatic solid tumors, and whose disease has progressed following all other satisfactory treatment options.1

The regulatory decision was supported by clinical efficacy and safety data observed in 3 clinical trials. In the phase 2 ROAR basket study (NCT02034110) and arm H of the NCI-MATCH study (NCT02465060), the doublet resulted in 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 Moreover, an additional study, Study X2101 (NCT02124772), demonstrated the clinical benefit and acceptable toxicity profile of the combination 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,” 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, stated 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 multi-cohort, multicenter, non-randomized, open-label ROAR trial included adult patients with selected tumors harboring BRAF V600E mutation; this included those with high-grade glioma (n = 45), biliary tract cancer (n = 43), low-grade glioma (n = 13), adenocarcinoma of small intestine (n = 3), gastrointestinal stromal tumor (n = 1), and anaplastic thyroid cancer.

Patients were enrolled based on local assessments of BRAF V600E mutation status. Moreover, BRAF mutation was confirmed via central laboratory in 93 of 105 patients.

Arm H of the single-arm, open-label NCI-MATCH study also enrolled patients with a BRAF V600E mutation. Here, patients with melanoma, thyroid cancer, or colorectal cancer were excluded, and BRAF V600E mutational status for enrollment was determined either by central or local laboratory test.

The study included 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 the 131 patients enrolled ito both trials, the median age at baseline was 51 years, with 20% of patients aged 65 years or older. Moreoverf, 56% of patients were female; 85% were White, 9% were Asian, and 3% were Black. The majority of patients (56%) 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% received prior systemic therapy.

Additional data from these trials showed that the objective response rate (ORR) achieved with the combination in those 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 those 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).

In those with low-grade glioma (n = 14), the ORR achieved with the doublet was 50% (95% CI, 23%-77%), with a DOR ranging from 6 months to 29 months. Moreover, dabrafenib plus trametinib resulted in ORRs of 80% and 50% in those with low-grade serous ovarian cancer (n = 5) and those with adenocarcinom of the small intestine (n = 4), respectively; the median DORs ranged from 12 months to 42 months, and 7 months to 8 months, respectively.

The multicenter, open-label, multiple cohort Study X2101 included pediatric patients with refractory or recurrent solid tumors. Part C was a dose escalation of dabrafenib in combination with trametinib in patients whose tumors harbored a BRAF V600E mutation. Part D was a cohort expansion phase of dabrafenib in combination with trametinib in patients with low-grade glioma and a BRAF V600E mutation.

The major efficacy outcome measure was ORR per ndependent review committee assessment and by RANO criteria. The efficacy of the doublet was examined in a total of 48 pediatric patients; 34 of these patients had low-grade glioma and 2 had high-grade glioma. For those 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. Moreover, 75% of patients were White, 8% were Asian, and 3% were Black. Fifty-eight percent of patients had a Karnofsky/Lansky performance status of 100.

Eighty-three percent of patients previously underwent surgery, 2.8% had prior external beam radiotherapy, and 92% previously received systemic therapy. Data showed that the combination elicited an ORR of 25% (95% CI, 12%-42%). For the 9 responders, the DOR was 6 months or longer for 78% of patients and 24 months or longer for 44% of patients.

The toxicity profile of the combination observed in these studies was consistent with the known profile in 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,” Reshema Kemps-Polanco, head of Novartis Oncology US, added 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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