FDA reviewing oral combination treatment for ovarian cancer
Verastem duo of avutometinib, defactinib aimed at LGSOC
The U.S. Food and Drug Administration (FDA) has agreed to review Verastem Oncology’s application seeking approval of a combination of avutometinib and defactinib for the treatment of certain patients with low-grade serous ovarian cancer (LGSOC).
The application covers the treatment duo for LGSOC patients who have received at least one prior systemic therapy and whose tumors have mutations in the KRAS gene. If approved, the treatment regimen would be the first FDA-approved therapy specifically for this patient population.
The application has been granted priority review, which shortens the standard FDA review time from 10 months to about six months. A decision is expected by June 30.
“The FDA filing acceptance and Priority Review for the combination of avutometinib and defactinib underscores the critical unmet need among patients diagnosed with this rare and insidious disease,” Dan Paterson, president and CEO of Verastem, said in a company press release. The company is “taking an important step forward in addressing a condition that has long been overlooked, and we look forward to working with the FDA during its review process and preparing for a commercial launch in mid-2025,” Paterson said.
The application to the FDA was largely supported by data from the Phase 2 RAMP 201 clinical trial (NCT04625270), which demonstrated that the treatment was well tolerated and led to favorable response rates, especially among patients with KRAS mutations.
Treatment for ovarian cancer
While that’s being reviewed, Verastem is also recruiting participants for a confirmatory Phase 3 trial called RAMP 301 (NCT06072781), which will compare the efficacy of avutometinib plus defactinib against standard-of-care treatments in about 270 patients with recurrent LGSOC. It’s recruiting participants at sites in the U.S., Canada, Europe, Australia, and New Zealand.
The company believes data from that trial has the potential to support an expanded indication for avutometinib and defactinib that would include LGSOC patients regardless of their KRAS mutation status.
LGSOC is a slow-growing form of ovarian cancer that is less responsive to chemotherapy than other types of ovarian cancer, and often comes back after treatment. There are currently no FDA-approved treatments specifically for LGSOC.
Avutometinib is an oral small molecule designed to ultimately inhibit a signaling pathway called RAS/MAPK, whose activation is implicated in about 70% of LGSOC tumors, according to Verastem. Moreover, up to around 30% of LGSOC tumors have KRAS gene mutations that are associated with RAS/MAPK activation. [slide 5]
Defactinib is an oral inhibitor of focal adhesion molecule, or FAK, another enzyme implicated in cancer cell growth. Inhibiting FAK is expected to enhance the anti-tumor activities of avutometinib.
Verastem believes that together, the two molecules will enable a more complete block of the signaling pathways that drive LGSOC tumor growth, leading to stronger and more durable responses. The company is also evaluating the treatment combination for other cancers associated with RAS/MAPK activation, including forms of lung and pancreatic cancer.
Testing safety, efficacy
The ongoing open-label RAMP 201 trial is designed to test the safety and efficacy of avutometinib, alone or combination with defactinib, in more than 200 women with LGSOC that progressed or recurred after at least one prior systemic therapy.
It includes a dose-finding portion (Part A) and two expansion phases (Parts B and C) in which the treatment’s safety and efficacy are being evaluated. In Parts A and B, participants received either avutometinib alone (4 mg twice weekly) or a combination of avutometinib (3.2 mg) taken twice weekly and defactinib (200 mg) taken twice daily. In Part C, all participants received the combination. A fourth segment called Part D is testing a lower dose of avutometinib — 1.6 mg twice weekly — in combination with defactinib.
The main goal of all parts of the trial was to determine the proportion of patients with a confirmed partial or complete treatment response – called an overall response rate (ORR).
Trial analyses, including patients given the treatment combination across parts A, B, and C, showed that the treatment combination led to a 31% ORR. Response rates were lower for those given avutometinib alone, where the ORR was 17%.
Response rates were higher in patients who had received fewer prior lines of therapy. They were also higher in the subset of trial participants with KRAS genetic mutations (44%) relative to those without them (17%). Still, 82% of all patients given the treatment combination experienced a tumor shrinkage, regardless of their mutation status.
Eighty-one percent of patients given the combination had a response that lasted at least six months. Treatment responses lasted a median of 31.1 months, or about 2.5 years, in all evaluable patients and among the subset of patients with KRAS mutations, and 9.2 months among those without KRAS mutations.
Most participants were alive without cancer progression after six months (79%) and a year (58%), with a median progression-free survival (PFS) time of a little over a year (12.9 months). PFS was longer in the KRAS mutant population (22 months) than in the non-mutant population (12.8 months).
The treatment was generally well tolerated, with the most common treatment-related side effects including nausea, diarrhea, and increased blood levels of creatine phosphokinase, an indicator of muscle damage.
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