Investigational Drug
Avutometinib
HealthScout AI Analysis
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Overview
Avutometinib (also known as RO-5126766, CKI-27, CH-5126766, R-7304, RG-7304, VS-6766) is an oral, small‑molecule “RAF–MEK clamp” developed to inhibit the MAPK pathway by simultaneously blocking MEK activity and preventing RAF from phosphorylating and reactivating MEK via feedback. In May 2025, the FDA granted accelerated approval to avutometinib combined with the FAK inhibitor defactinib for adults with recurrent, KRAS‑mutated low‑grade serous ovarian cancer (LGSOC) after prior systemic therapy. (pubmed.ncbi.nlm.nih.gov)
Mechanism of action
- Dual RAF/MEK inhibition: CH5126766/RO5126766 binds MEK allosterically, locks MEK in a conformation that forms a stable complex with RAF, and prevents RAF‑mediated phosphorylation of MEK, thereby suppressing ERK signaling and feedback reactivation that limits activity of MEK‑only inhibitors. This “clamp” effect yields deeper pathway inhibition in RAS/MAPK‑driven tumors. (pubmed.ncbi.nlm.nih.gov)
- First‑in‑human PK/PD: Intermittent dosing was established due to on‑target toxicities (e.g., CPK elevations, rash) with a terminal half‑life ~60 hours and evidence of ERK pathway suppression in tumors. (aacrjournals.org)
Efficacy
Low‑grade serous ovarian cancer (LGSOC)
- Phase 2, RAMP‑201 (ENGOT‑OV60/GOG‑3052): In the randomized selection/expansion study of recurrent LGSOC, avutometinib + defactinib achieved a confirmed ORR of 31% overall (44% in KRAS‑mutant; 17% in KRAS‑wild‑type), median PFS 12.9 months overall (≈31.0 months KRAS‑mutant; 12.8 months KRAS‑wild‑type) by blinded independent central review. These primary results were published in the Journal of Clinical Oncology in July 2025. (pmc.ncbi.nlm.nih.gov)
- Regulatory endpoint subset: For FDA accelerated approval (May 8, 2025), efficacy was based on 57 patients with KRAS‑mutant recurrent LGSOC treated with the combination in RAMP‑201; confirmed ORR was 44% (95% CI 31–58) with DOR 3.3–31.1 months at cutoff. (fda.gov)
- Earlier signal: The investigator‑initiated FRAME phase 1/2 trial reported ORR 42.3% and median PFS 20.1 months in all evaluable LGSOC patients; in KRAS‑mutant LGSOC, ORR 58.3% and median PFS 30.8 months. (investor.verastem.com)
Other tumor types (emerging data)
- Metastatic pancreatic ductal adenocarcinoma (first‑line): Ongoing phase 1b/2 RAMP‑205 adds avutometinib/defactinib to gemcitabine/nab‑paclitaxel; early cohorts show combinability and preliminary activity (e.g., CA19‑9 reductions; partial responses in dose‑finding cohorts). Formal response rates are maturing. (ascopubs.org)
Confirmatory/ongoing trials
- Phase 3 RAMP‑301 (GOG‑3097/ENGOT‑ov81): Randomized study of avutometinib + defactinib vs investigator’s choice in recurrent LGSOC (KRAS‑mutant or wild‑type); primary endpoint PFS; estimated primary completion 2028. (pubmed.ncbi.nlm.nih.gov)
Safety
- Combination (RAMP‑201 primary analysis): Discontinuation due to AEs ~10%. Common AEs included nausea, diarrhea, and increased creatine phosphokinase; grade ≥3 rates were low to moderate for these events. (pmc.ncbi.nlm.nih.gov)
- FDA label (accelerated approval population): Most common adverse reactions/laboratory abnormalities (≥25%) included increased CPK, nausea, fatigue, transaminase elevations, rash/dermatitis acneiform, diarrhea, musculoskeletal pain, edema, cytopenias, bilirubin/triglyceride elevations, and ocular events (e.g., vitreoretinal disorders/visual impairment). Recommended regimen: avutometinib 3.2 mg orally twice weekly (Days 1 and 4) plus defactinib 200 mg orally twice daily, both 3 weeks on/1 week off per 28‑day cycle until progression or unacceptable toxicity. (fda.gov)
- Monotherapy experience (phase 1): On‑target toxicities include rash‑related disorders, CPK elevation, diarrhea, and ocular effects; half‑life ~60 hours supported intermittent dosing schedules. (aacrjournals.org)
Further reading
- Primary RAMP‑201 results in recurrent LGSOC (JCO, 2025). (pmc.ncbi.nlm.nih.gov)
- FRAME first‑in‑human combination study (Nature Medicine, 2025). (investor.verastem.com)
- FDA accelerated approval announcement and dosing/AE details (May 8, 2025). (fda.gov)
- First‑in‑human RO5126766 monotherapy (Clinical Cancer Research, 2012). (aacrjournals.org)
- Mechanistic characterization of CH5126766 “RAF–MEK clamp” (Cancer Research, 2013; PNAS, 2021). (aacrjournals.org)
- Phase 3 RAMP‑301 trial design and timelines (PubMed abstract, 2024). (pubmed.ncbi.nlm.nih.gov)
- Early RAMP‑205 pancreatic study abstracts/updates. (ascopubs.org)
Notes: As of October 7, 2025, avutometinib + defactinib holds U.S. accelerated approval for recurrent, KRAS‑mutated LGSOC based on ORR; confirmatory benefit on PFS is being tested in RAMP‑301. (fda.gov)
Last updated: Oct 2025
Active trials using Avutometinib
Found 12 active trials using this drug:
HealthScout AI summary: This trial enrolls adults with unresectable or metastatic, anti-EGFR-refractory, KRAS/NRAS/BRAF V600E/EGFR WT advanced colorectal cancer (progressed on EGFR antibody and standard chemotherapy), and treats them with avutometinib (a dual RAF/MEK inhibitor), defactinib (FAK inhibitor), and cetuximab. Prior BRAF/MEK/ERK inhibitor therapy and active CNS metastases are exclusion criteria.
ClinicalTrials.gov ID: NCT06369259
HealthScout AI summary: Adults with unresectable/metastatic diffuse-type gastric or GEJ cancer (including poorly cohesive/signet ring or CDH1/RHOA-mutant tumors) after at least one prior platinum/fluoropyrimidine regimen, ECOG 0–1, and tumor amenable to fresh biopsy. Treatment is oral avutometinib (dual RAF/MEK “clamp”) plus defactinib (FAK/PYK2 inhibitor) on a 3-weeks-on/1-week-off schedule; prior MEK/RAF/FAK inhibitor exposure excluded.
ClinicalTrials.gov ID: NCT06487221
HealthScout AI summary: This trial is enrolling adults with advanced, LKB1-mutant, anti-PD1-refractory lung adenocarcinoma (including KRAS-mutant subset), testing the combination of oral defactinib (FAK/Pyk2 inhibitor), oral avutometinib (dual RAF/MEK inhibitor), and intravenous nivolumab. Eligible patients must have progressed on prior anti-PD1 therapy and first line chemotherapy, and have ECOG 0-1.
ClinicalTrials.gov ID: NCT06495125
HealthScout AI summary: Upfront therapy for adult women with measurable low-grade serous ovarian or primary peritoneal carcinoma who are not candidates for primary cytoreduction or have residual disease after suboptimal debulking. Patients receive avutometinib (dual RAF/MEK clamp) plus defactinib (FAK inhibitor) on a 3-weeks-on/1-week-off schedule with continuous letrozole (and ovarian suppression if pre/perimenopausal).
ClinicalTrials.gov ID: NCT06394804
HealthScout AI summary: Adults with recurrent low-grade serous ovarian, fallopian tube, or primary peritoneal cancer after prior systemic therapy are randomized to avutometinib (a dual RAF/MEK “clamp”) plus defactinib (FAK/Pyk2 inhibitor) versus investigator’s choice of pegylated liposomal doxorubicin, weekly paclitaxel, letrozole, or anastrozole. Requires measurable disease, ECOG 0–1, and known KRAS status; crossover to the combo is allowed at progression.
ClinicalTrials.gov ID: NCT06072781
HealthScout AI summary: Adults with cutaneous melanoma and measurable brain metastases after immune checkpoint inhibitors, including BRAF V600E/K–mutant and non‑BRAF cohorts; requires at least one untreated 0.5–4 cm parenchymal lesion, ECOG 0–1, and known RAS/BRAF/NF1 status. Treatment is avutometinib (dual RAF/MEK “clamp”) plus defactinib (FAK/Pyk2 inhibitor), with an added encorafenib (BRAF inhibitor) dose‑finding and expansion for BRAF V600E/K disease.
ClinicalTrials.gov ID: NCT06194929
HealthScout AI summary: Pediatric and young adult patients (3–30 years) with refractory or recurrent solid tumors, including CNS tumors, harboring activating MAPK pathway alterations (e.g., BRAF/RAF fusions or mutations, RAS, PTPN11, SOS1/2, NF1 loss) receive oral avutometinib. Avutometinib is a first-in-class RAF/MEK “clamp” that allosterically inhibits RAF and MEK to suppress MAPK signaling; prior RAF/MEK monotherapy is allowed, and key exclusions include significant ocular, cardiac, or rhabdomyolysis risk.
ClinicalTrials.gov ID: NCT06104488
HealthScout AI summary: Adults with RAF dimer–driven thyroid cancers: RAIR differentiated (papillary/follicular/Hürthle cell/poorly differentiated) with recent progression or anaplastic, harboring RAS or NF1 mutations, RET/NTRK/ALK fusions, or non‑V600E/K/class 2–3 BRAF alterations; ECOG 0–1, measurable disease, any prior lines, but no prior MEK/class II–III BRAF/FAK inhibitors. Treatment is oral avutometinib (dual RAF/MEK clamp) plus defactinib (FAK/Pyk2 inhibitor) on a 3-weeks-on/1-week-off schedule, with ORR as the primary endpoint.
ClinicalTrials.gov ID: NCT06007924
HealthScout AI summary: This trial enrolls adults with metastatic or unresectable HR+/HER2- breast cancer that has progressed on prior CDK4/6 inhibitor and fulvestrant therapy, allowing up to two prior chemotherapy lines. Patients receive the investigational dual RAF/MEK inhibitor VS-6766 (which allosterically inhibits both RAF and MEK to overcome resistance), in combination with standard abemaciclib and fulvestrant.
ClinicalTrials.gov ID: NCT05608252
HealthScout AI summary: Enrolling adult women with recurrent/progressive gynecologic cancers (e.g., endometrioid, mucinous ovarian, high-grade serous ovarian, others) harboring MAPK-pathway alterations (RAS activation/mutation, BRAF class I–III mutation, and/or NF1 loss), ECOG 0–1, and prior systemic therapy; excludes prior RAF/MEK inhibitor exposure and LGSOC. Treatment is oral avutometinib (dual RAF/MEK “clamp”) plus defactinib (FAK inhibitor).
ClinicalTrials.gov ID: NCT05512208
HealthScout AI summary: Adults with metastatic KRAS-mutant colorectal adenocarcinoma after failure/intolerance of standard 5-FU/capecitabine, oxaliplatin, irinotecan, and anti-VEGF therapy (and prior IO for MSI-H) receive avutometinib (a dual RAF/MEK inhibitor that stabilizes inactive RAF–MEK complexes) plus cetuximab. Excludes prior MEK/EGFR/KRAS/SOS1/SHP2 inhibitors and those with significant cardiovascular/ocular risks or unstable CNS metastases.
ClinicalTrials.gov ID: NCT05200442
HealthScout AI summary: This trial targets adult patients with KRAS G12C mutant non-small cell lung cancer, evaluating the safety and efficacy of the combination of avutometinib, a dual RAF/MEK inhibitor, with sotorasib, with or without defactinib, for those with or without prior exposure to KRAS G12C inhibitors.
ClinicalTrials.gov ID: NCT05074810
