A study published by David Gershenson, MD, and colleagues in The Lancet reported that the MEK inhibitor trametinib reduced the risk of disease progression or death by 52% compared to standard-of-care therapies in low-grade serous ovarian carcinoma.
The international, multicenter phase II/III trial (GOG 281/LOGS) is the first positive randomized clinical trial of any therapy to demonstrate significantly increased progression-free survival and objective response rate in low-grade serous carcinoma, a rare and understudied form of ovarian cancer.
Median progression-free survival for patients receiving trametinib was 13 months compared to 7.2 months in those receiving standard-of-care therapies. The objective response rate with trametinib was 26%, with 59% of patients having stable disease for at least 8 weeks. The median duration of response on trametinib and standard-of-care was 13.6 months and 5.9 months, respectively. Median overall survival was 37.6 months in the trametinib group and 29.2 months in the standard-of-care group.
“Previous treatment recommendations for patients with low-grade serous carcinoma were based on studies that focused on the more common high-grade serous carcinoma, despite the subtypes having distinct developmental pathways, molecular biology, and clinical behaviors. Now we have encouraging data for this specific group of patients,” said Dr. Gershenson, Professor of Gynecologic Oncology & Reproductive Medicine at The University of Texas MD Anderson Cancer Center. “The results from our study show trametinib should be considered a new standard-of-care option for women with progressive or relapsed low-grade serous carcinoma.”
The results from our study show trametinib should be considered a new standard-of-care option for women with progressive or relapsed low-grade serous carcinoma.— David Gershenson, MD
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GOG 281/LOGS
In the study, researchers enrolled and randomly assigned 260 patients aged 18 years or older with recurrent low-grade serous carcinoma of the ovary or peritoneum from 84 hospitals in the United States and United Kingdom between February 2014 and April 2018. Half received oral trametinib once daily, while the other half received one of five standard-of-care treatment options, including paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole, or tamoxifen. The racial breakdown included 229 White participants (88%), 9 Black (3%), 7 Asian (3%), 1 Native Hawaiian or Pacific Islander (0.4%), and 14 undisclosed (5%), with a median age of 56.6 years in the trametinib group and 55.3 years in the standard-of-care group.
The most frequent grade 3 or 4 adverse events related to trametinib were skin rash (13%), anemia (13%), hypertension (12%), diarrhea (10%), nausea (9%) and fatigue (8%). In the standard-of-care group, the most frequent grade 3 or 4 adverse events were abdominal pain (17%), nausea (11%), anemia (10%) and vomiting (8%). No treatment-related deaths occurred.
Median progression-free survival in patients in the standard-of-care group who crossed over to trametinib following disease progression was 10.8 months, and the objective response rate was 15%. Of the 66 standard-of-care patients who progressed or died after crossing over to trametinib, 43 (65%) had a longer time to disease progression on trametinib than they had on their preceding standard-of-care therapy.
“The findings associated with this trial are hypothesis-generating and provide important clues for future investigations,” Dr. Gershenson said. “While the results of this study represent a major advance in the treatment of women with this rare ovarian and peritoneal cancer subtype, we need to accelerate our efforts toward the discovery of additional novel drugs or regimens. Ongoing trials include combinations of endocrine therapy and CDK 4/6 inhibitors and combinations of drugs directed at the MAPK signaling pathway plus other targeted agents.”
Disclosure: The study was funded by NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis. For full disclosures of the study authors, visit thelancet.com.
