Combining 5-azacytidine (a demethylating drug) with a histone deacetylase (HDAC) inhibitor may prime non–small cell lung cancers (NSCLC) to better respond to immunotherapy, according to research published in Cell.1
The combination under study emerged from laboratory more than 10 years ago and has been in clinical trials ever since, said Stephen B. Baylin, MD, of the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Several years ago, there was a “chance collision,” Dr Baylin said, in which his group noticed that, when 5 patients on a trial for epigenetic therapy had NSCLC progression, those treated with the first of the new checkpoint inhibitors responded. Three “did extremely well, with long-term responses and remissions.”
As the unexpected responses could be explained by immunotherapy alone or the combination with epigenetic therapy, Dr Baylin’s group has been studying this since and “went from bedside back to the lab” to determine what (if any) correlations they could find.
Immune checkpoint therapy is “a tremendous step forward, but less than half of patients with lung cancer have benefited to date,” Dr Baylin said. In their study, “the 2-drug epigenetic therapy combination worked exceedingly well in a small percentage of patients with NSCLC — even before they received the immune checkpoint inhibitor. In 2 animal models of NSCLC, the 2 agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors.”
Dr Baylin, Peter Jones, PhD, of the Van Andel Research Institute (VARI) in Grand Rapids, Michigan, and Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center in New York, New York — all with the Stand Up To Cancer (SU2C) team — were selected to take the concept to a clinical trial for patients with NSCLC in the inaugural SU2C Merck Catalyst Project.2
The group initiated a phase 1/1b trial to evaluate whether the HDAC inhibitor, mocetinostat, in combination with the demethylating drug, guadecitabine, can boost responses to pembrolizumab in patients with advanced NSCLC.
Dr Baylin said that “bringing in immune cells is really a key issue for checkpoint therapy; the cells have to be in the tumor to break the tolerance with immune checkpoint therapy and be effective with treatment.”
Researchers hypothesized that to reverse DNA methylation, there would need to be chronic, low-doses to both enable patient tolerance and prevent the abnormality from returning. It was unclear, however, how to give the combination over long periods of time in the clinic.
“The big surprise we found while studying the NSCLC cell culture was that, in addition to augmenting the tumor induction for immune signaling through an interferon generating response that we knew the DNA demethylating agent itself can produce, the HDAC inhibitor not only augmented this but was occurring with down-regulation of signaling, best seen with both drugs, for the very important tumor oncogene, CMYC,” Dr Baylin said.
“MYC was found to directly antagonize the up-regulation of the tumor immune signaling. So we were getting a ‘two-fer,’ because we were down-regulating MYC, which was fighting against us, and simultaneously allowing for better up-regulation of the tumor immune signaling.”
The SU2C Catalyst project has just started enrolling patients with a goal of “augmenting the performance of immune checkpoint therapy in these patients with NSCLC. It is possible that many more patients may respond initially to the combination, and if we see this, we will also work in the future on whether we can reverse resistance,” Dr Baylin said.
Presuming the initial 1-year outcomes are favorable, “that would help this combination rise to the top in terms of getting approval for a registration trial,” he said. A “best case” scenario would have this therapy in a registration trial within 2 years, but Dr Baylin acknowledged there are too many variables at this point to predict that far into the future.
“We will also retrospectively examine whether there’s an aggregation of those patients who respond to specific categories of gene mutations in their tumors. Do we improve outcomes across the spectrum of the mutational burden? These are questions we need to answer,” he said.