BRAF and MEK inhibitors

Mechanism & Class Overview

• Class mechanism: Target BRAF V600E (the most common BRAF mutation) or MEK-1/2 → inhibit MAPK/ERK pathway signaling → ↓ tumor cell growth.
• Resistance: Activation of alternative MAPK pathways (NRAS, MEK-1/2, upstream activators), ↑ MAP kinase, feedback-loop reactivation, and ↑ HER2 pathway (for MEK inhibitors).

Combination Rationale (BRAF + MEK)

• BRAF and MEK inhibitors are given together because combined blockade at two points of the MAPK pathway is more effective and, importantly, reduces the paradoxical MAPK activation that a BRAF inhibitor alone triggers in cells with wild-type BRAF/RAS. This paradoxical activation drives secondary cutaneous squamous cell carcinoma and keratoacanthoma; adding a MEK inhibitor lowers those secondary skin cancers; however, adding trametinib to dabrafenib increases pyrexia rather than mitigating it.

BRAF V600E Inhibitors

Vemurafenib (Zelboraf)

• Mechanism: Preferentially active against V600-mutant BRAF; also inhibits wild-type BRAF, CRAF, and ARAF in vitro (clinical use requires a BRAF mutation because RAF inhibition paradoxically activates MAPK in BRAF-WT cells).
• Indications: Melanoma (BRAF V600E+, metastatic or unresectable; with cobimetinib, see coBRIM/BRIM-3), Erdheim-Chester disease (BRAF V600E+); off-label in BRAF V600E+ Langerhans cell histiocytosis.
• Pharmacokinetics: CYP3A4 substrate (~95% hepatic elimination); half-life ~60h; food improves absorption.
• Toxicities: Cutaneous SCC/keratoacanthoma (see class note), photosensitivity (strict sun avoidance, SPF >30), rash, arthralgia, fatigue, QT prolongation (hold if >500 ms; correct electrolytes, avoid QT-prolonging meds), ↑ total bilirubin/↑ LFTs, uveitis/eye reactions, severe cutaneous reactions (SJS/TEN, rare).

Dabrafenib (Tafinlar)

• Mechanism: Inhibits wt-BRAF and BRAF V600E (more selective for V600E) → ↓ MAP kinase pathway.
• Indications: Melanoma (BRAF V600E or V600K; with trametinib, metastatic and adjuvant; COMBI-d/COMBI-v/COMBI-AD), NSCLC (BRAF V600E+, with trametinib), anaplastic thyroid cancer (with trametinib).
• Pharmacokinetics: Hepatic metabolism (CYP2C8, CYP3A4); half-life ~8h.
• Toxicities: Cutaneous SCC/keratoacanthoma (see class note), fever/pyrexia (hold if truly febrile), uveitis/eye reactions, hand-foot syndrome, ↑ glucose, constipation, headache, nausea, diarrhea.

Encorafenib (Braftovi)

• Mechanism: BRAF V600E inhibitor (and other kinases); used with a MEK inhibitor (binimetinib) or with cetuximab.
• Indications: Melanoma (BRAF V600E+, with binimetinib; see COLUMBUS), NSCLC (BRAF V600E+, with binimetinib; PHAROS), CRC (BRAF V600E+, with cetuximab; 1L with cetuximab + mFOLFOX6, BREAKWATER).
• Pharmacokinetics: CYP3A4 metabolism; ~50/50 urine/feces elimination; half-life ~3.5h; high-fat meal lowers Cmax ~36% without changing AUC (take with or without food).
• Toxicities: Cutaneous SCC (see class note; lower rate/later onset than dabrafenib and vemurafenib), GI bleed and CNS bleed in patients with brain mets, ↑ QTc, photosensitivity, rash, diarrhea, nausea, fatigue, muscle pain, hair color change, ↑ glucose, hepatotoxicity, CPK elevation; less pyrexia than dabrafenib.

MEK-1/2 Inhibitors

Trametinib (Mekinist)

• Mechanism: Inhibits MEK1 and MEK2 → ↓ ERK pathway → ↓ growth of BRAF V600E cells; commonly paired with a BRAF inhibitor.
• Indications: Melanoma (BRAF V600E/K+, usually with a BRAF inhibitor; adjuvant or metastatic), NSCLC (BRAF V600E+ with dabrafenib), anaplastic thyroid cancer (with dabrafenib), BRAF V600E solid tumors (tumor-agnostic) and pediatric low-grade glioma (with dabrafenib).
• Pharmacokinetics: Metabolized mainly by deacetylation (non-CYP; few drug interactions); hepatic elimination; half-life ~5 days.
• Toxicities: Second primary cancers (cutaneous and non-cutaneous), cardiotoxicity (↓ EF in ~10%, ~2 months in; baseline and serial TTE; for an asymptomatic LVEF drop of at least 10 percentage points that is also below the institutional LLN, withhold up to 4 weeks and resume reduced if it recovers; permanently discontinue if symptomatic, if the absolute drop from baseline exceeds 20 points with LVEF below LLN, or if no recovery within 4 weeks), visual disturbance (retinal detachment or retinal vein occlusion), pneumonitis/ILD, dermatologic toxicity (skin infection, erythema, hand-foot syndrome, photosensitivity), lymphedema (~10%, can be severe), diarrhea, mucositis.

Cobimetinib (Cotellic)

• Mechanism: MEK-1/2 inhibitor; used with a BRAF inhibitor (vemurafenib).
• Pharmacokinetics: Hepatic metabolism (glucuronidation and CYP3A); no starting-dose adjustment for hepatic impairment; half-life ~2 days; no clinically meaningful food effect (take with or without food).
• Indications: Melanoma (BRAF V600E or V600K, with vemurafenib); histiocytic neoplasms as monotherapy (FDA 2022).
• Toxicities: Cardiotoxicity (↓ EF in ~10%, ~4.5 months in; baseline TTE), diarrhea, nausea, vomiting, rash, peripheral edema, ↑ LFTs, CPK elevation, photosensitivity, vision changes (RVO).

Binimetinib (Mektovi)

• Mechanism: MEK-1/2 inhibitor (mechanism/resistance similar to trametinib); used with encorafenib.
• Pharmacokinetics: Glucuronidation, mainly hepatic elimination (dose reduce in moderate hepatic dysfunction); half-life ~3h.
• Indications: Melanoma (BRAF V600E/K+) and BRAF V600E+ metastatic NSCLC (PHAROS), both with encorafenib.
• Toxicities: Cardiotoxicity (↓ EF in ~10%, ~4.5 months in; baseline TTE), ↑ CPK (watch for rhabdomyolysis), CNS/GI bleeding, ILD, visual problems, diarrhea, nausea, rash, ↑ LFTs.

Selumetinib (Koselugo)

• Mechanism: MEK-1/2 inhibitor (similar to trametinib); reduces ERK phosphorylation and neurofibroma volume/proliferation. Glucuronidation and CYP3A metabolism.
• Indications: Neurofibromatosis type 1 (adults and children ≥1 yr) with symptomatic inoperable plexiform neurofibromas.
• Toxicities: MEK class effects: cardiotoxicity, dermatologic toxicity, ocular toxicity, hepatotoxicity, ↑ CPK.

• Do a baseline and periodic dermatologic exam/referral for all BRAF inhibitors. Adding a MEK inhibitor blunts the paradoxical MAPK activation that drives these secondary skin cancers.

2026 update: new BRAF/MEK indications

Tovorafenib (Ojemda): type II RAF inhibitor

• Mechanism: type II RAF inhibitor (locks RAF in an inactive conformation); active against BRAF fusions (which resist type I inhibitors like dabrafenib/vemurafenib because of dimer signaling); also active against BRAF V600 mutations.
• FIREFLY-1 (Kilburn Nat Med 2024): tovorafenib in R/R pediatric low-grade glioma with a BRAF alteration; ORR 67%. FDA Apr 23, 2024 accelerated approval for pediatric R/R pLGG with a BRAF fusion/rearrangement or V600 mutation.
• Toxicities: hair color change, elevated CK, macrocytic anemia, rash, growth deceleration in pediatrics.

BREAKWATER: BRAF V600E metastatic CRC 1L

• BREAKWATER (Elez NEJM 2025; OS benefit, full FDA approval Feb 24, 2026): encorafenib + cetuximab + mFOLFOX6 vs SOC chemo ± bevacizumab in 1L BRAF V600E mCRC; ORR 61% vs 40%; mPFS 12.8 vs 7.1 mo. FDA Dec 20, 2024 accelerated approval for 1L BRAF V600E mCRC, adding a 1L option (encorafenib + cetuximab, BEACON, remains for previously treated BRAF V600E mCRC).

Dabrafenib + trametinib: tumor-agnostic

• FDA Jun 22, 2022 tumor-agnostic approval for unresectable/metastatic BRAF V600E solid tumors that progressed on prior treatment with no satisfactory alternative options (except CRC, which needs added EGFR blockade), based on ROAR (Subbiah Lancet Oncol 2020) and NCI-MATCH data. Includes anaplastic thyroid, biliary, and high-grade and low-grade (pediatric) glioma.
• Study G2201 (Bouffet NEJM 2023): pediatric BRAF V600E low-grade glioma, dabrafenib + trametinib vs carboplatin/vincristine; FDA Mar 16, 2023 pediatric extension of dabrafenib + trametinib.

Selumetinib (Koselugo): MEK-i

• Indication: pediatric NF1 inoperable plexiform neurofibroma (FDA Apr 10, 2020) based on SPRINT (Gross NEJM 2020). Adult NF1 approval FDA Nov 2025 (KOMET, Chen Lancet 2025). Mirdametinib (Gomekli): MEK-i, FDA Feb 11, 2025 for NF1-PN in adults and children ≥2 yr (ReNeu). MEK-i class toxicities.

Class pearls (2024 to 2026)

• Type I RAF-i (vemurafenib, dabrafenib, encorafenib): active vs BRAF V600 monomers; can paradoxically activate WT-RAS/wt-BRAF (→ secondary keratoacanthoma/SCC).
• Type II RAF-i (tovorafenib, exarafenib): active vs BRAF fusions/dimers; no paradoxical MAPK activation.
• Avutometinib + defactinib (Avmapki Fakzynja): RAF/MEK clamp + FAK inhibitor; FDA May 8, 2025 accelerated approval for KRAS-mutated recurrent low-grade serous ovarian cancer after prior systemic therapy (RAMP 201, ORR 44%).
• BRAF V600E CRC now has both post-chemo (BEACON: encorafenib + cetuximab) AND 1L (BREAKWATER: encorafenib + cetuximab + FOLFOX) options.