Advanced Cutaneous Squamous Cell Carcinoma Management in Immunotherapy Era: Achievements and New Challenges

Luigi  Lorini; Andrea Alberti; Paolo Bossi

doi:10.5826/dpc.1304a251

Advanced Cutaneous Squamous Cell Carcinoma Management in Immunotherapy Era: Achievements and New Challenges

Authors

Luigi Lorini Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
Andrea Alberti Medical Oncology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, University of Brescia, ASST Spedali Civili, Brescia, Italy
Paolo Bossi Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano; Department of Biomedical Sciences, Humanitas University, Milan, Italy

Keywords:

Cutaneous Squamous Cell Carcinoma, Immunotherapy, Frail Patients, Neoadjuvant Treatment

Abstract

Introduction of immunotherapy has radically changed the therapeutic scenario in patients affected by locally advanced and/or metastatic cutaneous squamous cell carcinoma patients. If it is well consolidated the role of immunotherapy in the setting of a disease not amenable to curative surgery and/or radiation, how to integrate immune checkpoint inhibitors in the curative setting is still under evaluation. Surgery combined or not with adjuvant radiotherapy remains the mainstay of curative treatment in localized cutaneous squamous cell carcinoma; however, promising data with neoadjuvant or perioperative immunotherapy could pave the way towards a treatment de-escalation according to the response achieved. On the other side, data on adjuvant treatment with pembrolizumab and cemiplimab after surgery and radiation are still awaited. Several questions related to the activity and safety of immunotherapy in real world setting still remain without answer, and several points need to be better explored. In the current review we will explore the updated literature on the use of immunotherapy in cutaneous squamous cell carcinoma, and we will show the current challenges in its use.

References

Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the US Population, 2012. JAMA Dermatol. 2015 Oct 1;151(10):1081.

Madeleine MM, Patel NS, Plasmeijer EI, Engels EA, Bouwes Bavinck JN, Toland AE, et al. Epidemiology of keratinocyte carcinomas after organ transplantation. Br J Dermatol. 2017 Nov;177(5):1208–16.

Li X, Zhao S, Bian X, Zhang L, Lu L, Pei S, et al. Signatures of EMT, immunosuppression, and inflammation in primary and recurrent human cutaneous squamous cell carcinoma at single-cell resolution. Theranostics. 2022;12(17):7532–49.

Lai C, August S, Albibas A, Behar R, Cho SY, Polak ME, et al. OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential. Clin Cancer Res. 2016 Aug 15;22(16):4236–48.

Bluth MJ, Zaba LC, Moussai D, Suárez-Fariñas M, Kaporis H, Fan L, et al. Myeloid Dendritic Cells from Human Cutaneous Squamous Cell Carcinoma Are Poor Stimulators of T-Cell Proliferation. J Invest Dermatol. 2009 Oct;129(10):2451–62.

Slater NA, Googe PB. PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis: PD-L1 expression in cutaneous squamous cell carcinoma. J Cutan Pathol. 2016 Aug;43(8):663–70.

Frohwitter G, Kerta M, Vogl C, Geppert CI, Werry JE, Ries J, et al. Macrophage and T-Cell Infiltration and Topographic Immune Cell Distribution in Non-Melanoma Skin Cancer of the Head and Neck. Front Oncol. 2022 Apr 7;12:809687.

Costache M, Georgescu TA, Oproiu AM, Costache D, Naie A, Sajin M, et al. Emerging concepts and latest advances regarding the etiopathogenesis, morphology and immunophenotype of basal cell carcinoma.

Tampa M, Mitran CI, Mitran MI, Nicolae I, Dumitru A, Matei C, et al. The Role of Beta HPV Types and HPV-Associated Inflammatory Processes in Cutaneous Squamous Cell Carcinoma. J Immunol Res. 2020 Apr 6;2020:1–10.

Hughes BGM, Munoz-Couselo E, Mortier L, Bratland Å, Gutzmer R, Roshdy O, et al. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial. Ann Oncol. 2021 Jul;S0923753421021864.

Maubec E, Boubaya M, Petrow P, Beylot-Barry M, Basset-Seguin N, Deschamps L, 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 Sep 10;38(26):3051–61.

Migden 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 Jul 26;379(4):341–51.

Migden MR, Khushalani NI, Chang ALS, Lewis KD, Schmults CD, Hernandez-Aya L, et al. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol. 2020 Feb;21(2):294–305.

Guminski AD, Lim AML, Khushalani NI, Schmults CD, Hernandez-Aya LF, Modi B,et al. Phase 2 study of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with metastatic cutaneous squamous cell carcinoma (mCSCC; Group 1): 12-month follow-up. Journal of Clinical Oncology 2019 37:15_suppl, 9526-9526.

Migden MR, Schmults C, Khushanlani N, Guminski A, Chang AL, Lewis K, et al. 814P Phase II study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC): Final analysis from EMPOWER-CSCC-1 groups 1, 2 and 3. Ann Oncol. 2022 Sep;33:S918–9.

Owonikoko TK, Papadopoulos KP, Johnson ML, Gil Martín M, Moreno V, Salama AK, et al. Phase I study of cemiplimab, a human monoclonal anti-PD-1, in patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Longer follow-up efficacy and safety data. Ann Oncol. 2018 Dec;29:x25.

Porceddu SV, Bressel M, Poulsen MG, Stoneley A, Veness MJ, Kenny LM, et al. Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial. J Clin Oncol. 2018 May 1;36(13):1275–83.

Ferrarotto R, Amit M, Nagarajan P, Rubin ML, Yuan Y, Bell D, et al. Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck. Clin Cancer Res. 2021 Aug 15;27(16):4557–65.

Gross ND, Miller DM, Khushalani NI, Divi V, Ruiz ES, Lipson EJ, et al. Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2022 Oct 27;387(17):1557–68.

Ascierto PA, Bossi P, Mandalà M, Queirolo P, Spagnolo F, Bassetto F, et al. NEO-CESQ study: Neoadjuvant plus adjuvant treatment with cemiplimab in surgically resectable, high risk stage III/IV (M0) cutaneous squamous cell carcinoma. J Clin Oncol. 2023 Jun 1;41(16_suppl):9576–9576.

Zuur CL, Breukers S, Machuca-Ostos M, Boere T, Smit L, De Boer JP, et al. Towards organ preservation and cure via 2 infusions of immunotherapy only, in patients normally undergoing extensive and mutilating curative surgery for cutaneous squamous cell carcinoma: An investigator-initiated randomized phase II trial—The MATISSE trial. J Clin Oncol. 2023 Jun 1;41(16_suppl):9507–9507.

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018 May 10;378(19):1789–801.

Judge TA, Wu Z, Zheng XG, Sharpe AH, Sayegh MH,et al. The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival. J Immunol. 1999 Feb 15;162(4):1947-51.

Kumar V, Shinagare AB, Rennke HG, Ghai S, Lorch JH, Ott PA, et al. The Safety and Efficacy of Checkpoint Inhibitors in Transplant Recipients: A Case Series and Systematic Review of Literature. The Oncologist. 2020 Jun 1;25(6):505–14.

Aguirre LE, Guzman ME, Lopes G, Hurley J. Immune Checkpoint Inhibitors and the Risk of Allograft Rejection: A Comprehensive Analysis on an Emerging Issue. The Oncologist. 2019 Mar;24(3):394–401.

Li W, Zheng XX, Kuhr CS, Perkins JD. CTLA4 Engagement is Required for Induction of Murine Liver Transplant Spontaneous Tolerance†. Am J Transplant. 2005 May;5(5):978–86.

Hanna GJ, Dharaneeswaran HJ, Giobbie-Hurder A, Harran JJ, Liao Z, Pai L, et al. Cemiplimab for kidney organ transplant recipients with advanced cutaneous squamous cell carcinoma: CONTRAC-1. J Clin Oncol. 2023 Jun 1;41(16_suppl):9519–9519.

Baggi A, Quaglino P, Rubatto M, Depenni R, Guida M, Ascierto PA, et al. Real world data of cemiplimab in locally advanced and metastatic cutaneous squamous cell carcinoma. Eur J Cancer. 2021 Nov;157:250–8.

Quaglino P, Baggi A, Depenni R, Guida M, Ascierto PA, Queirolo P, et al. 833P Longer follow up of a real-world study of cemiplimab in advanced cutaneous squamous cell carcinoma: Focus on late toxicities and long term benefit. Ann Oncol. 2022 Sep;33:S929–30.

Salzmann M, Leiter U, Loquai C, Zimmer L, Ugurel S, Gutzmer R, et al. Programmed cell death protein 1 inhibitors in advanced cutaneous squamous cell carcinoma: real-world data of a retrospective, multicenter study. Eur J Cancer. 2020 Oct;138:125–32.

Hober C, Fredeau L, Pham-Ledard A, Boubaya M, Herms F, Celerier P, et al. Cemiplimab for Locally Advanced and Metastatic Cutaneous Squamous-Cell Carcinomas: Real-Life Experience from the French CAREPI Study Group. Cancers. 2021 Jul 15;13(14):3547.

Extermann M, Hurria A. Comprehensive Geriatric Assessment for Older Patients With Cancer. J Clin Oncol. 2007 May 10;25(14):1824–31.

Martinez-Tapia C, Canoui-Poitrine F, Bastuji-Garin S, Soubeyran P, Mathoulin-Pelissier S, Tournigand C, et al. Optimizing the G8 Screening Tool for Older Patients With Cancer: Diagnostic Performance and Validation of a Six-Item Version. The Oncologist. 2016 Feb 1;21(2):188–95.

Castagneto B, Di Pietrantonj C, Stevani I, Anfossi A, Arzese M, Giorcelli L, et al. The importance of negative predictive value (NPV) of vulnerable elderly survey (VES 13) as a pre-screening test in older patients with cancer. Med Oncol. 2013 Dec;30(4):708.

Tagliamento M, Frelaut M, Baldini C, Naigeon M, Nencioni A, Chaput N, et al. The use of immunotherapy in older patients with advanced non-small cell lung cancer. Cancer Treat Rev. 2022 May;106:102394.

Gomes F, Lorigan P, Woolley S, Foden P, Burns K, Yorke J, et al. A prospective cohort study on the safety of checkpoint inhibitors in older cancer patients – the ELDERS study. ESMO Open. 2021 Feb;6(1):100042.

Bruijnen CP, Koldenhof JJ, Verheijden RJ, van den Bos F, Emmelot‐Vonk MH, Witteveen PO, et al. Frailty and checkpoint inhibitor toxicity in older patients with melanoma. Cancer. 2022 Jul 15;128(14):2746–52.

Rischin D, Khushalani NI, Schmults CD, Guminski AD, Chang ALS, Lewis KD, et al. Phase II study of cemiplimab in patients (pts) with advanced cutaneous squamous cell carcinoma (CSCC): Longer follow-up. J Clin Oncol. 2020 May 20;38(15_suppl):10018–10018.

Starkings R, Shilling V, Jenkins V, Fallowfield L. A structured review of quality of life in advanced and high‐risk cutaneous squamous cell carcinoma shows the need for more studies and better measures. Skin Health Dis [Internet]. 2021 Sep [cited 2023 Aug 1];1(3). Available from: https://onlinelibrary.wiley.com/doi/10.1002/ski2.39

Gibbons E, Casañas i Comabella C, Fitzpatrick R. A structured review of patient-reported outcome measures for patients with skin cancer, 2013. Br J Dermatol. 2013 Jun;168(6):1176–86.

Basra MKA, Salek MS, Fenech D, Finlay AY. Conceptualization, development and validation of T‐QoL © (Teenagers’ Quality of Life): a patient‐focused measure to assess quality of life of adolescents with skin diseases. Br J Dermatol. 2018 Jan;178(1):161–75.

Lee EH, Klassen AF, Cano SJ, Nehal KS, Pusic AL. FACE-Q Skin Cancer Module for measuring patient-reported outcomes following facial skin cancer surgery. Br J Dermatol. 2018 Jul;179(1):88–94.

Burdon-Jones D, Gibbons K. The Skin Cancer Quality of Life Impact Tool (SCQOLIT): a validated health-related quality of life questionnaire for non-metastatic skin cancers: A quality of life impact tool for non-metastatic skin cancers. J Eur Acad Dermatol Venereol. 2013 Sep;27(9):1109–13.

Waalboer-Spuij R, Hollestein L, Timman R, Poll-Franse L, Nijsten T. Development and Validation of the Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) Questionnaire. Acta Derm Venereol. 2018;98(2):234–9.

Müller K, Karrer S, Szeimies RM, Steinbauer J, Kohl E, Steinbauer D, et al. Quality of life assessment in patients with nonmelanoma skin cancer - psychometric validation of the EORTC QLQ-C30 questionnaire: Validation of EORTC QLQ-C30 in patients with NMSC. JDDG J Dtsch Dermatol Ges. 2017 Nov;15(11):1090–100.