You have full access to this article via your institution.

Credit: natasaadzic/iStock/Getty Images Plus

The FDA has granted accelerated approval to Verastem’s FAK inhibitor defactinib (Fakzynja) in combination with its MEK inhibitor avutometinib (Avmapki) for KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC). The approval is a rare green light for a novel–novel drug combination, made up of two drugs that had not previously been approved by the FDA.

The novel–novel approval path “is a hard route, no question about it,” says Verastem CSO Jonathon Pachter. But phase II data of the MEK inhibitor alone compared with the MEK inhibitor plus the FAK inhibitor showed that the combination was more effective, he adds. “More people should be open to novel–novel combinations,” says Pachter. “How many good products are left on the cutting room floor because people didn't try it,” he asks.

Verastem launched in 2010 to develop drugs to kill cancer stem cells, and licensed its FAK inhibitor defactinib from Pfizer in 2012. When a phase II trial of defactinib failed in mesothelioma in 2015, Verastem started looking for other uses for the drug.

Internal and external data suggested that it might pair well with a MEK inhibitor, potentially because it can prevent compensatory upregulation of FAK signalling following MEK inhibition. In 2020, Verastem licensed the MEK inhibitor avutometinib, previously called CH5126766, from Roche subsidiary Chugai to complete its combo. Avutometinib is an allosteric small-molecule glue that acts to clamp MEK and RAF into an inactive complex, says Pachter. This inhibits MEK and also suppresses feedback reactivation of RAF activity. BRAF and MEK inhibitor combinations already show that dual blockade of these signalling nodes can work better than single-agent inhibitors, points out Pachter. With avutometinib, you get “two nodes with one agent”.

Verastem prioritized the combination for the treatment of LGSOC, a cancer that is thought to affect around 6,000–8,000 women in the US. The disease tends to be resistant to chemotherapy, and the optimal treatment approach remains unclear. Around 30% of LGSOC patients have KRAS mutations, with increased dependency on RAF–MEK signalling that could make them more responsive to Verastem’s combination.

“FAK inhibitors are unusual, and avutometinib is unusual. Being brave enough to go for a relatively rare cancer is unusual. And we put all that together,” says Pachter.

The FDA approved the combination on the basis of the RAMP-201 trial, an open-label trial that included 57 adult patients with KRAS-mutated recurrent LGSOC who had received at least one prior systemic therapy. Patients received avutometinib twice weekly and defactinib twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. The drug had an overall response rate of 44%, with durations of response ranging from 3.3 months to 31.1 months, shows the combination’s label. The average duration of treatment was 18 months, says Pachter.

Overall survival data is not yet mature. Patients with KRAS-mutated LGSOC have a median overall survival of around 12 years, adds Verastem.

The combination’s label warns of ocular toxicities, serious skin toxicities and hepatotoxicities.

A confirmatory trial of the drug is ongoing, evaluating avutometinib and defactinib versus standard chemotherapy or hormonal therapy for recurrent LGSOC with and without a KRAS mutation. Longer term, the company hopes to also advance the drug for first-line treatment of LGSOC.

The company is also collaborating with Amgen to test avutometinib and Amgen’s KRAS inhibitor sotorasib with or without defactinib in a phase I/II trial in patients with KRAS-G12C mutant non-small-cell lung cancer. A phase Ib/II trial is evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in front-line metastatic pancreatic cancer.

A few other FAK inhibitors are in development, including InxMed’s ifebemtinib, licensed from Boehringer Ingelheim, Signet Therapeutics’ SIGX-1094, and Ascentage’s APG-2449, a FAK/ALK/ROS1 inhibitor.

The FDA has granted a few other approvals to novel–novel combinations in recent years, including one in oncology. In 2018, it approved Array’s novel–novel pairing of the BRAF inhibitor encorafenib (Braftovi) with the MEK inhibitor binimetinib (Mektovi) for unresectable or metastatic melanoma with BRAF V600E or V600K mutations. The FDA first approved a BRAF plus MEK inhibitor combination with its green light for GSK’s dabrafenib (Tafinlar) plus trametinib (Mekinist) in 2014, however, a year after each of those agents was approved for monotherapy use.

Two other novel–novel approvals were for infectious diseases. In 2016, the FDA approved Merck & Co’s fixed-dose combination of the NS5A inhibitor elbasvir plus its NS3/4A protease inhibitor grazoprevir (Zepatier) for chronic hepatitis C virus. In 2020, the FDA approved Regeneron’s triple-novel antibody cocktail of atoltivimab plus maftivimab plus odesivimab (Inmazeb) for Ebola virus infection.