Some Reassurance on Neurologic Effects of Checkpoint Inhibitors

Cancer patients treated with immune checkpoint inhibitors (ICIs) had different tradeoffs in neurologic side effects compared with users of other medications, according to a meta-analysis of over three dozen randomized trials.

Pooling data from 39 trials, the risk of neurologic adverse events (NAEs) was a relative 41% lower for ICI patients compared with comparator groups taking other drug regimens or placebo (15% vs 19.9%, respectively; RR 0.59, 95% CI 0.45-0.77), reported Ankit Mangla, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio, and colleagues in JAMA Network Open.

Against chemotherapy in particular, the risk of NAEs associated with ICIs was substantially lower (6.0% vs 17.4%, RR 0.22, 95% CI 1.10-1.59), including the following specifically:

• Peripheral neuropathy: RR 0.09 (95% CI 0.05-0.17)
• Dysgeusia: RR 0.42 (95% CI 0.21-0.85)
• Paresthesia: RR 0.29 (95% CI 0.13-0.67)

However, headache, insomnia, and dizziness were all less common with chemotherapy.

The neurologic risk with ICIs was higher than that for placebo (17.5% vs 12.4%; RR 1.57, 95% CI 1.30-1.89), a finding driven in part by headaches in particular (RR 1.63, 95% CI 1.32-2.02).

Daniel Vargas Pivato de Almeida, MD, of Grupo Oncoclinicas in Brasilia, Brazil, noted that ICIs are increasingly being recommended for patients who are elderly, frail, and more severely ill — “a population underrepresented in clinical trials and for whom the impact of an [immune-related adverse event] may be even more dangerous than in the general population,” he wrote in an editorial accompanying the study.

The study “serves to help us more clearly determine the risks to which we are exposing our patients during treatment with ICIs and to offer more data for our discussions of risk vs benefits with our patients,” he wrote.

Vargas Pivato de Almeida highlighted the “particularly remarkable” finding that peripheral neuropathy was less of a risk among ICI users than placebo controls (RR 0.30, 95% CI 0.17-0.51). He noted that peripheral neuropathy is a NAE of “particular interest owing to its dose-cumulative and dose-limiting profile.”

Against other drugs and placebo, the risk of dysgeusia (RR 0.41, 95% CI 0.27-0.63) was also significantly lower in the ICI group, while headache was more common (RR 1.32, 95% CI 1.10-1.59), according to Mangla’s group.

The meta-analysis included 13,110 patients in the control arm and 10,595 in the ICI arm.

It included 16 trials evaluating ICI use in patients with non-small cell lung cancer, five trials in melanoma, four in renal cell carcinoma, three in multiple myeloma, two each in small cell lung cancer and head and neck cancer, and one each in colorectal, gastric, bladder, gastroesophageal junction, urothelial cancer, prostate, and mesothelioma.

The authors acknowledged that a limitation of the study was the inclusion of trials in which chemotherapy was used in both arms, potentially leading to an overestimation of risk in the ICI arm. They noted the subgroup analyses of ICIs versus chemotherapy and ICIs versus placebo were performed to address this limitation.