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High-dose steroids for treatment-induced hypophysitis reduce melanoma survival
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High-dose glucocorticoid therapy failed to benefit patients with melanoma who developed hypophysitis following treatment with ipilimumab, according to results of a retrospective review.
“Our study helps better define treatment strategies for patients with hypophysitis following treatment with checkpoint inhibitors. It also adds to the discussion of whether high dosages of glucocorticoids affects the antitumor efficacy of checkpoint inhibitors,” Alexander T. Faje, MD, endocrinologist at Massachusetts General Hospital, told HemOnc Today. “As the mechanisms underlying various immune-related adverse events are better understood, the utilization of more tailored and specific anti-inflammatory regimens would appear advantageous.”
High doses of glucocorticoids inhibit immune response, including some pathways linked to checkpoint inhibitor resistance.
Data suggest immune-related adverse events — often treated with glucocorticoids — may be associated with higher tumor response rates.
Studies have consistently shown that patients receiving glucocorticoids or other immunosuppressive therapy during checkpoint inhibitor therapy do not have shorter survival than patients who don’t require these treatments. However, no study has examined the effects of glucocorticoids on antitumor efficacy among patients with the same immune-related adverse event.
Using an electronic repository of medical records from the Partners HealthCare system, Faje and colleagues identified 98 patients (mean age, 63.4 years; 67% men) with melanoma diagnosed with hypophysitis after undergoing treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) between 2008 and 2017.
Investigators stratified patients based on doses of glucocorticoid therapy; low-dose glucocorticoid therapy included a maximum average daily dose of 7.5 mg prednisone or equivalent during the first 2 months after hypophysitis diagnosis, and high-dose glucocorticoid therapy included anything about the maximum dose level.
Researchers analyzed the effects of low and high doses of glucocorticoid on different patient outcomes, including OS and time to treatment failure.
“Our patient cohort provided a rather unique opportunity to examine the effects of differing glucocorticoid dosages on antitumor efficacy in a group with the same immune-related adverse event, thereby avoiding a potential confounding factor in many prior analyses,” Faje said.
Patients were diagnosed with hypophysitis at a median 9.8 weeks after the first dose of ipilimumab.
Overall, the median glucocorticoid dose was 5.5 mg (interquartile range [IR], 3.75-7.5) in the low-dose group and 22.4 mg (IR, 11-35.7) in high-dose group.
Researchers limited oncologic analyses to the 64 patients who received ipilimumab as monotherapy. For these patients, median glucocorticoid dose was 5 mg (IR, 3.75-7.5) in the low-dose group and 22.4 mg (IR, 13.2-36.5) in the high-dose group.
Results showed longer OS among patients in the low-dose group (not reached vs. 23.3 months; HR = 0.24; 95% CI, 0.07-0.61), as well as longer time to treatment failure (not reached vs. 14.5 months; HR = 0.28; 95% CI, 0.11-0.62) than among patients in the high-dose group.
These differences remained significant when researchers based analyses on peak glucocorticoid dose above or below a threshold of 15-mg prednisone or equivalent.
Multivariate analyses indicated low-dose glucocorticoid use significantly predicted longer OS (HR = 0.24; 95% CI, 0.07-0.62) and longer time to treatment failure (HR = 0.31; 95% CI, 0.12-0.7).
Researchers observed similar results when measured based on the peak glucocorticoid
dose, which remained a significant predictor for time to treatment failure and trended toward significance for OS.
“Our data suggested that higher dosages of glucocorticoids may affect the antitumor efficacy of ipilimumab in patients with melanoma,” Faje said. “A treatment paradigm of supportive care with hormone replacement rather than targeting inflammation with pharmacologic dosages of glucocorticoids may be appropriate.”
Patients who received ipilimumab monotherapy and developed hypophysitis demonstrated longer OS than 217 patients who received ipilimumab monotherapy but did not develop hypophysitis (28.2 months vs. 9.5 months; HR = 0.53; 95% CI, 0.36-0.75).
Faje cited the retrospective design and smaller cohort of the study as limitations; however, the cohort was still severalfold larger than “any prior study of hypophysitis with checkpoint inhibitors,” he said.
“The incidence of hypophysitis following treatment with ipilimumab may approach 12%, and the applications for this medication (as part of combination therapy) have continued to expand in recent years,” Faje added. “Therapeutic parsimony is a desirable goal from a standpoint of treatment-related side effects and potentially more importantly if it can affect antitumor efficacy.”
The study adds important insights into the understanding of immunotherapy and toxicities, Douglas B. Johnson, MD, MSCI, assistant professor in the department of medicine in the division of hematology and oncology at Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, wrote in a related editorial.
Hypophysitis usually occurs during the first four doses of ipilimumab monotherapy, which “avoids the confounding factor of many studies, which have linked toxicities (that may occur at any time during therapy) with response: toxicities occur at higher rates when patients continue to receive therapy, but they only continue to receive therapy if they are benefiting,” Johnson wrote. “Thus, the study provides further evidence that at least this particular toxicity is truly linked with improved outcomes.
“Hypophysitis, a condition nearly unique to ipilimumab therapy, will only continue to grow as a clinical problem for providers across disciplines,” Johnson added.
Despite early insights, much remains to be learned about the mechanisms of immune checkpoint inhibitor toxicities, Johnson wrote.
“Currently, we have no ability to predict which patients will experience complications from therapy, including seemingly obvious factors like toxicities with prior immune therapies, history of autoimmune disease, or pre-existing organ dysfunction,” he wrote. “Developing more effective immunomodulators and optimizing those currently available to preserve antitumor immunity while suppressing tissue-specific inflammation remain critical and unmet needs.” – by Melinda Stevens
For more information:
Alexander T. Faje, MD, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; email: afaje@mgh.harvard.edu.
Disclosures: Faje reports no relevant financial disclosures. One author reports consultant roles with Bristol-Myers Squibb and Merck unrelated to the study. Johnson reports advisory board roles with Array Biopharma, Bristol-Myers Squibb, Genoptix, Incyte and Merck, and grant funding from Bristol-Myers Squibb and Incyte outside the submitted work.
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