Trametinib new standard-of-care option for recurrent low-grade serous ovarian cancer
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Trametinib should be a new standard of care for women with recurrent low-grade serous carcinoma, according to study published in The Lancet that showed a 52% reduction in risk for disease progression or death vs. current treatment options.
The international, open-label phase 2/phase 3 GOG 281/LOGS study is the first positive randomized clinical trial of any therapy for recurrent low-grade serous carcinoma, David M. Gershenson, MD, professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, and a HemOnc Today Editorial Board Member, told Healio.
“Mutations in the [mitogen-activated protein kinase (MAPK)] signaling pathway are relatively frequent in low-grade serous carcinoma, so studying the activity of a MEK inhibitor, trametinib (Mekinist, Novartis), in a large group of patients makes sense based on preclinical data,” Gershenson said. “Because low-grade serous carcinoma is relatively resistant to conventional chemotherapy, there is an unmet need for more effective therapy for this rare cancer.”
Methodology
The analysis included 260 women aged 18 years or older from 84 hospitals in the U.S. and U.K. between Feb. 27, 2014, and April 10, 2018. Researchers randomly assigned them 1:1 to 2 mg oral trametinib once daily (n = 130; median age, 56.6 years; 89% white) or one of five standard-of-care treatments (n= 130; median age, 55.3 years; 6; 88% white), which included paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole or tamoxifen.
“The control group included both standard chemotherapy agents and endocrine therapies, since these were the most commonly used drugs for recurrent low-grade serous carcinoma,” Gershenson said.
Gershenson and colleagues stratified randomization by geographical region (U.S. or U.K.), number of previous regimens (one, two, or three or more), performance status (0 or 1) and planned standard-of-care regimen.
Investigator-assessed PFS based on imaging at baseline, once every 8 weeks for 15 months, and once every 3 months thereafter — within the intention-to-treat population served as the primary endpoint. Additionally, researchers assessed safety among patients who received at least one dose of study therapy.
Key findings
Results showed trametinib reduced the risk for disease progression or death by 52% compared with standard-of-care therapies.
Gershenson and colleagues reported 217 PFS events: 101 (78%) in the trametinib group and 116 (89%) in the standard-of-care group at primary analysis, with median PFS of 13 months (95% CI, 9.9-15) in the trametinib group vs. 7.2 months (95% CI, 5.6-9.9) in the standard-of-care group (HR= 0.48; 95% CI, 0.36-0.64).
Researchers reported no treatment-related deaths. The most frequent grade 3 or grade 4 adverse events in the trametinib group included 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 grade 4 adverse events included abdominal pain (17%), nausea (11%), anemia (10%) and vomiting (8%).
Implications
Gershenson said although the investigators wanted to correlate the presence or absence of mutations in the MAPK signaling pathway with outcomes — and, by utilizing whole-exome sequencing, they found the observed treatment effect of PFS favored trametinib in both mutation-positive and mutation-negative patients — the research yielded no evidence that mutation status could predict PFS.
“In addition, [objective response rate] was markedly more favorable for trametinib than standard of care in mutation-positive patients (50% vs. 9%) but not in mutation-negative patients (8% vs. 7%); however, this did not reach statistical significance,” he told Healio. “In the future, we would like to study further the molecular biology of low-grade serous carcinoma using techniques such as whole-genome sequencing, RNA sequencing and proteomics.”
Taken as a whole, the results suggest histologic diagnosis of relapsed low-grade serous carcinoma is sufficient to initiate trametinib, at least from a PFS perspective, Sarah P. Blagden, PhD, professor of experimental oncology in the department of oncology, medical sciences division, at University of Oxford, wrote in an accompanying editorial.
“The results of the GOG 281/LOGS trial have shifted the paradigm in ovarian cancer toward treatment selection by histological type,” Blagden wrote. “This represents a welcome step away from the histologically agnostic approach, and the end of the road for cytotoxic chemotherapy in recurrent low-grade serous ovarian cancer.”
References:
Blagden SP. Lancet. 2022;doi:10.1016/S0140-6736(21)02338-2.
Gershenson DM, et al. Lancet. 2022;doi:10.1016/S0140-6736(21)02175-9.
Trametinib represents potential new standard-of-care for patients with recurrent low-grade serous ovarian carcinoma. https://www.mdanderson.org/newsroom/trametinib-represents-potential-new-standard-of-care-for-patients-with-recurrent-low-grade-serous-ovarian-carcinoma.h00-159537378.html. Published Feb. 3, 2022. Accessed Feb. 4, 2022.
For more information:
David M Gershenson, MD, can be reached at Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; email: dgershen@mdanderson.org.
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