Verastem Oncology Granted Fast Track Designation for Combination of Avutometinib and Sotorasib for the Treatment of KRAS G12C-Mutant Non-Small Cell Lung Cancer (NSCLC)

BOSTON, Mass. —  Verastem Oncology, a biopharmaceutical company committed to advancing new medicines for patients with cancer, today announced the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation to Verastem Oncology’s investigational RAF/MEK clamp, avutometinib, in combination with Amgen’s KRAS G12C inhibitor, LUMAKRAS^TM (sotorasib), for the treatment of patients with KRAS G12C-mutant metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy and have not been previously treated with a KRAS G12C inhibitor. Fast Track is a process designed to facilitate the development and expedite the review of new drugs intended to treat or prevent serious conditions and address unmet medical need.

“Receiving Fast Track Designation for the combination of avutometinib and sotorasib reinforces the importance of improving the depth of MAPK pathway inhibition to enhance tumor regression relative to KRAS G12C inhibition alone and the potential of the combination of avutometinib and sotorasib in KRAS G12C mutant locally advanced or metastatic NSCLC,” said Dan Paterson, President and CEO, Verastem Oncology. “Given that KRAS G12C is the most common KRAS mutation in NSCLC, the advancement of the combination is important in understanding potential new treatment approaches. We look forward to continued interaction with the FDA as we advance the development of this promising treatment regimen.”

While newer targeted therapies specific to KRAS G12C-mutant NSCLC have shown significant promise, avutometinib targets the RAS pathway, which is a common source of acquired mutation. Preclinical proof-of-concept studies demonstrated improvements with the combination of avutometinib and sotorasib vs sotorasib alone, including deeper tumor regression through enhanced blockade of ERK activation and a decrease in the frequency of relapse of tumors. The RAMP 203 clinical development program will determine whether the promising preclinical results observed with the combination of avutometinib with sotorasib translate into improved clinical outcomes for patients with KRAS G12C-mutant locally advanced or metastatic NSCLC who have received prior therapy for metastatic disease and have not been previously treated with a KRAS G12C inhibitor.

Initial results of the RAMP 203 (NCT05074810) Phase 1/2, multicenter, open label, dose evaluation/expansion study evaluating the efficacy and safety of avutometinib + sotorasib in patients with KRAS G12C-mutant NSCLC who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have been previously treated with a KRAS G12C inhibitor demonstrated confirmed responses in both KRAS G12C inhibitor resistant and naïve patients. The pharmacokinetic profile of avutometinib in combination with sotorasib in the RAMP 203 trial was similar to results in monotherapy studies. No drug-drug interactions were observed between avutometinib and sotorasib. Avutometinib 4.0 mg PO BIW 21/28 days + sotorasib 960 mg PO QD 28/28 days was selected as RP2D based on dose limiting toxicity (DLT) assessment. These initial RAMP 203 results were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October, 2023. Enrollment of patients with KRAS G12C-mutant NSCLC who are either naïve to or previously treated with a KRAS G12C inhibitor is ongoing in the expansion phase of RAMP 203 with updated results expected in the first half of 2024.

 

About Avutometinib

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. Avutometinib is currently in late-stage development.

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 RAMP (Raf And Mek Program) trials. 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.

 

About Verastem Oncology

Verastem Oncology (Nasdaq: VSTM) is a development-stage biopharmaceutical company committed to the development and commercialization of new medicines to improve the lives of patients diagnosed with cancer. Our pipeline is focused on novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition and focal adhesion kinase (FAK) inhibition.