UV radiation is the most significant risk factor for cutaneous squamous cell carcinoma (cSCC), which has one of the highest rates of somatic mutations. This high tumor mutational burden (TMB) leads to numerous neoantigens that can be recognized by the immune system, providing a strong biological rationale for the development of immunotherapies. Indeed, cSCC exhibits a high expression of Programmed Death-Ligand 1 (PD-L1), which interacts with Programmed Death-1 (PD-1) on T cells to inhibit the anti-tumor immune response, allowing cancer cells to evade immune detection (Figure). This mechanism underlies the rationale for using PD-1 inhibitors in cSCC treatment.1
Figure. PD-L1 is overexpressed on tumor cells and antigen-presenting cells (APCs) in the tumor microenvironment and interacts with PD-1 on T cells. When PD-L1 binds to PD-1, PD-1 can recruit the tyrosine phosphatase SHP2, leading to the inactivation of CD28 and the T cell receptor (TCR) function and signaling pathways: PI3K/PIP3/Akt or RAS/MEK/ERK. This results in decreased CD8+ T cell proliferation, survival, and cytokine production.
Immunotherapy has shown significant efficacy in treating advanced cSCC, particularly when curative radiotherapy or surgery is not feasible for locally advanced, recurrent, or metastatic disease. Two phase II trials, KEYNOTE 629 and CARSKIN, investigated the efficacy of pembrolizumab in cSCC.3 In KEYNOTE 629, the objective response rate (ORR) was 34%, with complete and partial response rates of 4% and 31%, respectively. The 12-month disease-specific survival was 95%, disease-free survival was 89%, and overall survival was 95%.4 In the CARSKIN trial, treatment-naïve patients had an ORR of 42%, with a higher response rate in PD-L1 positive patients compared to PD-L1 negative ones.5
Cemiplimab’s efficacy was demonstrated in the phase II EMPOWER-CSCC 1 study. Patients with metastatic or locally advanced cSCC showed ORRs of 50.8% and 44.9%, respectively. The responses were durable, with the median duration of response not reached in metastatic cases and exceeding 41 months in locally advanced cases.6,7 Based on these results, the FDA approved cemiplimab for treating metastatic cSCC or locally advanced cSCC ineligible for surgery. Current NCCN guidelines reflect the efficacy and tolerability of systemic therapy for advanced cSCC, including in the neoadjuvant setting (Table 1).8
Despite optimal loco-regional treatment, up to 30% of advanced cSCC patients experience recurrence and up to 5% progress to a stage where curative treatment is not possible. In advanced cases where surgery is borderline feasible, the risk of incomplete resection, disfigurement, and functional morbidity is high. This underscores the rationale for neoadjuvant anti-PD-1 therapy in advanced cSCC.3
Several studies support the potential of neoadjuvant therapy. Ferrarotto et al. reported a 30% clinical response rate and a 50% pathological complete response in a phase II study of neoadjuvant cemiplimab in advanced resectable head and neck cSCC.9 Similarly, Gross et al. found a 51% pCR and a 68% response rate in a phase II study using cemiplimab for stage II-IV cSCC.10 Results from the NEOCESQ study showed a 39% pCR rate in patients treated with neoadjuvant cemiplimab.11
Despite these promising results, two main questions remain. First is whether treatment can be de-escalated in responders to neoadjuvant immunotherapy. The DESQUAMATE trial is exploring this by avoiding surgery in patients with negative restaging after neoadjuvant pembrolizumab. Second, patient selection is crucial, as up to 10% may experience disease progression during neoadjuvant treatment. Gene expression studies have indicated an inflamed tumor microenvironment in responders, but PD-L1 expression and tumor mutational burden are unreliable predictive biomarkers.3
Intralesional treatments, directly administered inside the tumor, offer a selective drug delivery approach, minimizing systemic side effects and preserving function and appearance. This is particularly useful for patients with comorbidities or those who refuse surgery. Several intralesional immunotherapy drugs are currently under clinical trial evaluation (Table 2).12
By understanding the underlying pathophysiology and leveraging recent advancements in immunotherapy, treatment for advanced cSCC continues to improve, offering hope for better patient outcomes.
