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Molecular profiling and tumour biomarker analysis of GOG281/LOGS: a positive late-phase trial of trametinib for recurrent/persistent low grade-serous ovarian cancer.

Molecular profiling and tumour biomarker analysis of GOG281/LOGS: a positive late-phase trial of trametinib for recurrent/persistent low grade-serous ovarian cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Hollis, R. L., Miller, A., Lankes, H. A., Wong, K. K., Rodgers, W., Millan, D., Carty, K., Coleman, R. L., Moore, K. N., Alvarez Secord, A., O'Malley, D. M., Chan, J. K., Hagemann, A. R., Gaillard, S., Guntupalli, S. R., Edelson, M., Rose, P. G., Dorigo, O., Banerjee, S., Ewing, A., Churchman, M., Sood, A. K., Herrington, C. S., Gourley, C., Gershenson, D. M. 2025

Abstract

Low-grade serous ovarian carcinoma(LGSOC) is a distinct form of ovarian cancer characterised by younger patient age and relative chemoresistance. The GOG281/LOGS trial(NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared to physician's choice standard of care(SOC) in LGSOC patients with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival(PFS) in the trametinib-treated arm.260 patients with recurrent/persistent LGSOC were enrolled and randomised in GOG281. We performed molecular analysis of 170 patients with available tumour specimens, comprising whole exome sequencing and phospho-ERK immunohistochemistry, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort(n=170) were comparable to the total trial cohort.High tumour pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs 5.6 months, log-rank P<0.0001; test for interaction P=0.023). Tumours harbouring canonical RAS-RAF-MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs 8.3%; Barnard's P=0.0004; test for interaction P=0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P=0.719). KRAS amplification (n=5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n=25 without KRAS/NRAS/BRAF mutation or KRAS copy-number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss(49% cases) was associated with lower pERK expression(P=0.021).This exploratory analysis suggests pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

View details for DOI 10.1158/1078-0432.CCR-25-3042

View details for PubMedID 41378992