The interaction between corticosteroids and immune checkpoint inhibitors (ICIs) remains one of the most misunderstood areas in clinical oncology, particularly among residents. Steroids are often perceived as inherently antagonistic to immunotherapy due to their immunosuppressive effects. However, evidence from pivotal clinical trials and large retrospective analyses shows that the clinical impact of steroids depends largely on timing, dose, and indication rather than their use per se.
Steroids and Immunotherapy
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Why Steroids Are a Concern in Immunotherapy
ICIs rely on immune activation to exert their antitumor effect. Corticosteroids, by contrast, are broadly immunosuppressive, inhibiting T-cell proliferation, cytokine production, and antigen presentation. This biological opposition has led to the long-standing fear that steroids may blunt or even negate the benefits of immunotherapy.
However, clinical evidence shows that the relationship between steroids and ICIs is far more nuanced than a simple “enemy” narrative.
When Steroids Are Harmful: Evidence from KEYNOTE Trials
Concerns about steroids first emerged from analyses of patients treated with pembrolizumab in non–small cell lung cancer (NSCLC). Although baseline steroid use was not randomized in KEYNOTE trials, post hoc and real-world analyses of KEYNOTE-representative populations consistently demonstrated inferior outcomes in patients receiving steroids at immunotherapy initiation.
In a landmark retrospective study by Arbour et al., which included patients treated with PD-1/PD-L1 inhibitors and closely mirrored KEYNOTE populations, baseline corticosteroid use (≥10 mg prednisone equivalent) at the start of immunotherapy was associated with significantly worse outcomes. Median progression-free survival was reduced, and overall survival was substantially shorter compared with patients not receiving baseline steroids. Importantly, most baseline steroids were prescribed for cancer-related symptoms such as dyspnea, brain metastases, or fatigue.
Similar observations were reported in pooled analyses of KEYNOTE-001 and KEYNOTE-010–like cohorts, where baseline steroid use correlated with lower response rates and inferior survival. These findings suggest that early immunosuppression during the immune priming phase may interfere with effective antitumor T-cell activation, particularly when steroids are used before or at the time of pembrolizumab initiation.
When Steroids Are Life-Saving: Evidence from CheckMate Trials
In contrast, steroids used to manage immune-related adverse events (irAEs) do not appear to compromise immunotherapy efficacy. This has been most clearly demonstrated in analyses from the CheckMate program evaluating nivolumab alone or in combination with ipilimumab.
In CheckMate 067, which compared nivolumab plus ipilimumab versus nivolumab or ipilimumab alone in advanced melanoma, high-grade irAEs were common in the combination arm, and a substantial proportion of patients required systemic corticosteroids. Despite this, long-term follow-up showed durable overall survival benefits in patients treated with combination immunotherapy, including those who received high-dose steroids for toxicity management.
Similarly, in CheckMate 017 and CheckMate 057 (nivolumab versus docetaxel in previously treated NSCLC), post hoc analyses demonstrated that patients who developed irAEs — many of whom required corticosteroids — had equal or improved overall survival compared with those who did not develop irAEs. Steroid treatment for toxicity did not negate the survival advantage of nivolumab.
These findings strongly suggest that once immune activation has occurred, appropriate immunosuppression to control toxicity does not eliminate antitumor benefit.
Dose and Timing: Lessons Across Trials
Across KEYNOTE and CheckMate programs, a consistent pattern emerges:
- Baseline steroids (≥10 mg prednisone equivalent) given before or at ICI initiation are associated with inferior outcomes.
- On-treatment steroids administered after immune activation, particularly for irAE management, do not appear to reduce efficacy.
- The negative impact of steroids is most pronounced when given early and for cancer-related symptoms rather than immune toxicity.
This supports the concept of a critical immune priming window early in immunotherapy, during which excessive immunosuppression may blunt effective T-cell expansion and tumor recognition.
Bottom Line
Steroids are not inherently incompatible with immunotherapy. Evidence from KEYNOTE and CheckMate trials demonstrates that steroids are harmful primarily when used early and unnecessarily, but are essential and safe when used appropriately for immune-related toxicity. For residents, the goal is not to avoid steroids, but to understand when they compromise immune priming and when they preserve patient safety without sacrificing efficacy.
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