FDA Grants BTD to VS-6766 With Defactinib for Recurrent Low-Grade Serous Ovarian Cancer

The FDA has granted breakthrough therapy designation to the combination of VS-6766, an investigational RAF/MEK inhibitor and defactinib (VS-6063), a FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after 1 or more lines of therapy, including platinum-based chemotherapy, according to a press release by Verastem, Inc.

RAS-mutated tumors tend to be recurrent and highly aggressive. VS-6766 is meant to vertically inhibit the RAF/MEK pathway. Due to the fact it has a dual mechanism of action, the agent is able to vertically inhibit the RAS pathways in a single drug, rationalizing its use in the recurrent LGSOC. It is being studied in different combinations for different cancers.

"Patients with low-grade serous ovarian cancer urgently need better solutions due to low response rates and tolerability issues associated with current therapies," said Melissa Aucoin, chief executive officer of the National Ovarian Cancer Coalition, in a press release. "A breakthrough therapy designation in this disease is a significant step forward for the women who often, at a relatively young age, start a lengthy battle with this highly recurrent and impactful disease."

The breakthrough therapy designation is based on the study of VS-6766 as a monotherapy or in combination with defactinib (NCT04625270). The parallel-assignment study has an estimated enrollment of 100 participants and an estimated completion date of December 2025. The primary outcome of part A is to determine the optimal regimen of the agent either as a combination with defactinib or a monotherapy. The primary outcome of part B is to determine the efficacy of the optimal regimen. Secondary outcomes include overall response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

During part A, patients were randomized to either received VS-6766 as a monotherapy in combination with defactinib. During part B, patients received the same regimen.

In order to participate, patients must have histologically proven LGSOC, progression or recurrence after one prior systemic therapy for metastatic disease, measurable disease, an ECOG performance status of 1 or greater, adequate organ function, adequate recovery from toxicities related to prior treatments, and agree to use contraception. Patients who have received systemic anti-cancer therapy within 4 weeks of the first dose of the study have co-existing high-grade ovarian cancer, a history of prior malignancy with recurrence, major surgery within 4 weeks, symptomatic brain metastases requiring steroids or other interventions, a SARS-Cov2 infection within 28 days prior to first dose, or prior MEK exposure are not eligible to participate.

In the most recent interim analysis, the ORR for the combination was 52%. For patients with a KRAS mutation, the ORR was 70%. For patients with KRAS wild-type, the ORR was 44%, and it was 0% for those with an undetermined KRAS status. The most common adverse event (AE) was rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea. Most of the AEs were grade ½ and reversable. A few patients have been on therapy for more than a year, indicating the combination has the potential for long-term benefit.

"Breakthrough Therapy designation will facilitate our efforts to verify the robust and durable response and compelling safety profile of VS-6766 with defactinib that we have seen in patients with LGSOC and potentially bring a new therapy to these patients as quickly as possible," said Brian Stuglik, CEO of Verastem Oncology in a press release. "The majority of LGSOC is RAS pathway-driven, and we are committed to exploring the potential for VS-6766 as a backbone therapy across RAS pathway-driven solid tumors."

_REFERENCE:

_{Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem Oncology. May 24, 2021. Accessed May 24, 2021. https://bit.ly/3yCF4oo.}