On behalf of the NGOD and GOG study teams, thank you for the opportunity today to present interim results from the RAMP 201 study. These are my disclosures. Low-grade serous ovarian cancer accounts for less than 10% of newly diagnosed epithelial ovarian cancer cases each year and is clinically, histologically, and molecularly distinct from high-grade serous disease. Unlike in high-grade serous ovarian cancer, where up to a quarter of patients will be found to have a germline or somatic BRCA mutation, these are rare in low-grade serous ovarian cancer, where the disease is instead driven by alterations affecting the MAP kinase pathway, most commonly RAS or RAF mutations. It has been well characterized that low-grade serous ovarian cancer is less responsive to chemotherapy than high-grade serous ovarian cancer. In the first-line neoadjuvant setting, response rates to chemotherapy range from 4% to 23%. Based on the prevalence of MAP kinase alterations within this disease and the less chemoresponsive nature of low-grade serous ovarian cancer, there has been considerable interest in the use of targeted therapies for treatment of this disease. Prior studies of single-agent MEK inhibitors, such as trametinib, have shown response rates as high as 26%, which is a good first step, but more efficacious and better-tolerated treatments are urgently needed for treatment of this disease. Avutametinib is a first-in-class oral RAF-MEK clamp that potently inhibits MEK kinase activity, while also blocking compensatory reactivation of MEK by upstream RAF. Dafactinib, also an oral drug, is a selective inhibitor of FAC, a signaling target that has been shown to mediate resistance to multiple anticancer agents. A prior study of the combination of avutametinib and dafactinib in a population that included low-grade serous ovarian cancer patients in the FRAME study showed a very promising response rate amongst those patients with low-grade serous ovarian cancer, with an objective response rate of 42%, a median duration of response of 26.9 months, and a median PFS of 20 months. Results of the FRAME study led to FDA breakthrough therapy designation for this combination and is the rationale for the Phase 2 RAMP 201 study presented here today. The RAMP 201 study enrolls women with recurrent, measurable, low-grade serous ovarian cancer who have received at least one prior line of platinum-based chemotherapy. Unlimited additional lines of therapy are allowed thereafter, including up to one prior line of MEK inhibitor. During parts A and B of the RAMP 201 study, patients were initially randomized to treatment with avutametinib alone or avutametinib in combination with dafactinib. An initial efficacy analysis was performed in order to choose the go-forward regimen for the remainder of the study. The results of this go-forward decision were reported by Dr. Susanna Banerjee at the ASCO annual meeting earlier this year and showed unprecedented response rates for those patients treated with the combination of avutametinib and dafactinib, with a confirmed objective response rate of 45%, 29% in the KRAS wild-type population, and 60% in the KRAS mutant population, with tumor reduction seen in 86% of patients treated with avutametinib and dafactinib. The study continued enrollment with subsequent patients receiving the combination. We present here today a pre-planned subgroup analysis of patients treated with the combination of avutametinib and dafactinib based on prior lines of therapy received before study entry. This analysis includes patients from the combination arm who were efficacy-evaluable for the April 2023 data cutoff. Confirmed objective response rate was assessed by blinded independent central review of 29 efficacy-evaluable patients from Part A. Incidence of treatment-emergent adverse events was evaluated in 81 patients treated with the combination from Parts A, B, and C. Efficacy and safety in patients with 1 to 3 prior lines of therapy versus 4 or more prior lines of therapy were analyzed. We see here that both in the less heavily pre-treated and in the more heavily pre-treated patients, the efficacy was almost identical with a response rate of 45.5% in those patients with 1 to 3 prior lines of therapy and 44.4% in those with 4 or more lines of therapy. Similarly, the disease control rates were almost the same, 90.9% versus 88.9%. When looking at the safety and tolerability of this combination, I think it's important to note that the dosing of the abutometinib and defactinib pills is intermittent. Abutometinib is taken twice a week, three weeks on, one week off, and defactinib is taken twice a day, three weeks on, one week off. I think that largely helps to explain why this combination has been so tolerable in our patients treated on study to date. Overall, the rate of grade 3 adverse events was quite rare, shown here in the lighter colored component of the columns, with the exception of elevated blood CPK, which is a class effect of MEK inhibitors and is generally asymptomatic. Overall, the drug combination was tolerable both in the less heavily pre-treated and more heavily pre-treated patients, with only 12.3% of patients discontinuing combination therapy as a result of a treatment emergent adverse event. Abutometinib and defactinib maintains exceptionally high tumor response rates in heavily pre-treated patients with recurrent low-grade serous ovarian cancer. The incidence of treatment emergent adverse events with the combination is similar in patients that are less heavily pre-treated and more heavily pre-treated. Based on the exceptional efficacy and tolerability of this combination, it is going to move forward to a phase 3 study. The RAMP 301 study will enroll patients with recurrent low-grade serous ovarian cancer who will be randomized to treatment with abutometinib and defactinib versus physicians' choice of chemotherapy or endocrine therapy, with the option for crossover to abutometinib and defactinib at time of progression for those patients that are treated with physicians' choice. The RAMP 301 study is set to open later this year with planned study sites that include North America, Europe, Australia, and Korea. Thank you to the NGOT and GOG study teams, Dr. Susanna Banerjee, the global PI of the RAMP 201 study, VeraSTEM Oncology, and most importantly, our patients who make these advancements possible.

RAMP 201 study

low-grade serous ovarian cancer

MAP kinase pathway alterations

avutametinib

dafactinib