Trametinib Emerges as New Standard Option for Recurrent, Low-Grade Ovarian Cancer

David Gershenson, MD

Treatment with the MEK inhibitor trametinib (Mekinist) significantly improved progression-free survival (PFS) and led to a strong trend toward improved overall survival (OS) in recurrent, low-grade serous ovarian cancer, a randomized trial showed.

Median PFS improved from 7.2 months with current standard-of-care (SOC) options to 13.0 months with trametinib. OS increased by 8 months, but just missed achieving statistical significance (P = .054).

More than four times as many patients achieved objective responses with the MEK inhibitor, and responses last more than twice as long, as reported at the 2019 ESMO Congress.

“Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma,” said David Gershenson, MD, of the University of Texas MD Anderson Cancer Center.

The significant PFS benefit and borderline survival improvement occurred despite the fact that 68% of patients in the SOC arm crossed over to trametinib at disease progression, said ESMO invited discussant Jonathan Ledermann, MD, of University College London. Patients who crossed over to the MEK inhibitor also benefited, he added, as indicated by a median PFS of 10.8 months.

“Recurrent low-grade serous ovarian cancer responds very poorly to chemotherapy,” said Ledermann. “It has a long natural history, so evaluation of disease stabilization with interventions can be difficult.”

As if anticipating the question of whether the results reflected a class effect of MEK inhibitors, Ledermann noted that a randomized trial of binimetinib (Mektovi) in recurrent serous ovarian cancer did not demonstrate superiority versus SOC, except in the subgroup of patients with KRAS mutations.

Low-grade serous ovarian or peritoneal cancer accounts for 5% to 10% of all serous ovarian cancers and may arise de novo or following a serous borderline tumor, Gershenson noted. The condition is characterized by alterations in the MAP kinase pathway, relative chemoresistance, and prolonged OS as compared with high-grade serous ovarian cancer.

A single-arm open-label trial of the investigational MEK inhibitor selumetinib provided preliminary evidence of activity in low-grade serous ovarian cancer, providing a rationale for additional clinical investigation of MEK inhibition in the disease.

Gershenson reported findings from a randomized phase II/III trial involving 260 patients with recurrent low-grade serous ovarian or peritoneal carcinoma. Patients were randomized to trametinib or to investigator’s choice of 5 different SOC therapies: letrozole, tamoxifen, pegylated liposomal doxorubicin, paclitaxel, or topotecan. Eligible patients could have received any number of prior regimens, including at least one prior platinum regimen, but not all 5 SOC regimens in the trial’s control arm.

The primary endpoint was PFS, and secondary endpoints included toxicity, quality of life, objective response, and OS. Baseline characteristics were evenly distributed between the two groups, including a median age of 56, primary site in the ovary in 91% of patients, US residence for 79% of study participants, and performance status of 0 in 71.5%.

Additionally, 48% of patients had received at least 3 prior systemic regimens. More than half of the patients had discontinued treatment because of disease progression at data analysis, but substantially fewer in the trametinib arm (42.3% vs 62.3%).

The primary analysis showed that patients treated with trametinib had a 52% reduction in the hazard for disease progression or death (HR, 0.48; 95% CI, 0.36-0.64; P <.0001). Trametinib led to objective responses in 26.2% of patients versus 6.2% of patients in the control arm (odds ratio, 5.4; P <.0001). Median duration of response was 13.6 months with the MEK inhibitor and 5.9 months with SOC.

The survival analysis yielded a median OS of 37.0 months for the trametinib arm and 29.2 months for the control group, representing a 25% reduction in the survival hazard (HR, 0.75; 95% CI, 0.51-1.11; P = .054).

With regard to treatment-emergent adverse events (all grades), trametinib resulted in more cases of rash (92.1% vs 48.5%), fatigue (72.5% vs 57.8), diarrhea (72.4% vs 33.6%), nausea (60.6% vs 50.8%), anemia (51.9% vs 43.0%), vomiting (45.7% vs 34.4%), and hypertension (38.6% vs 21.2%). The most common grade ≥3 adverse events in the trametinib arm were rash (15.0%), anemia (12.6%), hypertension (11.8%), and diarrhea (10.2%).

Among adverse events of special interest for trametinib, decreased left ventricular ejection fraction was the most frequent (7.9%), followed by pneumonitis (2.4%), retinal vascular disorder, LV systolic dysfunction, QTc prolongation (all <2 events each), and retinal tear (0.8%).

As Ledermann noted, almost 70% of patients randomized to SOC crossed over to trametinib. Those 88 patients had a median PFS of 10.8 months, a 15% response rate, and a median response duration of 15.9 months.

Gershenson D, Miller A, W. Brady W, et al. A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer. Presented at 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract LBA62.

<<< View more from the 2019 ESMO Congress