BOSTON– Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.
“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.
There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.
“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”
Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.
The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.
Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.
He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.
Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.
Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.
As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.
“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.
PD-1 inhibitors
Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.
In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.
The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.
Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.
Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.
In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.
For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.