Background
GOG-281/LOGS was an international phase 2/3 randomized open-label trial (n=260) evaluating the MEK inhibitor trametinib versus physician's choice standard-of-care therapy in patients with recurrent low-grade serous carcinoma (LGSOC) of the ovary or peritoneum. LGSOC is characterized by MAPK pathway aberrations (KRAS/BRAF/NRAS mutations in ~30–50%) and relative chemoresistance compared with high-grade serous carcinoma, providing the rationale for MEK inhibition.
Interventions and follow up
Arm A (standard of care): Physician's choice (paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole, or tamoxifen)
Arm B (trametinib): Trametinib 2 mg PO daily until progression
Primary endpoint: Investigator-assessed PFS in ITT (crossover permitted at progression)
Median follow-up: 31.5 months
Arm B (trametinib): Trametinib 2 mg PO daily until progression
Primary endpoint: Investigator-assessed PFS in ITT (crossover permitted at progression)
Median follow-up: 31.5 months
Results
mPFS: 13.0 (trametinib) vs 7.2 months; HR 0.48, 95% CI 0.36–0.64, P<.0001
ORR: 26% vs 6%, P<.0001
mOS: 37.6 vs 29.2 months; HR 0.76, 95% CI 0.53–1.09, P=.13 (not statistically significant)
Disease control rate: 84% vs 60%
ORR: 26% vs 6%, P<.0001
mOS: 37.6 vs 29.2 months; HR 0.76, 95% CI 0.53–1.09, P=.13 (not statistically significant)
Disease control rate: 84% vs 60%
Adverse events
Trametinib: Skin rash 13%, anemia 13%, hypertension 12%, diarrhea 10%, nausea 9%, fatigue 8%
Standard of care: Abdominal pain 17%, nausea 11%, anemia 10%; treatment discontinuation 10% (trametinib) vs 12% (SoC); no treatment-related deaths
Standard of care: Abdominal pain 17%, nausea 11%, anemia 10%; treatment discontinuation 10% (trametinib) vs 12% (SoC); no treatment-related deaths
Conclusions
Trametinib significantly improved PFS and ORR compared with standard therapy in recurrent LGSOC, with a clinically meaningful quadrupling of ORR (26% vs 6%), establishing MEK inhibition as a new standard-of-care option in this chemotherapy-resistant disease and validating the MAPK pathway as a therapeutic target in LGSOC.
Key Limitations
Open-label design; physician's choice comparator creates heterogeneity; OS not significantly improved (HR 0.76, P=.13), likely confounded by crossover and subsequent therapies; MAPK mutation-selected subgroup benefit not pre-specified; MEK inhibitor toxicity (rash, hypertension, ocular) requires management; LGSOC is rare (4 years to enroll 260 patients); benefit in MAPK-wildtype patients not separately analyzed at primary.
Clinical Context
GOG-281/LOGS is the first positive randomized trial specifically designed for LGSOC, a histologically and molecularly distinct entity from HGSOC long managed with extrapolated HGSOC protocols. Trametinib received FDA approval for recurrent LGSOC in 2023. The dramatic ORR improvement (26% vs 6%) and PFS doubling (HR 0.48) represent a practice change; ESMO and ASCO recognize trametinib as a recurrent-LGSOC option. Ongoing research evaluates MEK inhibitors in MAPK mutation-enriched populations and in combination with hormonal therapy.