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Time for Targeted Treatment in Low-Grade Serous Ovarian Cancer?
Limited treatment options exist for low-grade serous ovarian or peritoneal carcinoma, a rare subtype of ovarian cancer that typically does not respond to standard chemotherapy. Characterized by slow cycling cells and frequently expressing the estrogen and progesterone receptors, low-grade ovarian tumors lack the characteristic TP53 mutated signature and DNA repair defects frequently observed in high-grade serous ovarian cancer. Instead, Ras, Raf and MAPK alterations are common, fueling the hypothesis that treatment with an inhibitor of this pathway could induce clinical benefit. Investigators tested the activity of trametinib, a selective inhibitor of the MEK1 and MEK2 kinases, in the GOG-281 study.
In the phase 2/3 trial, 260 patients with recurrent low-grade serous carcinoma who were previously treated with at least one platinum-based regimen were randomized to either oral trametinib (2 mg daily) or one of five standard-of-care treatment options including chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) or hormonal therapy (letrozole or tamoxifen), per physician's choice. There were no limits on the prior lines of therapy, as long as at least one standard of care option remained available. All patients had received prior chemotherapy, with 28% having received three or more lines of treatment; 58% of patients had also received hormonal treatment. Among the 134 patients for whom tumor mutation status was known, 34% harbored KRAS, NRAS or BRAF somatic tumor mutations.
Progression-free survival – the primary outcome – was longer with trametinib than with physician's choice treatment (median, 13.0 vs. 7.2 months; hazard ratio 0.48; P<0.0001). Severe toxicities associated with the agent included rash, anemia, hypertension, diarrhea, nausea, and fatigue, which led to modest decreases in quality-of-life indices.
Although prior studies investigating other inhibitors of the MAPK pathway (selumetinib and binimetinib) have yielded modest results, this study's results support the inclusion of trametinib as a new standard of care for women with recurrent low-grade serous ovarian cancer, preferably before use of second-line chemotherapy. Outperforming standard second-line chemotherapy or hormonal therapy, trametinib prolonged the duration of remission, irrespective of tumor mutational status. Whether trametinib could be combined with other agents or be brought to the adjuvant setting remains to be investigated.
Daniela Matei, MD, is Chief of Reproductive Science in Medicine, Department of Obstetrics and Gynecology and Diana, Princess of Wales Professor of Cancer Research, Feinberg School of Medicine, Northwestern University.
Gershenson DM et al.
Title: Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): An international, randomised, open-label, multicentre, phase 2/3 trial.
Source: Lancet 2022 Feb 5; [e-pub]. (Abstract/FREE Full Text)