Neurological Toxic Effects Associated With Treatment With Immune Checkpoint Inhibitors—Are We Really Safer Now?

More than a decade from the first US Food and Drug Administration (FDA) approval of an immune checkpoint inhibitor (ICI) for treatment of cancer,¹ prompt identification and management of immune-related adverse events (IRAEs) remain challenges faced in clinical practice daily. This systematic review and meta-analysis by Farooq and colleagues,² assesses the risks of neurological adverse events (NAEs) during treatment with ICIs compared with control groups of randomized studies, including placebo and active treatments, such as chemotherapy and targeted therapies.

Since the initial enthusiasm resulting from the long-term efficacy demonstrated by the treatment of metastatic cutaneous melanoma with a monoclonal antibody directed against cytotoxic T lymphocyte–associated molecule-4 ([CTLA-4] ipilimumab),³ diverse ICIs targeting programmed cell death 1 (PD-1; cemiplimab, nivolumab, and pembrolizumab) and programmed cell death ligand 1 (PD-L1; avelumab, atezolizumab, and durvalumab) have been evaluated in clinical trials and subsequently received regulatory FDA approval for the treatment of diverse neoplasms. However, the unique mechanism of action of ICIs also emphasizes the importance of the early identification and adequate management of the toxic effects of this class of drugs, as some of them may be permanent or even fatal.

In this context, IRAEs from cancer treatment have important singularities. First, unlike traditional chemotherapy toxic effects, there is no predictable period of first onset of IRAEs. Although the median onset is usually within 2 to 16 weeks from treatment start, some reports have suggested that toxic effects can development as early as a few days after initiation or even 1 year or longer after its suspension.^4-6 Second, different classes of ICIs have particular incidences and predominant system–specific toxic effects. Owing to the greater magnitude of induction of T-cell proliferation and deeper suppression of regulatory T-cell (CD4+ and CD25+) immunosuppressive action, anti–CTLA-4 drugs have higher rates of grades 3 and 4 IRAEs compared with anti–PD-1 drugs (31% and 10%, respectively). In particular, treatment with anti–CTLA-4 antibodies is associated with higher rates of colitis, hypophysitis and rash, while treatment based on anti–PD-1 drugs is expected to cause pneumonitis, hypothyroidism, arthralgia, and vitiligo more frequently.⁷

Because of the risk of permanent duration and the impact of dose-limiting, neurological toxic effects represent 1 of the most important AEs during treatment with chemotherapy. However, the exact profile, risk factors, and management of neurological IRAEs secondary to treatment with ICIs are still part of a developing body of evidence. In the study conducted by Farooq and colleagues,² they found that the relative risk (RR) of NAEs was lower during treatment with ICIs (RR, 0.59; 95% CI, 0.45-0.77) compared with control groups of analyzed studies, including both active treatment agents and placebo. Particularly remarkable are the results of the analysis regarding peripheral neuropathy, an NAE of particular interest owing to its dose-cumulative and dose-limiting profile, in which Farooq et al² reported a clinically relevant lower risk with the use of ICIs compared with the overall control group (RR, 0.30; 95% CI, 0.17-0.51). Farooq and colleagues² also compared the incidence of NAEs separately with chemotherapy and placebo in the control groups. As some might have expected, chemotherapy treatment was associated with higher rates of NAEs, whereas placebo groups reported lower rates of NAEs than those found in ICI groups.

So, what is the importance of these findings to our clinical practice? The oncology community adopted immunotherapy in clinical practice soon after the first efficacy results were presented. While this represents a very favorable change in paradigm for the treatment of some advanced tumors, we have faced only modest benefits for other tumors. In addition to this, we are experiencing an increasing rate of recommendation of this class of drugs for patients who are elderly, frail, and more severely ill, a population underrepresented in clinical trials and for whom the impact of an IRAE may be even more dangerous than in the general population. The study by Farooq and colleagues² 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.

Published: April 19, 2022. doi:10.1001/jamanetworkopen.2022.7731

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Vargas Pivato de Almeida D. JAMA Network Open.

Corresponding Author: Daniel Vargas Pivato de Almeida, MD, Grupo Oncoclínicas, Oncovida – SGAS 915, Ed Advance 2, Rm 112, Asa Sul, Brasília, DF, Brazil 70390-150 (daniel.pivato@medicos.oncoclinicas.com).

Conflict of Interest Disclosures: Dr Vargas Pivato de Almeida reported personal fees from Astellas, AstraZeneca, Bayer, Eli Lilly, Janssen-Cilag, and Sanofi-Aventis outside the submitted work.