Trametinib Tx Shows Promise in Tough-to-Treat LGSOC

September 30, 2019 6:00 pm

The following article is provided by The Clearity Foundation to support women with ovarian cancer and their families. Learn more about The Clearity Foundation and the services we provide directly to women as they make treatment decisions and navigate emotional impacts of their diagnosis.


By Pam Harrison

Targeted drug provokes good response in chemoresistant, low-grade serous ovarian or peritoneal cancer.

Trametinib (Mekinist) treatment was associated with better outcomes in women with recurrent or progressive low-grade serous ovarian or peritoneal cancer versus treatment with standard-of-care chemotherapy, researchers reported here.

In the phase II/III study, median progression-free survival (PFS) was 52% longer in women who received the MEK inhibitor at 13.0 months (95% CI 9.9-15.0 months) versus 7.2 months (95% CI 5.6-9.9 months) at a hazard ratio of 0.48 (95% CI 0.36-0.64, P<0.0001) compared with the treating physicians’ choice of chemotherapy, reported David Gershenson, MD, of the MD Anderson Cancer Center in Houston at the European Society for Medical Oncology (ESMO) annual meeting.

Moreover, the duration of response was a median of 13.6 months (95% CI 8.1-18.8 months) for women randomized to trametinib versus 5.9 months (95% CI 2.8-12.2 months) for women receiving a variety of chemotherapy agents.

“Low-grade serous ovarian or peritoneal cancer (LGSOC) is a rare subtype accounting for 5% to 10% of all serous cancers [but] because of the subtype’s relative chemoresistance, the search for novel therapeutics has predominated over the past decade,” Gershenson explained. “Our findings suggest that trametinib represents a new standard of care treatment option for women with recurrent low-grade serous carcinoma.”

ESMO discussant Jonathan Ledermann, MD, of UCL Cancer Institute in London, agreed, stating that “this is the first positive randomized trial in LGSOC and demonstrates that trametinib is a new treatment for LGSOC.”

However, Ledermann cautioned that similar results were not seen with binimetinib (Mektovi), another MEK inhibitor, in the MILO trial, and that oncologists need to continue to identify which patients will benefit from MEK inhibitors as a whole.

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

Also, “we [need to clarify] when trametinib should be used and how to manage common toxicities,” he observed.

For the current study, a total of 260 women with recurrent LGSOC who had received at least one prior platinum regimen, but no prior treatment with either a MEK or a BRAF inhibitor, were randomized to either trametinib (2 mg a day) continuously until disease progression or to standard-of-care chemotherapy.

Chemotherapy could consist of letrozole (2.5 mg a day); pegylated liposomal doxorubicin (40 to 50 mg) given intravenously every 28 days; weekly paclitaxel (80 mg/m2) tamoxifen (20 mg) twice a day or topotecan (4.0 mg/m2) on days 1, 8, 15 of every 28-day cycle, all until disease progression.

Upon progression, patients on standard chemotherapy were allowed to cross over to the same daily dose of trametinib, given continuously until they again progressed.

Median patient age was approximately 56. The primary site of involvement was the ovary in >90% of the patients. Almost half of both treatment groups had also received three or more prior lines of therapy.

The authors reported that the objective response rate (ORR) by RECIST 1.1 criteria was 26.2% (95% CI 19.0-34.0%) in the trametinib arm while disease stabilized in 59.2% of the same treatment group.

In the control arm, the overall ORR was 6.2% (95% CI 2.0-10%) while disease stabilized in 70.8% of patients in the same arm, with stable disease responses being highest for patients treated with pegylated liposomal doxorubicin at 80% and lowest for patients treated with topotecan at 50%, Gershenson pointed out.

Median overall survival (OS) was also 25% longer at 37 months (95% CI 30.3 to NE months) in the trametinib arm at an HR 0.75 (95% CI 0.51 -1.11) versus 29.2 months (95% CI 23.5- 51.6 months, P=0.054), but the OS hazard in the standard chemotherapy arm included the effect of trametinib among crossover patients, Gershenson said.

Once patients had crossed over to trametinib from the control arm, their median PFS was 10.8 months (95% CI 7.3-12 months) and the duration of response while on the MEK inhibitor was 15.9 months (95% CI 4.2-22.1 months).

The most common treatment-emergent ≥grade 3 adverse events (TRAEs) among trametinib patients were hematologic at 13.4% and gastrointestinal at 27.6%, as well as vascular toxicities in approximately 19% of patients; skin rash in 15% of patients; high blood pressure and anemia in approximately 12%; and diarrhea in approximately 10% overall.

The most common TRAEs among standard chemotherapy patients included grade ≥3 abdominal pain in approximately 17% of patients and nausea and anemia in roughly 10%.

“Most patients diagnosed with LGSOC are diagnosed in advanced stages and over 70% of women with stage III and IV LGSOC relapse,” Gershenson stressed, noting that LGSOC is characterized by alterations in the MAP kinase pathway, suggesting that a MEK inhibitor such as trametinib could be expected to have activity in this particular chemoresistant cancer.

This article was published by MedPage Today.

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