Despite the excellent overall prognosis of cutaneous squamous cell carcinoma (cSCC), approximately 3-7% of patients will experience locoregional or distant metastasis which portends a poor prognosis (1). Unfortunately, cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) therapies, such as cetuximab, have had limited success due to a short durable response. First-line therapy has therefore shifted to immune checkpoint inhibitors (ICI), such as programmed cell death protein 1 (PD-1) inhibitors, demonstrating a mixed response with half of patients experiencing no benefit or progression (2, 3). Improving the ICI response rate may lie in cetuximab use post-ICI rather than pre-ICI due to greater efficacy ( Table 1 ). Here, we report three cases of advanced cSCC initially unresponsive to anti-PD-1 therapy but improved significantly with subsequent cetuximab therapy and provide a comprehensive review of the available literature on this subject.

We identified three patients from 2018 to 2023 at the Siteman Cancer Center of Washington University School of Medicine who presented for the management of advanced metastatic cSCC. All patients initially progressed on pembrolizumab, after which cetuximab was added with significant clinical response (two complete responses [CR] and one partial response [PR]). All patients were amenable to their respective treatment plans. Treatments were well-tolerated overall. Patient demographics and clinical data are reported in Table 2 .

In this case series, three adults with advanced cSCC achieved clinical and radiographic responses (1 PR and 2 CR) with cetuximab (either as a monotherapy or combination therapy) after progression on pembrolizumab. Treatment was well-tolerated with rapid responses within seven months of initiating cetuximab.

Cutaneous SCC is an immunogenic cancer capable of immune surveillance escape via an immune-tolerant microenvironment (9). Upregulation of inhibitory immune checkpoint expression, such as programmed death ligand 1 (PD-L1) promotes T-cell exhaustion. PD-1 inhibitors, such as pembrolizumab, promote T-cell activation via PD-1 blockade thus rejuvenating tumor-specific cytotoxic T cells in the tumor microenvironment (TME) and an anti-tumor effect (9). Cetuximab (EGFR inhibitor) also exerts anti-tumor activity through several immune-based mechanisms including natural killer (NK) cell-mediated killing via antibody-dependent cytotoxicity (ADCC) and tumor cell death via cytotoxic T-cell priming (10).

The KEYNOTE-629 and CARSKIN trials ushered in the pembrolizumab era for recurrent and advanced metastatic cSCC (2). However, almost half of patients lack benefit from PD-1 blockade thus warranting investigation into other therapies (9). A small phase 2 trial showed a 69% (n=25) disease control rate (DCR) after 6 weeks of cetuximab first-line monotherapy, with 8 patients (22%) achieving PR and 2 patients (6%) achieving CR (8). The median duration of response (DOR) was 6.8 months (95% CI, 4.1 to 8.3 months), sustained for 2.5 years after therapy cessation (8). Despite this, second-line cetuximab therapy may have a role in the setting of PD-1 blockade therapy failure (1). A single institution retrospective review (n=13) found that cetuximab use immediately after PD-1 progression had a greater and longer-lasting overall response compared to cetuximab use before PD-1 blockade from historical data (1). This study showed a 6-month DCR of 77% and an objective response rate (ORR) of 54% with 6 PR and 1 CR (1). In the I-Tackle phase 2 trial, patients with locally advanced or metastatic cSCC who progressed or had stable disease on pembrolizumab received cetuximab while continuing pembrolizumab therapy (n=23/43) (4). Cetuximab reversed the resistance to pembrolizumab (the response rate to combinatory treatment was nearly double that of cetuximab monotherapy), suggesting a rationale in adding cetuximab to pembrolizumab-refractory cSCC. However, while promising, the underlying mechanism is unclear (4). Of relevance, all patients had a molecular or clinical basis for their initial poor response to immunotherapy. Patient 1 had a low tumor mutational burden (TMB) of 7 mutations/Mb; moreover, immunotherapy response in patients with Marjolin ulcers is not well described (although presumably, these patients are less likely to have high TMB compared to traditionally sun-induced cSCC). Patient 3 also had a low TMB of 1.3 mutations/Mb, while Patient 2 is chronically immunosuppressed due to their history of renal transplantation. Nonetheless, our study further supports the use of cetuximab after PD-1 inhibitor failure either as a monotherapy or in combination with other systemic treatments (chemotherapy or immunotherapy).

Cetuximab and PD-1 inhibition synergism has been demonstrated in head and neck squamous cell carcinoma (HNSCC) with PD-1 blockade and cetuximab contributing to anti-tumor NK cell response (11). PD-1 inhibition also increased cetuximab-mediated NK cell activation and cytotoxicity, preferentially targeting HNCSS with high PD-L1 expression. These patients had an increased number of PD-1+ NK cells, correlating with diminished NK cell activity (11). PD-L1 expression correlated with a lack of response to cetuximab monotherapy, whereas concurrent administration with a PD-1 inhibitor (nivolumab) successfully reversed NK cell dysfunction and enhanced cetuximab-mediated ADCC in vitro (11). Thus, there may be synergy between PD-1 inhibitors and cetuximab in immune system priming to target cancer cells. PD-1 blockade of PD-1+ NK cells allows cetuximab to activate and restore their activity, thus enhancing their cytotoxicity. A group observed HNSCC patients treated with cetuximab after immunotherapy to have a longer median overall survival (OS) (11.3 months vs 8.0 months) and ORR (37.5% vs 19.0%, respectively), than those without post-immunotherapy cetuximab (10). Relatedly, separate treatment avenues exist whereby the effect of cetuximab may be potentiated following immunotherapy. A recent retrospective cohort study assessing combinatory cetuximab and radiation in locally advanced cSCC observed great outcomes (ORR 83.2% with 55.5% CR and 27.7% PR) in a small number of patients (n=18) (7). While promising, further prospective studies are required to investigate this relationship in patients who have received or are receiving immunotherapy. Table 1 pools key information from cited studies assessing cetuximab use after PD-1 inhibition.

While the benefit of cetuximab and immunotherapy in HNSCC has growing evidence, information remains limited in cSCC. One report observed clinical remission of auricular cSCC with combinatory nivolumab and cetuximab (5). This benefit was also observed with other anti-EGFR inhibitors – several metastatic cSCC patients refractory to immunotherapy achieved durable CRs after the addition of panitumumab (6) Our report is unique as it adds three cases to this underreported body of evidence. Interestingly, it does not appear that cetuximab before PD-1 inhibition offers the same benefits. In the same study, patients with cetuximab use before PD-1 inhibition had significantly worse progression-free survival (PFS) (3.0 months vs 4.4 months; p=0.024 after multivariable analysis) and median OS (13.6 months vs 19.8 months; p=0.003 after multivariable analysis) than patients who did not have prior cetuximab use (10). Additionally, the ORR (to PD-1 inhibition) in this group was lower than that of patients who did not have prior cetuximab use (19.0% vs 27.2%, respectively; p=0.44), although this difference was not statistically significant (10). One hypothesis is that cetuximab dampens the response of subsequent immunotherapy by down-regulating PD-L1 expression and recruiting regulatory T cells (12). Taken together, immunotherapy alters the TME in a way that amplifies cetuximab’s effect, whereas the reverse may not be true.

In conclusion, this study supports a growing body of evidence on the efficacy of cetuximab (and other anti-EGFR agents) in treating advanced cSCC otherwise unresponsive to PD-1 inhibition. Our study is limited by a small sample size and its retrospective nature. The efficacy of cetuximab after progression on PD-1 blockade therapy in treating advanced cSCC requires investigation by larger, randomized controlled trials to further understand its mechanism of action and establish this approach as the standard of care.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

RM: Investigation, Project administration, Visualization, Writing – original draft, Writing – review & editing. JP: Investigation, Project administration, Visualization, Writing – original draft, Writing – review & editing. AZ: Writing – review & editing. OB: Writing – review & editing. KK: Writing – review & editing. TJ: Writing – review & editing. GA: Conceptualization, Methodology, Resources, Supervision, Writing – review & editing.