Systemic Therapy for Squamous Cell Carcinoma and Non-Melanoma Skin Cancer

Educational Objectives

The goal of this program is to improve the treatment of squamous cell carcinoma and non-melanoma skin cancer with systemic therapy. After hearing and assimilating this program, the clinician will be better able to:

1. Manage previously untreated advanced Merkel cell carcinoma using avelumab.

Summary

Introduction: the National Comprehensive Cancer Network (NCCN) guidelines — immunotherapies have surpassed the role of chemotherapy in Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (CSCC); targeted therapies and immunotherapy are options for basal cell carcinoma (BCC) treatment; US Food and Drug Administration (FDA)-approved therapies — for metastatic MCC, programmed death-ligand 1 inhibitors (anti-PDL1 agents) and programmed cell death-1 inhibitors (anti-PD1 agents) are approved; for CSCC, anti-PD1 agents and for BCC, anti-PD1 and hedgehog inhibitors are approved; data supporting adjuvant and neoadjuvant anti-PD-1 therapy for MCC are available

Merkel cell carcinoma: the JAVELIN Merkel 200 trial (D’Angelo et al [2020]) — the phase-2 study warranted the approval of avelumab in patients with previously treated advanced MCC (33% overall response rate); in treatment-naive patients, the response rate was 62%; 74% of patients had durable response >12 mo; a 75% survival at 3 yr was observed with avelumab therapy (for ≥1 yr); a 3-yr survival of 70% was observed with 1 yr of avelumab second-line therapy for metastatic MCC; a 80% survival at 2 yr was observed with avelumab therapy for 2 yr

Recurrence: biomarkers (eg, cell-free DNA), and imaging (eg, positron emission tomography) can be used to monitor patients for early identification of the recurrences after stopping immune checkpoint inhibitor (ICI) therapy; studies on increasing the duration between the ICI therapy doses to ≈3 mo instead of stopping ICI therapy in metastatic MCC (to prevent recurrence) are ongoing

Key points: studies on ICI therapy (including pembrolizumab) for locally advanced or metastatic MCC demonstrate an overall response rate of >50% and an improved median duration of response; referral to radiation oncologist after surgery and time to radiation for high-risk MCC are important

Basal cell carcinoma: targeted oral therapies are available for locally advanced or metastatic BCC that cannot be treated with definitive surgery or radiation, ie, smoothened inhibitors and hedgehog inhibitors (HHIs; eg, sonidegib and vismodegib); HHIs result in significant durable treatment responses, however, they cause systemic toxicity, eg, myalgias, muscle cramps, weight loss; dosing strategies to improve tolerability are being investigated

ICIs for BCC: the EMPOWER BCC-1 study — anti-PD-1 therapy with cemiplimab is indicated for frail patients who may not tolerate the adverse effects of HHIs and can accept oral therapy; the overall response rate for locally advanced BCC was ≈30% and in metastatic BCC ≈20% with complete remission of ≈6%

Cutaneous squamous cell carcinoma: the EMPOWER CSCC-1 study — in treatment-naive patients with unresectable CSCC, the overall response rate with cemiplimab therapy was 45% (Hughes et al [2025]); it produces a significant response in a short period; a ≈50% disease control rate was observed; however, cemiplimab can cause severe toxicities, eg, type-1 insulin dependent labile blood sugar diabetes mellitus or severe myositis; its toxicity rate is <20%

Anti-PD-1 therapy for CSCC: pembrolizumab therapy — across the studies, the overall response rate for locally advanced CSCC was 50% and for metastatic CSCC was 35% (Hughes et al [2022]) and 40% (in the CARSKIN study; Maubec et al [2020]); pembrolizumab results in a durable response; 15% to 20% of patients reported grade 3 and 4 toxicities; cosibelimab — it is a recently approved anti-PD-1 agent that has demonstrated good overall responses (≈50%) with lower complete response rates

Neoadjuvant anti-PD-1 therapy for CSCC: a pathologic complete response (pCR) of 51% has been observed with neoadjuvant therapy (fewer recurrences); durability is associated with pCR across cutaneous malignancies

Readings

D’Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer. 2020;8(1):e000674. doi:10.1136/jitc-2020-000674; Hughes BGM, Guminski A, Bowyer S, et al. A phase 2 open-label study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1): final long-term analysis of groups 1, 2, and 3, and primary analysis of fixed-dose treatment group 6. J Am Acad Dermatol. 2025;92(1):68-77. doi:10.1016/j.jaad.2024.06.108; Hughes BGM, Munoz-Couselo E, Mortier L, et al. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial [published correction appears in Ann Oncol. 2022 Aug;33(8):853. doi: 10.1016/j.annonc.2022.05.517.]. Ann Oncol. 2021;32(10):1276-1285. doi:10.1016/j.annonc.2021.07.008; Maubec E, Boubaya M, Petrow P, et al. Phase II study of pembrolizumab as first-line, single-drug therapy for patients with unresectable cutaneous squamous cell carcinomas. J Clin Oncol. 2020;38(26):3051-3061. doi:10.1200/JCO.19.03357; Stratigos AJ, Sekulic A, Peris K, et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):848-857. doi:10.1016/S1470-2045(21)00126-1.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Bollin's lecture contains information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Bollin was recorded at the Melanoma and Cutaneous Oncology Symposium, held January 25-26, 2025, in Coronado, CA, and presented by Scripps. For information on upcoming CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and Scripps for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

ON160802

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.