Trametinib Presents Potential New Standard-of-Care for Low-Grade Serous Ovarian Carcinoma

Trametinib emerged as a novel therapeutic approach for low-grade serous carcinoma due to a high prevalence of activating mutations in the mitogen-activated protein kinase signaling pathway.

Treatment with the MEK inhibitor trametinib reduced the risk of disease progression or death by 52% compared to standard-of-care treatments for low-grade serous ovarian carcinoma, according to researchers at the University of Texas MD Anderson Cancer Center.

The findings are from an international, multi-center phase 2/3 trial, which is the first positive randomized clinical trial of any therapy to demonstrate significantly increased progression-free survival (PFS) and objective response rate (ORR) in low-grade serous carcinoma.

“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 researcher David Gershenson, MD, a professor of gynecologic oncology and reproductive medicine, in a press release. “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.”

Serous carcinoma is a rare and largely understudied form of ovarian cancer. The disease accounts for approximately 5% of all cases of epithelial ovarian cancer and is often diagnosed at a younger age in advanced stages, with a relapse rate of more than 70%.

Frontline treatment typically consists of chemotherapy followed by aromatase inhibitor therapy. However, because serous carcinoma is relatively resistant to platinum-based chemotherapy, finding an effective targeted therapy has remained an unmet clinical need.

Trametinib emerged as a novel therapeutic approach for low-grade serous carcinoma due to a high prevalence of activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, which includes the MEK protein, according to the researchers. The drug is approved by the FDA for use in combination with dabrafenib for a range of BRAFV600 mutation-positive cancers, including unresectable or metastatic melanoma, non-small cell lung cancers, and anaplastic thyroid cancer.

Investigators in the study enrolled and randomly assigned 260 patients 18 years of age or older with recurrent low-grade serous carcinoma of the ovary or peritoneum between February 2014 and April 2018. Half of the participants received oral trametinib once daily, whereas the other half received 1 of 5 standard-of-care treatment options. Participants in the trametinib group had a median age of 56.6 years, whereas the standard-of-care group had a median age of 55.3.

Researchers found that the median PFS for patients receiving trametinib was 13 months compared to 7.2 months in patients receiving standard-of-care therapies. Furthermore, the ORR was 26% with trametinib and 59% of patients had stable disease for at least 8 weeks.

The median duration of response on trametinib and standard-of-care therapies were 13.6 months and 5.9 months, respectively. Median overall survival was 37.6 months in the trametinib group compared with 29.2 months in the standard-of-care group.

Median PFS was 10.8 months among patients in the standard-of-care group who crossed over to trametinib following disease progression, and the ORR was 15%. Of the 66 standard-of-care patients who progressed or died after crossing over to trametinib, 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,” Gershenson said in the press release. “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.”

The most frequent grade 3 or 4 adverse events (AEs) 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 AEs were abdominal pain (17%), nausea (11%), anemia (10%), and vomiting (8%). No treatment-related deaths occurred.

REFERENCE

Trametinib represents potential new standard-of-care for patients with recurrent low-grade serous ovarian carcinoma. News release. MD Anderson Cancer Center; February 3, 2022. Accessed February 4, 2022. https://www.mdanderson.org/newsroom/trametinib-represents-potential-new-standard-of-care-for-patients-with-recurrent-low-grade-serous-ovarian-carcinoma.h00-159537378.html