Investigational Drug
Avutometinib
TrialFetch AI Analysis
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Overview
Avutometinib (RO5126766/CH5126766/VS-6766) is an oral small-molecule RAF/MEK inhibitor developed for RAS–RAF–MEK–ERK pathway-driven cancers. Although still investigational in most settings, it is no longer wholly investigational in the United States: on May 8, 2025, the FDA granted accelerated approval to avutometinib plus the FAK inhibitor defactinib for adults with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) previously treated with systemic therapy. (fda.gov)
Mechanism of action
Avutometinib is described as a RAF/MEK clamp. It binds allosterically to MEK1/2, inhibits MEK activity, and stabilizes an inactive RAF–MEK complex in which MEK cannot be phosphorylated and released by RAF. This suppresses both MEK activity and the compensatory RAF reactivation that can limit conventional MEK inhibitors, thereby reducing downstream ERK signaling. (pmc.ncbi.nlm.nih.gov)
Defactinib inhibits focal adhesion kinase (FAK), an adaptive signaling pathway that may become activated after RAF/MEK inhibition. This provides the rationale for combining the two drugs. (pubmed.ncbi.nlm.nih.gov)
Efficacy
The principal clinical evidence comes from the phase II RAMP-201 study of avutometinib plus defactinib in 115 heavily pretreated patients with recurrent LGSOC:
- Confirmed objective response rate (ORR): 31% overall
- ORR by tumor genotype: 44% in KRAS-mutated and 17% in KRAS-wild-type disease
- Median duration of response: 31.1 months
- Median progression-free survival (PFS): 12.9 months overall, with longer PFS in the KRAS-mutated subgroup. (pubmed.ncbi.nlm.nih.gov)
At approximately two years of follow-up, median duration of response remained 31.1 months and median PFS was 12.9 months overall. Median PFS was 19.6 months in KRAS-mutated and 12.7 months in KRAS-wild-type disease. (pubmed.ncbi.nlm.nih.gov)
The FDA approval population comprised 57 patients with KRAS-mutated LGSOC; blinded independent review found a 44% ORR (95% CI, 31%–58%), with responses lasting 3.3 to 31.1 months at the analysis cutoff. (fda.gov)
Earlier phase I monotherapy testing in 52 patients with advanced solid tumors produced three partial responses—two in BRAF-mutated melanoma and one in NRAS-mutated melanoma—and tumor shrinkage in approximately 40% of patients, although this was not a tumor-specific response rate. (pubmed.ncbi.nlm.nih.gov)
Safety
In the 115-patient RAMP-201 combination cohort, the most frequent grade 3 or higher treatment-related adverse events were:
- Increased creatine phosphokinase: 24%–26%
- Diarrhea: 8%
- Anemia: 5%–7%
Approximately 10%–12% discontinued treatment because of adverse events, and no treatment-related deaths were reported in the two-year analysis. (pubmed.ncbi.nlm.nih.gov)
Other commonly reported toxicities include rash or acneiform dermatitis, nausea, fatigue, liver-enzyme elevations, edema, musculoskeletal symptoms, gastrointestinal effects and ocular or vitreoretinal disorders. Early monotherapy studies also identified creatine phosphokinase elevation and blurred vision as dose-limiting toxicities. (fda.gov)
Further reading
- RAMP-201 primary phase II analysis
- Two-year RAMP-201 follow-up
- FDA accelerated-approval summary
- First-in-human monotherapy study
- Preclinical RAF/MEK-clamp mechanism study
Last updated: Sep 2026
Active trials using Avutometinib
Found 11 active trials using this drug:
TrialFetch AI summary: Adults with unresectable or metastatic colorectal adenocarcinoma that progressed after an initial response to cetuximab or panitumumab, following prior chemotherapy, receive cetuximab plus avutometinib, a RAF/MEK clamp, and defactinib, a FAK/PYK2 inhibitor. Patients must have had KRAS, NRAS, EGFR ectodomain, and BRAF V600E wild-type disease before anti-EGFR therapy.
ClinicalTrials.gov ID: NCT06369259
TrialFetch AI summary: Adults with previously treated unresectable or metastatic diffuse-type, poorly cohesive, signet ring cell, or mixed gastric or gastroesophageal junction cancer are eligible; patients with pathogenic CDH1 or RHOA mutations are eligible regardless of histology. All participants receive oral avutometinib, a RAF–MEK pathway inhibitor, plus defactinib, a focal adhesion kinase inhibitor.
ClinicalTrials.gov ID: NCT06487221
TrialFetch AI summary: Adults with unresectable, LKB1-mutant advanced lung adenocarcinoma that has progressed after checkpoint inhibition and first-line chemotherapy receive defactinib (FAK/PYK2 inhibitor), avutometinib (RAF–MEK pathway inhibitor), and nivolumab (anti-PD-1). One cohort also requires a KRAS mutation.
ClinicalTrials.gov ID: NCT06495125
TrialFetch AI summary: Adults with measurable, previously untreated low-grade serous ovarian or peritoneal cancer who are not candidates for primary debulking or have measurable disease after attempted debulking receive upfront avutometinib (RAF–MEK pathway inhibitor), defactinib (FAK inhibitor), and letrozole. Premenopausal or perimenopausal patients with an ovary in situ also receive leuprolide for ovarian suppression.
ClinicalTrials.gov ID: NCT06394804
TrialFetch AI summary: Patients with measurable recurrent low-grade serous ovarian, fallopian tube, or peritoneal cancer after prior systemic therapy, including platinum, are randomized to oral avutometinib (a RAF–MEK signaling inhibitor) plus defactinib (a FAK inhibitor) or investigator’s choice of pegylated liposomal doxorubicin, paclitaxel, letrozole, or anastrozole. Documented KRAS status and ECOG performance status 0–1 are required.
ClinicalTrials.gov ID: NCT06072781
TrialFetch AI summary: Adults with cutaneous melanoma brain metastases progressing after immunotherapy and at least one untreated, measurable brain lesion receive defactinib (a FAK/PYK2 inhibitor) plus avutometinib (a RAF/MEK clamp). Patients with BRAF V600E/K-mutant disease also receive encorafenib, a BRAF inhibitor.
ClinicalTrials.gov ID: NCT06194929
TrialFetch AI summary: Patients aged 3–30 years with recurrent or refractory solid tumors, including CNS tumors, harboring activating MAPK pathway alterations receive oral avutometinib monotherapy; eligible patients also include those with specified NF1-associated tumors or progressive optic pathway gliomas. Avutometinib is a RAF/MEK clamp that inhibits MEK and stabilizes an inactive RAF–MEK complex to suppress ERK signaling.
ClinicalTrials.gov ID: NCT06104488
TrialFetch AI summary: Adults with a qualifying RAS, NF1, RET, NTRK, ALK, or class 2/3 BRAF alteration and either progressive, radioiodine-refractory recurrent/metastatic differentiated thyroid cancer or anaplastic thyroid cancer receive avutometinib plus defactinib. Avutometinib is a RAF/MEK clamp that suppresses ERK signaling; defactinib inhibits FAK/PYK2.
ClinicalTrials.gov ID: NCT06007924
TrialFetch AI summary: Adults with HR-positive, HER2-negative metastatic or unresectable locally recurrent breast cancer who have progressed on a CDK4/6 inhibitor regimen and fulvestrant receive VS-6766 (avutometinib), a RAF/MEK inhibitor, with abemaciclib and fulvestrant. Eligible patients must have ECOG performance status 0–1; stable, treated brain metastases are permitted.
ClinicalTrials.gov ID: NCT05608252
TrialFetch AI summary: Adults with previously treated, measurable recurrent or progressive gynecologic cancer and a RAS/BRAF pathway alteration receive avutometinib, a dual RAF/MEK inhibitor, plus defactinib, a focal adhesion kinase inhibitor. Low-grade serous ovarian cancer and prior RAF or MEK inhibitor exposure are excluded.
ClinicalTrials.gov ID: NCT05512208
TrialFetch AI summary: Adults with previously treated, measurable KRAS-mutated metastatic colorectal adenocarcinoma and ECOG performance status 0–1 receive oral avutometinib, a RAF/MEK clamp that suppresses ERK signaling, plus intravenous cetuximab, an EGFR-targeting antibody. This single-arm study evaluates dose tolerability and preliminary antitumor activity.
ClinicalTrials.gov ID: NCT05200442
