On January 29, 2024 Verastem Oncology (Nasdaq:VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported key 2024 strategic priorities and upcoming catalysts to support advancement of its clinical programs in RAS pathway-driven cancers (Press release, Verastem, JAN 29, 2024, View Source [SID1234639687]).

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"We have made significant progress in our commitment to advancing new solutions for RAS pathway-driven cancers and look forward to an exciting and catalyst-filled year ahead. With plans to submit an NDA for Accelerated Approval for the combination of avutometinib and defactinib in recurrent low-grade serous ovarian cancer in the first half of this year, we are working rapidly to bring forward the first potential therapy approved by the U.S. Food and Drug Administration for patients with LGSOC in need of better treatment options," said Dan Paterson, President and Chief Executive Officer of Verastem Oncology. "Further, we plan to provide data read-outs with avutometinib and defactinib combinations in KRAS G12C-mutant non-small cell lung cancer and frontline metastatic pancreatic cancer, as well as supporting our collaborator GenFleet in advancing oral KRAS G12D inhibitor GFH375/VS-7375 into a Phase 1 clinical trial this year."

2023 and Recent Accomplishments

· Presented interim results from the Phase 1/2 RAMP 201 trial of avutometinib and defactinib in LGSOC, including an objective response rate (ORR) of 45% (13/29) and disease control in 86% (25/29) of evaluable patients. Safety and tolerability continued to be favorable and consistent with previously reported data.
· Finalized design with the FDA and initiated confirmatory Phase 3 RAMP 301 trial to evaluate the efficacy and safety of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent LGSOC.
· Launched patient and healthcare professional initiatives, including Let’s Talk About LGSOC , designed to support clinicians in the diagnosis and management of LGSOC and to provide information, resources and support to patients. Engaged with more than 25% of the recurrent LGSOC patient population.
· Presented initial results from Phase 1/2 RAMP 203 trial evaluating the efficacy and safety of avutometinib and sotorasib in patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) who have or have not been previously treated with a KRAS G12C inhibitor. The confirmed ORR was 25% (3/12) across efficacy-evaluable patients and responses observed in both KRAS G12C inhibitor resistant (14.3%; 1/7) and naïve (40%; 2/5) patients. Avutometinib 4.0 mg by mouth biweekly (BIW) 21/28 days and sotorasib 960 mg by mouth once-daily (QD) 28/28 days was selected as the recommended Phase 2 dose based on dose limiting toxicity assessment.
· Received Fast Track designation from the FDA for avutometinib, in combination with Amgen’s G12C inhibitor, LUMAKRAS (sotorasib), for the treatment of patients with KRAS G12C-mutant metastatic NSCLC who have received at least one prior systemic therapy and have not been previously treated with a KRAS G12C inhibitor.
· Entered into a discovery and development collaboration with GenFleet Therapeutics ("GenFleet") to advance three oncology discovery programs targeting RAS pathway-driven cancers. Completed investigational new drug (IND)-enabling GLP toxicology studies for oral KRAS G12D inhibitor GFH375/VS-7375, selected as lead program.

Strategic Priorities and Anticipated 2024 Milestones and Catalysts

LGSOC Program

· Begin submission of an NDA to the FDA for Accelerated Approval for the combination of avutometinib and defactinib in recurrent LGSOC in H1 2024; prepare for potential commercial launch in 2025.
· Present full data from Part A and Part B of RAMP 201 trial in LGSOC at a scientific medical conference in H1 2024.
· Initiate discussions with European and Japanese regulatory authorities for the avutometinib and defactinib regimen in LGSOC to address patient needs outside the U.S.

KRAS G12C-Mutant NSCLC Program

· Based on stronger tumor regressions in KRAS G12C-mutant NSCLC preclinical models when FAKi is added along with G12Ci + avutometinib, add defactinib to the RAMP 203 trial of avutometinib with sotorasib.

· Data updates from RAMP 203 and RAMP 204 trials planned for mid-2024.

Frontline Metastatic Pancreatic Cancer Program

· Present initial safety and efficacy results from RAMP 205 trial of avutometinib and defactinib in combination with standard of care gemcitabine and nab-paclitaxel in frontline metastatic pancreatic cancer in H1 2024.

GenFleet Collaboration

· GenFleet expected to submit an IND for GFH375/VS-7375 in China for patient with KRAS G12D mutations in H1 2024 and begin a Phase 1 trial for GFH375/VS-7375 in China in H2 2024.
· Companies to continue discovery/lead optimization for second and third programs.

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 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 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.