Binimetinib tablets at a 45 mg dose received tentative approval from the FDA for its Abbreviated New Drug Application (ANDA) to be used in combination with encorafenib (Braftovi) for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, or for metastatic non–small cell lung cancer (NSCLC) with a BRAF V600E mutations.1
The approved ANDA is therapeutically equivalent to the reference listed drug of Mektovi at 15 mg. According to the press release, the drugs developer is the sole first applicant to file a Paragraph IV certification for this strength under the Hatch-Waxman Act, positioning it for potential 180 days of generic marketing exclusivity once final approval is granted.The 45-mg tentative approval follows an earlier tentative approval the company received for binimetinib 15-mg tablets initial approval in June 2018.
Regulatory and Indication Background
Binimetinib is a reversible MEK1/MEK2 inhibitor approved, in combination with encorafenib, for 2 BRAF-driven malignancies: unresectable or metastatic melanoma harboring a BRAF V600E or V600K mutation, and metastatic NSCLC harboring a BRAF V600E mutation, each as detected by an FDA-approved test.2 The labeled dosage is 45 mg orally twice daily, taken with or without food and continued until disease progression or unacceptable toxicity; patients with moderate or severe hepatic impairment require a reduced dose of 30 mg twice daily.2 Mutation status must be confirmed before treatment initiation—via tumor specimen for melanoma, or tumor or plasma specimen for NSCLC.2
Melanoma Efficacy: The COLUMBUS Trial
The melanoma indication is supported by COLUMBUS (NCT01909453), a randomized, open-label, phase 3 trial that randomly assigned 577 patients with BRAF V600E/K-mutant unresectable or metastatic melanoma 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib monotherapy, or vemurafenib.3 In the original analysis, the combination reduced risk of progression or death by 46% compared with vemurafenib (Zelboraf; median progression-free survival [PFS], 14.9 vs 7.3 months; HR, 0.54) and improved median overall survival (OS; 33.6 vs 16.9 months; HR, 0.67), with an objective response rate (ORR) of 63% vs 40%. A subsequent 7-year landmark update reported 7-year PFS and OS rates of 21.2% and 27.4%, respectively, with encorafenib plus binimetinib, compared with 6.4% and 18.2% with vemurafenib, reinforcing durable long-term benefit with the combination across an extended follow-up period.
NSCLC Efficacy: The PHAROS Trial
The NSCLC indication derives from PHAROS (NCT03915951), an open-label, single-arm phase 2 study of encorafenib plus binimetinib in 98 patients with BRAF V600E-mutatated metastatic NSCLC, with 59 who were treatment-naive and 39 previously treated.4 By independent radiology review, the ORR was 75% (95% CI, 62%-85%) in patients who were treatment-naive and 46% (95% CI, 30%-63%) in patients who were previously treated. The disease control rate after 24 weeks was 64% (95% CI, 51%-76%) in the treatment-naive arm and 41% (95% CI, 26%-58%) in the previously treated arm. The investigators concluded that encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved melanoma indication.
Safety Profile
Across both indications, the FDA label carried warnings for new primary malignancies, cardiomyopathy, venous thromboembolism, ocular toxicities (including serous retinopathy and retinal vein occlusion), interstitial lung disease, hepatotoxicity, rhabdomyolysis, hemorrhage, and embryo-fetal toxicity. In COLUMBUS, the most common adverse reactions (≥30%) were fatigue, nausea, diarrhea, vomiting, and arthralgia; serous retinopathy occurred in 13.6% of patients. In PHAROS, the most common treatment-related adverse effects (≥25%) included fatigue, nausea, diarrhea, and vomiting. Routine monitoring of left ventricular ejection fraction, liver function, and ophthalmologic status is recommended throughout treatment.
References
1. Alembic Pharmaceuticals Limited announces USFDA tentative approval for binimetinib tablets, 45 mg. Press release. Alembic Pharmaceuticals Limited. June 19, 2026. Accessed June 22, 2026. https://tinyurl.com/zvvjz73c
2. Mektovi (binimetinib) tablets, for oral use [prescribing information]. Array BioPharma Inc.; revised March 2025. Accessed June 22, 2026. https://tinyurl.com/3c9ay3c7
3. Schadendorf D, Dummer R, Flaherty KT, et al. COLUMBUS 7-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma. Eur J Cancer. 2024;204:114073. doi:10.1016/j.ejca.2024.114073
4. Riely GJ, Smit EF, Ahn MJ, et al. Phase II, open-label study of encorafenib plus binimetinib in patients with BRAF V600-mutant metastatic non–small-cell lung cancer. J Clin Oncol. 2023;41(21):3700-3711. doi:10.1200/JCO.23.00774
