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

Study Details

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:

• Paclitaxel at 80 mg/m² on days 1, 8, and 15 of 28-day cycles (n = 14)
• Pegylated liposomal doxorubicin at 40 to 50 mg/m² once every 4 weeks (n = 37)
• Topotecan at 4 mg/m² on days 1, 8, and 15 of 28-day cycles (n = 9)
• Letrozole at 2.5 mg once daily (n = 43)
• Tamoxifen at 20 mg twice daily (n = 27).

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.

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.

Adverse Events

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.