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SEOUL, South Korea -- The combination of avutometinib and defactinib achieved "exceptionally" high response rates in heavily pretreated patients with recurrent low-grade serous ovarian cancer (LGSOC), according to the ENGOT-ov60/GOG-3052/RAMP 201 trial.

Moreover, responses were consistently high no matter how many previous lines of therapy patients received prior to study entry, reported Rachel N. Grisham MD, of the Memorial Sloan Kettering Cancer Center in New York City, at the International Gynecologic Cancer Society annual meeting. Findings also were presented at the 2023 (ASCO) meeting.

Part A of showed that among 29 evaluable patients, 45% achieved a response when treated with the combination -- results that Grisham called "unprecedented."

In addition, the overall response rate (ORR) was 29% in patients with KRAS wild-type LGSOC and 60% in patients with KRAS-mutant LGSOC. Tumor shrinkage was observed in 86% of patients.

In a pre-planned subgroup analysis based on the number prior therapies received before entering RAMP 201, the 11 patients treated with one to three previous lines of therapy achieved an ORR of 45% while the 18 who received four or more previous lines of therapy had a comparable ORR of 44.8%.

Disease control rates were also consistent in these two groups of patients -- 90.9% versus 89.7%, respectively.

Further investigation of avutometinib-defactinib are planned with the randomized RAMP 301 trial,"based on the exceptional efficacy and tolerability of this combination," Grisham said.

Verastem Oncology has announced it intends to for the avutometinib-defactinib based on mature data from RAMP 201, together with the results of the investigator-initiated trial, and plans to use as the follow-up confirmatory study.

Regarding the safety and tolerability of the combination, Grisham pointed out that avutometinib is taken twice a week (3 weeks on, 1 week off) while defactinib is taken twice a day (3 weeks on, 1 week off).

"I think that largely helps to explain why this combination has been so tolerable in our patients treated on this study to date," Grisham said.

She noted that overall the rate of grade 3 adverse events (AE) was rare, with the exception of elevated blood creatine phosphokinase, "which is a class effect of MEK inhibitors and is generally asymptomatic." Furthermore, she pointed out that just 10 of the 81 patients evaluated for safety discontinued treatment with the combination because of a treatment-emergent AE.

Grisham explained that LGSOC is fairly rare, accounting for less than 10% of newly diagnosed cases of ovarian cancer. However, there has been increasing interest in the use of targeted therapies for treating the disease, with prior studies of single-agent MEK inhibitors demonstrating 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," she said.

Avutometinib is a first-in-class oral RAF/MEK clamp that "potently inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF," Grisham explained, while defactinib is a selective inhibitor of FAK that has shown synergistic antitumor activity with avutometinib.

The combination demonstrated an ORR of 42%, with a median duration of 26.9 months, and a median progression-free survival of 20 months in recurrent LGSOC in FRAME, leading to FDA breakthrough therapy designation and providing the rationale for RAMP 201.

Patients were initially randomized to treatment with avutometinib monotherapy or to the combination of avutometinib-defactinib, with the results from the part A selection phase of the study determining that the combination would be the "go-forward regimen" studied in the expansion (part B) phase of the study.

In part A, the median age of patients who received the combination was 55. These patients had received a median of four previous lines of therapy, all of whom had received prior platinum-based chemotherapy, while 90% received prior hormonal therapy, and 64% prior bevacizumab.

Four patients had previously been treated with a MEK inhibitor, three of whom achieved a response when treated with avutometinib-defactinib.

RAMP 301 will evaluate the efficacy and safety of avutometinib-defactinib versus standard of care (SOC) chemotherapy and hormonal therapy in patients with recurrent LGSOC.

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