KEY TAKEAWAYS
- The phase 2 trial studied the impact of avutometinib ± defactinib in patients with KRAS mt and KRAS wt recurrent LGSOC.
- The study’s objective was to identify an optimal regimen based on confirmed ORR by blinded independent central review (Part A) and determine efficacy (Part B) (NCT04625270).
- Initial data suggested that avutometinib and defactinib effectively treat recurrent LGSOC, regardless of KRAS status.
LGSOC, a cancer influenced by RAS/MAPK, accounts for less than 10% of ovarian cancers and lacks FDA-approved treatments. Avutometinib is a new RAF/MEK clamp molecule. Resistance to RAF/MEK inhibition often comes through Focal adhesion kinase (FAK) activation. Defactinib, an inhibitor of FAK, synergizes with avutometinib to counter this. The combination of avutometinib and defactinib showed a significant and lasting response, with an objective response rate (ORR) of 46% in recurrent LGSOC.
This phase 2 multi-center trial assessed avutometinib alone or combined with defactinib in patients (pts) with either KRAS mutant (mt) or KRAS wild-type (wt) recurrent LGSOC. The aim was to determine the best regimen based on a confirmed ORR from a blind, independent review (Part A) and then gauge its efficacy (Part B) (Study ID: NCT04625270). Participants were either given avutometinib by itself or alongside defactinib. To be included, they needed a confirmed diagnosis of recurrent LGSOC, knowledge of their KRAS status, and previous treatment with platinum-based chemotherapy. Patients undergoing various prior treatments, including those with an MEK inhibitor, were also accepted. The effectiveness findings from Part A included 64 pts, while safety data comprised 151 pts as of April 2023.
From Part A data, the average number of prior treatments was 3 for those on avutometinib alone and 4 for the combination group. A 45% confirmed ORR was noted for the combination, breaking down to 60% for KRAS mt and 29% for KRAS wt pts. In contrast, the solo treatment had a 10% ORR (13% KRAS mt, 6% KRAS wt). Interestingly, three out of four pts who had been treated with an MEK inhibitor before showed a partial positive response when on the combination treatment. The median time to see a response was 7.3 months for avutometinib alone and 5.5 months for the combination. The majority of side effects linked to the combination treatment in 81 pts were of a mild to moderate nature (grade 1-2). Additionally, only a small fraction required dosage adjustments (17%) or stopped treatment due to side effects (12.3%).
Preliminary results favored the combined use of avutometinib and defactinib for treating recurrent LGSOC, even in cases heavily treated before and regardless of KRAS status. The safety profile was consistent, and most side effects were on the milder side.
Source: https://www.emma.events/site/programme/?sessiondetail=4534544&trackid=0&a=esgo2023#!
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04625270
Banerjee, S.N., Ring, K.L., Niewenhuysen, E.V., Fabbro, M., Aghajanian, C., Oaknin, A., Colombo, N., Santin, A.D., Clamp, A.R., Moore, K.N., Rose, P.G., O’Malley, D.M., Chon, H.S., Salinas, E.A., Prendergast, E.N., Lustgarten, S., Rodrigues, M., Gennigens, C., Monk, B.J., Grisham, R.N. Initial Efficacy And Safety Results From ENGOT-Ov60/GOG-3052/RAMP 201: A Phase 2 Study Of Avutometinib (VS-6766) ± Defactinib In Recurrent Low-Grade Serous Ovarian Cancer (LGSOC).
