Positive results stemming from the NRG Oncology international phase II/III clinical trial NRG-GOG 0281/LOGS indicate that the MEK-inhibitor trametinib would provide benefit as the new standard of care for treating women with recurrent low-grade serous carcinoma (LGSC) of the ovary/peritoneum. Study results demonstrate that trametinib significantly reduced the hazard of disease progression or death, increased probability of response to therapy and showed a trend toward higher rates of overall survival when compared to the previous standard of care options. These results were published in The Lancet on February 3, 2022.
NRG-GOG 0281/LOGS is the first successful randomized trial of any therapy in LGSC. The trial compared trametinib to an investigator’s choice from one of five standard of care treatment options including: intravenous (IV) paclitaxel, IV pegylated liposomal doxorubicin, IV topotecan, oral letrozole, and oral tamoxifen. The goal was to determine and compare the investigator-assessed progression-free survival (PFS) between trametinib and any of the standard options.
LGSC is typically diagnosed at a younger age, is less sensitive to platinum-based chemotherapy, and has longer overall survival rates than the more common high grade ovarian cancers. Most patients with LGSC are diagnosed in an advanced stage. Of these, over 70% will relapse, and response rates to subsequent chemotherapy are low.LGSC tumors have frequent mutations in KRAS and BRAF leading to exploration of drugs active in this pathway such as was shown for activity of trametinib in mutation-associated melanoma and anaplastic thyroid cancers. NRG-GOG 0281 aimed to explore trametinib alone in its approved dose in LGSC of the ovary.
“We are incredibly pleased with the outcome of this international trial and the ability to make more advances for women with this rare ovarian cancer. This is an exceptionally challenging disease to accrue enough patients for a successful clinical trial because of the limited patient population. The study team decided to expand eligibility to include patients who had received an unlimited number of prior regimens, which helped with the accrual for this trial,” stated David M. Gershenson, MD, of the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center and the lead author of the NRG-GOG 0281 manuscript.
NRG-GOG 0281 accrued 260 patients who were randomized to each treatment arm (130 patients per arm). At the primary analysis of the study, 217 Progression-Free Survival (PFS) events occurred (101 on the trametinib treatment arm and 116 on the standard of care treatment arm). The median PFS on the trametinib arm was 130 months (95% confidence interval [CI], 99-150) versus 72 (95% CI, 56-99) months on the standard of care arm (hazard ratio 048; 95% CI, 036-064; p <0.0001). The most frequent grade 3/4 adverse events on trametinib were skin rash (17/128; 13%), anemia (16/128; 13%), hypertension (15/128;12%) and diarrhea (13/128; 10%) nausea (12/128; 9%), and fatigue (10/128; 8%). There were no treatment-related deaths.
Future research should focus on discovering a suggested sequence for chemotherapy, hormonal therapy, and trametinib for treatment of women with LGSC of the ovary/peritoneum, as well as exploring the potential of combining trametinib and aromatase inhibitors.
This project was supported by U10CA180868 (NRG Oncology Operations) and U10CA180822 (NRG Oncology SDMC) grants from the National Cancer Institute, part of National Institutes of Health, as well as the National Cancer Research, Cancer Research UK (Grant Reference: C9422/A15800) and Experimental Cancer Medicine Centre Network (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.The whole exome sequencing of samples was 50% funded by a Target Ovarian Cancer Translational Award. The study was led and conducted by NRG with participation of NCI funded network groups. Novartis Pharmaceuticals Corporation provide support through a Cooperative Research and Development Agreement with the NCI.
Gershenson DM, Miller A, Brady WE, Paul J, Carty K, Rodgers P, Millian D, Coleman RL, Moore KN, Banerjee S, Connolly K, Alvarez Secord A, O’Malley DM, Dorigo O, Gaillard S, Gabra H, Slomovitz B, Hanjani P, Farley J, Churchman M, Ewing A, Hollis RL, Herrington CS, Huang HQ, Wenzel L, Gourley C. Trametinib versus Standard of Care in PAtinets with Recurrent Low-grade Serous Ovarian Cancer (GOG 0281/LOGS): A Randomized, Open-label Phase 2/3 Trial. The Lancet. 5 Feb 2022. DOI: https://doi.org/10.1016/S0140-6736(21)02175-9
Embargoed until 23:30hrs UK time on 3 February 2022.
About NRG Oncology
NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the legacy National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG) programs. The research network seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology’s extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1,300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI’s National Clinical Trials Network.
Trametinib versus Standard of Care in PAtinets with Recurrent Low-grade Serous Ovarian Cancer (GOG 0281/LOGS): A Randomized, Open-label Phase 2/3 Trial