In a phase II/III trial reported in The Lancet, David M. Gershenson, MD, and colleagues found that trametinib improved progression-free survival vs standard of care treatment in women with low-grade serous ovarian carcinoma.
As stated by the investigators, “Low-grade serous carcinoma of the ovary or peritoneum is characterized 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.”
David M. Gershenson, MD
The open-label trial included 260 patients from sites in the United States and United Kingdom with measurable disease who had received at least one platinum-based regimen. They were randomly assigned between February 2014 and April 2018 to receive trametinib at 2 mg once daily (n = 130) or one of five physician’s choice of standard-of-care options selected prior to random assignment (n = 130). Patients with serous borderline tumors or tumors containing low-grade serous and high-grade serous carcinoma were excluded.
Standard-of-care options consisted of:
Treatment continued until disease progression or unacceptable toxicity; patients in the standard-of-care group were permitted to discontinue therapy after six cycles at the investigator’s discretion. After disease progression, patients in the standard-of-care group could cross over to receive trametinib. The primary endpoint was investigator-assessed progression-free survival.
At data cutoff (July 2019), median duration of follow-up was 31.5 months (interquartile range [IQR] = 18.1–43.3 months) in the trametinib group and 31.3 months (IQR = 15.7–41.9 months) in the standard-of-care group. Median progression-free survival was 13.0 months (95% confidence interval [CI] = 9.9–15.0 months) in the trametinib group vs 7.2 months (95% CI = 5.6–9.9 months) in the standard-of-care group (hazard ratio [HR] = 0.48, 95% CI = 0.36–0.64, P < .0001).
In a post-hoc analysis of 87 patients preplanned to receive letrozole if randomly assigned to the standard-of-care group, those randomly assigned to the trametinib group had longer progression-free survival vs those in the standard-of-care group (median = 15.0 months, 95% CI = 7.7–23.1 months, vs 10.6 months, 95% CI = 6.5–12.8 months; HR = 0.58, 95% CI = 0.36–0.95, P = .0085). Hazard ratios favored trametinib in analysis of patients preplanned to receive each of the other standard-of-care treatments, ranging from 0.22 to 0.71.
Objective response was achieved in 26% of patients in the trametinib group vs 6% of patients in the standard-of-care group (odds ratio = 5.4, 95% CI = 2.4–12.2, P < .0001). Objective response rates for the individual standard-of-care treatments were 14% for letrozole, 9% for paclitaxel, 3% pegylated liposomal doxorubicin, 0% for tamoxifen, and 0% for topotecan. Median duration of response was 13.6 months (IQR = 7.2–19.9 months) for trametinib vs 5.9 months (IQR = 4.0–12.2 months) for standard of care.
A total of 88 patients (68%) in the standard-of-care group crossed over to receive trametinib. Median overall survival was 37.6 months (95% CI = 32.0 months–not evaluable) in the trametinib group and 29.2 months (95% CI = 23.5–51.6 months) in the standard-of-care group (HR = 0.76, 95% CI = 0.51–1.12, P = .056), with the analysis including the effect of the patients crossing over to receive trametinib.
The most common grade 3 or 4 adverse events in the trametinib group were skin rash (13%), anemia (13%), hypertension (12%), diarrhea (10%), nausea (9%), and fatigue (8%). The most common in the standard-of-care group were abdominal pain (17%), nausea (11%), anemia (10%), and vomiting (8%). Adverse events of special interest in the trametinib group included decreased ejection fraction in 10 patients (8%; grade 2 in 8, grade 3 in 2) and pneumonitis in 3 (2%; grade 1, 2, and 3 in 1 each). Adverse events led to discontinuation of treatment in 36% vs 30% of patients. No treatment-related deaths were reported.
The investigators concluded, “Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.”
Dr. Gershenson, of the Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet article.
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.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.