Bedside-to-Bench Research Uncovers How Steroids Impact Survival in Patients Undergoing Immune Checkpoint Inhibitor Therapy for NSCLC

Jorge Nieva, MD, of the University of Southern California (USC) Norris Comprehensive Cancer Center, joined Lung Cancers Today to discuss new research that shows how corticosteroids affect patients who are receiving immune checkpoint inhibitors for non–small cell lung cancer (NSCLC).

With steroids having known effects on the immune system and being commonly used in patients with NSCLC who are undergoing treatment with immune checkpoint inhibitors, it was critical to understand how steroids affect survival outcomes with immune checkpoint inhibitors, Dr. Nieva said.

“If those patients were receiving corticosteroids prior to the institution of the immune checkpoint inhibitors, they didn’t do as well,” Dr. Nieva said. “They didn’t do as well from the standpoint of overall survival. They didn’t do as well from the standpoint of progression-free survival.”

Dr. Nieva, who coauthored a recent study published in Cancer Research Communications with senior author Fumito Ito, MD, PhD, and first author Lauren Polyakov, both of USC, explained that the work has important implications.

“If you give people treatments that make those immune cells less functional overall, you’re not going to see the benefit of the immune checkpoint inhibitors,” Dr. Nieva said.

The researchers conducted the study by evaluating the clinical outcomes of 277 patients with NSCLC who received treatment with immune checkpoint inhibitors at two academic institutions, Roswell Park Comprehensive Cancer Center (n=88) and University of Southern California (n=189).

The study showed that among the 277 patients, 21 (8%) were receiving steroids at the start of immune checkpoint inhibitor therapy. The patients who were receiving steroids at baseline showed a “lower overall response rate with markedly shorter progression-free survival and overall survival compared with those not receiving steroids,” the study authors wrote.

For example, in the overall population, the median progression-free survival was 10.7 months in those who were not receiving steroids, compared with just 3.2 months in those receiving steroids, Dr. Nieva said.

A multivariate analysis showed that “steroid use was the only significant independent risk factor for disease progression and mortality in both independent cohorts,” the researchers explained. In addition, a baseline peripheral blood neutrophil-to-lymphocyte ratio of less than 5 “was a strong prognostic indicator; however, the prognostic value of neutrophil-to-lymphocyte ratio was absent in patients receiving steroids,” they wrote.

Dr. Nieva explained that it was critical to “make sure that the association was consistent in separate databases across different institutions.”

“One of the important things to do when you’re doing retrospective research is to make sure that it’s not just an accident of the particular database that you’re looking at,” he said. “Here, we looked at databases from two different cancer centers and found that the direction of the association and the magnitude of the association were very similar.”

With these clinical data, the researchers then used a bedside-to-bench approach to further evaluate their findings in cell lines and in vivo mouse studies. This approach showed that concurrent steroid use “significantly decreased antitumor efficacy of anti–PD-1 therapy and attenuated the increase of CX3CR1⁺CD8⁺ T cells in mice with MC38 tumors whereas discontinuation of steroid at the start of treatment did not make a negative impact on survival,” the study authors explained.

“That implicates that specific group as being one of the important drivers of the treatment effect that we observed,” Dr. Nieva said.

Dr. Nieva explained why it was critical to use this bedside-to-bench approach.

“There’s a lot of value in taking clinical associations and bringing them back to the bench to try to understand the ‘why’ and the ‘how.’ That’s an approach that I’d like to see used more often,” he said.

Dr. Nieva explained that this bedside-to-bench approach was possible due to complementary areas of expertise in the research team.

“Dr. Fumito Ito is a surgeon at USC who has a strong interest in chemokine receptors and how CD8 T cells work. That was the driving force behind developing the project,” Dr. Nieva said. “We had Robert Hsu, who does a great deal of database research here at USC, looking at large numbers of lung cancer patients, and trying to understand the clinical factors that impact the response to different therapeutics.”

With these bedside-to-bench findings, Dr. Nieva highlighted the implications of the research and what could come from these data. For example, they could help researchers develop more refined steroids.

“Sometimes, when we give these checkpoint inhibitors to patients, we need to shut the immune system down because we’ve had too much of an immune response,” Dr. Nieva said. “And patients sometimes need to get steroids because the checkpoint inhibitors have caused an autoimmune condition to occur…. We can treat these folks with steroids, but maybe we only need to treat them with something that affects the CX3CR1 subset of T cells. That might make for a cleaner drug. It might make for a drug, for example, that doesn’t have all the other toxicities that steroids have.”

Overall, this research shows the importance of bridging the gap between clinical observation and laboratory science, he said.

“Being able to go back to the laboratory to try to tease out the fundamental principles that underlie clinical observations—that’s invaluable,” Dr. Nieva said. “My hat’s off to Dr. Ito for going back and doing the benchtop work that he did, once the clinical association was readily apparent.”