8-K: Verastem Oncology Announces Positive Phase 2 Trial Results for Avutometinib and Defactinib Combination in Recurrent Low-Grade Serous Ovarian Cancer

Verastem Oncology reported positive mature data from the RAMP 201 trial, showing promising results for the combination of avutometinib and defactinib in treating recurrent low-grade serous ovarian cancer, and is on track to complete its NDA submission in October 2024.

Summary

• Verastem Oncology presented updated data from the Phase 2 RAMP 201 trial at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting.
• The trial evaluated the combination of avutometinib and defactinib in patients with recurrent low-grade serous ovarian cancer (LGSOC).
• The primary analysis showed an overall response rate (ORR) of 31% in all evaluable patients.
• Patients with KRAS mutant LGSOC had a 44% ORR, while those with KRAS wild-type LGSOC had a 17% ORR.
• The median duration of response (DOR) was 31.1 months in all evaluable patients.
• The median progression-free survival (PFS) was 12.9 months in all evaluable patients, with 22 months in the KRAS mutant population and 12.8 months in the KRAS wild-type population.
• The combination therapy was generally well-tolerated, with a 10% discontinuation rate due to adverse events.
• The company is on track to complete the New Drug Application (NDA) submission in October 2024 for recurrent KRAS mutant LGSOC.
• Verastem plans to seek Accelerated Approval and Priority Review from the FDA.
• The ongoing RAMP 301 Phase 3 trial will serve as a confirmatory study and has the potential to expand the indication regardless of KRAS mutation status.

Sentiment

Score: 9

Explanation: The document presents very positive clinical trial results, a clear regulatory path, and a significant market opportunity, indicating a strong positive sentiment from an investment perspective.

Positives

• The combination of avutometinib and defactinib demonstrated clinically meaningful responses in patients with recurrent LGSOC.
• The treatment showed a durable benefit with a median duration of response of 31.1 months.
• The progression-free survival was over one year, with 22 months in the KRAS mutant population.
• The safety profile of the combination was consistent with previous reports, with a low discontinuation rate of 10% due to adverse events.
• The company is on track to complete the NDA submission in October 2024 for recurrent KRAS mutant LGSOC.
• The RAMP 301 Phase 3 trial is enrolling patients regardless of KRAS mutation status, potentially expanding the treatment's applicability.

Negatives

• The low-dose regimen of avutometinib (1.6 mg BIW) + defactinib (200 mg BID) was determined to be suboptimal and will not be pursued as a starting dose.
• The ORR for KRAS wild-type patients was lower at 17% compared to 44% in KRAS mutant patients.
• Some patients experienced adverse events leading to dose interruptions and reductions, although most were manageable.
• There were 4 deaths within 30 days of discontinuation, though none were considered related to the study treatment.

Risks

• The FDA did not recommend pursuing a KRAS wild-type indication under Accelerated Approval at this time.
• The success of the NDA submission and the potential for accelerated approval are subject to FDA review and approval.
• The commercial success of the treatment depends on market acceptance and reimbursement.
• There are risks associated with the development and commercialization of the product, including manufacturing and supply interruptions.
• The company faces competition from other companies developing treatments for LGSOC.
• The RAMP 301 trial is still enrolling and the results are not yet available.

Future Outlook

Verastem is focused on completing the NDA submission for the avutometinib and defactinib combination in recurrent KRAS mutant LGSOC, seeking accelerated approval and priority review, and continuing enrollment in the RAMP 301 Phase 3 trial to potentially expand the indication to all LGSOC patients. They also plan to present updated results from other trials in the near future.

Management Comments

• Professor Susana Banerjee stated that the results confirm the potential of the combination therapy to change practice and be the new standard of care for recurrent low-grade serous ovarian cancer.
• John Hayslip, M.D., chief medical officer of Verastem Oncology, expressed confidence in the potential of the combination to change how patients with recurrent LGSOC are treated.
• Dan Paterson, president and chief executive officer of Verastem Oncology, stated that they are on track to complete the NDA submission in October and look forward to working with the FDA to potentially bring the first and only FDA-approved treatment specifically for patients with recurrent KRAS mutant LGSOC to the U.S. market in 2025.

Industry Context

The announcement is significant as it addresses a high unmet need in the treatment of recurrent low-grade serous ovarian cancer, a rare and challenging disease with limited effective treatment options. The positive results from the RAMP 201 trial position Verastem as a potential leader in this space, with a clear path towards regulatory approval and commercialization. The company is also actively exploring the use of the combination in other cancer types, indicating a broader potential impact.

Comparison to Industry Standards

• Current standard of care for LGSOC includes chemotherapy and hormonal therapy, which have shown limited efficacy with objective response rates (ORR) between 6-13% and progression-free survival (PFS) below 12 months.
• Trametinib and binimetinib, other MEK inhibitors, have shown response rates of 26% and 16% respectively, but with high discontinuation rates due to toxicity (36% and 31%).
• The RAMP 201 trial results for the avutometinib and defactinib combination show a 31% ORR overall, 44% in KRAS mutant patients, and a median PFS of 12.9 months overall, with 22 months in KRAS mutant patients, which is a significant improvement over existing treatments.
• The discontinuation rate due to adverse events for the combination is 10%, which is lower than the rates observed with other MEK inhibitors.
• The MILO study of binimetinib showed a 16% ORR and a median PFS of 10.6 months, while the GOG 281 study of trametinib showed a 26% ORR and a median PFS of 13 months, both of which are inferior to the results of the RAMP 201 trial.
• The RAMP 201 results suggest that the combination of avutometinib and defactinib could become a new standard of care for recurrent LGSOC, particularly in the KRAS mutant population.

Stakeholder Impact

• Shareholders: The positive trial results and regulatory progress are likely to positively impact the company's stock price.
• Patients: The potential approval of the avutometinib and defactinib combination offers a new treatment option for patients with recurrent LGSOC.
• Employees: The progress in clinical development and regulatory submissions may boost employee morale and job security.
• Customers: Healthcare providers will have a new treatment option for their patients with LGSOC.
• Suppliers: The potential commercialization of the drug may lead to increased demand for raw materials and manufacturing services.
• Creditors: The positive results and regulatory progress may improve the company's creditworthiness.

Next Steps

• Complete the rolling NDA submission in October 2024 for recurrent KRAS mutant LGSOC.
• Seek Accelerated Approval and Priority Review from the FDA.
• Continue enrollment in the RAMP 301 Phase 3 confirmatory trial.
• Present updated results from the RAMP 205 study in Q1 2025.
• Report updated interim data from the RAMP 203 NSCLC trial in H2 2024.
• Report initial interim data from the RAMP 204 NSCLC trial in H2 2024.
• Prepare for a potential US IND for GFH375/VS-7375 by early 2025.

Key Dates

Keywords

Avutometinib, Defactinib, LGSOC, Ovarian Cancer, KRAS Mutant, KRAS Wild-type, RAMP 201, RAMP 301, NDA, FDA, Oncology, Targeted Therapy, MEK Inhibitor, FAK Inhibitor