A combination of the immune checkpoint inhibitor Keytruda (pembrolizumab) and the melanoma therapy Mektovi (binimetinib) is safe and well-tolerated by people with advanced triple negative breast cancer, preliminary findings from a Phase 1/2 clinical trial show.
Safety data from the Phase 1 portion of the trial was presented in the poster, “Phase I results of the phase I/II study of pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer,” at the ASCO-SITC Clinical Immuno-Oncology Symposium on Feb. 6 in Orlando, Florida.
The ongoing clinical trial (NCT03106415) initially enrolled 12 triple negative breast cancer patients whose cancer was locally advanced and inoperable, or had spread to distant regions in the body (metastatic), and who had received no more than three prior lines of therapy. (The term “triple negative” means that the cancer growth is not driven by estrogen, progesterone, or by the protein HER2.)
The primary goal of the initial phase of the trial was to determine the maximum dosage of Mektovi that patients could tolerate without a severe adverse reaction.
To test this, patients were split into two groups, each receiving a distinct oral dose of Mektovi. Four of the 12 patients received Mektovi at 45 mg twice daily, while the other eight received it at 30 mg twice daily. All patients were given a consistent 300 mg dose of Keytruda every three weeks, starting two weeks after the introduction of Mektovi.
Participants were evaluated for a measure called dose limiting toxicity (DLT), which is defined as experiencing an adverse reaction to the treatment that is severe enough to prevent an increase in dosage. Of the four patients enrolled at the higher dosage level of Mektovi, three were evaluated, and two of those were found to have a DLT due to abdominal pain and abnormal levels of liver enzymes.
Of the eight patients enrolled at the lower Mektovi dosage level, six were evaluated, and only one was found to have a DLT due to abnormal levels of liver enzymes. However, that one patient had enzyme abnormalities at the beginning of the trial due to the cancer spreading to the liver, and those abnormalities were no longer observed three weeks after the treatment had been stopped.
From those data, researchers concluded that Mektovi was safe for breast cancer patients at a 30 mg, twice-daily dose. However, additional data from Phase 2 of the study, which will provide more information about safety and the effectiveness of the treatment, is forthcoming.
The primary goal of that second part is to measure the objective response rate, or the proportion of patients who show at least a partial reduction in tumor size. Secondary objectives include duration of response, proportion of patients achieving at least disease stabilization, time to disease worsening or death, and overall survival.
Researchers are recruiting 23 additional patients at the Mayo Clinic in Minnesota and the Mayo Clinic in Florida for the second phase of the trial.
The study was launched based on previous data indicating that the RAS/MAPK signaling pathway, which is a chain of proteins that communicates messages from the surface to the interior of a cell, may limit immune system activity and responsiveness to chemotherapy.
Array Bioharma‘s small molecule inhibitor Mektovi was designed to block the protein MEK, which is part of the pathway’s protein chain, and is thought to improve immune cell migration into tumors.
In animal studies, MEK inhibition significantly reduced breast cancer growth through immune-mediated mechanisms, and this effect was significantly more pronounced when a MEK inhibitor was used in combination with an inhibitor of the PD-1/PD-L1 pathway, like Keytruda.
Keytruda, developed by Merck (known as MSD outside the U.S. and Canada) prevents the binding of PD-1, a receptor found on the surface of immune T-cells, to proteins produced by cancer cells that dampen immune responses. The approach boosts the body’s own immune system, increasing survival outcomes in many tumor types.
The clinical trial of Mektovi and Keytruda is scheduled to end in May 2020, and an interim analysis of the combination treatment’s effectiveness is expected soon.