Tolerance to First-Line Immunotherapy in Elderly Patients with Advanced Solid Tumours

Methodology

This retrospective study examined the outcomes of elderly patients with advanced solid cancer who received immunotherapy as first-line treatment at Blackrock and St Vincent Private Hospital. We conducted an electronic database search to identify patients treated with immunotherapy as a monotherapy between March 2024 and February 2025.

For each patient, data were collected on demographics, treatment details, baseline laboratory results, adverse events, and disease outcomes. We analysed the data to explore potential associations between immunotherapy, clinical characteristics, and baseline laboratory investigations in relation to disease outcome. Statistical analysis included chi-square tests and independent samples t-tests to identify significant relationships between these factors.

Results

We identified 17 elderly patients with advanced solid cancers who received immunotherapy as first-line systemic treatment. The mean age of the cohort was 77 ± 11 years, with 12 (70%) males. In terms of Eastern Cooperative Oncology Group (ECOG) performance status, 4 (24%) had an ECOG score of 0, 7 (41%) had an ECOG score of 1, and 6 (35%) had an ECOG score of 2. Additionally, 13 (76%) of the patients had pre-existing comorbidities. The cancer types included 6 (36%) head and neck cancer, 4 (24%) malignant melanoma, 4 (24%) renal cell carcinoma, 2 (11%) lung cancers, and 1 (5%) colon cancer. Radical surgery was offered to 6 (35%) patients, radical radiotherapy to 7 (41%), and concomitant chemotherapy to 4 (24%). The mean duration of immunotherapy was 65 weeks (ranging from 5 to 292 weeks) (Table 1).

Among the patients, 11 (64%) experienced autoimmune side effects, with 3 (17%) reporting more than one side effect. The most common adverse effects included fatigue in 6 (35%), skin rash of grades 1-2 in 3 (17%), hypothyroidism in 3 (17%), diarrhoea in 3 (17%), and arthralgia in 1 (5%). The severity of side effects was classified as grade 1 in 6 (35%) patients, grade 2 in 9 (52%), and grade 3 in 1 (5%). Four patients (24%) discontinued immunotherapy, with 3 (17%) due to disease progression and 1 (5%) due to toxicity. Notably, there was no significant difference in demographics, treatment modalities or laboratory findings between patients who experienced adverse events and those who did not (Table 2).

Discussion

This study investigated the tolerance and side effects of first-line immunotherapy in elderly patients with advanced solid tumours. While elderly patients could tolerate immunotherapy for extended periods, 64% experienced autoimmune side effects. Notably, these side effects were generally mild to moderate, though some patients (5%) discontinued treatment due to severe toxicity. This real-world data highlights the potential for immunotherapy in geriatric oncology, with a need for close monitoring.

This study highlights the impact of immune-senescence — the age-related decline in immune system function — that may influence both the therapeutic response to immune checkpoint inhibitors (ICIs) and the profile of irAEs. As patients age, immune functions diminish, leading to the accumulation of senescent immune cells, reduced naïve T-cell reserves, and altered immune regulation. These age-related changes may not necessarily increase the severity of toxicity but could influence the type and timing of immune-related adverse events. Emerging evidence also suggests that older adults may experience different patterns of irAEs (e.g., more endocrine and cutaneous events), whereas younger patients may have more gastrointestinal or hepatic irAEs, highlighting age-related variability in toxicity presentation [9].

In our cohort, 11 (64%) patients developed irAEs, which underscores that, while older adults can benefit from immunotherapy, vigilance in monitoring remains key. While some real-world data in older adult ICI recipients show no significant increase in high-grade toxicity or treatment discontinuation across age groups [1], other reviews highlight that immuno-senescence may contribute to distinct patterns of irAEs in elderly patients [10]. More recent real-world studies further support this, showing that frailty, comorbidities, and immune function—rather than chronological age—play a greater role in predicting toxicity and treatment outcomes [11,12].

Together, these findings suggest that chronological age alone is insufficient to predict safety; rather, comprehensive assessment of immune reserve, functional status, and comorbidity should inform the use of ICIs in older adults.

A major challenge identified in this study is the frequent presence of comorbidities in elderly patients, with 13/17 76% of the cohort having pre-existing conditions. This high rate is clinically important because multiple chronic illnesses complicate treatment regimens and may increase susceptibility to immune-related adverse events (irAEs) [8,13]. The presence of comorbidities, combined with polypharmacy, can exacerbate treatment complications, making the management of adverse effects more difficult.

Our findings align with previous research emphasising the importance of individualised treatment in older adults. Yildiz et al reported that most geriatric cancer patients receiving immunotherapy have significant comorbidities and that treatment decisions should account for overall health status rather than chronological age alone [3]. Similarly, Granier et al discussed how age-related immune changes, frailty, and comorbid conditions necessitate a tailored approach to immunotherapy, as older patients often differ from those represented in clinical trials [14]. Collectively, these observations support the need for personalised, comorbidity-aware, and polypharmacy-conscious treatment strategies to balance efficacy with safety in elderly cancer patients.

In our cohort, 11/17 (64%) patients experienced immune-related adverse events (irAEs)—most commonly fatigue (6/17, 35%), skin rash (3/17, 17%; grades 1–2), hypothyroidism (3/17, 17%), diarrhoea (3/17, 17%), and arthralgia (1/17, 5%). Most irAEs were grade 1–2, and only 1/17 (5%) patients had a grade ≥ 3 adverse event. These findings are consistent with prior studies in older adults receiving ICIs, which generally report similar overall and high-grade toxicity compared with younger patients [6,15].

In our study, adverse-event incidence did not differ by demographics, treatment modality, or baseline laboratory parameters. Importantly, emerging evidence indicates that chronological age alone does not dictate irAE risk; functional vulnerability and certain patient-level factors may be more informative [11,12]. These data support close monitoring and individualised toxicity management in older adults to sustain treatment adherence and outcomes.

A notable finding from this study is that 24% of patients discontinued treatment, primarily due to disease progression (17%) and toxicity (5%). This discontinuation rate is comparable to other studies examining immunotherapy in older populations, such as Elkrief, et al. who observed that elderly patients are more likely to discontinue treatment due to toxicity [5].

While the rate of discontinuation in our cohort was not markedly high, even a small percentage of toxicity-related discontinuations underscores the importance of close monitoring and early detection of immune-related adverse events (irAEs) to improve treatment adherence and overall patient outcomes [16]. An additional aspect that may influence treatment outcomes in elderly patients is the type of ICI used, treatment cycles, and the lack of standardised biomarker use in this population. Emerging studies suggest that these variables may predict both toxicity patterns and response rates, yet such data remain limited in older cohorts [7].

Study limitations and areas for future research

This study has some notable limitations that should be considered when interpreting the findings. The retrospective design is a key limitation, as it is prone to biases associated with the use of existing patient data, such as incomplete records or inconsistencies in how information was recorded. Additionally, the small sample size of only 17 patients reduces the statistical power of the study and limits its ability to generalise the results to a broader elderly cancer population. To confirm the findings and improve their applicability, larger, prospective studies with more diverse patient cohorts are necessary.

Further research should aim to identify predictive biomarkers that could help identify elderly patients at higher risk of severe immune-related adverse events (irAEs). Biomarkers that predict adverse outcomes would allow clinicians to tailor immunotherapy regimens more effectively, reducing the incidence of toxicity while maintaining efficacy. Moreover, exploring ways to optimise treatment schedules for elderly patients, adjusting dosages or treatment frequency to account for age-related changes in drug metabolism and immune function, could improve tolerance and minimise side effects.

Another critical area for future research is polypharmacy, which is common in elderly patients. Polypharmacy increases the risk of drug interactions and complicates the management of cancer treatment. Research into simplifying medication regimens or finding safer alternatives for comorbidities could significantly improve the overall safety and effectiveness of immunotherapy. Additionally, closer monitoring of comorbid conditions is crucial, as they can affect how elderly patients respond to immunotherapy and exacerbate adverse effects.

Conclusion

In conclusion, this study offers valuable insights into the use of first-line immunotherapy in elderly patients with advanced solid tumours. While many elderly patients tolerate immunotherapy well, autoimmune-related side effects remain a significant challenge. As the ageing population grows and immunotherapy becomes more common in oncology, further research is crucial to refine treatment strategies for older patients. This will help maximise the therapeutic benefits of immunotherapy while minimising associated risks.

This study suggests that elderly patients receiving immunotherapy for advanced solid cancers can tolerate the treatment for an extended period (mean 65 weeks), although a majority (64%) develop autoimmune side effects. While these effects were mostly mild to moderate, a small percentage (5%) developed severe toxicity, leading to treatment discontinuation in some cases (24%).

This highlights the need for close monitoring but supports immunotherapy feasibility in elderly cancer patients.

This ‘real-world’ data can provide a foundation for further research into predicting tolerance to immunotherapy in elderly cancer patients.