Early Introduction of Corticosteroids May Alter the Efficacy of Immune Checkpoint Inhibitors

Findings from two retrospective analyses of patients with advanced non-small cell lung cancer (NSCLC), melanoma, and urothelial cancer indicate that the use of corticosteroids at baseline or early during the course of treatment with immune checkpoint inhibitors (ICIs) should be carefully considered, according to results presented at the ESMO Immuno-Oncology Congress 2019 in Geneva, Switzerland (11-14 December).

Although the administration of steroids during the first 8 weeks of ICI therapy did not alter efficacy in most patients with advanced NSCLC, Dr Laura Mezquita of the Institut Gustave Roussy in Villejuif, France and colleagues found there was profound effect on survival when steroids were indicated for the alleviation of cancer symptoms.

They investigated whether the use of steroids during the early period of treatment with ICI may alter patient outcome by conducting a retrospective analysis of patients with advanced NSCLC treated at Gustave Roussy. Their study also identified patients that were steroid-naïve at baseline, but began steroid therapy consisting of ≥10 mg of prednisone-equivalent within the first 8 weeks of ICI therapy. They derived the association between steroid use and patient outcome, including progression-free survival (PFS) and overall survival (OS).

The survival analysis comprised 424 patients who were treated with ICI, of whom 250 patients were steroid-naïve at baseline. The patients’ median age was 63 years (range, 30 to 92), 65.5% were male, and 90.6% were current or former smokers (90.6%). Most (76.1%) patients had non-squamous histology and 76.8% had ECOG performance status (PS) 0/1.

Of the 49 patients identified as having early steroid use, 39 patients received steroid treatment for cancer-related indications, including dyspnoea (50%), brain metastasis (15.8%), pain (7.9%), superior vena cava syndrome (7.9%), and fatigue (5.3%), and other (13.1%). The 10 other indications making up the 13.1% included immune-related adverse events (54.6%), COPD exacerbation (27.1%), and others (18.2%).

Median PFS was 1.9 months (95% confidence interval [CI], 1.77-2.40) and median OS was 10 months (95% CI, 8.11-12.91). No differences were observed between the group of patients that started steroids for other indications and patients receiving no steroid treatment; patients receiving steroids for other indications had median PFS of 2.7 months (95% CI, 1.21-NR) and median OS of 13.4 months (95% CI, 4.30-NR) while the group not treated with steroids had median PFS of 2.6 months (95% CI, 2.20-3.94) and median OS of 13.8 months (95% CI, 11.4-18).

Steroids use at early period of treatment was linked to poorer outcomes, particularly when the steroid was indicated for relief of cancer symptoms

The early use of steroids during ICI therapy was associated with a shorter median PFS of 1.3 months (p < 0.0001), and median OS of 2.3 months (p < 0.0001).

Patients receiving steroids for cancer-related symptoms demonstrated significantly poorer outcomes; in these patients median PFS was just 1.1 months (95% CI, 0.85-1.51) and median OS was 1.9 months (95% CI, 1.54-2.4).

The investigators found that the introduction of steroids for cancer-related symptoms early in the course of ICI therapy was a significant independent prognostic factor for both poorer PFS (hazard ratio [HR] 3.04; 95% CI, 1.38-6.66; p = 0.006) and OS (HR 1.21; 95% CI, 0.53-2.8; p < 0.0001].

Systemic corticosteroids associated with a poorer prognosis in patients receiving immunotherapy for advanced melanoma, NSCLC or urothelial cancer

Alexandra Drakaki of the Ronald Reagan UCLA Medical Center in Los Angeles, CA, USA and colleagues explained in their abstract that, althoughcorticosteroids are often prescribed for patients with cancer to alleviate disease symptoms, manage treatment-related adverse events, or treat underlying comorbidities, the immunosuppressive properties of corticosteroids may impact the efficacy of cancer immunotherapy if given concomitantly.

Their retrospective observational study investigated the association of baseline corticosteroids use with outcomes in patients treated with immunotherapy for advanced melanoma, NSCLC, or urothelial cancer in routine clinical practice.

The investigators identified patients in the Flatiron Health de-identified electronic health record–derived database who were diagnosed with advanced melanoma, advanced NSCLC, or advanced urothelial cancer from January 2011 to June 2017 and were treated with any line of immunotherapy as monotherapy. Most of the patients were white males aged 66 to 72 years at the first immunotherapy treatment. Baseline corticosteroids use was defined as intravenous or intramuscular administration or oral corticosteroids within 14 days prior to and within 30 days after initiation of immunotherapy. The association of baseline corticosteroids use with OS was estimated using multivariable Cox proportional hazards models that adjusted for key baseline characteristics.

The patient population included 862 patients with advanced NSCLC, 742 with advanced melanoma, and 609 patients with advanced urothelial cancer. The majority of patients with advanced NSCLC (56%) or advanced urothelial carcinoma (59%) received immunotherapy in the second-line setting, whereas 89% of melanoma patients received immunotherapy as first-line.

Among those with advanced NSCLC, melanoma, or urothelial cancer, 258, 182, and 116 patients also received corticosteroid therapy at baseline. Overall, 19% to 30% of patients using baseline corticosteroids were more likely to have stage IV disease at diagnosis, or brain metastases. Patients with advanced urothelial cancer and baseline corticosteroid use tended to have poorer ECOG PS scores at baseline and those with advanced NSCLC or advanced urothelial cancer and baseline corticosteroid use were likely to have liver metastases.

Known prognostic factors as well as observed confounders were accounted for in multivariate Cox proportional hazards models. Among the patient characteristics that were adjusted for were sex, age at ICI initiation, race, Charleston Co-morbidity Index, treatment sequence (whether immunotherapy was administered as first- or second-line), disease stage at diagnosis, and the presence of brain metastasis at ICI.

Baseline corticosteroid use decreases the benefit of immunotherapy and results in poorer survival

The investigators found that the use of baseline corticosteroids was associated with a 23% to 47% higher risk of death compared with no use.

According to model 1, baseline corticosteroid use associated with poorer OS in patients with advanced NSCLC (HR 1.35; 95% CI, 1.12, 1.62), in patients with advanced melanoma (HR 1.23; 95% CI, 0.97, 1.57), and in patients with advanced urothelial cancer.

Using model 2, which included the prior use of steroids in addition to the variables included in model 1, baseline corticosteroid use associated with poorer OS in patients with advanced NSCLC (HR 1.34; 95% CI, 1.12, 1.61), advanced melanoma (HR 1.24; 95% CI, 0.97, 1.57), and advanced urothelial carcinoma (HR 1.44; 95% CI, 1.12, 1.87).

Conclusions

The authors of the first analysis concluded that the introduction of steroids within the first 8 weeks of ICI therapy in patients with advanced NSCLC had no detrimental impact on prognosis if the indication for steroid use was not related to cancer symptoms. However, patients receiving steroids for the treatment of cancer symptoms early on during the course of immunotherapy experienced significantly poorer survival.

They further determined that the initiation of steroids for cancer-related symptoms early in the course of ICI therapy was a significant independent prognostic factor for poorer survival.

Findings from the second study demonstrated that baseline corticosteroid use was associated with shorter survival in patients with advanced NSCLC, melanoma, or urothelial cancer treated with immunotherapy that was not explained by measured confounders.

These results suggest that avoidance of corticosteroid should be considered at the initiation of ICI treatment, when possible and appropriate.

Avoiding or delaying the use of corticosteroids may result in maximising the potential treatment benefits of immunotherapy. Further studies are needed to confirm these observations.

Disclosure

No external funding was disclosed for the study in abstract 46O. The study in abstract 47O was funded by F. Hoffmann-La Roche, Ltd. 

References

• 46O - De Giglio A, Mezquita L, Auclin E, et al. Impact of early introduction of steroid on immune-checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer treated.
• 47O – Drakaki A, Luhn P, Wakelee H, et al. Association of systemic corticosteroids with overall survival in patients receiving cancer immunotherapy for advanced melanoma, non-small cell lung cancer or urothelial cancer in routine clinical practice.