Rachel N. Grisham, MD, section head of Ovarian Cancer, director of Gynecologic Medical Oncology, Memorial Sloan Kettering Cancer Center, discusses the rationale to explore the combination of VS-6766 (formerly CH5126766) and defactinib in patients with low-grade serous ovarian cancer.

Patients with low-grade serous ovarian cancer and those with the more common high-grade serious ovarian cancer differ in molecular distinction, Grisham explains. Low-grade serious ovarian cancer accounts for less than 10% of all ovarian cancer cases, according to Grisham. Unlike high-grade serious ovarian cancer, low-grade serious ovarian cancers are usually 

 wild-type and the most commonly observed alterations affect the MAPK pathway, Grisham explains.

mutations primarily affect this pathway, but other less common mutations such as 

 mutations have also been observed, Grisham adds. Based on this molecular profile, there has been interest in examining the use of targeted therapies in the treatment of the disease, Grisham says. This is particularly because patients with low-grade serious ovarian cancer have demonstrated historically low response rates to standard systemic therapies like chemotherapy and endocrine therapies, Grisham concludes.

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Rachel N. Grisham, MD, discusses the rationale to explore the combination of VS-6766 and defactinib in patients with low-grade serous ovarian cancer.

Dr. Grisham on the Combination of VS-6766 With Defactinib in Ovarian Cancer

Rachel N. Grisham, MD, section head of Ovarian Cancer and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center, discusses rationale for evaluating binimetinib as a treatment option for patients with low-grade serous ovarian cancer (LGSOC).

The phase 3 MILO/ENGOT trial (NCT01849874) examined binimetinib (Mektovi) vs physician’s choice of chemotherapy in patients with recurrent LGSOC. Binimetinib was utilized on the trial because it is a MEK inhibitor that targets alterations in the MAPK pathway, and most alterations seen in LGSOC are those that impact this pathway, according to Grisham. This makes LGSOC molecularly distinct from high-grade serous disease, where alterations such as 

, homologous recombination deficiency, and 

, are more common. The alterations that most frequently occur in LGSOC are 

Rachel N. Grisham, MD, discusses rationale for evaluating binimetinib as a treatment option for patients with low-grade serous ovarian cancer.

Dr. Grisham on the Rationale for Binimetinib in Low-Grade Serous Ovarian Cancer 

Rachel N. Grisham, MD, section head of Ovarian Cancer and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center, discusses the mechanism of action of VS-6766 (formerly CH5126766) in patients with recurrent low-grade serous ovarian cancer.

VS-6766 is a dual RAF/MEK inhibitor that is currently under investigation in a phase 2 trial (NCT04625270) in combination with defactinib (GOG305), according to Grisham, who is a principal investigator of the trial in the United States. The agent is currently being developed for patients with low-grade serous ovarian cancer, a disease in which MEK inhibitors have recently demonstrated promising clinical activity.

As a dual RAF/MEK inhibitor, it may be possible to enhance the population of patients who can benefit from targeted therapies, as well as target a larger population of patients, Grisham concludes.

Rachel N. Grisham, MD, discusses the mechanism of action of VS-6766 in patients with recurrent low-grade serous ovarian cancer.

Dr. Grisham on the Mechanism of Action of VS-6766 in Recurrent Low-Grade Serous Ovarian Cancer

Rachel N. Grisham, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses MEK inhibition in the treatment of patients with low-grade serous ovarian cancer.

The GOG-239 study was the first prospective clinical trial performed in this setting, Grisham says. For the trial, investigators evaluated the use of single-agent selumetinib, a MEK inhibitor, for the treatment of patients with recurrent low-grade serous ovarian cancer, and the response rate was promising at 15%. In that trial, there was also molecular analysis to assess if patients with 

 mutations were more likely to benefit from treatment. However, Grisham notes, only a small number of patients had molecular results available; as such, investigators were unable to find an association between molecular alteration and response to treatment. Moving forward, newer modalities such as next-generation sequencing may allow for researchers to make these determinations.

Following the results of GOG-239, there have been subsequent studies looking at MEK inhibition in this patient population. There is an ongoing phase III GOG study of trametinib (Mekinist) versus physician’s choice of chemotherapy or hormonal therapy, which has finished accruing but results are not yet available. There was also a study of binimetinib (Mektovi), a single-agent MEK inhibitor, versus physician’s choice of chemotherapy in this patient population. That study was stopped after enrolling over 300 patients, as it crossed a predefined futility endpoint for the hazard ratio for progression-free survival. However, adds Grisham, the results of the study were interesting and will be published soon.

Dr. Grisham on MEK Inhibition in Low-Grade Serous Ovarian Cancer

Rachel N. Grisham, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses frontline treatment options for patients with low-grade serous ovarian cancer.

This is a very rare subset of ovarian cancer, Grisham says, with approximately 1300 cases every year in the United States. The low incidence of this disease makes it difficult for investigators to develop effective, personalized therapy. In the upfront setting, there is a GOG study (NRGGY019) that will open soon to investigate the role of chemotherapy in this setting. In the trial, newly diagnosed patients will be randomized to receive either chemotherapy followed by hormonal therapy with letrozole or hormonal therapy with letrozole alone—both following initial surgical resection.

An unanswered question in this space is whether chemotherapy, which has demonstrated meager activity in the frontline setting, can be replaced by hormonal therapy for patients with advanced-stage disease. Grisham says that in the absence of any prospective data, she still recommends upfront chemotherapy for these patients; however, she feels that results from his study will help identify the roles of chemotherapy and hormonal therapy in the upfront setting.

Rachel N. Grisham, MD

Articles

Dr. Grisham on the Combination of VS-6766 With Defactinib in Ovarian Cancer

Dr. Grisham on the Rationale for Binimetinib in Low-Grade Serous Ovarian Cancer

Dr. Grisham on the Mechanism of Action of VS-6766 in Recurrent Low-Grade Serous Ovarian Cancer

Dr. Grisham on MEK Inhibition in Low-Grade Serous Ovarian Cancer

Dr. Grisham on Frontline Treatment for Low-Grade Serous Ovarian Cancer