To our knowledge, this is the first report analyzing the prognostic role of corticosteroid intake during first-line CT-ICI in patients with advanced NSCLC. This information, unfortunately, cannot be extrapolated from randomized CT-ICI trials since these studies did not allow the enrollment of patients requiring steroid use. The warning on the steroids introduction during an immune-stimulating treatment was based on the clinical evidence of increased infectious disease rate for patients taking at least 10 mg of prednisone equivalents daily . Thus, patients overcoming this threshold have been excluded from clinical trials regardless of clinical indication.
Herein, we provide retrospective evidence that baseline intake of steroids is associated with hampered survival outcomes while, on the contrary, intercurrent steroid intake does not have a survival impact independently from other relevant clinical variables.
Several retrospective studies have explored the impact of steroids on single-agent ICI in lung cancer patients either in first or further treatment lines. The prognostic impact of baseline steroid intake on survival outcomes was investigated among 640 advanced NSCLC patients receiving ICI. Baseline steroids were associated with significantly reduced mPFS (1.7 vs 1.8 months; HR: 1.5; p < 0.001) and mOS (3.3 vs 9.4 months; HR: 2.00; p < 0.001) . Patients with poor ECOG PS or active brain metastasis were more likely to take steroids. Another retrospective work confirmed the negative association between baseline steroid administration and survival among PD-L1-high NSCLC patients treated with first-line pembrolizumab, with a 2.3-fold increased risk of death . Comparably, we evidenced a significant increase in the risk of disease progression (HR 3.84, 95% CI, 1.82–8.08, p < 0.001) and death (HR 2.94, 95% CI, 1.18–7.31, p = 0.02) after adjusting for pivotal variables.
Two observational studies evidenced that an early introduction of steroids during immunotherapy was independently associated with poor outcomes. Drakaki et al. showed that steroids introduced within the first month of ICI treatment negatively impacted survival outcomes in a large cohort of 862 advanced NSCLC patients . Fucà et al. speculated that the detrimental ICI results found among 35 patients receiving steroids in the first 28 days of treatment were related to the variation of circulating lymphocyte subpopulations .
Even if the stimulation of glucocorticoid receptor is predominantly associated with a depressed innate and adaptive immune response, data indicating a precocious but short-lasting immune activation leads to hypothesize a biphasic model of response under steroid treatment .
Interestingly, analyzing the reasons for steroid prescription and distinguishing between cancer-related (brain edema, dyspnea, fatigue) and unrelated (irAEs, COPD reactivation, rheumatological disease) medical conditions, the introduction of steroids seemed not to influence treatment outcomes.
Ricciuti et al. demonstrated that NSCLC patients on ICI treatment receiving baseline ≥ 10 mg prednisone equivalents for cancer-unrelated conditions and patients taking < 10 mg prednisone equivalents for any reason had longer mPFS (4.6 vs. 3.4 vs. 1.4 months; p < 0.001) and mOS (10.7 vs. 11.2 vs. 2.2 months; p < 0 .001) compared with patients taking ≥ 10 mg prednisone equivalents for cancer-related conditions .
Likewise, a monocentric experience explored the outcomes of 413 advanced NSCLC patients under ICI single-agent treatment, stratifying survival outcomes according to timing (baseline vs. intercurrent) and reason (palliative vs. non-palliative) for steroids prescription. Intercurrent steroid introduction for cancer-unrelated symptoms was not associated with poor survival . Conversely, intercurrent administration for cancer palliation was independently associated with poor PFS and OS (p < 0.0001).
Our analysis could not efficiently explore the impact of cancer-related and unrelated clinical indications due to the retrospective nature of the study and its limited sample size. Nevertheless, we should consider that all patients treated with CT-ICI received steroids premedication according to the chemotherapy regimen administered. Moreover, all baseline steroid-treated patients included in our report were prescribed only for cancer-related indications. De facto, our analysis demonstrated that the steroid intake for palliative reasons at baseline constituted an independent risk factor for disease progression and death despite the routine premedication prescription.
Belonging to an unfavorable prognostic group may affect the reliability of the pure effect of steroids on ICI or CT-ICI efficacy. Mainly, the baseline steroid intake was more frequently associated with the presence of symptomatic brain metastases. Remarkably, our analysis did confirm the negative prognostic relevance of brain metastasis at diagnosis in the univariate but not in the multivariable model, probably due to the limited sample size.
Concerning the intercurrent administration, the inclusion of a small subset of patients receiving steroids for both palliative and non-palliative indications did not allow to draw a robust conclusion in this field of debate. This setting should be furtherly investigated in a larger population, considering the risk of immortal time bias.
The novelty of the population investigated for this research question, and the number of key variables included in the multivariable assessment represented the strengths of the present investigation.
In conclusion, baseline steroid intake constitutes an independent poor risk factor for CT-ICI efficacy and, therefore, this information should be taken into account when choosing this treatment strategy in advanced NSCLC. On the contrary, intercurrent steroids, when needed, can be prescribed without the worry of hampering CT-ICI efficacy. However, larger prospective studies are required to assess the real impact of the steroids according to various clinical indications both at baseline and during the CT-ICI regimens.