On May 24, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported that it has initiated the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval of the combination of avutometinib, a RAF/MEK clamp, and defactinib, a selective FAK inhibitor, for adult patients with recurrent KRAS mutant (KRAS mt) low-grade serous ovarian cancer (LGSOC), who received at least one prior systemic therapy (Press release, Verastem, MAY 24, 2024, View Source [SID1234643702]). The rolling review process allows the Company to submit completed sections of an application for review by the FDA before all sections become available. The initial sections of the application will include the nonclinical and quality sections. In discussions with the FDA, Verastem reached agreement to submit a primary efficacy analysis based on the RAMP 201 study with 12 months of follow up. Based on discussions with the FDA, we understand that the proposed indication for final submission of the clinical module can be expanded in the event Verastem provides data that demonstrates a substantial improvement over available therapy in the KRAS wild-type (KRAS wt) population. FDA has accepted Verastem’s plan to submit the clinical module in the second half of 2024 to complete the NDA application. Previously, the FDA granted Breakthrough Therapy Designation (BTD) for the combination for treatment of patients with recurrent LGSOC, regardless of KRAS status, following one or more previous lines of therapy and Orphan Drug Designation (ODD) for the combination in certain LGSOC indications. The Company plans to request a priority review of the NDA. Currently, there are no FDA-approved treatments specifically for recurrent LGSOC.
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 initiation of our rolling NDA submission of the avutometinib and defactinib combination for accelerated approval, is an important step towards addressing the significant unmet needs that patients face living with KRAS mutant low-grade serous ovarian cancer," said Dan Paterson, president and chief executive officer of Verastem Oncology. "The data from our ongoing RAMP 201 trial continues to support our belief that the avutometinib and defactinib combination has the potential to be a new standard of care in patients with recurrent low-grade serous ovarian cancer, if approved. In the second half of this year, we anticipate completing our NDA submission with the mature data from the RAMP 201 trial and discussing with the FDA a path forward for patients with KRAS wild-type disease. We also expect to present the mature dataset at a medical meeting in the second half of 2024."
RAMP 201 is a Phase 2 registration-directed study evaluating avutometinib and defactinib combination in patients with recurrent LGSOC. The enrollment in RAMP 201 is completed, with 115 patients being treated at the recommended Phase 2 dose (RP2D) of avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily for 3 out of every 4 weeks, and follow-up continues. Verastem expects to complete the NDA submission after obtaining mature safety and efficacy data from the RAMP 201 trial, including 12 months of follow-up, anticipated in the second half of 2024. Verastem also plans to further discuss the KRAS wt data with FDA to inform the potential path forward for approval for this patient population. The Company plans to present the mature dataset from RAMP 201 at a medical meeting in the second half of 2024. As of February 2024, the interim data continued to show robust overall response rates (ORR) and durable responses with low discontinuation rates due to adverse events (AEs) in patients from RAMP 201 Parts A, B, C, who had a minimum follow-up of five (5) months.
The FDA granted Breakthrough Therapy Designation of the investigational combination of avutometinib and defactinib for the treatment of all patients with recurrent LGSOC regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy in May 2021. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC in March 2024. The Company believes that this Orphan Drug Designation signifies that LGSOC is a rare ovarian cancer that is a distinct and different disease from other forms of ovarian cancer such as high-grade serous ovarian cancer (HGSOC). LGSOC is highly recurrent and fatal, with no FDA-approved treatment options, and the current standard of care treatments include hormonal therapy or chemotherapy, which have demonstrated an ORR between 6-13% with discontinuation due to AEs of 17-30%.
The Company is currently enrolling patients and activating sites for RAMP 301, an international confirmatory Phase 3 trial, evaluating the avutometinib and defactinib combination versus standard of care chemotherapy or hormonal therapy for the treatment of patients with KRAS mt and KRAS wt recurrent LGSOC.
Conference Call and Webcast Information
Verastem will hold an investor conference call and webcast on Friday, May 24 at 8:00 am EDT, to review the initiation of the NDA submission and limited, topline data from the RAMP 201 trial, with a minimum follow-up of five (5) months and the RAMP 205 data. The call will feature members of Verastem’s management team. 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 accompany slides, will be accessible here. The Company expects to file an 8-K pertaining to this update.
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 RAMP 301
RAMP 301 (GOG-3097; ENGOT-ov81/NCRI) is an international collaboration between The GOG Foundation, Inc. (GOG) and the European Network of Gynaecological Oncological Trial groups (ENGOT) sponsored by Verastem Oncology. The trial is expected to enroll a total of 270 patients in the U.S., Canada, the United Kingdom, Europe, Australia and South Korea, who will be randomized to either the combination of avutometinib and defactinib or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan) or hormone therapy (letrozole, anastrozole). The primary endpoint is progression free survival (PFS) by Blinded Independent Central Review. Secondary endpoints include ORR, duration of response, disease control rate, safety and tolerability, patient reported outcomes, and overall survival.
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 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 n investigational RAF/MEK clamp that is designed to induce 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. Avutometinib is designed to block both MEK kinase activity and the ability of RAF to phosphorylate MEK. This differentiated proposed mechanism potentially allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation of the investigational combination of avutometinib and defactinib, a selective FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status 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 is currently conducting clinical trials with avutometinib in RAS/MAPK driven tumors as part of its Raf And Mek Program or RAMP. RAMP 301 (NCT06072781) is an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent 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 in each of the dose optimization and expansion phases and the low-dose evaluation.
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 a PanCAN Therapeutic Accelerator Award.