Clinical Significance
- In May 2025, the FDA granted accelerated approval to the combination of avutometinib (VS-6766) and defactinib (VS-6063), marketed together as AVMAPKI FAKZYNJA CO-PACK, for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received at least one prior systemic therapy.
- This marks the first targeted treatment option for this patient population, and reiterates the importance of molecular profiling for patients.
On May 8, 2025, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the combination of avutometinib (VS-6766) and defactinib (VS-6063), marketed together as AVMAPKI FAKZYNJA CO-PACK, for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received at least one prior systemic therapy. This approval marks a significant milestone as the first-ever FDA-approved therapy specifically indicated for this rare and difficult-to-treat subtype of ovarian cancer.
“This first-ever FDA approval in this disease was based on the primary analysis of the Phase 2 RAMP 201 trial, in which the combination of avutometinib and defactinib resulted in a significant overall response rate for patients with a KRAS mutation while being generally well tolerated. The approval… establishes this combination as the new standard of care,” Dr. Rachel Grisham, medical oncologist at the Memorial Sloan Kettering Cancer Center, who served as global lead principal investigator of RAMP 201 and RAMP 301, said.
Low-Grade Serous Ovarian Cancer (LGSOC)
LGSOC represents a small subset of epithelial ovarian cancers, with unique molecular characteristics and clinical behavior distinct from high-grade serous ovarian carcinoma (HGSOC).
It tends to affect younger women, exhibits indolent growth, and is less responsive to conventional chemotherapy. Approximately 70% of LGSOC tumors are driven by alterations in the MAPK pathway, with KRAS mutations occurring in about 30% of cases.
Until now, there were no FDA-approved treatments specifically targeting this patient population. The data reiterates the importance molecular testing for patients.
“There is simply no reason now not to test and detect such an important driver of disease that can lead to a much more optimal therapy as opposed to just giving chemotherapy or giving more aggressive treatments where there is no biomarker,” Dr. Dejan Juric, medical oncologist at Mass General Cancer Center, told SurvivorNet Connect during a previous conversation on molecular profiling in general.
“These approaches [testing via tissues obtained during biopsy or liquid biopsy] are now very reliable. In early days, we struggled with sensitivity … We couldn’t detect the mutations even when we knew they were there. But now the tests are much better and a lot more straightforward to do,” Dr. Juric added.
Clinical Development and Rationale for Combination Therapy
The approval of avutometinib and defactinib is based primarily on data from the Phase 2 RAMP 201 (ENGOT-ov60/GOG-3052) trial (NCT04625270), supported by the Phase 1 FRAME trial (NCT03875820).
Avutometinib is a dual RAF/MEK inhibitor that functions as a “MEK clamp,” inhibiting both RAF and MEK signaling and suppressing feedback reactivation within the MAPK pathway. Defactinib is a selective focal adhesion kinase (FAK) inhibitor. Preclinical and early-phase data suggested that inhibition of FAK can counteract resistance mechanisms to MEK inhibition, offering a biologically rational and synergistic approach to treating KRAS-mutated tumors.
Study Design and Patient Population
RAMP 201 was an open-label, multicenter study that enrolled 57 adult patients with measurable KRAS-mutated recurrent LGSOC who had received at least one prior systemic treatment, including a platinum-based regimen.
Key eligibility criteria included ECOG performance status 0–1, adequate organ function, and prior recovery from treatment-related toxicities. Patients with active skin or ocular disorders or those receiving warfarin were excluded.
Treatment consisted of:
- Avutometinib 3.2 mg orally twice weekly (Day 1 and Day 4)
- Defactinib 200 mg orally twice daily Both agents were administered for the first 3 weeks of each 4-week cycle, continued until progression or unacceptable toxicity.
Efficacy Results
The combination therapy demonstrated clinically meaningful and durable responses:
- Confirmed ORR (primary endpoint): 44% (95% CI, 31–58)
- Complete response: 3.5%
- Partial response: 40%
- Duration of response: Range of 3.3 to 31.1 months
- 6-month disease control rate (DCR): 70%
- Median progression-free survival (PFS): 22 months (95% CI, 11.1–36.6)
In contrast, patients with KRAS wild-type disease showed a lower ORR of 17% (95% CI, 8–30), a DCR of 50%, and a median PFS of 12.8 months, supporting the specificity of the regimen’s efficacy in KRAS-mutated LGSOC.
Safety Profile and Adverse Events
Overall, the regimen was generally well-tolerated, with manageable toxicity. The most common adverse events (AEs) included:
- Nausea (74%)
- Fatigue (72%)
- Rash (72%)
- Diarrhea (68%)
- Musculoskeletal pain (68%)
- Edema (67%)
- Vomiting (49%)
- Dermatitis acneiform (37%)
- Vitreoretinal disorders (37%)
Serious AEs occurred in 32% of patients. Dose interruptions and reductions due to AEs were required in 84% and 44% of patients, respectively. Permanent discontinuation of therapy occurred in 14%.
Despite these toxicities, no new safety signals were identified. An aggressive mitigation strategy, particularly for dermatologic toxicities such as acneiform rash, has been incorporated into clinical practice.
Dosing Schedule
- Avutometinib: 3.2 mg orally twice weekly (Days 1 and 4)
- Defactinib: 200 mg orally twice daily
- Both agents are administered 3 weeks on, 1 week off in each 4-week cycle
Regulatory and Development Pathway
The approval utilized the FDA’s Real-Time Oncology Review (RTOR) program and benefited from several expedited pathways:
- Breakthrough Therapy Designation: Granted May 2021
- Orphan Drug Designation: For avutometinib alone and in combination
- Priority Review: Application accepted and approved ahead of the June 30, 2025 PDUFA date
The confirmatory Phase 3 RAMP 301 trial (NCT06072781) is actively enrolling patients with both KRAS-mutated and wild-type LGSOC to validate the clinical benefit and support continued approval.
Implications for Practice
This approval shifts the standard of care for patients with KRAS-mutated recurrent LGSOC.
Key implications include:
- Routine molecular profiling of LGSOC tumors is now essential to identify KRAS mutations
- Recognition of LGSOC as a distinct clinical entity, separate from HGSOC in behavior, biology, and treatment
- Integration of MEK and FAK dual inhibition as a viable strategy for overcoming resistance in RAS-driven tumors
The approval of avutometinib plus defactinib marks a significant advancement in the management of low-grade serous ovarian cancer. It reflects the successful translation of biologic rationale into meaningful clinical benefit and highlights the power of international collaboration, precision medicine, and targeted therapy in rare cancer subtypes.
Ongoing research through RAMP 301 will be critical in confirming the benefit and expanding access to this regimen globally. For now, the availability of AVMAPKI FAKZYNJA CO-PACK offers new hope to patients with KRAS-mutated recurrent LGSOC — a population that, until now, had no targeted treatment options.
