As reported in The Lancet by David M. Gershenson, MD, of the Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, and colleagues, the phase II/III GOG 281/LOGS trial showed that trametinib improved progression-free survival vs standard-of-care treatment in women with low-grade serous ovarian carcinoma.¹

David M. Gershenson, MD

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.”

Study Details

In the open-label trial, 260 patients from sites in the United States and United Kingdom with measurable disease who had received at least one platinum-based regimen 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 choices of standard-of-care options selected prior to randomization (n = 130). Randomization was stratified by region (United States or United Kingdom), number of previous regimens, Eastern Cooperative Oncology Group (ECOG) performance status, and planned standard-of-care regimen. 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 = 11); pegylated liposomal doxorubicin at 40 to 50 mg/m² once every 4 weeks (n = 40); topotecan at 4 mg/m² on days 1, 8, and 15 of 28-day cycles (n = 8); letrozole at 2.5 mg once daily (n = 44); and 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 the 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).

For stratification factors, hazard ratios for trametinib vs the standard of care were 0.43 (95% CI = 0.23–0.81) among 55 patients from the United Kingdom and 0.46 (95% CI = 0.34–0.64) among 205 patients from the United States; 0.33 (95% CI = 0.18–0.61) for one (n = 59), 0.48 (95% CI = 0.30–0.78) for two (n = 76), and 0.51 (95% CI = 0.34–0.76) for at least three (n = 125) prior regimens; and 0.39 (95% CI = 0.28–0.55) for an ECOG performance status of 0 (n = 186) and 0.65 (95% CI = 0.39–1.10) for a performance status of 1 (n = 74).

In an analysis of 87 patients preplanned to receive letrozole if randomly assigned to the standard-of-care group, those assigned to the trametinib group had longer progression-free survival vs those in the standard-of-care group (median = 15.0 months vs 10.6 months, HR = 0.58, 95% CI = 0.36–0.95, P = .0085). For those preplanned to receive other standard-of-care treatments, median progression-freesurvival rates for those assigned to trametinib vs standard-of-care treatment were 11.8 vs 10.0 months (HR = 0.71, 95% CI = 0.44–1.17) for pegylated liposomal doxorubicin (n = 77), 9.5 vs 5.0 months (HR =0.47, 95% CI = 0.21–1.06) for paclitaxel (n = 54), 9.8 vs 3.1 months (HR = 0.22, 95% CI = 0.07–0.64) for topotecan (n = 17), and 19.1 vs 3.7 months (HR = 0.19, 95% CI = 0.10–0.35) for tamoxifen (n = 54).

An 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% for 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 treatment in the total population.

A total of 88 patients (68%) in the standard-of-care group crossed over to receive trametinib following disease progression. Median overall survival was 37.6 months (95% CI = 32.0 months to 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 patients crossing over to receive trametinib. Median progression-free survival in patients in the standard-of-care group who crossed over to trametinib was 10.8 months (95% CI = 7.3–12.0 months), and the objective response rate was 15%.

Adverse Events

The most common adverse events of any grade were fatigue (73%), diarrhea (73%), and acneiform rash (63%) in the trametinib group and fatigue (58%), nausea (51%), and abdominal pain (47%) in the standard-of-care group. 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 grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (17%), nausea (11%), anemia (10%), and vomiting (8%).

Among adverse events of special interest in the trametinib group, decreased ejection fraction occurred in 10 patients (8%; grade 2 in 8, grade 3 in 2), and pneumonitis occurred in 3 (2%; grade 1, 2, and 3 in 1 each). Adverse events led to discontinuation of treatment in 36% vs 30% of patients.

The investigators concluded: “Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.” 

DISCLOSURE: The study was funded by NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis. Dr. Gershenson has royalties or licenses from Elsevier and UpToDate; has stock or stock options from Johnson & Johnson, Bristol Myers Squibb, and Biogen; has served as a consultant to Genentech, Springworks, and Onconova; and has served as a member of the CTAC Committee of the National Cancer Institute.

REFERENCE

1. Gershenson DM, Miller A, Brady WE, et al: Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): An international, randomised, open-label, multicentre, phase 2/3 trial. Lancet 399:541-553, 2022.