Adverse events related to immune activation with ipilimumab (Yervoy, Bristol-Myers Squibb Company) may be higher than clinical trials have previously suggested, according to a study of real-world clinical data from patients treated at Memorial Sloan Kettering Cancer Center, in New York City. The study was published online August 17 in the Journal of Clinical Oncology.
Ipilimumab was the first of the novel immunotherapies launched for melanoma, and so far it is the only one that is an anticytotoxic T-cell lymphocyte-4 (anti-CTLA-4) antibody. It can cause immune activation and adverse reactions, such as diarrhea, rash, hepatitis, and pituitary inflammation. These reactions are often treated with steroids; severe reactions may require treatment with an anti–tumor necrosis factor alpha (anti-tNFα), such as infliximab (Remicade, Janssen Biotech, Inc).
"Among our small group of physicians highly experienced with ipilimumab, we felt that 35% of the patients required systemic steroids to treat adverse events," commented lead author Paul Chapman, MD, a specialist in metastatic melanoma at Memorial Sloan Kettering Cancer Center.
The study also found that treatment with steroids did not affect overall survival, leading experts to stress clinical judgment about when to start steroids, and also to suggest starting earlier treatment with infliximab in cases of steroid failure.
"In patients who do not respond to steroids, physicians should not hesitate to treat with infliximab," Dr Chapman emphasized. "In our patients, a third of the patients receiving steroids ultimately required infliximab. We believe that giving infliximab early is safer than prolonged courses of steroids."
Use Clinical Judgment
Clinical trials utilize grades of toxicity to determine the need for steroids, using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). The distinction between CTCAE grades 2 and 3 may be arbitrary and not well suited for grading immune-related adverse events from ipilimumab, according to background information in the article.
Rather than strictly following the CTCAE grading system, clinicians in this study used their clinical judgment and the manufacturer's guidelines for treating immune-related adverse events (Yervoy [Ipilimumab] Immune-Mediated Adverse Reaction Management Guide. Princeton, NJ, Bristol-Myers Squibb Pharmaceuticals, 2012).
The study looked at the medical records of 298 patients who received care from one of the study authors between April 2011 and July 2013. Patients received a standard dose of ipilimumab (3 mg/kg); 70% (n = 210) completed all four doses.
Results showed that 254 (85%) of these patients experienced immune-related adverse events, 31% of which were considered grade 3 or higher, using CTCAE criteria. Nineteen percent (n = 56) stopped treatment because of adverse reactions, the most common of which was diarrhea (n = 34).
Thirty-five percent of patients (n = 103) needed systemic corticosteroids, which is more than twice the rate previously reported in clinical trials, at the standard 3 mg/kg dose, the authors point out.
Thirty percent of those needing steroids (n = 31) did not completely respond and needed further therapy, with the majority (n = 29) requiring only a single dose of infliximab.
The estimated median time to treatment failure, defined by death or starting a new treatment, was 5.7 months. The estimated median overall survival was 16.5 months (95% confidence interval [CI], 12.6 - 21.1), and the estimated 2-year survival was 39% (95% CI, 33% - 46%). Twelve percent of patients achieved long-term disease control without further need for antimelanoma therapy.
Neither immune-related adverse events nor systemic corticosteroids influenced overall survival or time to treatment failure.
"Physicians should not rely entirely on standard CTCAE toxicity criteria to start steroids. Patients can have serious toxicities requiring steroids even though by CTCAE criteria, the toxicity is only grade 2," Dr Chapman advised. "CTCAE can be used as a guideline, but ultimately, the physician needs to use his/her clinical judgement."
One or more of the authors reports consulting, advisory roles, research funding, travel or accommodation fees, and honoraria for one or more of the following: Bristol-Myers Squibb, Amgen, Kiowa Hakko Kiran, GlaxoSmithKline, Aura Biosciences, AstraZeneca, Novartis, Biogen Idec, Daiichi Sankyo, Incyte, Bayer, Celldex, Pﬁzer, EMD Serono, Janssen Oncology, Merck, MedImmune, Ziopharm, Polynoma, Polaris, Jounce, Genentech/Roche, Provectus, Momenta Pharmaceuticals. Dr Callahan has been an employee of Bristol-Myers Squibb. Dr Wolchok is a coinventor of a patent for DNA vaccines for the treatment of cancer in companion animals.
J Clin Oncol. Published online August 17, 2015. Abstract
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Cite this: Ipilimumab Side Effects in Real World, and What to Do - Medscape - Aug 21, 2015.