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

Gershenson, D. M. et al. (2022) 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. Lancet, 399(10324), pp. 541-553. (doi: 10.1016/S0140-6736(21)02175-9) (PMID:35123694) (PMCID:PMC8819271)

Abstract

Background: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma. Methods: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40–50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting. Findings: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9–15·0) compared with 7·2 months (5·6–9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36–0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths. Interpretation: Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.

• Item Type: Articles
• Additional Information: In the USA, GlaxoSmithKline, Novartis, and the Gynecologic Oncology Group Foundation provided supplemental financial support to NRG Oncology (U10CA180822, NRG Oncology Statistical and Data Management Center; U10CA180868, NRG Oncology Operations). In the UK, infrastructure support was provided by the National Cancer Research Institute, Cancer Research UK (C9422/A15800) and the Experimental Cancer Medicine Centre Network, which is jointly funded by Cancer Research UK, the National Institute for Health Research In England, and the Departments of Health for Scotland, Wales and Northern Ireland. The study was coordinated by the Cancer Research UK Clinical Trials Unit at the University of Glasgow with an educational grant from Novartis UK.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Paul, Mr James and Millan, Dr David and Carty, Mrs Karen and Gourley, Prof Charlie
• Authors: Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A. A., O'Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., Churchman, M., Ewing, A., Hollis, R. L., Herrington, C. S., Huang, H. Q., Wenzel, L., and Gourley, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Lancet
• Publisher: The Lancet Publishing Group
• ISSN: 0140-6736
• ISSN (Online): 1474-547X
• Published Online: 03 February 2022
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in Lancet 399(10324): 541-553
• Publisher Policy: Reproduced under a Creative Commons licence