Avutometinib/Defactinib Shows Activity in KRAS Wild-Type Recurrent LGSOC

Avutometinib plus defactinib (Avmapki Fakzynja Co-pack) demonstrated clinically meaningful activity across molecularly defined subgroups of KRAS wild-type recurrent low-grade serous ovarian cancer (LGSOC), according to a new molecular profiling analysis of the phase 2 RAMP 201 trial (NCT04625270) presented at the 2026 International Gynecologic Cancer Society (IGCS) Annual Global Meeting, per a news release from the developer, Verastem Oncology.¹ A separate external control arm analysis found higher response rates and progression-free survival (PFS) with the combination vs conventional care.¹

What did the RAMP 201 molecular profiling analysis show in KRAS wild-type LGSOC?

Investigators profiled baseline tumor samples from RAMP 201 to assess activity across molecular subgroups of KRAS wild-type disease.¹ Among these patients, 81% had no NRAS or BRAF mutations.¹ In this triple KRAS/NRAS/BRAF wild-type population, the confirmed objective response rate (ORR) was 18% (n = 7/39) and median progression-free survival (PFS) was 13 months.¹ Among patients with KRAS wild-type disease and an NRAS or BRAF mutation, the confirmed ORR was 22% (n = 2/9).¹

“Patients whose tumors are wild-type for KRAS, NRAS, and/or BRAF have typically experienced response rates under 10% with trametinib [Mekinst], chemotherapy or endocrine therapy,” stated Susana Banerjee, MBBS, MA, PhD, FRCP, consultant medical oncologist at The Royal Marsden NHS Foundation Trust, team leader in women's cancers at The Institute of Cancer Research in London, and global lead principal investigator of RAMP 201, in the press release.¹ “This analysis provides additional insight into molecular biology of recurrent LGSOC and suggests that targeting RAF, MEK, and FAK with avutometinib plus defactinib may provide clinically meaningful benefit beyond tumors driven by KRAS, NRAS or BRAF mutations.”

How did avutometinib plus defactinib compare with conventional care in the external control analysis?

An external control arm analysis compared patients treated in RAMP 201 with a matched and reweighted cohort who received conventional care, chemotherapy or anti-estrogen therapy, in the phase 2/3 GOG 281 trial (NCT02101788).¹ This was a comparison between patients from separate trials, not a randomized comparison.

Among patients with KRAS-mutated LGSOC, the weighted ORR was 38.7% with avutometinib plus defactinib vs 0% with conventional care. The median weighted PFS was 22.1 months vs 6.5 months, respectively. Among patients with KRAS wild-type LGSOC, the weighted ORR was 22.7% vs 7.9%, and the median weighted PFS was 11.3 months vs 7.7 months.

“The molecular profiling data show activity across biologically distinct subgroups of KRAS wild-type disease, including triple wild-type tumors, while the external control analysis shows higher response rates and statistically significant improvements in PFS over conventional care,” stated Michael Kauffman, MD, PhD, president of development at Verastem Oncology, in the press release.¹

What did the RAMP 201J study in Japanese patients show?

An encore presentation featured results from the phase 2 RAMP 201J study, which were first reported at the Annual Meeting of the Japanese Society of Gynecologic Oncology in July 2026. As of May 29, 2026, 16 efficacy-evaluable patients with recurrent LGSOC had received avutometinib plus defactinib.

With a median follow-up of 12.4 months, the ORR was 44%, and the disease control rate was 94% across all patients.¹ Among patients with KRAS-mutated tumors, the ORR was 71%, and in those with KRAS wild-type tumors, it was 22%; the disease control rates were 100% and 89%, respectively. Overall, 94% of patients had tumor shrinkage, and 11 of 16 remained on treatment at data cutoff.

How was the RAMP 201 trial designed?

The adaptive, 2-part RAMP 201 trial evaluated the efficacy and safety of avutometinib alone and in combination with defactinib for the treatment of patients with LGSOC. After the first part of the trial determined the go-forward regimen based on ORRs, the expansion phases of the trial evaluated avutometinib at 3.2 mg twice weekly and defactinib at 200 mg twice daily.

What is the regulatory and trial context for avutometinib plus defactinib?

The FDA granted accelerated approval to avutometinib plus defactinib on May 8, 2025, for adult patients with KRAS-mutated recurrent LGSOC who have received prior systemic therapy.² Continued approval may be contingent on verification of clinical benefit in a confirmatory trial. The combination is not approved for KRAS wild-type disease, and the new analyses do not change the approved indication.

Verastem is conducting the phase 3 RAMP 301 trial (NCT06072781), which is evaluating the combination vs standard chemotherapy or hormonal therapy in recurrent LGSOC with and without a KRAS mutation.³ Avutometinib inhibits MEK kinase activity while blocking the compensatory reactivation of MEK by upstream RAF, and defactinib is a FAK inhibitor; the combination was designed to more completely block signaling that drives growth and drug resistance in RAS/MAPK pathway–dependent tumors.

References

1. Verastem Oncology announces new RAMP 201 molecular profiling and external control arm analyses describing outcomes for avutometinib plus defactinib in recurrent low-grade serous ovarian cancer to be presented at IGCS 2026. News release. Verastem Oncology. October 2, 2026. Accessed October 6, 2026. https://tinyurl.com/5n63sja9
2. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. News release. FDA. May 8, 2025. Accessed October 6, 2026. https://tinyurl.com/ywyd4ps3
3. A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Updated August 14, 2026. Accessed October 6, 2026. https://tinyurl.com/djz727u5