Steroid Use During ICI Treatment Lessens Effectiveness in Patients With NSCLC

High doses of steroids, whether administered before or during treatment with an immune checkpoint inhibitor (ICI), caused the tumors of patients with non-small cell lung cancer (NSCLC) to shrink less than those not on steroids, according to recent study results published by investigators in Cancer Research Communications. The authors wrote that their findings could serve as a baseline for the steroids’ negative independent prognostic factor in patients with NSCLC undergoing ICI therapy.¹

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ICI therapy has become revolutionary for patients with NSCLC, the authors wrote, with anti–PD-1/PD-L1 regimens becoming a foundation of treatment. Although improved clinical outcomes with the addition of chemotherapy to ICI have been recorded for some patients, there is ongoing research to understand how prognostic factors (eg, smoking history, tumor histology, performance status) can provide some predictive values for patient response to ICI therapy. Additionally, the authors wrote that, prior to this study, it was unclear whether the immunomodulatory mechanisms of steroids had negative impacts on ICI treatment outcomes. For this study, the authors specifically evaluated the impact of baseline steroid use on clinical outcomes and blood-based predictive correlates of response to ICI therapy in patients with NSCLC.¹

The investigators enrolled patients with stage II to IV NSCLC who were treatment-naïve or previously treated with an anti–PD-1 antibody alone (pembrolizumab [Keytruda; Merck] or durvalumab [Imfinzi; AstraZeneca]), anti–PD-1/CTLA-4 antibodies (nivolumab/ipilimumab [Opdivo/Yervoy; Bristol Myers Squibb]), or a combination of chemotherapy and anti–PD-1/PD-L1 antibody (pembrolizumab or atezolizumab [Tecentriq; Genentech]). Patients were treated at Roswell Park Comprehensive Cancer Center (RPCCC; n = 88) or at the University of Southern California (USC) Norris Comprehensive Cancer Center or Los Angeles General Medical Center (n = 189). A total of 277 patients (median age: 66 years; range: 30–89 years) with NSCLC who initiated treatment between October 2013 and August 2023 were enrolled.¹

The median time of follow-up was about 10.4 months for patients from RPCCC (range: 0.7–52.0 months) and 6.4 months for those from USC (range: 0.7–88.3 months). Among the 21 patients receiving steroids, indications included brain metastases (n = 17; 80%) or comorbid lung conditions (n = 4; 20%) such as chronic obstructive pulmonary disease. Of note, all 21 patients had remained on steroids for at least 12 weeks after initiating ICI therapy. The investigators had also observed mouse models with MC38 tumors to assess how steroid use influenced T cells.¹

In both RPCCC and USC, patients on baseline steroids were observed to have a lower overall response rate (RPCCC: P = .0141; USC: P = .0454) with noticeably shorter progression-free survival (PFS; RPCCC median: 10.7 months; USC median: 6.6 months) and overall survival (OS; RPCCC median: 21.0 months; USC median: 16.4 months) compared with those not receiving steroids (RPCCC respective median PFS and OS: 3.2 and 7.7 months; USC median PFS and OS: 3.0 and 3.7 months). Additionally, in multivariate analysis, steroid use was the only significant independent risk factor for disease progression and mortality in both the RPCCC and USC cohorts.¹

Further, a baseline peripheral blood neutrophil-to-lymphocyte ratio below 5 was observed to be a strong prognostic indicator; however, the prognostic value of the neutrophil-to-lymphocyte ratio was not present in patients receiving steroids. Additionally, the baseline frequency of circulating CX3CR1+CD8+ T cells was noticeably lower in patients on steroids. Using a bedside-to-bench approach, the investigators determined that concurrent steroid use had significantly decreased antitumor efficacy of anti–PD-1 therapy and weakened the increase of CX3CR1+CD8+ T cells in mouse models bearing MC38 tumors, whereas discontinuation of steroids at treatment initiation did not make a negative impact on survival. Generally, baseline steroid use was associated with worse outcomes and decreased frequency of circulating differentiated effector T cells in patients with NSCLC.¹

“Steroids were the biggest predictor of why certain immunotherapies may not be effective, even when considering multiple other factors such as stage and progression of the disease,” lead author Fumito Ito, MD, PhD, oncologist and immunologist at Keck Medicine, said in a news release. “Our findings reveal that steroids stop the body’s natural cancer-fighting cells, T-cells, from maturing. This makes them unable to attack the cancer as vigorously as they usually would, leading to worse outcomes for patients. While other research has indicated steroids may negatively impact immunotherapy’s efficacy, we are one of the first to pinpoint a probable cause and effect.”²

The authors emphasized that the findings show how high-dose baseline steroid use can decrease the efficacy of ICI in patients with NSCLC. Additionally, they noted that the findings regarding immune-related biomarkers in patients on steroids should be interpreted with caution.¹ However, they ultimately concluded that the findings could help oncologists and health care providers make informed decisions that can benefit patients.²

“Without the presence of circulating biomarkers to inform our decisions, oncologists cannot treat the cancer as effectively, and patients may miss out on the best treatment for their cancer,” Ito explained. “We know that steroids will continue to play an important role in lung cancer care, but it is important to understand their potential limitations. Each patient should talk to their oncologist to make sure they have the best possible care plan tailored to their specific needs.”²

REFERENCES

1. Polyakov L, Lim A, Meyer A, et al. Impact of Glucocorticoids on Immune Checkpoint Inhibitor Efficacy and Circulating Biomarkers in Non–Small Cell Lung Cancer Patients. Cancer Res Commun. 2025;5(7):1082–1094. doi:10.1158/2767-9764.CRC-25-0051

2. University of Southern California – Health Sciences. Common medication for lung cancer symptoms found to limit effectiveness of cancer treatment. News release. July 7, 2025. Accessed July 7, 2025. https://www.eurekalert.org/news-releases/1089842