Trametinib Excels Over Standard of Care in Patients with Rare Ovarian Cancer

David Gershenson, MD

The MEK inhibitor, trametinib (Mekinist), was found to reduce the risk of progression or death compared to the standard of care (SOC) treatment in patients with low-grade serous ovarian carcinoma in a study conducted by the University of Texas MD Anderson Cancer Center. David Gershenson, MD, professor of gynecologic oncology and reproductive medicine, led the study with the intention to find progression-free survival (PFS) and overall response rate (ORR).¹

“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,” Gershenson said, 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.”

Spanning from February 27, 2014 to April 10, 2018, this randomized, open-label, multi center, phase 2/3 trial (NCT02101788) enrolled 260 patients. Patients were randomized 1:1 to receive trametinib (n = 130) or SOC (n = 130). PFS events occurred in 78% (n = 101) of the trametinib group and 89% (n = 116) of the SOC group. Median PFS for patients in the trametinib group was 13.0 months (95% CI, 9.9-15.0) versus 7.2 months (95% CI, 5.6-9.9) in the SOC group (HR, 0.48; 95% CI, 0.36-0.64; P < .0001). The ORR of the trametinib group was 26% with 59% of patients having stable disease for at least 8 weeks. The ORR of the SOC group was 6%.²

Patients received either 2 mg of trametinib once daily or 1 of 5 SOC treatments: intravenous paclitaxel 80 mg/m² by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40–50 mg/m² by body surface area once every 4 weeks; intravenous topotecan 4 mg/m² by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2.5 mg once daily; or oral tamoxifen 20 mg twice daily. The primary end point was investigator assessed PFS, and the secondary end points were safety, ORR, quality of life, the effect of MAPK pathway activation on response or PFS, the prognostic effect of phosphorylated ERK expression, and overall survival (OS).²

The trametinib group had a median duration of response of 13·6 months (interquartile range, 7.2-19.9; 95% CI 8.1-18.8) versus 5.9 months (4.0-12.2; 2.8-12.2) for SOC group. Of the 260 patients, 111 (43%) died which included 51 (39%) of 130 in the trametinib group and 60 (46%) of 130 in the SOC group. The median OS was 37.6 months (95% CI 32.0–non-evaluable) in the trametinib group and 29.2 months (23.5-51.6) in the SOC group. The HR for death favored the trametinib group (0.76 [95% CI 0.51–1.12; one-sided P value 0.056]).

The adverse events (AEs) of grade 3 or 4 in the trametinib group were most commonly skin rash (13%), anemia (13%), hypertension (12%), diarrhea (10%), nausea (9%), and fatigue (8%). In the SOC group, the most common grade 3 or 4 AEs were abdominal pain (17%), nausea (11%), anemia (10%), and vomiting (8%). No deaths were caused by treatment.

Gershenson added, “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.”

_References:

_{1. Trametinib represents potential new standard-of-care for patients with recurrent low-grade serous ovarian carcinoma. Press release. The University of Texas MD Anderson Cancer Center; February 3, 2022. Accessed February 7, 2022. https://bit.ly/3GzoatB}

_{2. 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. 2022;399(10324):541-553. doi:10.1016/S0140-6736(21)02175-9}