Alterations in the MAPK pathway: promising biomarkers for MEK1/2 inhibition

Low-grade serous ovarian carcinoma (LGSOC) is a distinct subtype of ovarian cancer that presents unique challenges in terms of treatment due to intrinsic chemoresistance. LGSOC, in comparison to high-grade serous ovarian carcinoma, has a high prevalence of mutations in KRAS (20–40%), NRAS (26%) and BRAF (5–10%) (1,2). Patients with activating mutations in canonical mitogen-activated protein kinase (MAPK) pathway components are reported to respond more frequently to targeted agents, such as MEK inhibitors, compared to patients without a mutation in the MAPK pathway (3,4). MEK inhibitors are a class of targeted therapies designed to block the activity of MEK1 and MEK2. These are proteins that play a crucial role in the MAPK signaling cascade and can contribute to uncontrolled cell growth, resistance to apoptosis and increased angiogenesis (5).

The post-hoc tumor tissue analysis from the phase 3 ENGOT-ov11/MILO study evaluated the efficacy of binimetinib, a potent MEK1/2 inhibitor, in treating recurrent LGSOC (6). The study enrolled 341 patients between June 2013 and April 2016, who were randomized 2:1 to receive either binimetinib or physician’s choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%), which is in accordance with literature (7-10).

The study found that patients with a KRAS mutation (KRASmut) treated with binimetinib were 3.4 times more likely to respond [complete remission (CR) or partial remission (PR)] compared to patients without a KRAS mutation (KRASwt) [95% confidence interval (CI): 1.57–7.67]. Among patients treated with binimetinib, 44% of KRASmut patients achieved a CR/PR compared to 19% of KRASwt patients.

The study also found that patients who harbor MAPK pathway alterations (NRAS, BRAF, NF1, RAF1 mutations) and are treated with binimetinib have longer progression-free survival (PFS) compared to those without MAPK pathway alterations [hazard ratio (HR) 0.50; 95% CI: 0.31–0.79]. A similar trend towards improved PFS was observed among patients harboring a MAPK pathway alteration treated with PCC (HR 0.82; 95% CI: 0.43–1.59). This is in line with other evidence suggesting that women with low-grade serous ovarian tumors containing a KRAS or BRAF mutation experience a more favorable outcome compared to those with tumors that lack these activating MAPK pathway mutations (11).

In vitro and in vivo data indicate that patients harboring the KRAS G12V mutation may be more sensitive to MEK inhibition compared to other KRAS variants. Despite this, the study found no difference in PFS in patients with KRAS G12V mutation (n=19) versus patients with other KRAS variants (n=26).

In the GOG-281/LOGS phase 2/3 trial, patients with recurrent LGSOC were treated with trametinib, a MEK1/2 inhibitor, versus PCC. PFS and overall response rate (ORR) were both markedly higher in patients with a KRAS, BRAF or NRAS mutation compared to patients with wild-type KRAS, BRAF and NRAS (3). This confirms the findings of the post-hoc tumor analysis of the MILO/ENGOT-ov11 trial. Additionally, the GOG-281/LOGS trial found that this mutation profile might be predictive for ORR, but not for PFS.

Similar impact of a KRAS mutation on ORR were described in the ENGOT-ov60/GOG-3052/RAMP201 study including patients with recurrent LGSOC (12). The initial results of this study showed that avutometinib, a dual RAF/MEK inhibitor, in monotherapy or in combination with defactinib, a FAK inhibitor, had a higher ORR in KRASmut patients (monotherapy 10% vs. combination 60%) compared to KRASwt patients (monotherapy 6% vs. combination 29%). Based on these results, the study will continue as a randomized phase 3 clinical trial of the combination of avutometinib and defactinib versus PCC.

In conclusion, this post-hoc analysis identifies alterations in the MAPK pathway as possible biomarkers to select patients for MEK1/2 inhibitor treatment in the future. MEK inhibitors could be an effective treatment option for LGSOC patients with alterations in the MAPK pathway and not limited to KRAS. Biomarker research is crucial in identifying the right patient population to select for targeted agents, making this type of translational research important in LGSOC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-50/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-50/coif). T.B. received a grant from Roche, honoraria for lectures or consultancy from AstraZeneca, BioNTech, Eisai Co, GSK, ImmunoGen, Incyte, MSD/Merck, OncXerna, Seagen, Tubulis and Zentalis support for attending meetings from GSK, MSD and Astrazeneca. All payments were made to the author’s institution. T.V.G. received research funding from Amgen, AstraZeneca and Roche, honoraria for lectures from Lilly, Novartis and Astrazeneca, support for attending meetings from AstraZeneca, GSK, ImmunoGen, MSD/Merck and PharmaMar. All payments were made to the author’s institution. The other authors have no conflicts of interest to declare.

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