This study supports the use of ICIs in older patients with advanced CSCC as an effective treatment option, with achievement of excellent response rates and an acceptable toxicity profile, similar to reports in younger trial populations [6, 9]. In our study, ICIs achieved an ORR of 57%, with 12-month OS and PFS of 63% and 41%, respectively. Of note, these 12-month survival statistics are lower than what was reported in the original phase 2 cemiplimab trial [6] (12-month OS 81% and PFS 53%), but are considerably higher than what would be expected with other treatment options such as chemotherapy or cetuximab (median OS 8.1 months, median PFS 4.1 months) [21]. As we only included patients ≥ 70 years, the median age of our patients of 81.8 years is higher than that for the key registrational studies (pembrolizumab 72 years, cemiplimab 71 years) and other real-world reports [6, 9, 14, 15]. Thus, the higher median age should be taken into consideration when reviewing the survival data for our study, as we are reporting on an older, frail, and comorbid population. Despite 17 patients in this cohort having died at study follow-up, most (n = 11) died from causes independent of their CSCC and its treatment. Our findings add to the growing literature base supporting the use of ICIs as a tolerable and effective treatment option for older patients [14, 15].

Our cohort is noteworthy for including a high proportion of ECOG ≥ 2 (n = 18, 34%) and immunocompromised (n = 18, 34%) patients. Strippoli et al. reported on a cohort of 30 older patients with advanced CSCC treated with cemiplimab and demonstrated an ORR of 76.7% (n = 23), including nine complete responses. The median PFS and OS were 16 and 18 months, respectively [22]. This Italian cohort included a predominance of patients with locally advanced disease (83.3%), which is in contrast to our predominantly metastatic cohort (73.6%). The Italian cohort also had fewer patients with poorer performance status and less immunocompromised patients, which may have contributed to the observed higher responses than those described in our report. A similar real-world report in a Canadian cohort reported a higher 12-month PFS (58.1%) and OS (76.7%) than we identified in our cohort. However, it must be noted that our cohort included patients with a median age of 81.8 years in contrast to 75.4 years in this study. Additionally, we had a higher number of ECOG 2 and 3 patients (34% vs 28%) [23].

ECOG performance status is an established prognostic marker in patients with advanced malignancies and correlates with OS [24]. A good performance status (ECOG ≤ 1) has thus become an important inclusion criterion for most clinical trials. However, whether as a consequence of their diagnosis, comorbidity, and/or age, patients with advanced cancer frequently have ECOG scores of ≥ 2, which requires the clinician to extrapolate findings from trial-eligible populations. In this study, we demonstrate that ECOG 0 and 1 patients derive benefit from ICIs; however, for ECOG ≥ 2 patients this benefit is markedly less, with a 12-month OS less than 40%. This finding is important to note when balancing discussions on the benefit of treatment relative to risks or impact on quality of life. Whilst ECOG 2 patients are still likely to derive benefit from the use of ICIs for their advanced CSCC, this benefit does appear smaller than for those with a better ECOG score. This highlights the pertinent role ECOG still plays in treatment decision making.

Despite all our participants being aged ≥ 70 years, we identified comparable toxicity to what was seen in the registrational ICI studies, with most irAEs being low grade. This is noteworthy given there are often concerns regarding the safety and tolerability of systemic cancer therapies in older patients. We also noted that although six of our patients with an autoimmune disease experienced an irAE, only three patients experienced an autoimmune disease-related flare. Of the 11 patients with autoimmune disease reported on by Baggi et al. in an Italian cohort, eight experienced an adverse event, but only two had to discontinue treatment from the toxicity [15]. Overall, whilst these numbers are small, there is growing retrospective data in this space for other tumour types demonstrating that ICIs can be safely given in certain patients with autoimmune disease and that irAEs or flares of autoimmune disease may even be associated with better efficacy [25].

The CCI represents a validated and widely recognised index of comorbidity that is frequently used in cancer studies [26, 27]. A large audit of colorectal cancer patients in the South Australian Cancer Registry, for example, found that increasing comorbidity was associated with increased cancer-specific and other cause mortality [28], and in head and neck malignancies, higher CCI values are associated with poorer OS [29]. Whilst our cohort was comorbid (mean CCI 8.5), we did not identify any association between CCI and OS or PFS in univariate analysis. Comorbidity was not evaluated in univariate or multivariate survival analyses for the other large real-world publications, but Strippoli et al. did report that having no comorbidity was associated with a more favourable ORR [14, 15, 22]. Comorbid patients are more likely to have compromised functional reserves, and thus there is a theoretical concern that these patients will face higher morbidity and mortality from immune-related toxicity, as has historically been seen with chemotherapy. For example, in the prospective MOST study, looking at patients aged ≥ 70 years who received chemotherapy for colon cancer, authors reported that during the first 500 days, 49.5% of patients experienced grade 3–4 toxicity and 30% of patients died [30]. However, despite our cohort being both comorbid and older, there were no patient deaths from treatment-related toxicity and the overall safety profile appeared acceptable.

There were 14 patients in our cohort who had locoregionally advanced disease. For many cases of locoregionally advanced CSCC, radiotherapy remains a treatment option; however, it too comes with the potential for toxicity. Whilst all patients included in this study were required to have a multidisciplinary discussion to ensure curative radiotherapy was not an option for them, there is growing interest in the use of ICIs in those for whom the morbidity of radiotherapy is deemed unacceptable. For example, there are now reports of ICIs in periorbital CSCC resulting in deep and durable responses in patients who declined curative surgery and/or radiotherapy due to concerns around the loss of their vision [31]. A single-centre retrospective review on the outcomes of radiotherapy for CSCC of the head and neck region reported radiotherapy could be well tolerated in an older cohort with CSCC without a significant impact on quality of life [2]. However, the toxicities associated with radiation can differ significantly in the aesthetically sensitive region of the head and neck based on the precise location treated, with common toxicities such as dermatitis, skin fibrosis, and alopecia to more specific toxicities such as ocular toxicity, mucositis, and xerostomia [32]. Thus a strong collaborative and multidisciplinary approach in the management of advanced CSCC remains paramount.

The limitations of this study include its retrospective nature, variation in imaging modality used for tumour assessment, lack of central review of imaging and disease assessments, and that imaging assessment intervals occurred as per standard of care, thus reducing the precision of PFS estimates. Additionally, whilst this study is, to the best of our knowledge, the largest real-world report in an older cohort with advanced CSCC treated with ICIs, it is still limited by its small sample size, and thus definitive conclusions cannot be reached.

Our study demonstrates that ICIs can be considered as an acceptable treatment option in select older patients with advanced CSCC. This is particularly noteworthy given this older cohort consisted of a large number of comorbid, frail, and immunocompromised patients. The results of this study also reinforce the importance of ECOG score in selecting older advanced CSCC patients for ICIs.