# Age and Clinical Outcomes of Immune Checkpoint Inhibitor Toxicities in Portugal: A Decade of Pharmacovigilance

## TL;DR

This study uses a decade of Portuguese data to show that while older adults don't report more serious immune checkpoint inhibitor side effects, they face higher fatality rates when severe toxicity occurs.

## Contribution

The study provides real-world evidence on age-related differences in ICI toxicity outcomes and patterns using national pharmacovigilance data.

## Key findings

- Serious adverse drug reactions were equally reported in older and younger adults, but older adults had higher fatality rates.
- Toxicity patterns differed by age, with older adults more likely to experience nervous and immune system events.
- Combination therapy increased the likelihood of serious adverse reactions, but not fatal outcomes.

## Abstract

Immune checkpoint inhibitors (ICIs) are widely used across many cancer types, yet their real-world safety in older adults is not well studied. Using a decade of national pharmacovigilance data from Portugal, we examined adverse drug reactions (ADRs) reported in patients treated with ICIs, focusing on whether age impacts the seriousness or pattern of toxicities. We found that serious ADRs were not more frequently reported in older adults than younger adults; however, when severe toxicity occurred, fatal outcomes were more common in patients aged 70 years or older. The types of organ systems affected also differed by age, with nervous and immune system events more frequently reported in older adults and hepatic or hematologic events more commonly in younger patients. Treatment regimen, particularly combination therapy, also influenced the likelihood of being classified as serious. These findings highlight the importance of early recognition and tailored management of ICI-related toxicities in older patients, rather than excluding them from this treatment based on age alone. Highlights/Key messages: Chronological age did not increase the odds of serious ICI ADRs; however, patients aged ≥70 years had higher fatality once toxicity occurred (aOR 1.66, 95% CI 1.31–2.09). Toxicity phenotype differed by age: more nervous/immune system events in patients aged ≥70 years, and more hepatobiliary/hematologic events in patients aged <70 years. Combination regimens involving anti-PD-1/PD-L1 plus anti-CTLA-4 were independently associated with a higher likelihood of being classified as a serious adverse drug reaction (aOR 1.57, 95% CI 1.13–2.18). However, in adjusted analyses, combination therapy was not associated with increased odds of fatal outcome. In contrast, CTLA-4–containing regimens showed the highest crude proportions of fatal reports in the cohort, reflecting their overall more severe toxicity profile.

Background: Real-world safety profiles of immune checkpoint inhibitors (ICIs) in older adults remain insufficiently characterized. Although ICIs are widely used across tumor types, older patients, particularly those with frailty, multimorbidity, or polypharmacy, are consistently under-represented in clinical trials, limiting the external validity of trial-derived toxicity estimates. Robust real-world data are therefore essential to clarify the incidence, seriousness, and age-related patterns of immune-related adverse events (irAEs) in routine practice. Methods: This is a nationwide retrospective study of spontaneous ICI-related ADRs reported in INFARMED’s Portal RAM (2011–2024). We evaluated the frequency, seriousness, fatality, and organ-specific patterns of ICI-related adverse drug reactions (ADRs) reported to the Portuguese National Pharmacovigilance System. The analytic unit was the ADR case. Endpoints included seriousness (primary), fatality, hospitalization, time-to-onset, and System Organ Class. Multivariable logistic regression adjusted for age, sex, regimen, tumor type, polypharmacy, and calendar period; sensitivity analyses using first ADR per patient were concordant. Results: We identified 2300 eligible ICI-related ADRs (corresponding to 925 patients). Median age at the time of ADR was 65 years (IQR not reported); 33.7% occurred in adults aged ≥70 years, and 62.8% of reports involved male patients. PD-1 inhibitors accounted for 77.5% of ADRs, and monotherapy for 72.9%. Overall, 85.8% of ADRs were classified as serious; 17.9% led to hospitalization and 19.1% were fatal. Serious-event reporting was similar in older and younger adults (≥70 vs. <70 years: 84.5% vs. 86.5%, p = 0.22), and the proportion explicitly labeled immune-related did not differ (9.3% vs. 8.7%, p = 0.56). In contrast, fatal outcomes were significantly more common in older adults (25.3% vs. 16.0%; p < 0.001). Age was associated with distinct organ-specific patterns. Adults ≥ 70 years had higher odds of nervous system disorders (aOR 1.75, 95% CI 1.23–2.48) and immune system disorders (aOR 1.42, 95% CI 1.02–1.98), but lower odds of hepatobiliary (aOR 0.52, 95% CI 0.36–0.76; p = 0.001) and blood/lymphatic disorders (aOR 0.50, 95% CI 0.32–0.79). In multivariable models, age ≥ 70 years did not predict seriousness (aOR 0.98, 95% CI 0.76–1.27), whereas combination therapy remained independently associated with increased seriousness (aOR 1.57, 95% CI 1.13–2.18). Conversely, age ≥ 70 years independently predicted fatal outcomes (aOR 1.66, 95% CI 1.31–2.09). Later calendar periods (2017–2024) were associated with substantially lower fatality (aOR 0.16; 95% CI 0.10–0.27). CTLA-4-containing regimens demonstrated a tendency toward higher fatality (aOR 1.50; 95% CI 0.94–2.37). Conclusions: Chronological age does not seem to increase the likelihood of reporting a serious ICI-related ADR, but, once toxicity occurs, older adults experience higher fatality rates. Age-related phenotypic differences and regimen-specific risks highlight the need for early recognition systems and tailored toxicity management in older populations.