FDA Grants Fast Track Designation to Avutometinib Plus Sotorasib for Treatment of NSCLC


The treatment is for patients with KRAS G12C-mutant metastatic NSCLC who have previously received at least 1 systemic therapy and were not treated with a KRAS G12C inhibitor.

The FDA has granted Fast Track Designation to avutometinib, an investigational RAF/MEK clamp, in combination with the KRAS G12C inhibitor sotorasib (Lumakras; Amgen Inc.) for the treatment of patients with KRAS G12C-mutant metastatic non-small cell lung cancer (NSCLC) who have previously received at least 1 systemic therapy and were not treated with a KRAS G12C inhibitor. The Fast Track process is designed to advance the development and accelerate the review of new drugs that are intended to either treat or prevent serious conditions while addressing unmet medical needs.

FDA Food and Drug Administration -- Image credit: wladimir1804 | stock.adobe.com

Image credit: wladimir1804 | stock.adobe.com

Avutometinib is a RAF/MEK clamp currently in late-stage development. It stimulates inactive complexes of MEK with ARAF, BRAF, and CRAF, potentially creating a more complete and robust anti-tumor response through maximal RAS pathway inhibition. Unlike available MEK inhibitor, avutometinib blocks both MEK kinase activity as well as RAF’s ability to phosphorylate MEK, allowing it to block MEK signaling without its compensatory activation which limits the efficacy of other inhibitors. Currently, avutometinib has a Breakthrough Therapy designation with defactinib for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after 1 or more previous lines of therapy (including platinum-based chemotherapy).

“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 of Verastem Oncology, in a press release.

Although newer targeted therapies specific to KRAS G12C-mutant NSCLC have demonstrated promise, avutometinib targets a common source of mutation, the RAS pathway. Prior research demonstrated improvements, such as deeper tumor regression and a decrease in the frequency of relapse of tumors, with the combination of avutometinib and sotorasib compared to sotorasib alone.

The RAMP 203 (NCT05074810) examined the outcomes, safety, and efficacy of avutometinib with sotorasib as a treatment in adult patients with KRAS G12C-mutant locally advanced or metastatic NSCLC who received prior therapy for metastatic disease and were not treated with a KRAS G12C inhibitor previously. The results of the trial indicate that the pharmacokinetic profile of avutometinib combined with sotorasib was similar to results in monotherapy studies. In addition, no drug-drug interacts were reported by the patients undergoing treatment with the combined avutometinib regimen.

Twice-weekly oral avutometinib (4.0mg) for 21 days plus daily oral sotorasib (960mg) for 28 days was selected as RP2D based on dose limiting toxicity assessment. Further, the enrollment of patients with KRAS G12C-mutant NSCLC who are either naïve to or previously treated with a KRAS G12C inhibitor is ongoing in expanded phases of the RAMP 203 trial.

“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,” said Paterson in the press release.


Verastem Oncology. 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). News release. January 18, 2024. Accessed January 19, 2024. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-granted-fast-track-designation-combination

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