Avutometinib/Defactinib Seeks FDA Approval for Ovarian Cancer via Rolling NDA

• Verastem Oncology has begun submitting a rolling new drug application (NDA) to the FDA for a combination therapy consisting of avutometinib (previously VS-6766) and defactinib to treat recurrent low-grade serous ovarian cancer (LGSOC).
• The FDA may consider a broader patient population, including those with KRAS wild-type disease, if sufficient improvement over current treatments is shown.
• The final clinical data module is planned to be submitted in the second half of 2024.

A rolling submission of a NDA to the FDA has been initiated, seeking accelerated approval of avutometinib, a RAF/MEK clamp, given in combination with defactinib, a selective FAK inhibitor, for the treatment of adult patients with recurrent KRAS-mutated LGSOC previously treated with at least 1 prior systemic therapy.¹

The rolling review process allows Verastem Oncology to submit completed sections of the NDA for FDA review before the entire application is finalized. The initial sections will focus on nonclinical and quality data.

Based on discussions with the FDA, the company will submit a primary efficacy analysis from the ENGOT-ov60/GOG-3052/RAMP 201 trial (NCT04625270) with 12 months of follow-up data. The FDA indicated that the final submission of the clinical module could potentially include a broader indication, including for patients with KRAS wild-type disease, if the results yield a substantial improvement over available therapies in this population.

"The initiation of our rolling NDA submission of the avutometinib and defactinib combination for accelerated approval, is an important step towards addressing the significant unmet needs that patients face living with KRAS-mutant low-grade serous ovarian cancer,"​ said Dan Paterson, president and chief executive officer of Verastem Oncology, in a press release. "The data from our ongoing RAMP 201 trial continues to support our belief that the avutometinib and defactinib combination has the potential to be a new standard of care in patients with recurrent low-grade serous ovarian cancer, if approved.”

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The FDA has accepted the company’s plan to submit the clinical module in the second half of 2024 to complete the NDA application. Verastem plans to request a priority review of the NDA.

About the Combination of Avutometinib and Defactinib

The FDA previously granted a breakthrough therapy designation for this combination for treatment of patients with recurrent LGSOC, regardless of KRAS status, who have received 1 or more previous lines of therapy. The combination has also received an orphan drug designation for specific LGSOC indications.

Currently, there are no FDA-approved therapies specifically for recurrent LGSOC.

Avutometinib and defactinib is being studied in the RAMP 201 study, a phase 2, registration-directed study in patients with recurrent LGSOC. Enrollment in RAMP 201 is completed, and 115 patients are being treated at the recommended phase 2 dose (RP2D) of avutometinib given at 3.2 mg twice a week along with defactinib at a dose of 200 mg twice a day for 3 out of every 4 weeks. Follow-up continues.

The NDA submission is expected to be completed once mature safety and efficacy data from the RAMP 201 trial, including 12 months of follow-up, are obtained. This is anticipated in the second half of 2024.

As of February 2024, interim data from the study continued to demonstrate high response rates, regardless of the number of prior lines of therapy patients received. A total of 45% (n = 13; 95% CI, 26%-46%) of patients (n = 29) had a confirmed response. Patients with KRAS mutations (n = 15) had an overall response rate (ORR) of 60%, and patients with KRAS wild-type disease (n = 14) had an ORR of 29%.² Further, tumor regression was seen in 86% of patients treated with the combination.

Confirmed responses were observed in 3 out of 4 patients who had previously received MEK inhibitors. Among the 13 patients with stable disease, 10 achieved tumor shrinkage, with 6 demonstrating at least a 15% reduction in tumor size. The median time from the last line of treatment was 1.84 months.

Safety findings also showed that the incidence of grade 3 or greater treatment-emergent adverse effects in patients treated with the combination was consistent between patients with 1 to 3 prior lines of therapy vs at least 4 prior lines of therapy.

REFERENCES:

1. Verastem Oncology announces the initiation of a rolling submission of NDA to FDA seeking accelerated approval of avutometinib and defactinib combination for the treatment of adult patients with recurrent KRAS mutant low-grade serous ovarian cancer. News release. Verastem Oncology. May 24, 2024. Accessed May 29, 2024. https://tinyurl.com/2fufcdj2

2. Banerjee SN, Nieuwenhuysen EV, Santin AD, et al. Avutometinib + defactinib in recurrent low-grade serous ovarian cancer (LGSOC): a subgroup analysis of ENGOT-ov60/GOG-3052/RAMP 201 part A. Presented at: 2024 SGO Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.