Verastem Oncology Presents New Data Supporting Avutometinib Plus Defactinib Across Molecular Subgroups in Recurrent LGSOC
Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company focused on developing new medicines for patients with cancers driven by the RAS/MAPK pathway, has announced new clinical and molecular analyses evaluating avutometinib in combination with defactinib in patients with recurrent low-grade serous ovarian cancer (LGSOC).
The findings, being presented at the International Gynecologic Cancer Society (IGCS) 2026 Annual Global Meeting in Montréal, Canada, from October 1-3, 2026, include molecular profiling and tumor biomarker data from the Phase 2 RAMP 201 clinical trial, as well as an external control arm analysis comparing outcomes from RAMP 201 with conventional care.
The company is also presenting encore data from RAMP 201J, a Phase 2 study evaluating the combination in Japanese patients with recurrent LGSOC.
Together, the analyses provide additional information on the activity of avutometinib plus defactinib across molecularly distinct forms of recurrent LGSOC, including tumors without KRAS, NRAS or BRAF mutations. The findings also provide a comparison with conventional treatment approaches using data from the GOG 281 trial.
Molecular Profiling Examines Activity Beyond KRAS-Mutated Disease
The molecular profiling analysis was designed to evaluate the activity of avutometinib plus defactinib across molecularly defined subgroups among patients with KRAS wild-type recurrent LGSOC enrolled in RAMP 201.
LGSOC is a distinct subtype of ovarian cancer that can be associated with alterations involving the RAS/MAPK signaling pathway. While KRAS mutations are relevant to a subset of tumors, patients with recurrent disease can have different molecular profiles, creating a need to understand whether targeted treatment approaches may have activity across multiple biological subgroups.
In the RAMP 201 analysis, 81% of patients with KRAS wild-type LGSOC also had no NRAS or BRAF mutations. This group, described as the triple wild-type KRAS/NRAS/BRAF population, represented an important subgroup for evaluating the combination’s activity in tumors lacking alterations in three key genes.
Among patients with triple wild-type disease, avutometinib plus defactinib produced a confirmed objective response rate (ORR) of 18%, with seven of 39 patients achieving a response. The median progression-free survival (mPFS) in this population was 13 months.
The combination also demonstrated activity among patients with KRAS wild-type LGSOC who had either NRAS or BRAF mutations. In this subgroup, the confirmed ORR was 22%, with two of nine patients achieving a response.
The findings indicate that treatment activity was observed across molecularly distinct groups within the KRAS wild-type population.
Targeting RAF, MEK and FAK
The biological rationale behind the combination centers on simultaneous targeting of multiple signaling components involved in tumor growth and survival.
Avutometinib is being developed as a targeted therapy designed to inhibit RAF and MEK, components of the RAS/MAPK pathway. Defactinib targets focal adhesion kinase (FAK), a signaling protein associated with tumor cell survival, proliferation and interactions with the tumor microenvironment.
By combining the two agents, Verastem is investigating whether simultaneous RAF/MEK and FAK inhibition can produce broader antitumor activity than approaches directed at individual components of the signaling network.
Professor Susana Banerjee, M.B.B.S., M.A., Ph.D., F.R.C.P., Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London, and Global Lead Principal Investigator of ENGOTov60/GOG3052/NCRI/RAMP201, discussed the significance of the molecular findings.
“Patients whose tumors are wild-type for KRAS, NRAS, and/or BRAF have typically experienced response rates under 10% with trametinib, chemotherapy or endocrine therapy,” Banerjee said.
“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,” she added.
The findings are particularly relevant to the ongoing investigation of whether the combination may have potential across a broader population of recurrent LGSOC patients rather than being limited to those whose tumors harbor a specific KRAS alteration.
External Control Analysis Compares Combination With Conventional Care
A second analysis presented at IGCS 2026 provides a comparison between outcomes observed with avutometinib plus defactinib and conventional treatment.
The “Poster Rounds with the Professor: Efficacy of Avutometinib and Defactinib vs Conventional Care in Low-Grade Serous Ovarian Cancer (LGSOC): An External Control Arm Analysis” presentation evaluates data from patients treated in RAMP 201 against a matched and reweighted cohort receiving conventional care in the GOG 281 trial.
The conventional-care group included patients treated with chemotherapy or anti-estrogen therapy. The external control methodology was used to compare outcomes while accounting for differences between the populations.
Among patients with KRAS-mutated LGSOC, the weighted ORR with avutometinib plus defactinib was 38.7%, compared with 0% with conventional care.
Median weighted progression-free survival was also longer in the combination group, at 22.1 months, compared with 6.5 months for conventional care.
The analysis also examined patients with KRAS wild-type LGSOC, providing another perspective on the potential activity of the combination in a population without a KRAS mutation.
In this group, the weighted ORR was 22.7% with avutometinib plus defactinib compared with 7.9% with conventional care. Median weighted PFS was 11.3 months for the combination versus 7.7 months for conventional care.
The results provide comparative evidence across both KRAS-mutated and KRAS wild-type disease, although external control analyses have methodological limitations because the treatment groups originate from different clinical trial settings and periods.
Verastem Highlights Broader Potential in Recurrent LGSOC
Michael Kauffman, M.D., Ph.D., president of development at Verastem Oncology, said the two analyses collectively add to the evidence supporting the combination in recurrent LGSOC.
“Taken together, the molecular profiling and external control arm analyses adds to the body of evidence of the potential of avutometinib plus defactinib to treat recurrent LGSOC in both KRAS-mutated and KRAS wild-type disease,” Kauffman said.
He noted that the molecular profiling findings demonstrated activity across biologically distinct KRAS wild-type subgroups, including tumors that are wild-type for KRAS, NRAS and BRAF.
“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,” Kauffman said.
According to Verastem, these findings build on the established activity of the combination in KRAS-mutated recurrent LGSOC. The company also highlighted the approved use of avutometinib plus defactinib at first recurrence for patients with KRAS-mutated LGSOC, while continuing to investigate the potential role of combined RAF/MEK and FAK targeting in a broader population.
Japanese Phase 2 Data Add Regional Clinical Experience
In addition to the RAMP 201 analyses, Verastem is presenting encore findings from RAMP 201J, a Phase 2 study evaluating avutometinib plus defactinib in Japanese patients with recurrent LGSOC.
The data were previously reported at the Annual Meeting of the Japanese Society of Gynecologic Oncology, held July 17-19, 2026, in Sapporo, Japan.
As of the May 29, 2026 data cutoff, 16 efficacy-evaluable patients with recurrent LGSOC had received treatment with the combination. Median follow-up was 12.4 months.
Across all patients, the combination produced an objective response rate of 44% and a disease control rate of 94%.
The results varied according to KRAS mutation status. Among patients whose tumors were KRAS-mutated, the ORR was 71%, while the ORR among patients with KRAS wild-type tumors was 22%.
Disease control rates were also high in both groups, reaching 100% among patients with KRAS-mutated disease and 89% among those with KRAS wild-type disease.
Overall, 94% of patients experienced tumor shrinkage, while 11 of the 16 patients remained on treatment at the data cutoff.
These results provide additional clinical experience with the combination in a Japanese patient population and complement the broader RAMP 201 findings being presented at the IGCS meeting.
Multiple Presentations at IGCS 2026
The molecular profiling and tumor biomarker analysis was scheduled as a rapid oral presentation on October 2, 2026, from 10:30 to 11:30 a.m. ET.
The external control arm analysis, titled “Poster Rounds with the Professor: Efficacy of Avutometinib and Defactinib vs Conventional Care in Low-Grade Serous Ovarian Cancer (LGSOC): An External Control Arm Analysis,” was scheduled for presentation on October 2 from 2:25 to 2:30 p.m. ET.
The RAMP 201J findings were also scheduled as a rapid oral presentation during the October 2 session.
The presentations give clinicians and researchers an opportunity to examine the combination from several perspectives, including molecular tumor characteristics, comparative outcomes and experience in Japanese patients.
Implications for the Future of LGSOC Treatment
The new data come amid continued efforts to improve treatment options for recurrent LGSOC, a disease in which molecular characteristics can influence therapeutic strategies.
The RAMP 201 molecular analysis is particularly relevant because it examines patients whose tumors lack KRAS mutations and further separates those patients according to NRAS and BRAF status. The activity observed in triple wild-type disease suggests that the biological effects of combined RAF/MEK and FAK inhibition may extend beyond tumors carrying alterations in individual RAS/MAPK pathway genes.
At the same time, the external control analysis provides context for the observed outcomes by comparing the RAMP 201 population with patients who received conventional treatment in GOG 281. The reported differences in response rates and progression-free survival provide additional evidence for continued investigation of the combination.
The Japanese RAMP 201J results add another layer of evidence, with responses observed in both KRAS-mutated and KRAS wild-type disease and a high overall disease control rate.
While these findings strengthen the clinical evidence supporting avutometinib plus defactinib, continued clinical evaluation will be important to further establish the combination’s role across molecular subgroups and treatment settings.
At the IGCS 2026 Annual Global Meeting, Verastem Oncology is also showcasing information about its approved therapy and ongoing cancer research at exhibition booth #01. The company’s presentations at the meeting collectively highlight its strategy of targeting the RAS/MAPK pathway and related signaling mechanisms in cancers where patients continue to face significant treatment challenges.
The data from RAMP 201, the external control analysis and RAMP 201J provide additional insight into the potential role of avutometinib plus defactinib in recurrent LGSOC, particularly as researchers seek treatment strategies capable of addressing both KRAS-mutated and KRAS wild-type disease.
About RAMP 201
RAMP 201 (ENGOTov60/GOG3052/NCRI) (NCT04625270) was an adaptive, two-part multicenter, parallel cohort, randomized, open-label Phase 2 registration-directed trial evaluating the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent low-grade serous ovarian cancer (LGSOC). The first part of the trial (Part A) determined the selection of the go-forward regimen, which was the combination of avutometinib and defactinib versus avutometinib alone, based on overall response rates.
The expansion phases of the trial (Parts B and C) evaluated the safety and efficacy of the go-forward regimen of avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily. The Part D portion of the trial evaluated a low dose of the combination to inform individualized dose reduction.
About Low-Grade Serous Ovarian Cancer (LGSOC)
LGSOC is a rare ovarian cancer that is insidious and persistent. LGSOC is distinct and different from high-grade serous ovarian cancer (HGSOC) and requires different treatment. LGSOC is highly recurrent and less sensitive to chemotherapy compared to HGSOC. Approximately 6,000-8,000 women in the U.S. and 80,000 worldwide are living with this disease.
LGSOC affects younger women with bimodal peaks of diagnosis at ages between 20-30 and 50-60 and has a median survival of approximately ten years. Approximately 70 percent of LGSOC shows RAS pathway-associated mutations, and 30 percent of people with LGSOC have a KRAS mutation. The majority of patients report a negative impact of LGSOC on their mental and physical health, fertility, and long-term quality of life.
About AVMAPKI and FAKZYNJA Combination Therapy
AVMAPKI (avutometinib) inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway. Blocking RAF and/or MEK activates FAK, a key mediator of drug resistance. FAKZYNJA (defactinib) is a FAK inhibitor and together, the avutometinib and defactinib combination was designed to provide a more complete blockade of the signaling that drives the growth and drug resistance of RAS/MAPK pathway-dependent tumors.
The U.S. Food and Drug Administration (FDA) approved AVMAPKI® FAKZYNJA® CO-PACK (avutometinib capsules; defactinib tablets) for the treatment of adult patients with KRAS-mutated recurrent LGSOC who have received prior systemic therapy on May 8, 2025. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Verastem is conducting RAMP 301 (GOG-3097/ENGOT-ov81/GTG-UK) (NCT06072781), an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC) with and without a KRAS mutation.
In June 2026, Verastem provided updated results on the Phase 1/2 RAMP 205 trial (NCT05669482), which is evaluating avutometinib plus defactinib in combination with standard-of-care chemotherapy as a first-line treatment for patients with advanced pancreatic cancer. Avutometinib and defactinib are not approved by the FDA or any other regulatory authority, either in combination or with other therapies, for any of these investigative uses. Neither avutometinib nor defactinib are approved by the FDA or any other regulatory authority on a stand-alone basis for any use.