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Verastem Oncology's Combination Therapy Advances in KRAS-Mutated Lung Cancer

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NEW YORK – Verastem Oncology has begun enrolling KRAS-mutated, recurrent non-small cell lung cancer patients into a Phase II registrational trial of its RAF/MEK inhibitor VS-6766 and FAK inhibitor defactinib after the combination showed encouraging activity in a Phase I basket study, according to researchers at the American Association for Cancer Research's virtual annual meeting on Saturday.

Matthew Krebs, who leads early-phase lung cancer clinical trials at The Christie NHS Foundation Trust, reported data from the Phase I FRAME trial, which explored the activity of the VS-6766-defactinib combination in various KRAS-mutated solid tumors. Krebs specifically broke out the data in the study from 20 NSCLC patients, in whom the overall response rate was 15 percent on the VS-6766-defactinib combination. The disease control rate was 65 percent and median progression-free survival was 16 weeks, as of the data cutoff in March.

The Phase I study also determined the recommended Phase II dose. Researchers found that an intermittent schedule of VS-6766 and defactinib had the lowest toxicity. They also said toxicity was manageable in the FRAME trial and that no patients had stopped treatment due to adverse events.

Patients had received prior anti-PD-1 or anti-PD-L1 checkpoint inhibitors and had tumors characterized by several different KRAS variants. Researchers reported that two patients with the KRAS G12V variant appeared to respond best to the VS-6766-defactinib combination. These patients comprised two of the three confirmed partial responses in the study. The other patient who saw a partial response had the G12C mutation.

Based on this data, Krebs said researchers are further exploring the combination's activity in KRAS G12V-mutated NSCLC patients and will enroll 10 more patients with these mutations to the FRAME study. He suggested that the VS-6766 and defactinib combination was especially effective in these patients because the G12V mutation signals through the RAF/MEK pathway, while other variants signal through the PI3K/AKT pathway.

"We also know that G12V in NSCLC models are especially dependent on CRAF, which is a target of VS6766," Krebs said. "The dependency on CRAF and the synergistic activity of the combination with defactinib provides a clear hypothesis for the differential activity in KRAS G12V variant, which is a high unmet clinical need."

Around a quarter of NSCLC patients have tumors driven by a KRAS mutation, with KRAS G12C mutations occurring in 13 percent of patients and KRAS G12V mutations occurring in 7 percent.

Although the FRAME study is still ongoing, the data so far have given Verastem confidence to advance the VS-6766-defactinib combination to a registrational trial. In the Phase II RAMP-202 trial, which Verastem initiated in December, researchers are enrolling 100 patients with recurrent KRAS-mutated NSCLC and randomizing them to either VS-6766 alone or in combination with defactinib. The first stage of the study will focus on patients with the KRAS G12V variant and an exploratory arm will include patients on other KRAS mutations.

Verastem CSO Jonathan Pachter previously said that the randomized design of the RAMP-202 study will allow the company to tease out the ability of defactinib to improve patients' outcomes on top of VS-6766. In the first stage, researchers will determine whether VS-6766 is more effective as a monotherapy or in combination with defactinib. Then, they will evaluate the efficacy and safety of the more effective regimen in the second stage of the Phase II study.

Krebs is optimistic that the Phase II study will be positive based on findings from the Phase I FRAME trial.

"This is a population who have exhausted all other treatment options," he said. "If we're getting a response rate in KRAS G12V-mutated patients of] over 30 percent and we're getting progression-free survival beyond six months, that would be encouraging. If we're seeing that kind of activity, the question is whether we'll bring the treatment regimen into earlier lines of treatment."

KRAS-mutated lung cancer is a competitive area for drug development. If successful, Verastem's VS-6766-defactinib combination will compete with treatments being developed by Amgen and Mirati Therapeutics, which are first going after NSCLC patients with KRAS G12C mutations.

Amgen submitted a new drug application for sotorasib for locally advanced or metastatic KRAS G12C-mutated NSCLC in December and received a priority review designation from the US Food and Drug Administration earlier this year. 

At the European Lung Cancer Virtual Congress in March, Mirati reported that 45 percent of 51 evaluable non-small cell lung cancer patients in the Phase I/II KRYSTAL-1 trial had partial responses to its investigational KRAS G12C inhibitor adagrasib, and 24 patients had stable disease. These patients harbored KRAS G12C mutations, but patients whose tumors also harbored STK11 mutations experienced an even greater response.

Verastem's focus on advancing a combination regimen, especially if it is active against KRAS G12V-mutated NSCLC in addition to KRAS G12C-mutated subtypes, may allow for differentiation. The company is also hoping its VS-6766-defactinib combination will demonstrate activity in KRAS-mutated tumors beyond NSCLC. The FRAME basket study also includes cohorts with KRAS-mutated colorectal cancer, ovarian cancer, and other solid tumors. Krebs said data from those cohorts will be presented at a future medical conference.

In November, Verastem also began a registrational Phase II study of VS-6766 in recurrent, low-grade serous ovarian cancer with KRAS mutations after early data from the FRAME trial was reported. That study is structured similarly to the RAMP-202 NSCLC trial and is evaluating VS-6766 as a monotherapy and in combination with defactinib.

Verastem paid $3 million upfront to Tokyo-based Chugai Pharmaceutical in January 2020 to license VS-6766. If the drug is commercialized, Verastem will also pay royalties to Chugai.