30 November 2020 - - US-based biopharmaceutical company Verastem, Inc. (NASDAQ: VSTM) (also known as Verastem Oncology) has initiated a Phase 2 registration-directed clinical trial of VS-6766, its RAF/MEK inhibitor, and defactinib, its FAK inhibitor, in patients with recurrent low-grade serous ovarian cancer (LGSOC), the company said.

The Phase 2 study (GOG3052) is an adaptive two-part multicenter, parallel cohort, randomized, open label trial to evaluate the efficacy and safety of VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC.

The first part of the study will determine the optimal regimen of either VS-6766 monotherapy or in combination with defactinib in patients with recurrent LGSOC randomized 1: 1 in each treatment arm.

The determination of which regimen to take forward into the expansion phase of the trial will be made based on objective response rate data.

The expansion phase of the study will examine efficacy and safety parameters of the regimen selected. Trial enrollment is underway in the United States with European sites to follow.

The company previously announced its successful meeting with the Food and Drug Administration in 3Q20 and the FDA's support of the company's development strategy and adaptive trial design for LGSOC.

The launch of the trial follows the recent results of two clinical trials led by Professor Udai Banerji, Deputy director of Drug Development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust.

The first, a Phase 1 trial published in The Lancet Oncology, showed that VS-6766 could be effective against a range of KRAS-mutated tumor types, including lung and gynecological cancers.

The second, a Phase 1/2 trial presented at the American Association for Cancer Research annual meeting 2020, showed the combination of a RAF/MEK and FAK inhibitor could be beneficial for patients with KRAS mutant LGSOC.

Low-grade serous ovarian cancer (LGSOC) is a recurrent, chemotherapy-resistant cancer with a high mortality rate.2 It comprises 5-10% of serous ovarian cancers and 6-8% of all ovarian cancers.

There are an estimated 6,000 patients in the US and 80,000 worldwide living with this disease.5 LGSOC is most often diagnosed in women between the ages of 45-55 years.

LGSOC has a median survival of approximately 10 years,2 with 85% of patients experiencing recurrence6 and enduring severe pain and complications as the disease progresses.

Chemotherapy is the standard of care for this disease.

VS-6766 is an oral small molecule inhibitor of the RAF/MEK signaling pathway. In contrast to other MEK inhibitors in development, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK.

This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors.

Defactinib (VS-6063) is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors.

The company has received Orphan Drug designation for defactinib in ovarian cancer in the US, EU and Australia.

Preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.

RAS mutant tumors are present in ~30% of all human cancers, have historically presented a difficult treatment challenge and are often associated with significantly worse prognosis.

Challenges associated with identifying new treatment options for these types of cancers include resistance to single agents, identifying tolerable combination regimens with MEK inhibitors and new RAS inhibitors in development addressing only a minority of all RAS mutated cancers.

The combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mutant tumors.

In an ongoing investigator-initiated Phase 1/2 FRAME study, the combination of VS-6766 and defactinib is being evaluated in patients with LGSOC, KRAS mutant NSCLC and colorectal cancer.

Updated data from this study presented at the 2nd Annual RAS-Targeted Drug Development Summit in September 2020 demonstrated a 56% overall response rate and long duration of therapy among patients with KRAS-G12 mt LGSOC.

Based on an observation of higher response rates seen in NSCLC patients with KRAS-G12V mutations in the study, Verastem will also be further exploring the role of VS-6766 and defactinib in KRAS-G12V NSCLC.

The FRAME study was expanded in August 2020 to include new cohorts in pancreatic cancer, KRAS mutant endometrial cancer and KRAS-G12V NSCLC.