Amid high expectations, the first clinical data with Merck & Co’s STING agonist at ESMO has proved a disappointment—at least as a monotherapy.
The preliminary results from the phase 1 trial showed that MK-1454 was unable to achieve any partial or complete responses when used on its own in patients with advanced solid tumors or lymphomas, but partial responses were seen when it was given alongside Merck’s PD-1 checkpoint inhibitor Keytruda (pembrolizumab).
STING (stimulator of interferon genes) has emerged as a hot new target in oncology, with companies rushing to develop drugs that activate the protein and—it is hoped—kickstart an innate immune response against cancer cells in the tumor microenvironment. The innate immune system is the body’s first line of defense against pathogens, and interest in the STING pathway stems from experiments showing that injecting killed bacteria into tumors can cause them to get smaller.
As Merck is one of the front-runners among companies developing STING agonists, the lackluster data are a bit of a cold shower for the emerging category, which also features candidates from Novartis/Aduro, Bristol-Myers Squibb/IFM Therapeutics, and Mavupharma, among others. However, it would be premature to write off the mechanism just yet—and it could be that the drug is actually working as one might expect.
| DOWNLOAD THE FULL ESMO 2018 CONFERENCE REPORT |
In the phase 1 study, MK-1454 was given as an injection into tumors every week for nine weeks, then every three weeks, at a range of doses, either alone or in combination with Keytruda. Patients who progressed on the monotherapy crossed over to the combination regimen with the PD-1 inhibitor.
Out of 25 patients on the combination therapy whose data were available at ESMO, six patients (24%) had a partial response, including three with advanced and neck cancer, one with triple-negative breast cancer, and two with thyroid cancer.
One of the issues with checkpoint inhibitor therapy is that a relatively low proportion of patients tend to respond to these drugs, and that is thought to be in part because there needs to be an established immune response against a cancer that the checkpoint inhibitors can rev up. So, one of the draws for companies developing STING agonists is that they may help checkpoint inhibitors can work in more patients and across a wider range of cancers.
MK-1454’s lack of efficacy on its own doesn’t preclude the possibility that it is ramping up the response to Keytruda, although as none of the six patients who responded to the combination had failed prior checkpoint inhibitor therapy, its impossible to draw any conclusions from this single phase 1 data set.
Eric Rubin, who heads up Merck’s early-stage development programs in clinical oncology, said that the company is “encouraged by these early findings” and has additional studies in play to further explore the potential of the STING agonist.