Encorafenib and Binimetinib Receive FDA Approval for BRAF V600E-Mutated Lung Cancer

On October 11, 2023, the US Food and Drug Administration (FDA) approved, for adult patients with a BRAF V600E mutation and metastatic non–small-cell lung cancer (NSCLC) , the combination of encorafenib (Braftovi, Array BioPharma, a wholly owned Pfizer subsidiary) and binimetinib (Mektovi, Array BioPharma).

This approval represents an important advance in lung cancer treatment and offers a new option for patients with a BRAF V600E mutation. It once again highlights the importance of personalized approaches and genetic information in cancer treatment.

The FDA previously, in 2017, approved dabrafenib plus trametinib (brand names Tafinlar and Mekinist) for BRAF V600E-mutated lung cancer. The current approval is the 2nd FDA approval for treating patients in this setting.

The combination of babrafenib + trametinib for all BRAF-mutated solid cancers (arising in organs and tissues) had also received accelerated FDA approval in June 2022 .

What Are the BRAF Gene and Its Mutation?

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

Approximately 2% of NSCLC patients have a BRAF V600E mutation that stimulates tumor-cell growth and proliferation.

FDA Approval Based on the PHAROS Study

Efficacy was evaluated in 98 patients with BRAF V600E-mutated metastatic NSCLC enrolled in PHAROS, an open-label, multicenter, single-arm study. Patients had not previously received BRAF or MEK inhibitors. They received encorafenib and binimetinib until disease progression or unacceptable toxicity.

The main efficacy outcomes were objective response rate (ORR) and duration of response (DoR), assessed by an independent review committee.

Results

• Among 59 treatment-naive patients, the objective response rate was 75% (confidence interval [CI]: 62, 85). Median response duration had not yet been reached among responders.
• Among 39 previously treated patients, the objective response rate was 46% (CI: 30, 63), and median response duration was 16.7 months.

For an indirect comparison , the objective response rates for the combination approved by the FDA for these patients in 2017, dabrafenib and trametinib, were as follows:

• The response rate was 61% in the previously untreated group.
• In patients who had previously received dabrafenib alone, the response rate was 27% and median response duration was 9.9 months.

The most common adverse reactions reported with encorafenib and binimetinib (in 25% or more) were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, shortness of breath, rash, and cough.

The recommended doses for BRAF V600E mutation-positive NSCLC are encorafenib 450 mg orally once daily and binimetinib 45 mg orally twice daily.

This development may open the door to more personalized treatments for NSCLC patients, offering hope for better and longer lives. The important approval highlights the continual evolution of innovative treatment options in oncology.