FROM JOURNAL OF CLINICAL ONCOLOGY
Patients treated with ipilimumab for metastatic melanoma should be prepared for immune-related adverse effects, and physicians should expect to treat them early and aggressively, according to a report published online Aug. 17 in Journal of Clinical Oncology.
Severe immune-related adverse effects such as diarrhea, hepatitis, and hypophysitis were common in a retrospective analysis of the medical records of 298 patients treated during a 27-month period at Memorial Sloan Kettering Cancer Center, New York. Corticosteroids were not adequate to control symptoms in a substantial number of cases, and additional systemic immunosuppressive therapy was required, said Dr. Troy Z. Horvat of Memorial Sloan Kettering and his associates.
From their institutional experience, the investigators suspected that the incidence of clinically significant adverse effects of ipilimumab was higher than has been previously reported and higher than would be expected just by counting the number of events qualifying as grade 3 or higher by National Cancer Institute criteria. They also suspected that the need for immunosuppressive therapy was greater than generally expected. Previous studies showed adverse event rates ranging from 6% to 19%, and did not give any information regarding corticosteroid use.
Their analysis confirmed these suspicions, showing that 31% of patients developed grade 3, 4, or 5 adverse effects and 35% required corticosteroid therapy. This is more than twice the rate of grade 3 or higher toxicity reported in clinical trials of ipilimumab. Adverse effects included diarrhea (50 patients), which led to bowel perforation in 3 patients; hepatitis (22 patients); dermatitis (21 patients); endocrinopathies (14); hypophysitis (6); uveitis (2); pneumonitis (1); seizure (1); arthritis (1); and hearing loss (1). These effects were severe enough to cause 19% of patients to discontinue ipilimumab.
About one-third of the patients who received systemic corticosteroids – 10% of the total study population – required additional immunotherapy, including infliximab, mycophenolate, or adalimumab, Dr. Horvat and his associates said (J Clin Oncol 2015 Aug 17 [doi:10.1200/JCO.2015.60.8448]).
This study’s higher rates of adverse events, of corticosteroid therapy, and of further immunosuppressive therapy are likely attributable to the treatment team’s considerable experience with ipilimumab in real-world patients. As clinicians gain such experience, they become more familiar with associated adverse events, allowing earlier identification and intervention, the investigators said.
“In our experience, if improvement in ipilimumab-related adverse effects is not evident early in the treatment with high-dose systemic corticosteroids, more prolonged treatment rarely leads to benefit, and patients usually end up requiring infliximab anyway. … We believe the overall risk-to-benefit ratio favors the early use of infliximab rather than prolonged treatment with corticosteroids,” they noted.
The median overall survival and median time to treatment failure were not affected by either the occurrence of adverse events or the use of corticosteroids. Overall, 12% of these patients achieved long-term disease control and didn’t require further melanoma treatment. Based on their findings and those of another research group, “we believe that patients and physicians should not be concerned that ipilimumab-related adverse events requiring systemic immunosuppression will compromise the therapeutic benefit,” Dr. Horvat and his associates said.
