Two aspects are important for the implementation of adjuvant ICI in elderly patients ≥75 years. The first is safety of adjuvant ICI in elderly patients in terms of irAE, co-morbidities and frailty. The other point is the efficacy in elderly patients considering the aging immune system leading potentially to reduced efficacy of adjuvant ICI.
Considering the first point, available data is rather scarce with regard to elderly melanoma patients. A subgroup analysis of the KEYNOTE studies in patients with non-small cell lung cancer ≥ 75 years reported 68.5% treatment-related events and 24.2% AEs ≥ grade 3 [14]. Endo et al. [15] found 51.2% adverse events in elderly lung cancer patients treated with PD-1 inhibitors, 17.1% were grade 3 or higher. In our study, we found comparable results. Adjuvant ICI with pembrolizumab or nivolumab was generally well tolerated in the group of elderly patients and 37.1% experienced no irAE at all. The occurrence of grade 3 or 4 irAE was rare with only 7 out of 117 patients (6%) and thus lower than in the group of younger patients (10%). Moreover, no deaths occurred in the elderly due to irAE with adjuvant ICI.
The association between occurrence of irAEs and prognosis in melanoma patients has been a subject of debate. On the one hand, several studies found no correlation between irAEs and PFS or overall survival [2,16,17]. On the other hand, an association between skin toxicity and improved PFS and OS in advanced melanoma has been observed in a number of other studies [18,19]. Freeman-Keller et al. [20] also reported a statistically significant association between overall survival and the occurrence of cutaneous irAEs as well as the total number of observed irAEs, respectively. Likewise, Eggermont et al. [21] found a longer recurrence-free survival in patients that experienced any treatment-related AE during palliative therapy with pembrolizumab. In our study, elderly patients experienced significantly more often cutaneous irAE. However, there was no correlation between skin toxicity and PFS.
Efficacy of adjuvant ICI in older patients is more difficult to assess, as there are a number of factors to be considered. Several studies have shown that elderly melanoma patients inherently have a poorer prognosis, as they are more likely to have a higher tumor stage at first diagnosis with higher tumor thickness, a higher mitotic rate and an increased likelihood for ulcerated tumors [22,23]. While some studies found no age-dependent difference in response rate to anti-PD1 therapy, others reported a shorter PFS in older patients [24,25]. In a large meta-analysis including more than 35,000 patients, Wu et al. [26] found no significant benefit of ICIs in terms of PFS and OS for patients aged 75 years or older. Similar results were obtained in our study. Elderly patients had a shorter progression-free survival and more often relapsed despite ICI than younger patients. Possible explanations include age-related alterations of the immune system, but also premature termination of adjuvant ICI due to other co-morbidities, hospitalization, deterioration of general condition or personal preference. However, the number of patients with premature termination of adjuvant ICI due to individual preference was low (n<10). Another limitation is the retrospective character of this study. Only irAE, that had been written in the medical records, have been included. There might have been other irAE in patients that had not been addressed during the consultation with their physician. Nevertheless, there is a high percentage of irAE in this evaluation corresponding to the rates in the literature.
In summary, adjuvant ICI therapy was well tolerated, also in elderly patients and irAE were manageable. In terms of efficacy, it has to be noted that PFS was significant shorter in the elderly cohort and there was significant more skin and nephrological toxicity and more often colitis/diarrhea occurred. According to our results, adjuvant ICI should be used with precaution in patients aged ≥75 years. Further studies are needed, i.e. concerning adjuvant targeted therapy in terms of efficacy and toxicity.