FDA Approves Dabrafenib/Trametinib Combo for BRAF V600E–Mutated Unresectable, Metastatic Solid Tumors


The FDA has granted accelerated approval to dabrafenib plus trametinib for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors who harbor a BRAF V600E mutation.

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

The basis of the approval is supported by clinical efficacy and safety data from 3 clinical trials:ROAR (NCT02034110), NCI-MATCH study (NCT02465060), and Study X2101 (NCT02124772).

In both the phase 2 ROAR basket study and arm H of the NCI-MATCH study (NCT02465060), dabrafenib plus trametinib resulted in overall response rates of up to 80% in patients with BRAF V600E–mutated solid tumors. These included high- and low-grade glioma, biliary tract cancer and select gynecological and gastrointestinal cancers.2 Additionally, the Study X2101 (NCT02124772), demonstrated the clinical benefit and acceptable toxicity profile of the doublet 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,” stated 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 the 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.”

In the multi-cohort, multicenter, non-randomized, open-label, phase 2 ROAR trial, adult patients with selected tumors harboring BRAF V600E mutation were enrolled. A total of 9 cohorts of patients with BRAF V600E mutation-positive rare cancers, including patients with high-grade and low-grade glioma were examined.3,4

Eligibility was open to patients with histologically confirmed recurrent or progressive high-grade (WHO grade 3 or 4) or low-grade (WHO grade 1 or 2) glioma at least 18 years old who had an ECOG performance status of 0 to 2, and adequate organ function as assessed by routine chemistry, hematology, and echocardiogram.

Patients enrolled in the low-grade glioma cohort needed to have measurable non-enhancing disease, excluding pilocytic astrocytoma, using RANO criteria. Additionally, patients with grade 1 low-grade glioma were required to be symptomatic and were evaluated by a panel of neurooncologists before enrollment.

Those included had 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, and BRAF mutations were confirmed via central laboratory in 93 of 105 patients.

An oral dose of dabrafenib at 150 mg twice daily and oral trametinib 2 mg once daily was administered to patientsuntil unacceptable toxicity, disease progression, or death. Dose adjustments and interruptions were permitted in order to improve tolerability for patients unable to tolerate the protocol dose. Disease assessments via contrast MRI of the brain were made by investigators every 8 weeks for the first 48 weeks, followed by every 3 months, until disease progression.

The primary end point was investigator-assessed overall response rate (ORR) using RANO, defined by CR (complete response) plus partial response (PR) for high-grade glioma, and CR plus PR and minor response for low-grade glioma. ORR was also assessed by independent radiology review. Secondary end points included progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety.

Findings showed that for the 45 patients with high-grade glioma, the ORR was 33% (95% CI, 20%-49%) by investigator assessment, including 3 CRs and 12 PRs. Median follow-up was 12.7 months (interquartile range [IQR], 5.4-32.3), and independent radiology review showed an ORR of 31% in this cohort, which included 3 CRs and 11 PRs. Additionally, the median DOR was 36.9 months (95% CI, 7.4-44.2) per investigator assessment and 13.6 months (95% CI, 4.6-43.4) per independent radiology review. Investigator assessment also showed a median PFS of 3.8 months (95% CI, 1.8-9.2), a median OS of 17.6 months (95% CI, 9.5-45.2), and independent radiology review reported a median PFS of 4.5 months (95% CI, 1.8-7.4).

For the 13 patients with low-grade disease the ORR was 69% (95% CI, 39%-91%) per investigator assessment and independent radiology review with 1 CR, 6 PRs, and 2 minor responses observed at a median follow-up of 32.2 months (IQR, 25.1-47.8). The median DOR by independent radiology review was 27.5 months (95% CI, 3.8-39.5). Additionally, while both the median PFS (95% CI, 7.4-not reached) and median OS were not reached (95% CI, 11.6-not reached) by investigator assessment, the median PFS was 14.0 months (95% CI, 4.7-46.9) according to independent radiology review.

In regard to safety, 93% of patients across both cohorts experienced any-grade adverse events (AEs), including fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%). Grade 3/4 AEs occurred in 53% of patients, including fatigue (9%), headache (5%), and neutropenia (5%). Additionally, AEs led to dose reductions in 38% of patients, treatment interruptions in 41%, and permanent discontinuation in 9%.

Arm H of the single-arm, open-label NCI-MATCH study also enrolled patients with a BRAF V600E mutation with the BRAF V600E mutational status for enrollment was determined either by central or local laboratory test.5

The open-label, single-arm study administered patients dabrafenib 150 mg twice per day and trametinib 2 mg per day continuously until disease progression or intolerable toxicity. The primary end point of the study was centrally assessed ORR with secondary end points consisting of PFS, 6-month PFS, and OS.

The confirmed ORR was 38% (90% CI, 22.9-54.9; P < .0001) against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4-16.3 months). Responses were seen in 7 distinct tumor types. A total of 7 patients had a DOR of more than 12 months, including 4 patients who had a DOR of over 24 months. An additional 8 patients had a PFS greater than 6 months. The median OS was 28.6 months.

Reported adverse events were comparable to those noted in previously reported profiles of dabrafenib and trametinib.

Finally, in the multicenter, open-label, multiple cohort Study X2101 examined the doublet in pediatric patients with refractory or recurrent solid tumors.6 Part C was a dose escalation of dabrafenib in combination with trametinib in patients whose tumors harbored a BRAF V600E mutation and part D was a cohort expansion phase of dabrafenib in combination with trametinib in patients with low-grade glioma and a BRAF V600E mutation.

Data showed that among those enrolled (n =48) 83% previously underwent surgery, 2.8% had prior external beam radiotherapy, and 92% were previously administered systemic therapy. The study showed that the combination of dabrafenib plus trametinib elicited 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 the combination observed in these studies remained 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,” added 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
  3. Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet. Published online November 24, 2021. doi:10.1016/S1470-2045(21)00578-7
  4. Hargrave DR, Bouffet E, Tabori U, et al. Efficacy and safety of dabrafenib in pediatric patients with BRAFV600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa study. Clin Cancer Res. 2019;25:7303-7311. doi:10.1158/1078-0432.CCR-19-2177
  5. Dabrafenib and trametinib in patients with tumors with BRAF V600E mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol. 2020; 38(33):3895-3904. doi: 10.1200/JCO.20.00762.

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