Avutometinib plus Defactinib Demonstrates Clinical Response for Recurrent Low-Grade Serous Ovarian Carcinoma in a Phase 2 RAMP-201 Trial

Low-Grade Serous Ovarian Carcinoma (LGSOC) is a relatively rare type of epithelial ovarian cancer, accounting for less than 10% of all ovarian cancer cases. LGSOC is characterized by recurrent RAS-MAPK pathway activating mutations in KRAS, NRAS, and RAF, occurring in 33%, 10%, and 10% of cases, respectively. Its molecular features markedly differ from the more common high-grade serous ovarian carcinoma (HGSOC), which constitutes approximately 70% of ovarian cancer cases.

Avutometinib, a first-in-class RAS/MEK clamp, allosterically inhibits MEK kinase activity and induces the formation of an RAF/MEK inactive heterodimer. This mechanism helps prevent compensatory activation of ARAF, BRAF, and CRAF, which can occur as an adaptive resistance to MEK-only inhibitors. Additionally, focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a crucial role in promoting cell survival in response to stressors such as chemotherapy or targeted therapy. Although FAK inhibitor monotherapy has demonstrated limited efficacy, combining FAK inhibitors with other anticancer agents has piqued interest for clinical trials aimed at testing this therapeutic combination. 

RAMP-201 enrolled heavily treated patients with low-grade serous ovarian carcinoma (LGSOC), both with and without KRAS mutations, during the part A selection phase. Specifically, 16 subjects had KRAS mutations, while 15 subjects did not. The combination of avutometinib and the FAK inhibitor defactinib demonstrated clinical benefit in these recurrent LGSOC patients.

The confirmed objective response rate (ORR) was 45% (13 out of 29 patients). For KRAS-mutant LGSOC, the ORR was even higher at 60%, while for KRAS wild-type (WT) LGSOC, it was 29% (4 out of 14 patients). Notably, 3 out of 4 patients showed a partial response despite previous treatment with a MEK inhibitor.

In patients who had poor responses to their last line of treatment (LoT) or were in a recurrent setting, the combination of avutometinib and defactinib provided efficacy. The ORR increased from 8.7% (2 out of 23 patients) in the LoT group to 43.5% (10 out of 23 patients) in the RAMP-201 regimen. Furthermore, investigators observed a similar ORR in patients who had received 1-3 prior LoTs (45.5% ORR) compared to those with more than 4 prior LoTs (44.4% ORR).

Given the promising antitumor activity of avutometinib plus defactinib in recurrent LGSOC, the confirmatory phase 3 RAMP 301 trial (NCT06072781) has been initiated. This trial aims to recruit subjects and compare avutometinib and defactinib against standard-of-care chemotherapy or hormonal therapy in recurrent LGSOC.

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References:

1. Susana N. Banerjee presented at 2024 SGO annual meeting, LBA session 1
2. Banerjee et al., poster at 2023 ASCO, abs. #5515
3. Hollis et al., Sci Rep. 2023 May 11;13(1):7681.
4. Dawson et al., Nat Rev Cancer. 2021 May;21(5):313-324.

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