FDA Designates VS-6766 Plus Defactinib as Breakthrough Therapy for Patients With LGSOC

The FDA recently granted Breakthrough Therapy Designation (BTD) to VS-6766, a RAF/MEK inhibitor, plus defactinib, a FAK inhibitor, for the treatment of patients with ovarian cancer.

Rachel N. Grisham, MD, Section Head of Ovarian Cancer, Memorial Sloan Kettering Cancer Center, New York, shared her thoughts with Oncology Learning Network on what this may mean for the future of treatment options for this patient population, specifically those with recurrent low-grade serous ovarian cancer (LGSOC).

“This is a very exciting time in research for patients with low grade serous ovarian cancer,” Dr Grisham said.

“For such a long period of time, we have had to explain to our patients that this is a rare subtype of cancer that is less responsive to chemotherapy and standard therapy for ovarian cancer,” she continued.

Limitations to treatment options for LGSOC include poor response rates and toxicity, which make it difficult for patients to stay on treatment long enough to see a potential response. This is an important factor as patients with this slow-growing disease tend to require therapy over a long duration of time. LGSOC, which comprises 6% to 8% of all ovarian cancers, has a median survival of approximately 10 years and is generally resistant to chemotherapy, Dr Grisham said, adding that the majority of patients will experience disease recurrence.

Early findings from the FRAME study of VS-6766 and defactinib showed “extremely promising results” for the treatment of patients with recurrent LGSOC. It also helped contribute to the FDA’s decision to grant the regimen a BTD, according to Dr Grisham.

In a more recent cohort (n = 24), the overall response rate (ORR) was 52%, with KRAS mutant ORR at 70%, KRAS wild-type ORR at 44%, and KRAS status undetermined ORR at 0%, Dr Grisham said.

In terms of side effects, the most common were grade 1 or 2 in severity, including rash, creatine kinase elevation, nausea, hyperbilirubinemia, and diarrhea, she said.

Dr Grisham said several patients were on therapy for more than a year, indicating the potential for a long duration of benefit. Notably, responses have been seen in multiple patients with LGSOC who had previously progressed on prior MEK inhibitors, including trametinib and binimetinib.

“It is imperative that we work to bring more effective therapies to our patients in need as quickly and efficiently as possible and the Breakthrough Therapy Designation granted to VS-6766 plus defactinib by the FDA will help us to do that,” Dr Grisham said.

Looking ahead, Dr Grisham said she hopes the larger, registration-directed, phase 2 RAMP 201 study will mirror the outcome of the FRAME study.

The RAMP 201 study of VS-6766 with or without defactinib in patients with recurrent LGSOC is active and ongoing at multiple sites throughout the United States through GOG Partners, Dr Grisham said. Its purpose is to evaluate whether VS-6766 in patients with recurrent LGSOC with or without a KRAS mutation works better alone or in combination with defactinib, for up to 1 year. The trial will measure effectiveness, including ORR, as well as safety, in approximately 100 patients.

“We are hopeful that we will continue to see deep and durable responses, and that the combination will be tolerable for our patients. If so, then this may change the standard of care for our patients with recurrent LGSOC,” Dr Grisham said.—Emily Bader