Dabrafenib-Trametinib Combination Receives FDA Approval for BRAF-Mutated Cancers

BRAF V600E mutation -positive unresectable or stage 4 solid (organ) tumors in adults and pediatric patients aged ≥ 6 years were the indication for accelerated FDA (US Food and Drug Administration) approval of dabrafenib (Tafinlar, Novartis) in combination with trametinib (Mekinist, Novartis) on June 22, 2022.

Eligibility for this combination required patients to have received prior treatment and have no satisfactory alternative treatment options. Patients with BRAF V600E-mutated colorectal tumors were excluded from this approval because they are resistant to BRAF inhibition.

Thus, BRAF became the 4th pan-cancer tumor biomarker to receive FDA approval regardless of the organ where the cancer originated. Previously, MSI, TMB and NTRK molecular targets had received approval in this way.

What Is the BRAF Gene and Its Mutation?

The BRAF gene encodes a protein with serine/threonine kinase activity involved in the intracellular mitogen-activated protein kinase signaling pathway (MAPKs). It controls cell division by acting through Kras. Somatic BRAF gene mutations  are most frequently detected in malignant melanoma skin cancer, colorectal cancers and papillary thyroid cancer. V600E is the mutation most commonly observed in patients.

Although the disease is generally known to behave more aggressively in patients with a BRAF mutation, studies suggest that the disease course (prognosis) is much better in stage 4 colon and rectal cancers with non-V600 BRAF mutations. Therefore, interpretation should not rely solely on mutation positivity; the codon in which the mutation is located should also be considered.

Studies Underlying FDA Approval

The trametinib-dabrafenib combination received FDA approval for patients in this situation based on several studies evaluating outcomes in a total of 131 adult and 36 pediatric patients.

Patients had BRAF V600E mutation-positive solid tumors, including high-grade glioma (YDG), biliary tract cancer, low-grade glioma (DDG), small intestine adenocarcinoma, gastrointestinal stromal tumor and anaplastic thyroid cancer. The pediatric group consisted of 36 patients with high- and low-grade glioma.

The studies enrolled patients with 24 tumor types, including different YDG and DDG subtypes. 

The main efficacy outcome measure in these studies was the overall response rate.

Results

• Of the 131 adult patients, 54 (41%) had an objective response to treatment.
• Among the most frequently represented tumor types in the study, the objective response rate was;
  • 46% for biliary tract cancer,
  • 33% for high-grade glioma, and
  • 50% for low-grade glioma.
  • The objective response rate for 36 pediatric patients was 25% (95% CI: 12, 42).
• Responses lasted ≥6 months for 78% of patients and ≥24 months for 44% of patients.

The most common (≥20%) adverse reactions in adult patients were fever, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, muscle pain, arthralgia (joint pain) and edema.

The most common (≥20%) adverse reactions in pediatric patients were fever, rash, vomiting, fatigue, dry skin, cough, diarrhea, acneiform dermatitis, headache, abdominal pain, nausea, hemorrhage, constipation and paronychia (nail fold infection).

The recommended dabrafenib dose in adults is 150 mg orally twice daily (two 75 mg capsules), and the trametinib dose is 2 mg orally once daily. Recommended pediatric doses of dabrafenib and trametinib are based on body weight. A recommended dose has not been established for patients weighing less than 26 kg.