On October 17, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported updated data from the Phase 2 RAMP 201 (ENGOTov60/GOG3052) clinical trial evaluating the combination of avutometinib, an oral RAF/MEK clamp, and defactinib, an oral, selective FAK inhibitor, in patients with recurrent low-grade serous ovarian cancer (LGSOC) (Press release, Verastem, OCT 17, 2024, View Source [SID1234647232]). The data were published as a late-breaking abstract and additional detailed findings will be presented today in an oral plenary session at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting in Dublin, Ireland.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The primary analysis of the RAMP 201 trial, with a data cutoff of June 30, 2024, showed a confirmed overall response rate (ORR) by blinded independent central review (BICR) of 31% (34/109; 95% CI: 23-41) in all evaluable patients with measurable disease with approximately 12 months of follow up. Among patients with KRAS mutant (mt) LGSOC, the confirmed ORR was 44% (25/57; 95% CI: 31-58) and for patients with KRAS wild-type (wt) LGSOC the confirmed ORR was 17% (9/52; 95% CI: 8-30). The median duration of response (DOR) was 31.1 months (95% CI: 14.8-31.1) in all evaluable patients, with 31.1 months (95% CI: 14.8-31.1) in the KRAS mt population and 9.2 months (95% CI: 5.5-NEi) in the KRAS wt population. The median progression-free survival (PFS) was 12.9 months (95% CI: 10.9-20.2) in all evaluable patients, with 22 months (95% CI: 11.1-36.6) in the KRAS mt population and 12.8 months (95% CI: 7.4-18.4) in the KRAS wt population. The disease control rate (DCR) at 6 or more months was 61% in the total evaluable population, 70% in KRAS mt population and 50% in KRAS wt population. The updated data continue to demonstrate avutometinib in combination with defactinib is generally well-tolerated, with a 10% discontinuation rate due to adverse events (AEs) and no new safety signals were identified. The most common treatment-related AEs (all grades, grade ≥3) for the combination were nausea (67.0%, 2.6%), diarrhea (58.3%, 7.8%), and increased blood creatine phosphokinase levels (60.0%, 24.3%).
"The notable response rates and low discontinuation rate seen with the combination of avutometinib and defactinib are significant. These updated results confirm the potential of this new combination therapy to change practice and be the new standard for care for recurrent low-grade serous ovarian cancer, which previously had limited effective treatment options," said Professor Susana Banerjee, M.B.B.S., M.A., Ph.D., F.R.C.P., Global Lead investigator of the study, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London.
Regulatory Update
A Type A meeting was recently held with the U.S. Food and Drug Administration (FDA), during which the Company aligned with the FDA on the Company’s plans to complete the New Drug Application (NDA) submission in October 2024 for adult patients with recurrent KRAS mt LGSOC, who received at least one prior systemic therapy, based on the mature data from the RAMP 201 trial. The Company plans to seek Accelerated Approval from the FDA and request Priority Review. At this time, the FDA did not recommend pursuing a KRAS wt indication under Accelerated Approval. This strategic approach allows the Company to potentially reach the market more efficiently while mapping out a path forward with the FDA for the KRAS wild-type indication, including leveraging data from the ongoing RAMP 301 Phase 3 trial. RAMP 301, which is currently enrolling patients with recurrent LGSOC regardless of KRAS mutation status, will serve as a confirmatory study for the initial indication and has potential to expand the indication regardless of KRAS mutation status.
"In the mature data from the RAMP 201 trial most patients achieved tumor reductions and a median progression-free survival that was greater than one year across both KRAS mutant and KRAS wild-type patient populations. These results reinforce our confidence in the potential of the combination of avutometinib and defactinib to change how patients with recurrent low-grade serous ovarian cancer are treated," said John Hayslip, M.D., chief medical officer of Verastem Oncology. "Encouraged by the durable clinical benefit seen in KRAS wild-type patients in RAMP 201 and the poorer prognosis in this subset of patients that are treated with sub-optimal treatment choices today, we believe that this treatment combination will be the preferred treatment option for all subgroups of patients with recurrent low-grade serous ovarian cancer. We are committed to making the combination available to these patients, including working with the FDA to outline a path forward to expand the indication with additional data."
"Now that we have the mature data from the RAMP 201 trial, we are on track to complete our NDA submission for recurrent KRAS mutant low-grade serous ovarian cancer in October," said Dan Paterson, president and chief executive officer of Verastem Oncology. "We look forward to working with the FDA to potentially bring the first and only FDA-approved treatment specifically for patients with recurrent KRAS mutant low-grade serous ovarian cancer to the U.S. market in 2025."
Conference Call and Webcast Information
Verastem will hold an investor conference call and webcast on October 17, 2024 at 4:30 p.m. EDT, to review the mature data from the RAMP 201 trial. To access the conference call, please dial (844) 763-8274 (local) or (412) 717-9224 (international) at least 10 minutes prior to the start time and ask to be joined into the Verastem Oncology conference call. A live audio webcast of the call, along with accompanying slides, will be accessible under "Events & Presentations" in the Investors & Media section of the company’s website at www.verastem.com.
The Company expects to file a current report on Form 8-K with the Securities and Exchange Commission (SEC) later today, which will include a copy of the IGCS oral presentation and the presentation which the Company intends to use on the investor conference call and webcast.
About RAMP 201
RAMP 201 (ENGOTov60/GOG3052) is an adaptive, two-part multicenter, parallel cohort, randomized, open-label trial to evaluate the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent low-grade serous ovarian cancer. The first part of the study (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) are evaluating 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 is evaluating a low dose of avutometinib in combination with defactinib to inform individualized dose reduction.
About Low-Grade Serous Ovarian Cancer (LGSOC)
LGSOC is a rare ovarian cancer that is insidious, persistent and ultimately fatal. 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. The majority of patients report a negative impact of LGSOC on their mental and physical health, fertility, and long-term quality of life. The current standard of care for this disease includes hormone therapy and chemotherapy, but there are no treatments specifically approved by the U.S. Food and Drug Administration to treat LGSOC.
About the Avutometinib and Defactinib Combination
Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors.
Verastem Oncology is currently conducting clinical trials with avutometinib in RAS/MAPK driven tumors as part of its Raf And Mek Program or RAMP. Verastem is currently enrolling patients and activating sites for RAMP 301 (NCT06072781) an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib, a selective FAK inhibitor, versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC). RAMP 201 (NCT04625270) is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and enrollment has been completed for the RAMP 201 trial.
Verastem initiated a rolling New Drug Application (NDA) submission in May 2024 to the U.S. Food and Drug Administration (FDA) for the investigational combination of avutometinib and defactinib in adults with recurrent KRAS mutant LGSOC who received at least one prior systemic therapy and expects to complete its NDA submission in the second half of 2024 with a potential FDA decision in the first half of 2025. The FDA granted Breakthrough Therapy Designation of the investigational combination of avutometinib and defactinib for the treatment of all patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.
Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) in combination with avutometinib and defactinib and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 (NCT05074810) and RAMP 204 (NCT05375994) trials, respectively. The RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award. FDA granted Orphan Drug Designation to avutometinib and defactinib combination for the treatment of pancreatic cancer.