Verastem Oncology has started a Phase 2 clinical trial evaluating its inhibitors, VS-6766 and defactinib, for the treatment of people with recurrent low-grade serous ovarian cancer (LGSOC), the company announced.

The trial seeks to recruit up to 100 female patients — more information is available here — and will investigate the company’s RAF/MEK inhibitor VS-6766, either alone or in combination with defactinib, a FAF inhibitor.

“Results to date have demonstrated the clinical activity of VS-6766 and defactinib in KRAS mutant cancers, signaling potentially promising clinical results in low-grade serous ovarian cancer and in KRAS-G12V mutant non-small cell lung cancer,” Brian Stuglik, CEO of Verastem, said in a press release.

“The start of our registration-directed trial in recurrent LGSOC is a significant milestone in our work to develop the backbone of therapy for RAS driven tumors, an area of minimal therapeutic results, significant toxicity and limited treatment options,” he added.

VS-6766 is an orally available small molecule that inhibits the activity of MEK and RAF, two proteins belonging to a pathway involved in several cancer processes, including cell proliferation, survival, and migration.

Mutations in KRAS, which are present in about 30% of all cancers, appear to result in the abnormal activation of this signaling pathway, and blocking this signaling has long been seen as an attractive treatment for these cancers.

Defactinib (VS-6063) is an oral small molecule inhibitor of FAK and PYK2 that targets cancer cells both directly and through modulation of the tumor microenvironment. It has already received orphan drug designation in the U.S., the European Union, and Australia for the treatment of ovarian cancers.

Preclinical and clinical data have demonstrated that these two inhibitors work in synergy to prevent tumor growth, particularly in cancers carrying KRAS mutations. In an ongoing Phase 1/2 trial (NCT03875820) — which is recruiting patients with LGSOC, lung cancer, and colorectal cancer — more than half (56%) of KRAS-mutant ovarian cancer patients responded to this combination.

The findings led Verastem to initiate the multicenter, open-label Phase 2 trial in LGSOC patients only, designed to support the medication’s accelerated approval pending positive results.

The study will be conducted in two parts. First, researchers will include LGSOC patients carrying KRAS mutations and randomly assign them VS-6766 alone or in combination with defactinib to determine the optimal treatment regimen for these patients.

Then, in an extension part, the efficacy of the selected regimen will be investigated in an additional group of patients, regardless of KRAS mutations. In addition to response rates, researchers will examine the duration of responses, the time patients live without disease worsening, and overall survival.

“Response rates with current therapies have historically been low and the toxicity profiles of these agents make it difficult to keep patients on therapy,” said Rachel Grisham, MD, director of gynecologic medical oncology at Memorial Sloan Kettering Cancer Center in Westchester, New York, and the study’s principal U.S. investigator. “This trial represents an opportunity to further evaluate the potential for improved outcomes for patients with LGSOC.”