The combination of avutometinib and sotorasib received FDA fast track designation for the treatment of KRAS G12C-mutant non–small cell lung cancer.
The FDA has granted a fast track designation the combination of avutometinib and sotorasib, for the treatment of patients with KRAS G12C-mutant metastatic NSCLC who have received at least 1 prior systemic therapy and have not been previously treated with a KRAS G12C inhibitor.1
Avutometinib is an investigational RAF/MEK clamp which targets the RAS pathway, a common source of acquired mutation, and sotorasib is a KRAS G12C inhibitor. The combination has been studied in preclinical proof-of-concept trials and has deepened tumor regression through enhanced blockade of ERK activation and a decrease in the frequency of relapse of tumors compared with sotorasib alone.
Now, the RAMP 203 clinical development program will continue to evaluate the combination among patients with KRAS G12C-mutant locally advanced or metastatic NSCLC.
“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 chief executive officer, Verastem Oncology, in a press release. “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.”
RAMP-203 is a phase 1/2, multicenter, open label, dose-evaluation and dose-expansion study.2 Initial results from the study showed that the confirmed ORR was 25% across the patients who were evaluable for efficacy and KRAS G12C inhibitor resistant (14.3%) or naive (40%). Avutometinib had a similar pharmacokinetic profile when given with sotorasib compared with monotherapy studies of the agent.
There were no drug-drug interactions observed between the combination of avutometinib and sotorasib, and avutometinib 4.0 mg orally twice a week for 21 of 28 days and oral sotorasib 960 mg twice a day for all 28 days was selected as the recommended phase 2 dose (RP2D) based on dose limiting toxicity assessment.
In part A, the dose-evaluation portion of the trial, investigators determined the RP2D of the combination regimen which will be further evaluated in part B, the dose-expansion phase.3 Secondary end points of the study seek to distinguish the safety and toxicity profile of the combination, evaluate additional efficacy parameters for the RP2D, and characterize the pharmacokinetics of avutometinib and sotorasib, as well as relevant metabolites.
Enrollment in the study is open to male and female patients ≥ 18 years of age with histologically or cytologically confirmed NSCLC without histological evidence of a small cell or neuroendocrine components that are either metastatic or locally advanced and unresectable disease, and they must have a known KRAS G12C mutation determined using a validated test prior to enrollment. In addition to having received at least 1 prior systemic therapy, they may have previously received adjuvant chemotherapy for early-stage disease.
Part A of the trial included patients who have either had exposure to a prior G12C inhibitor or no exposure. If they have received a prior G12C inhibitor, they are required to have had a best response to a prior G12C inhibitor of confirmed response by RECIST 1.1 or stable disease for ≥4 cycles. For part B, patients in cohort 1 must have not received prior therapy with a G12C inhibitor, and for cohort 2, patients must have had a best response to prior G12C inhibitor of confirmed response by RECIST 1.1 or stable disease for ≥4 cycles.
Further, patients are eligible for enrollment if they have measurable disease according to RECIST 1.1, an ECOG performance status ≤1, adequate organ function, adequate hepatic function, adequate renal function, adequate cardiac function, and adequate recovery from toxicities related to prior treatments to at least grade 1 by CTCAE v5.0. Female patients must have a baseline QTc interval < 460 ms and males must have a baseline QTc interval of ≤ 450 ms using Fredericia’s QT correction formula. All patients of reproductive age must use a highly effective contraceptive method throughout the trial and for 3 months (males) or 1 month (females) after their last dose.