FDA Greenlights Encorafenib/Binimetinib for BRAF V600E-Mutated NSCLC

• The combination of encorafenib (Braftovi) and binimetinib (Mektovi) offers a new option for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring a BRAF V600E mutation.

• Findings from the phase 2 PHAROS trial (NCT03915951) support this FDA decision.

• Encorafenib with binimetinib is already FDA-approved for the treatment of unresectable or metastatic melanoma and colorectal cancer with a BRAF V600E or V600K mutation.

The FDA has approved encorafenib and binimetinib for patients with metastatic NSCLC harboring a BRAF V600E mutation, as detected by an FDA-approved test.¹

Findings from the phase 2 PHAROS trial support this regulatory decision as the primary end point of objective response rate (ORR) was met. Among the 59 patients included in the treatment-naïve cohort and 39 in the previously treated cohort, the ORRs were 75% (95% CI, 62%-85%) vs 46% (95% CI, 30%-63%), respectively, and the median duration of response (DOR) was not estimable (NE; 95% CI, 23.1-NE) vs 16.7 months (95% CI, 7.4-NE).²

The disease control rate after 24 weeks in the treatment-naive cohort was 64% compared with 41% in patients who were previously treated. The median progression-free survival was not evaluable (95% CI, 15.7 to NE) and 9.3 months (95% CI, 6.2 to NE) in the in treatment-naïve and previously treated cohorts.

Regarding safety, treatment-related adverse events (TRAEs) most frequently reported consisted of nausea (50%), diarrhea (43%), and fatigue (32%). Among patients treated with encorafenib plus binimetinib, TRAEs led to dose reductions in 24 (24%) patients, and permanent discontinuation of the combination in 15 (15%) patients. There was 1 grade 5 TRAE reported, which was intracranial hemorrhage.

Previously, the combination was approved in the United States for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test, and is also approved for adult patients with metastatic colorectal cancer (CRC) who have a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

In the phase 2 study, the TKI combination of encorafenib plus binimetinib was evaluated for patients with BRAF V600-mutated NSCLC to determine the safety, tolerability, and efficacy of the combination. Patients received encorafenib 450 mg once daily with binimetinib 45 mg twice daily in a 28-day cycle.

Patients aged 18 years and older with a histologically confirmed diagnosis of NSCLC that is currently stage IV harboring a BRAF V600E mutation who were either treatment-naïve or have received first-line platinum-based chemotherapy or first-line treatment with an anti-PD-1/PD-L1 inhibitor given alone or in combination with platinum-based chemotherapy were eligible for enrollment in the study.³ Patients must have had presence of measurable disease, an ECOG performance status of 0 or 1, and adequate bone marrow, hepatic, and renal function.

Ninety-eight patients were enrolled between June 4, 2019, and June 2, 2022, across 5 countries.² Among those enrolled, 59 patients were treatment-naïve and 39 were previously treated. The median age of patients in the overall patient population was 70 years, 88% were White, 53% were women, 30% had never smoked, 73% had an ECOG PS of 1, 97% had adenocarcinoma, and 8% had baseline brain metastases. BRAF V600E mutations were present in all patients, and 1 patient who was previously treated had both BRAF V600E and BRAF V600D mutations in their tumor tissue.

Overall, this trial is the first of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC, and data from the study showed substantial antitumor activity in this patient population.

REFERENCES:

1.FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation. FDA. October 11, 2023. Accessed October 11, 2023. https://tinyurl.com/4zu57fdp

2. Riely GJ, Smit EF, Ahn MJ, et al. Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer. J Clin Oncol. 2023;41(21):3700-3711. doi:10.1200/JCO.23.00774

3. An open-label study of encorafenib + binimetinib in patients with BRAFV600-mutant non-small cell lung cancer. ClinicalTrials.gov. Updated March 17, 2023. Accessed October 4, 2023. https://clinicaltrials.gov/ct2/show/NCT03915951