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

Overview

abstract

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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). CONCLUSION: This exploratory analysis suggests pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.