High-Dose Glucocorticoids for Hypophysitis Are Worse in Melanoma Patients


Melanoma patients who were treated with glucocorticoids for ipilimumab-induced hypophysitis had improved survival outcomes if they received low doses.

Patients with melanoma who were treated with glucocorticoids for ipilimumab-induced hypophysitis had improved survival outcomes if they received low-dose vs high-dose glucocorticoids. This is the first study to show that these high doses could affect checkpoint inhibitor (CPI) therapy after an immune-related adverse event (irAE).

“Defects in the immune response are associated with primary and acquired resistance to CPIs,” wrote study authors led by Alexander T. Faje, MD, of Massachusetts General Hospital in Boston. “High doses of glucocorticoids inhibit the immune response, including some pathways linked to CPI resistance.”

To test whether glucocorticoid therapy can change outcomes with CPI treatment, the investigators retrospectively reviewed data on a series of patients with the same irAE. They included 98 patients with melanoma and ipilimumab-induced hypophysitis; these were divided between those who received high doses of glucocorticoids (69 patients) and those who received low doses (29 patients). The results of the analysis were published in Cancer.

The full cohort had a median age of 63.4 years, and 67% were men. Most patients were diagnosed with the irAE after several treatment cycles with ipilimumab, at a median of 9.8 weeks from the first dose. Headache and fatigue were the most common presenting symptoms in the study.

Overall survival was significantly longer in the low-dose glucocorticoid group when compared with the high-dose group, with a hazard ratio (HR) of 0.24 (95% CI, 0.07–0.61; P = .002). The same was true for time to treatment failure (TTF), with an HR of 0.28 (95% CI, 0.11–0.62; P = .001). The median overall survival and TTF were not yet reached in the low-dose patients, compared with 23.3 months and 14.5 months, respectively, in the high-dose group. A multivariate analysis did not change these results, specifically in the patients who received ipilimumab as monotherapy.

The median progression-free survival was 35.0 months with low-dose glucocorticoids, compared with 4.9 months with high-dose glucocorticoids, for an HR of 0.36 (95% CI, 0.14–0.77; P = .007).

The patients who received ipilimumab monotherapy and developed hypophysitis (64 patients) had improved overall survival, regardless of glucocorticoid dose, compared with control patients who were treated with the same drug but did not develop the irAE, with an HR of 0.53 (95% CI, 0.36–0.75; P = .0003). The median overall survival in the two groups was 28.2 months and 9.5 months, respectively. This is consistent with other reports that showed that irAEs could be associated with improved survival when treated with CPIs.

“In the current study, patients with hypophysitis, including those who received higher doses of glucocorticoids, had improved overall survival compared with those who did not develop hypophysitis,” the authors wrote. “This finding highlights the importance of comparing the effects of glucocorticoid doses within a population experiencing the same irAE.” They recommended against the routine use of high-dose glucocorticoids in this setting.

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