A combination of the investigational agent MK-1454 and Keytruda (pembrolizumab) induced robust and durable responses in solid tumor and lymphoma patients in a Phase 1 trial, Merck (known as MSD outside the U.S. and Canada) announced.
The findings were announced at the recent European Society for Medical Oncology (ESMO) 2018 Congress in Munich, Germany. The poster was titled, “Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas.”
STING is a molecule that plays a key role in fighting bacteria and viruses by activating the immune system and initiating the deployment of T-cells. Researchers believe that activating this pathway could thus increase the number of T-cells — immune cells that eliminate cancer cells — within tumors, and that this could work well with treatments that boost the activity of such cells.
MK-1454 is a small molecule activator (agonist) of STING being developed by Merck for a variety of tumors. In preclinical studies, MK-1454 improved the responses to a PD-1 inhibitor, supporting its use in combination with immune checkpoint inhibitors.
Thus, Merck designed a Phase 1 trial (NCT03010176) to test the combination of MK-1454 and its PD-1 inhibitor Keytruda in patients with advanced or metastatic solid tumors or lymphomas.
Patients received increasing doses of either MK-1454 alone or in combination with Keytruda. While Keytruda was injected into the blood every three weeks, MK-1454 was injected directly into tumors every week for nine weeks, and every three weeks thereafter.
For those receiving MK-1454 alone, doses ranged from 10 to 3,000 micrograms of the investigational agent, while the combination group received 90 to 1,500 micrograms.
Patients who progressed while on MK-1454 were eligible to cross over to the combination arm of the study.
Researchers now presented data from 26 patients receiving MK-1454 alone, 25 patients on the combination, and nine patients who crossed over to the combination.
MK-1454 treatment increased the levels of pro-inflammatory molecules in both patient groups.
However, only 20% of patients who received MK-1454 alone achieved stable disease. The combination, on the other hand, induced a partial response in 24% of patients, including three patients with head and neck cancer, one with triple-negative breast cancer, and two with thyroid cancers.
Interestingly, tumor reductions were seen in both injected and non-injected tumors, and tumor burden was reduced by a median of 83%. An additional six patients (24%) achieved stable disease on the combination.
At the time of analysis, all partial responses were still ongoing and had lasted for six months or longer.
“We are encouraged by these early findings with our STING agonist, most notably the observations of several robust anti-tumor responses in patients receiving MK-1454 in combination with Keytruda. Further studies are ongoing,” Eric H. Rubin, senior vice president, early-stage development, clinical oncology, at Merck Research Laboratories, said in a press release.
The most common adverse events reported during the study were fever, chills, fatigue, and injection site pain. Overall, 83% of patients treated with MK-1454 and 82% receiving the combination experienced adverse events, but only two patients on the combination discontinued treatment.
Dose-limiting toxicities were reported at the 1,500-microgram dose, leading to severe vomiting and injection site pain. The safety of higher doses is yet to be determined. The optimal dose of the investigational STING agonist has not yet been determined, and the dose escalation study is still ongoing.
“Combined MK-1454 plus Keytruda resulted in encouraging efficacy and an acceptable safety profile supporting continued development of the combination regimen,” researchers said.
The trial is still recruiting participants in the United States, France, Israel, and the United Kingdom. For information, visit the trial website.