Perioperative Systemic Therapy for High-Risk Cutaneous Squamous Cell Carcinoma.

Rapid response to cemiplimab for advanced cutaneous squamous cell carcinoma

Real-world assessment of response to anti-programmed cell death 1 therapy in advanced cutaneous squamous cell carcinoma

Concurrent radiation therapy with programmed cell death protein 1 inhibition leads to a complete response in advanced cutaneous squamous cell carcinoma

The use of chemotherapy in organ transplant recipients (OTRs) with advanced and metastatic cutaneous squamous cell carcinoma (SCC) remains relatively unexplored in dermatology. Advances in the use of chemotherapy in metastatic head and neck squamous cell carcinoma (HNSCC) may be applicable to this increasingly common disease. The objective of this study was to determine whether recent advances in the role of chemotherapy in the management of HNSCC and cutaneous SCC offer insights into treatment strategies for metastatic cutaneous SCC. We reviewed the literature pertaining to treatment of advanced and metastatic HNSCC and cutaneous SCC, with particular attention to the role of chemotherapy. In addition, specialists in the fields of cutaneous oncology and dermatologic surgery, head and neck surgery, medical oncology, and radiation oncology were consulted for expert multidisciplinary advice. Specific roles for chemotherapy in the management of advanced and cutaneous HNSCC are discussed and summarized. In addition, we propose theoretical analogies in the treatment of advanced and metastatic cutaneous SCC in OTRs. The head and neck surgery and oncology literature is rich with experience in locoregionally advanced and metastatic HNSCC, and adaptation of management concepts may prove feasible in the management of OTRs with advanced and metastatic cutaneous SCC.

Advanced cutaneous squamous cell carcinoma is a challenge to treat. Conventional systemic treatment options include chemotherapy and epidermal growth factor receptor-inhibitors. The aim of this study was to assess clinical outcomes with systemic treatments in advanced cutaneous squamous cell carcinoma. Patients receiving systemic treatment at the Tübingen Dermato-Oncology centre between 2007 and 2017 were identified (n = 59). Median age was 76 years (interquartile range (IQR) 71–80 years), 83.1% of patients were male, 72.9% had metastatic cutaneous squamous cell carcinoma, and 27.1% had unresectable locally advanced cutaneous squamous cell carcinoma. During median follow-up of 52 weeks (IQR 27–97 weeks), overall response rate was 14.3%, and disease control rate was 53.6%. Median progression-free survival was 15 weeks (IQR 8–42 weeks), and median overall survival was 52 weeks (IQR 27–97 weeks). Patients receiving chemoradiation vs chemotherapy alone showed better overall survival (hazard ratio 0.41, p = 0.014,) and progression-free survival (hazard ratio 0.42, p = 0.009); no differences were observed for metastatic cutaneous squamous cell carcinoma vs locally advanced cutaneous squamous cell carcinoma patients. Although chemotherapy and/or cetuximab showed limited outcomes in advanced cutaneous squamous cell carcinoma, such therapy may still be an option when anti-PD-1 treatment is contraindicated.

195 Background: There is no established standard of care for unresectable locally advanced or metastatic CSCC. UV-induced DNA damage causes hypermutation in most CSCCs. Therefore, these tumors may be responsive to PD-1 checkpoint blockade. In the dose escalation portion of the phase 1 study of cemiplimab (REGN2810), a durable (19 + months) radiologic complete response was observed in a patient (pt) with metastatic CSCC (ASCO 2015, #3024). Methods: ECs enrolled pts with distantly metastatic (EC 7) and locally advanced (EC 8) CSCC. All patients received cemiplimab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks for up to 48 weeks. Research biopsies were performed at baseline and Day 29 (and at progression, if possible). Tumor measurements were performed every 8 weeks according to RECIST 1.1 to determine overall response rate (ORR). Data cutoff date was 31 Jan 2017. Results: 26 pts were enrolled (10 in EC 7 and 16 in EC 8): median age, 72.5 y (range, 56–88y); median PS 1 (range, 0–1); 21M:5F; median number of prior systemic therapy regimens, 1 (range, 0–2). Median exposure to cemiplimab was 7 doses (range, 1–22). The most common treatment-related adverse event of any grade was fatigue (19.2%). Each of the following ≥ Grade 3 related AEs occurred once: AST elevation, ALT elevation, arthralgia, and rash. ORR (PR + CR, including unconfirmed) and disease control rate (ORR+SD) were 52% (12/23; 4uPR, 5 PR, 2CR, 1 uCR) and 70% (16/23, including 4SD), respectively. Three patients are not yet evaluable. Median PFS and OS have not been reached, and only one patient has experienced PD during cemiplimab treatment after initial response. Correlative studies are in process, including PD-L1 status and whole exome tumor DNA sequencing. Conclusions: Cemiplimab is well tolerated and produces antitumor activity in patients with advanced CSCC. A pivotal trial of cemiplimab for patients with advanced CSCC is enrolling patients. Clinical trial information: NCT02383212.

9503 Background: There is no established standard of care for unresectable locally advanced or metastatic CSCC. UV-induced DNA damage causes hypermutation in most CSCCs. Therefore, these tumors may be responsive to PD-1 checkpoint blockade. In the dose escalation portion of the phase 1 study of REGN2810, a durable (19 + months) radiologic complete response was observed in a patient (pt) with metastatic CSCC (ASCO 2015, #3024). Methods: ECs enrolled pts with distantly metastatic (EC 7) and locally advanced (EC 8) CSCC. All patients received 3 mg/kg REGN2810 by intravenous infusion over 30 minutes every 2 weeks for up to 48 weeks. Research biopsies were performed at baseline and Day 29 (and at progression, if possible). Tumor measurements were performed every 8 weeks according to RECIST 1.1 to determine overall response rate (ORR). Data cutoff date was 31 Jan 2017. Results: 26 pts were enrolled (10 in EC 7 and 16 in EC 8): median age, 72.5 y (range, 56-88y); median PS 1 (range, 0 – 1); 21M:5F; median number of prior systemic therapy regimens, 1 (range, 0 – 2). Median exposure to REGN2810 was 7 doses (range, 1-22). The most common treatment-related adverse event of any grade was fatigue (19.2%). Each of the following ≥ Grade 3 related AEs occurred once: AST elevation, ALT elevation, arthralgia, and rash. ORR (PR + CR, including unconfirmed) and disease control rate (ORR+SD) were 52% (12/23; 4uPR, 5 PR, 2CR, 1 uCR) and 70% (16/23, including 4SD), respectively. Three patients are not yet evaluable. Median PFS and OS have not been reached, and only one patient has experienced PD during REGN2810 treatment after initial response. Correlative studies are in process, including PD-L1 status and whole exome tumor DNA sequencing. Conclusions: REGN2810 is well tolerated and produces antitumor activity in patients with advanced CSCC. A pivotal trial of REGN2810 for patients with advanced CSCC is enrolling patients (NCT02760498). Clinical trial information: NCT02383212.

Introduction: Immune checkpoint inhibitor (ICI) therapies have redefined the treatment landscape of advanced cutaneous squamous cell carcinoma (CSCC). NeoPOWER is an ongoing, single-arm, phase II clinical trial studying the role of preoperative cemiplimab in patients with high risk/unresectable CSCC. Based on recent data, patients with CSCC who attain a pathologic complete response with neoadjuvant ICI have a 12-month disease free survival of 92%. Response rates to ICI; however, are approximately 50-60% and CSCC refractory to ICI is associated with an inferior survival, highlighting a need to stratify patients who are most likely to benefit from neoadjuvant cemiplimab. We employ Visium (v2, 10x genomics) to comprehensively analyze the CSCC tumor immune microenvironment of patients with divergent responses to immunotherapy. Methods: We performed Visium spatial transcriptomics (ST) profiling on formalin fixed paraffin embedded biopsy samples from patients with high risk or unresectable CSCC treated with neoadjuvant cemiplimab. Nine patients were included and divided into two groups as defined by presence of residual disease (RD) or no residual disease (NRD). An integrated RD and NRD pre-treatment (pre-iRD/NRD) analysis (n = 8 samples) was performed to identify factors predictive of treatment response. Separately, an integrated RD pre-treatment and post treatment (iRD) analysis was explored to assess for mechanisms of treatment resistance (n = 7 samples). Gene expression data generated by Visium was imported and analyzed in Seurat. Results: We observed that 2 distinct clusters identified as CSCC, histologically and transcriptionally, formed a substructure comprised of an outer and inner layer tumor edge (TE) and tumor core (TC), respectively. This association of spatial adjacency was visually evident in both pre-iRD/NRD and iRD groups. Comparative gene set enrichment analysis between pre-iRD/NRD showed alterations in KRAS signaling pathways and down-regulation of multiple immune response pathways, implying fundamental differences in the TC of both response groups. In contrast, comparisons of the iRD TC showed post-treatment enrichment of epithelial mesenchymal transition, hypoxia, and metabolic pathways. Post treatment TE was similarly enriched in EMT and hypoxia with down-regulation of immune response pathways. Alterations in immune cell proportions post-treatment were notable in the iRD group following ICI, as were differences in baseline B and T cell proportions in pre-iRD/NRD tumor clusters. Ligand receptor analysis highlighted key immune-inhibitory interactions within the TE and TC. Conclusions: ST analysis of the pre- and post-treatment CSCC microenvironment captures tumor edge/core dynamics associated with different response outcomes. Citation Format: Ali Baghian, Hugo Lara-Martinez, Rania Bassiouni, Gino In, Homa Dadrastoussi, Paniz Zarand, Harley Wu, Kaijin Wu, Brittney K. DeClerck, Ashley Gochoco, Kevin Kelly. Decoding resistance: Spatial transcriptomics reveals tumor core and edge dynamics in high-risk cutaneous squamous cell carcinoma treated with neoadjuvant cemiplimab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 757.

TPS9593 Background: The PD-1 inhibitor cemiplimab was approved in 2018 for treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable with surgery or radiation. This approval was based on the results of the phase 2 EMPOWER-CSCC-1 trial, which demonstrated an objective response rate of 47% with a significant number of these patients experiencing a durable response. However, patients with high risk cSCC that are able to undergo curative intent surgery are not candidates for checkpoint inhibitor therapy but still experience high rates of recurrence and/or systemic progression even when offered adjuvant radiotherapy. In light of data using checkpoint inhibitor therapy in the neoadjuvant setting in other cutaneous malignancies, we hypothesized that cemiplimab therapy would improve surgical outcomes and reduce long-term recurrence rates in patients with high-risk resectable cSCC if used in the perioperative setting. Methods: Winship 4851-19 is a single arm pilot study of cemiplimab in the neoadjuvant and adjuvant setting for high-risk resectable cSCC (NCT04428671). In the neoadjuvant phase, patients receive three doses of cemiplimab every three weeks followed by standard of care surgery. Radiation may be offered when clinically appropriate at the discretion of the investigator. In the adjuvant phase (following surgery +/- radiation), patients receive cemiplimab every three weeks to complete one year total of treatment. Eligible patients must have surgically resectable histologically proven high risk cSCC defined as: nodal disease with extracapsular extension or one node ≥20mm; in transit metastases > 2cm from primary lesion; T4 head and neck primary tumor; perineural invasion; or recurrent cSCC with concurrent ≥N2b nodal disease, size ≥4cm or bony invasion, or poorly differentiated histology. Patients cannot have received prior immunotherapy and must have a ECOG performance status of 0 or 1. Primary objective is to establish pathologic response rate. Secondary objectives include assessments of local and distant recurrence and overall survival rates. We also plan to evaluate the immune profile of fresh tumor and blood to assess the impact of neoadjuvant cemiplimab on the tumor microenvironment and circulating immune responses. To date 5 of 20 patients have been enrolled; this sample size was selected based on feasibility and ability enroll within a timely fashion. Clinical trial information: NCT04428671.

BackgroundPD-1 blockade achieves response rates of ~50% in patients with unresectable or metastatic cutaneous squamous cell carcinoma (CSCC); furthermore, responses are durable lasting greater than 6 months in 60% of...

High-risk cutaneous squamous cell carcinoma (CSCC): Challenges and emerging therapies

e21516 Background: Immunotherapy has revolutionized the treatment of advanced malignancies, including CSCC. Cemiplimab, a PD-1 immune checkpoint inhibitor, is the first PD-1 inhibitor approved for the systemic treatment of locally advanced CSCC (laCSCC) and metastatic CSCC (mCSCC) that are not curable with surgery or radiation. Objectives: The purpose of this retrospective study is to determine the efficacy and safety of cemiplimab in patients with CSCC in routine clinical practice in Slovenia. Methods: This retrospective analysis includes data from patients with laCSCC and mCSCC who were initiated on first-line cemiplimab therapy. The data collected included baseline patient characteristics (gender, age, ECOG performance status [PS], primary tumor site, site of disease dissemination, and comorbidities, including autoimmune diseases), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between May 2020 and October 2024, 37 patients started treatment. The median age of patients in this real-world cohort was 73 years (range: 48–90), and 22% had an ECOG PS of 2 or higher. Thirty patients (81%) had comorbidities, most commonly cardiovascular diseases, and 5 patients (14%) had a history of autoimmune disease. In total, 17 patients achieved a physician-assessed partial response (PR) or complete response (CR), resulting in an ORR of 45.9%. Five patients had stable disease (SD), yielding a disease control rate (DCR) of 59.5%. The median PFS was 9.3 months (95% CI, 4.1–14.5), and the median OS was 11.5 months (95% CI, 6.9–16.1), with a median duration of follow-up of 10.8 months. Nine patients (24.3%) experienced at least one immune-related adverse event (irAE), two of whom had two irAEs. All irAEs were grade 1 or 2, with only one irAE being grade 2–3. Skin toxicity was the most common irAE (73%), followed by thyroid dysfunction (27%). A higher response rate was observed in patients with irAEs, with an ORR of 56% and a DCR of 78%. Conclusions: Cemiplimab proved to be highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC in Slovenia, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Patients who developed irAEs had a higher response rate.

BackgroundPD-1 inhibitors were approved for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC) in 2019.1 The identification of tumor characteristics that predict potential responders to immune checkpoint inhibitors (ICI) is an area of ongoing research. Here we present a series of consecutive patients with locally advanced, recurrent, or metastatic CSCC treated with PD-1 inhibitors and analyze tumor and blood genomics as well as PD-L1 expression with the aim of correlating with treatment response.MethodsWe analyzed cases of CSCC treated with single agent PD-1 inhibitors in the last 2 years at Wake Forest. Demographic and outcome data were collected. Tumor tissue, whenever available, was tested for PD-L1, TMB, MSI, and genetic mutations. Blood was tested for circulating tumor at the beginning of treatment and at the time of maximum response.ResultsFourteen patients with CSCC treated with PD-1 ICI were included in this study. Six had locally advanced disease, seven had recurrent locally advanced disease, and one had metastatic disease. Four patients received treatment for >12 months and all had complete response (CR). Five patients had 6–12 months of treatment and all had near CR (pending imaging studies and ctDNA to confirm). Three patients had <6 months of treatment and had partial response (PR). Two of the patients had progressive disease, although one with possible pseudoprogression based on review of post-treatment surgical pathology specimen. Treatment was well tolerated with no immune related side-effects except one case of grade I hypothyroidism. Eleven patients had sufficient tumor tissue for genomic and PD-L1 testing. Initial blood genomic testing was performed in 12 of 13 patients and in follow up in patients who achieved maximum response. Patients with CR had PD-L1 of at least 30%. The additional tested patients had PD-L1 above 10%. The most frequently mutated gene was TP53 present in tumor in all tested patients and in blood in 6 patients, followed by NOTCH1/2 detected in the tumor of 10 of 11 patients tested. TMB was intermediate/high in tested patients except in the only patient who presented clear tumor progression.ConclusionsTreatment of locally advanced, recurrent, and metastatic CSCC with ICI led to a dramatic change in the management and prognosis of CSCC. Our series of patients with CSCC had a higher than reported rate of response. This corresponded with high TP53 alterations, NOTCH 1/2 alterations, high/intermediate TMB, and high level of expression of PD-L1. PD-L1 rates were higher than previously published.1 2Ethics ApprovalThe study was approved by Wake Forest University Institution’s Ethics Board, approval number IRB00056249.ReferencesMigden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379:341–51.Garcia-Pedrero JM, Martinez-Camblor P, Diaz-Coto S, et al. Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. J Am Acad Dermatol 2017;77(3):527–533.

818P Phase II confirmatory study of cemiplimab (350mg IV Q3W) in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Study 1540 Group 6

Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy. Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method. Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy. Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.