Commonly Prescribed Medication to Manage Symptoms of Lung Cancer Limit Effectiveness of Treatment

Treatment with immune checkpoint inhibitor has been revolutionary for patients diagnosed with non–small cell lung cancer (NSCLC), with anti–PD-1/PD-L1 regimens like pembrolizumab (Keytruda®; Merck & Co/MSD), becoming a cornerstone of treatment.[1] The addition of chemotherapy to immune checkpoint inhibitor therapy in patients with negative to low PD-L1 expression, further expanded treatment options.[2]

However, glucocorticoids, a commonly prescribed medication for palliation to alleviate cancer-related symptoms for NSCLC patients treated with immunotherapy, are the main reason certain immunotherapies may fail in treating the disease.

This conclusion is based on results from a study by researchers at Keck Medicine of USC.

The study, published in the July 1, 2025 issue of Cancer Research Communications, and funded by grants from the National Cancer Institute as well as the Department of Defense Lung Cancer Research Program and the Uehara Memorial Foundation, showed that high doses of steroids, when given before and/or during a specific type of immunotherapy, caused patients’ tumors to shrink less than those of patients not on steroids. [3]

Those patients also did not live as long.

In contrast, the study showed that patients who discontinued steroids before the induction of immune checkpoint inhibitor therapy had a better response rate compared with those who continued during immune checkpoint inhibitor therapy.[3]

“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,” noted Keck Medicine oncologist and immunologist Fumito Ito, MD, PhD, whi was the lead author of the research.

Additionally, researchers believe they have found the mechanism behind why steroids and some immunotherapies may not mix.

“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,” said Ito, who is also a member and co-leader of the translational and clinical sciences research program at USC Norris Comprehensive Cancer Center. “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.”

Ito and his colleagues also discovered that steroids blocked circulating biomarkers in the body — bits of cells in the bloodstream that signal when cancer is progressing so oncologists can adjust the patient’s treatment.

“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,” said Ito.

Two competing medications
The study examined the effect of steroids on immune checkpoint inhibitors.

Immune checkpoint inhibitors are designed to help the body’s immune system fight cancer by blocking proteins that prevent T-cells from attacking cancer cells. They are often used to treat non-small cell lung cancer, the most common form of lung cancer.

Steroids are often prescribed to alleviate symptoms of the cancer or treatments given for a variety of reasons, such as fatigue and vomiting, or more serious side effects like brain swelling and lung inflammation. Steroids suppress the immune system, which reduces the inflammation that can cause these conditions.

How the studies were conducted 
Ito and his fellow researchers retrospectively studied the medical records of 277 patients with Stage II-IV non-small cell lung cancer who were treated with Immune checkpoint inhibitors alone or in combination with other therapies.

Among the participating patients, 22 (8%) were prescribed steroids at the start of their treatment with Immune checkpoint inhibitors.

The researchers compared outcomes, including tumor shrinkage and survival rate, between patients prescribed steroids and those who were not at three centers, including USC Norris Comprehensive Cancer Center.

The researchers analyzed up to eight years of data. Based on their analysis, they were able to determine that patients prescribes baseline steroids had a lower overall response rate with markedly shorter progression-free survival (PFS) and overall survival (OS) compared with those not receiving steroids.

Interpreting data from a multivariate analysis, the researchers concluded that steroids use were the only significant independent risk factor impeding the effectiveness of the immunotherapy, leading to disease progression and mortality in two independent cohorts (Roswell Park Comprehensive Cancer Center; n = 88 and University of Southern California; n = 189).

A baseline peripheral blood neutrophil-to-lymphocyte ratio <5 was a strong prognostic indicator. However, the researchers concluded that the prognostic value of neutrophil-to-lymphocyte ratio was absent in patients receiving steroids.  They also determined that the baseline frequency of circulating peripheral CX3C chemokine receptor 1 (CX3CR1)⁺ CD8⁺ T cells was substantially lower in a significant number of patients on steroids.

In a separate preclinical study using mice to observe the effects of steroids on Immune checkpoint inhibitors therapy in real time, the researchers discovered that steroids given before and during immunotherapy inhibit T-cells from fully maturing.

The future of steroids 
While the Keck Medicine research indicates steroids can interfere with Immune checkpoint inhibitors, Ito acknowledges that for some patients, steroids may be necessary to manage their cancer-related symptoms.

“We know that steroids will continue to play an important role in lung cancer care, but it is important to understand their potential limitations,” Ito said.

“Each patient should talk to their oncologist to make sure they have the best possible care plan tailored to their specific needs,” he added.

Ito hopes that this research will lead to more studies examining the effect of steroids on immunotherapy so oncologists can make fully informed decisions that will best benefit their patients.

Other study authors include Keck Medicine medical oncologists Jorge Nieva, MD and Robert Hsu, MD.

Clinical trials
Study of Pembrolizumab (MK-3475) Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non-Small Cell Lung Cancer (MK-3475-024/​KEYNOTE-024) – ClinicalTrials.gov ID NCT02142738

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]

Reference
[1] Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8. PMID: 27718847.
[2] Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. doi: 10.1056/NEJMoa1810865. Epub 2018 Sep 25. PMID: 30280635.
[3] Polyakov L, Lim A, Meyer A, Mades A, Ni J, Cooper R, Ye S, Kajihara R, Oba T, Contreras L, Abdelfatah E, Sarkar J, Matsuzaki J, Li M, Sharma R, Segal BH, Hsu RC, Chen H, Nieva J, Ito F. Impact of Glucocorticoids on Immune Checkpoint Inhibitor Efficacy and Circulating Biomarkers in Non-Small Cell Lung Cancer Patients. Cancer Res Commun. 2025 Jul 1;5(7):1082-1094. doi: 10.1158/2767-9764.CRC-25-0051. PMID: 40622275.

Featured image courtesy ©2025 Getty Images/Unsplash. Used with permission.

DOI