Author Insight: Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS) | David M. Gershenson, MD
David M. Gershenson, MD
GOG 281, “Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomized, open-label, multicentre, phase 2/3 trial,” was recently published in The Lancet. This was the first positive randomized trial of any therapy in low-grade serous carcinoma (LGSOC), and, for that matter, the first positive randomized trial in any rare epithelial ovarian/peritoneal cancer (clear cell, mucinous, endometrioid, or LGSOC).
From inception, this trial has consumed over a decade of my life. In January 2011, on the heels of preliminary results from the GOG 239 trial of selumetinib, Professor Stan Kaye, an icon in the drug development world, contacted me to strategize about a potential follow-up randomized trial of a MEK inhibitor in recurrent LGSOC. Following a few email exchanges, we met during a GCIG meeting in Chicago in June 2011, at which time he introduced me to one of his protégées, Charlie Gourley from Edinburgh. Three years later, in February 2014, GOG 281, an international collaboration between the US and UK, became a reality.
Principal findings of GOG 281 included improvement in multiple outcomes for trametinib versus standard of care (SOC), including progression-free survival (median PFS, 13.0 vs 7.2 months); objective response rate (26% vs 6%); and duration of response (median, 13.6 vs 5.9 months). There was a trend for improved median overall survival—37.6 versus 29.2 months—but it was not statistically significant.
During the trial, we quickly learned that managing adverse events associated with trametinib can be complex, particularly related to skin rash; 13% of patients had grade 3/4 skin rash. Other common grade 3/4 adverse events included anemia, hypertension, diarrhea, nausea, and fatigue. Seventy percent of patients on trametinib required at least one dose reduction. Quality of life was somewhat worse in the trametinib group compared to SOC at 12 weeks, but there was no difference at all other time points.
Probably the most frequent question I receive is why GOG 281 and the MILO trial had such disparate findings. The potential reasons for the differences are explained in the Discussion of the paper. And although both studies suggested that mutations (KRAS or KRAS/NRAS/BRAF) in the MAPK signaling pathway may be a biomarker for response to MEK inhibitor therapy, the combined findings are hypothesis-generating; further studies are needed.
The publication of GOG 281 and MILO have clearly generated a buzz that seems to have stimulated a growing number of biotech companies and investigators to focus their gaze more sharply on LGSOC. Although our understanding of the MAPK pathway and estrogen signaling is still nascent, these are currently the principal targets for novel drug development, which is greatly needed for this rare ovarian cancer. Ongoing trials of endocrine therapy plus CDK 4/6 inhibitors and next-generation inhibitors of the MAPK pathway are underway and will provide valuable insights. Concomitantly, a much better mastery of the biology of LGSOC is a priority.
Along those lines, through the generous support of a New Zealand family, an international consortium of physicians and scientists dedicated to the study of LGSOC was established in 2020 with the vision of making a dramatic difference in the lives of women with this rare subtype.