乌鸦传媒

Higher peak doses of corticosteroids to counter the immune-related adverse effects (irAEs) of immune checkpoint inhibitor (ICI) combination therapy had a significant association with worse survival across multiple tumor types, according to a post hoc analysis of clinical trial data.

Compared with a peak prednisolone dose of 0.5 mg/kg, a dose of 1 mg/kg increased the progression-free survival (PFS) hazard by 15% and a 2 mg/kg dose increased the hazard by 43%. The higher peak corticosteroid doses increased the overall survival (OS) hazard by 21% and 66%, respectively, versus the lower dose. Neither cumulative steroid dose nor duration of steroid treatment significantly affected survival, reported Karijn P.M. Suijkerbuijk, MD, PhD, of University Medical Center Utrecht in the Netherlands, and colleagues in the .

"Taken together, using high-quality prospective clinical trial data, we observed that corticosteroid peak dose for anti-PD-1 plus anti-CTLA-4-related adverse events was associated with impaired survival across multiple tumor types, whereas cumulative dose was not," the authors concluded. "Although use of second-line immunosuppressants was similarly associated with reduced survival as in previous studies, the association was not significant."

"Current guidelines recommend a step-down approach for corticosteroids, advising 1-2 mg/kg prednisone for many grade 3 or higher irAEs," they noted. "These data argue for a reconsideration of irAE management approaches. Although prompt immunosuppression is needed to prevent chronicity and fatality in some cases, clinicians should consider starting with lower corticosteroid doses whenever possible."

The study added more data to the unresolved issue of appropriate corticosteroid dosing for patients who receive ICIs for cancer, said Jason Luke, MD, of the UPMC Hillman Cancer Center in Pittsburgh. The results are consistent with a showing a significant relationship between high-dose steroid therapy and worse outcomes as compared with no steroids in advanced melanoma patients treated with single-agent anti-PD-1.

The results also align conceptually with a suggesting that treatment with anti-TNF-alpha agents limit ICI effectiveness in steroid-refractory patients with melanoma.

Analyses based on "real-world" data for missing data and lacking data integrity to rule out confounding factors, Luke continued. The concept that high-dose anti-TNF-alpha therapy has a deleterious effect on outcomes also is not supported by preclinical data.

"To date, most investigators have had the experience, and generally been aligned, that the duration of exposure to corticosteroids likely is deleterious on its own but also ... is associated with other poor prognostic features such as biochemical factors, performance status, etc.," Luke, who was not involved with the study, told 乌鸦传媒.

The analysis had several potential confounders that the authors could not address, Luke continued. For example, investigators attempted to adjust peak or cumulative dose by irAE grade at toxicity, but the extent to which such an adjustment is possible is "suspect." Additionally, corticosteroid therapy was ongoing or stop data were missing for a fifth of the patients, calling into question how well the investigators could measure the impact of cumulative steroid dose.

"Given all of this, these are interesting data that emphasize the need to be judicious with steroids, but do not have a definitive impact on the field," said Luke.

In his own practice, Luke said he ascribes to the belief that rapid resolution of irAEs by any means, and avoidance of steroids, whenever possible are the key to optimal patient management. As an example, he described a hypothetical patient with grade 3 diarrhea. He would begin with a steroid dose of 1 mg/kg, increasing to 2 mg/kg on day 2 if the diarrhea does not respond, and then use an anti-TNF-alpha agent on day 3 if the diarrhea remains unresponsive.

"In all of these scenarios, I then taper steroids in 10-14 days and do not pursue the long tapers that have been classically recommended in guidelines," said Luke. "I believe this is most consistent with the underlying mechanism and our clinical experience to support optimal outcomes. I think all of this emphasizes the lack of clarity and patient-specific considerations that go into these management decisions. Best practices in this space remain as an art of medicine consideration."

In an effort to bring more clarity to the steroid issue, Suijkerbuijk and co-authors analyzed individual patient data from six international clinical trials evaluating combined anti-PD-1/L1 and anti-CTLA-4 therapy for melanoma, microsatellite instability or deficient mismatch repair (MSI-high/dMMR) colorectal cancer, renal cell carcinoma, esophageal squamous cell carcinoma, mesothelioma, and non-small cell lung cancer (NSCLC). They identified patients who received systemic immunosuppression for irAEs and examined associations of peak and cumulative steroid dose and use of second-line immunosuppression with OS and PFS.

The analysis included 1,959 patients, 834 of whom received systemic immunosuppression for irAEs. All but two patients received corticosteroids, and 81 (10%) received second-line immunosuppression.

The results showed that, compared with a peak dose of 0.5 mg/kg, peak doses of 1 mg/kg and 2 mg/kg significantly increased the adjusted hazard ratio for PFS (HR 1.15, 95% CI 1.02-1.29 and HR 1.43, 95% CI 1.05-1.96) and for OS (HR 1.21, 95% CI 1.06-1.39 and HR 1.66, 95% CI 1.17-2.37).

Significant associations with the higher doses and either worse PFS or OS were seen among trials of melanoma, esophageal cancer, and NSCLC.

In contrast to some prior studies, the data did not show an association between higher cumulative steroid dose and worse survival. Too few patients received second-line immunosuppression to confirm or reject an association with survival, the authors stated. However, their analysis showed a trend toward worse PFS (HR 1.25, 95% CI 0.90-1.68) and OS (HR 1.25, 95% CI 0.88-1.77).

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