Verastem Oncology Publishes Phase 2 RAMP 201 Results: Avutometinib + Defactinib in Recurrent LGSOC
Primary analysis from the ENGOT‑OV60/GOG‑3052/RAMP 201 study reported in the Journal of Clinical Oncology, showing a 31% overall response rate in recurrent low‑grade serous ovarian cancer.
Verastem Oncology, focused on therapies for RAS/MAPK pathway-driven cancers, today announced the primary outcomes of the Phase 2 RAMP 201 trial have been published online in JCO. The full manuscript—“Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low‑Grade Serous Ovarian Cancer: Primary Analysis of ENGOT‑OV60/GOG‑3052/RAMP 201”—includes key safety and efficacy findings and will appear in print.
Key Findings: A Clinically Meaningful Response
- Confirmed Overall Response Rate (ORR): 31% among all evaluable patients (34/109).
- 44% ORR in patients with KRAS mutations (25/57)
- 17% ORR in KRAS wild-type patients (9/52)
- Median Duration of Response (DOR): 31.1 months (overall and KRAS-mutant); 9.2 months in wild-type.
- Median Progression-Free Survival (PFS): 12.9 months (overall); 22.0 months in KRAS-mutant and 12.8 months in wild-type.
- Disease Control Rate (DCR ≥6 months): 61% overall; 70% in KRAS-mutant; 50% in wild-type patients.
- Tumor Reduction: 82% of participants had measurable reduction in target lesions irrespective of KRAS status.
Supporting FDA Approval and Expanding NCCN Guideline Coverage
Dr. John Hayslip, CMO emphasized the significance of the data, stating:
“The publication reflects the impactful clinical progress delivered by the combination in recurrent LGSOC.”
These results paved the way for FDA accelerated approval (May 2025) of AVMAPKI FAKZYNJA™ CO‑PACK (avutometinib + defactinib) for KRAS-mutant recurrent LGSOC. It is simultaneously supporting NCCN® review to expand guidelines to include KRAS wild-type patients based on these findings, in addition to the FRAME study. Currently, approval is aligned with the Category 2A NCCN recommendation for KRAS-mutated patients.
Clinical Insights from Global Experts
Professor Susana Banerjee (The Royal Marsden / Institute of Cancer Research), Global Lead Investigator of RAMP 201, noted:
“Durable responses and reduction in lesions, independent of mutation status, mark a major advancement in this rare ovarian cancer.”
Safety data showed acceptable tolerability with just a 10% discontinuation rate due to adverse events (AEs). Common AEs included:
- Nausea: 67% (2.6% grade ≥3)
- Diarrhea: 58.3% (7.8% grade ≥3)
- Elevated CPK: 60% (24.3% grade ≥3)
Phase 3 RAMP 301: Expanding the Evidence Base
Building on RAMP 201, Verastem is advancing the Phase 3 RAMP 301 international trial, led by Dr. Rachel Grisham (Memorial Sloan Kettering) in collaboration with ENGOT, GOG, GTG‑UK, and NCRI. This confirmatory study will enroll patients with and without KRAS mutations to compare the combination therapy vs standard chemotherapy or hormonal agents.
Dr. Grisham explains:
“We aim to validate findings across broader patient populations and establish the combination as a new standard of care.”
RAMP 201 Trial Design Overview
- Adaptive, randomized, two-part, open-label Phase 2 study
- Part A: Compared avutometinib alone vs combination with defactinib
- Expansion (Parts B, C, D):
- Part B/C: Evaluated the go-forward combination dosing regimen (avutometinib 3.2 mg twice weekly + defactinib 200 mg twice daily)
- Part D: Tested a lower-dose combination to inform individualized dose reductions
Understanding Low-Grade Serous Ovarian Cancer (LGSOC)
- LGSOC is distinct from high-grade serous ovarian cancer and often less responsive to chemotherapy.
- Affects approximately 6,000–8,000 U.S. women and 80,000 worldwide.
- Occurs in younger women (peaking in ages 20–30 and 50–60) and typically has long disease course (median survival ~10 years).
- Around 70% of cases involve RAS pathway mutations, including KRAS mutations in ~30% of patients.
Mechanism: MEK + FAK Dual Inhibition Strategy
- Avutometinib (MEK inhibitor): Targets MEK and blocks RAF-driven reactivation.
- Defactinib (FAK inhibitor): Suppresses FAK, which can mediate resistance when RAF/MEK are inhibited.
- The combination provides a broader blockade of the RAS/RAF/MEK/ERK (MAPK) pathway, addressing mechanisms of tumor growth and therapeutic resistance.
Approved Treatment: AVMAPKI FAKZYNJA™ CO‑PACK
U.S. Indication
Approved under accelerated pathway for adult patients with KRAS-mutant recurrent LGSOC following prior systemic therapy. Continued approval depends on confirmatory trials.
Key Safety Considerations
- Ocular Toxicities: Requires baseline and periodic ophthalmic exams—discontinue for grade 4 events.
- Serious Skin Reactions: Monitor for photosensitivity and SCARs.
- Liver Toxicity: Monitor LFTs regularly; manage dosage accordingly.
- Rhabdomyolysis Risk: Monitor creatine phosphokinase (CPK).
- Embryo-Fetal Toxicity: Use effective contraception; advise against breastfeeding.
Common Adverse Reactions (≥25%)
Include elevated CPK, nausea, fatigue, elevated liver enzymes, rash, diarrhea, musculoskeletal pain, edema, hemoglobin decrease, increased triglycerides, alopecia, and visual impairment.
Drug Interaction Warnings
- Avoid strong/moderate CYP3A4 inhibitors or inducers
- Caution with warfarin and acid-reducing agents
Special Populations
- May impair fertility
- Contraindicated during breastfeeding
Broader Pipeline Activity
- Verastem is exploring avutometinib + defactinib combinations in additional RAS/MAPK-driven malignancies:
- Advanced pancreatic cancer (RAMP 205)
- KRAS G12C mutant non-small cell lung cancer (RAMP 203)
These investigational uses are not yet FDA-approved.
Strategic and Clinical Significance
- RAMP 201 represents a milestone in rare ovarian cancer treatment, demonstrating both depth and durability of response.
- Regulatory acceleration, publication in JCO, and planned guideline updates mark critical momentum.
- The ongoing Phase 3 RAMP 301 trial and expanded research in other RAS/MAPK tumors reinforce Verastem’s strategic direction in oncology.
As the field continues to evolve, Verastem’s combination therapy offers new hope for patients with recurrent LGSOC and may pave the way for transformative advances across cancers driven by RAS/MAPK pathway alterations.
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a biopharmaceutical company committed to developing and commercializing new medicines to improve the lives of patients diagnosed with RAS/MAPK pathway-driven cancers. Verastem markets AVMAPKI™ FAKZYNJA™ CO-PACK in the U.S. Our pipeline is focused on novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition, FAK inhibition, and KRAS G12D inhibition. For more information, please visit www.verastem.com and follow us on LinkedIn.
