On October 14, 2023 Verastem Oncology (Nasdaq: VSTM) (the "Company"), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported the initial safety, pharmacokinetics and recommended Phase 2 dose (RP2D) in the RAMP 203 trial evaluating the safety, tolerability and efficacy of avutometinib in combination with sotorasib in patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) (Press release, Verastem, OCT 14, 2023, View Source [SID1234635977]). The results will be presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) October 11-15, 2023 in Boston, Massachusetts.
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"The RAMP 203 study is investigating the potential benefits of a more complete vertical blockade of the RAS pathway with the combination of avutometinib and sotorasib in KRAS G12C-mutant locally advanced or metastatic NSCLC," said Mark Awad, M.D., Associate Professor of Medicine at Harvard Medical School and Director of Clinical Research of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, investigator on the trial, and presenting author. "These initial findings, including the recommended Phase 2 dose and the encouraging preliminary efficacy and safety results, provide support for the combination, and I look forward to completing the expansion phase of the trial."
RAMP 203 (NCT05074810) is a 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. The confirmed objective response rate (ORR) was 25% (3/12) across efficacy-evaluable patients and seen in both KRAS G12C inhibitor resistant (14.3%; 1/7) and naïve (40%; 2/5) patients.
The pharmacokinetic profile of avutometinib in combination with sotorasib 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. 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.
"The RAMP 203 trial builds on preclinical data which demonstrated the addition of avutometinib to sotorasib improved the depth of MAPK pathway inhibition and substantially enhanced tumor regression relative to sotorasib alone," said Dan Paterson, President and CEO, Verastem Oncology. "Given KRAS G12C mutations are the most common KRAS mutation in NSCLC and acquired mutations and amplifications occur upon clinical progression to KRAS G12C inhibitor monotherapy, the results of the RAMP 203 trial are important in understanding potential new treatment approaches for patients."
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 increased 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 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). 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.