On November 6, 2023 Verastem Oncology (Nasdaq: VSTM) (the "Company"), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported results of the efficacy and safety of avutometinib and defactinib in recurrent low-grade serous ovarian cancer (LGSOC) following prior systemic therapy (Press release, Verastem, NOV 6, 2023, View Source [SID1234637068]). The results of this planned subgroup analysis of Part A of the Phase 2 RAMP 201 (ENGOT-ov60/GOG-3052) trial were presented as a late-breaking abstract in an oral presentation during a plenary session at the Annual Global Meeting of the International Gynecologic Cancer Society (IGCS 2023) November 5-7, 2023, in Seoul, Korea.
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"Patients with recurrent LGSOC currently have no medicines approved by the U.S. Food and Drug Administration and limited treatment options for their disease," said Rachel Grisham, M.D., Section Head, Ovarian Cancer and Director, Westchester Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center N.Y., and the lead U.S. investigator of RAMP 201. "The results from this analysis are encouraging as the combination of avutometinib and defactinib demonstrates robust efficacy in recurrent LGSOC irrespective of the number of prior therapies, and for most of which, response to previous therapy was poor."
This planned subgroup analysis was performed to assess efficacy (confirmed objective response rate (ORR) via blinded independent central review per RECIST v1.1) and safety in prior lines of therapy (LoT) (1-3 LoT, ≥4 LoT). The analysis also evaluated efficacy in the context of best response to most recent prior treatment in the metastatic/recurrent setting.
In the combination arm, the observed ORRs were consistent across patients who received 1-3 (45.5%, 5/11, 95% CI 17-77) and ≥4 lines of therapy (44.4%, 8/18, 95% CI 22-69). Prior to enrollment in RAMP 201, only 2/23 (8.7%) patients responded to their last prior treatment in the metastatic/recurrent setting, whereas the combination of avutometinib and defactinib yielded an ORR of 43.5% (10/23) in this subgroup. The safety profiles of avutometinib and defactinib were similar in the less and more heavily pretreated subgroups and both analyses were consistent with previously reported safety data. The majority of treatment-emergent adverse events were mild to moderate.
Initial results of RAMP 201 Part A, presented at the American Society for Clinical Oncology Annual Meeting in May 2023, demonstrated an ORR of 45% (13/29) and tumor shrinkage in 86% (25/29) of evaluable patients that were treated with the combination of avutometinib and defactinib. Safety and tolerability were favorable and consistent with previously reported data. As previously announced, Verastem Oncology intends to file for accelerated approval with the FDA for the combination of avutometinib and defactinib based on mature data from the RAMP 201 trial, together with the results of the investigator-initiated FRAME trial. The Company plans to initiate its Phase 3 confirmatory trial (RAMP 301) of avutometinib and defactinib in LGSOC versus standard of care (SOC) chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan) or hormone therapy (letrozole, anastrozole) before the end of the year.
Dr. Grisham is a paid consultant for Verastem Oncology.
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 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 inhibitors. The U.S. Food and Drug Administration granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, its 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.
Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS pathway-driven tumors as part of its (Raf And Mek Program). RAMP 301 is a 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 is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and has completed enrollment in the dose optimization and expansion phases and is enrolling for low-dose evaluation. Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively. Supported by the "Therapeutic Accelerator Award" Verastem Oncology received from PanCAN, the Company is conducting RAMP 205, a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.