Treatment of Cutaneous Squamous Cell Carcinoma with Immune Checkpoint Inhibitors in Special Populations

Paolo Bossi; Luigi Lorini

doi:10.5826/dpc.11S2a170S

Treatment of Cutaneous Squamous Cell Carcinoma with Immune Checkpoint Inhibitors in Special Populations

Authors

Paolo Bossi Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Brescia, Italy
Luigi Lorini Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, ASST Spedali Civili of Brescia, University of Brescia, Brescia, Italy

Keywords:

cutaneous squamous cell carcinoma, special population, auto-immune disease, immunosuppression, immunodepression

Abstract

Cutaneous squamous cell carcinoma (cSCC) may develop in patients with dysregulated immune activation (pre-existing autoimmune diseases or immunosuppression due to hematopoietic/solid organ transplant recipients), patients with a compromised immune function (long-term immunosuppression), and patients carrying chronic viral infections, or those affected by lymphoproliferative diseases. It should be also considered that patients presenting with immunosuppression have a high incidence of cSCC (65–250-times higher than general population), highlighting the central role played by the immune system in the development of cSCC. All these cases must be considered as “special populations” for treatment with immune checkpoint inhibitors (ICIs), as the safety and activity of these drugs have not been studied on these specific cases, since these patients were excluded from clinical trials leading to approval of ICIs. It is therefore important to gain as much information as possible from the analysis of real-life data, to derive an indication to be adopted in everyday clinical setting. Moreover, therapeutic alternatives other than ICIs are scarce, mainly consisting in chemotherapy and anti-EGFR agents, whose activity is lower than immunotherapy and whose toxicity (particularly with chemotherapy) are not sustainable by this frail population. Here, we describe the current evidence of treatment with ICIs in special populations and conclude that it is necessary to find a balance between treatment risks (toxicities) and benefits (efficacy), as well as engaging a multidisciplinary team of experts to thoroughly manage and treat these patients.

References

Rogers HW, Weinstock MA, Harris AR, et al. Incidence Estimate of Nonmelanoma Skin Cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287. DOI:10.1001/archdermatol.2010.19. PMID: 20231499.

Green AC, Olsen CM. Cutaneous squamous cell carcinoma: an epidemiological review. Br J Dermatol. 2017;177(2):373–81. DOI. 10.1111/bjd.15324. PMID: 28211039.

Boyers LN, Karimkhani C, Naghavi M, Sherwood D, Margolis DJ, Hay RJ, et al. Global mortality from conditions with skin manifestations. J Am Acad Dermatol. 2014;71(6):1137-1143.e17. DOI: 10.1016/j.jaad.2014.08.022. PMID: 25282129.

Eisemann N, Jansen L, Castro FA, et al. Survival with nonmelanoma skin cancer in Germany. Br J Dermatol. 2016;174(4):778–85. DOI: 10.1111/bjd.14352. PMID: 26676514.

Patel R, Chang ALS. Immune Checkpoint Inhibitors for Treating Advanced Cutaneous Squamous Cell Carcinoma. Am J Clin Dermatol. 2019;20(4):477–82. DOI: 10.1007/s40257-019-00426-w. PMID: 30737731.

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. JCO. 2020;38(15_suppl):10018–10018. DOI: 10.1200/JCO.2020.38.15_suppl.10018.

Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122(17):3062–73. DOI: 10.1182/blood-2013-05-500801. PMID: 24030385.PMCID: PMC3811178.

Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations: Immune Therapy in Difficult Populations. Cancer. 2017;123(11):1904–11. DOI: 10.1002/cncr.30642. PMID: 28241095. PMCID: PMC5445005.

Chae YK, Galvez C, Anker JF, Iams WT, Bhave M. Cancer immunotherapy in a neglected population: The current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients. Cancer Treatment Reviews. 2018;63:116–21. DOI. 10.1016/j.ctrv.2017.12.004. PMID: 29276997.

Gassmann D, Weiler S, Mertens JC, Reiner CS, Vrugt B, Nägeli M, et al. Liver Allograft Failure After Nivolumab Treatment—A Case Report With Systematic Literature Research. Transplantation Direct. 2018;4(8):e376. DOI: 10.1097/TXD.0000000000000814. PMID: 30255136. PMCID: PMC6092180.

De Bruyn P, Van Gestel D, Ost P, Kruse V, Brochez L, Van Vlierberghe H, et al. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go? Current Opinion in Oncology. 2019;31(2):54–64. DOI: 10.1097/CCO.0000000000000505. PMID: 30694841.

Manohar S, Thongprayoon C, Cheungpasitporn W, Markovic SN, Herrmann SM. Systematic Review of the Safety of Immune Checkpoint Inhibitors Among Kidney Transplant Patients. Kidney International Reports. 2020;5(2):149–58. DOI: 10.1016/j.ekir.2019.11.015. PMID: 32043028. PMCID:PMC7000848.

d’Izarny‐Gargas T, Durrbach A, Zaidan M. Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review. Am J Transplant. 2020;20(9):2457–65. DOI: 10.1111/ajt.15811. PMID: 32027461.

Esfahani K, Al-Aubodah T-A, Thebault P, Lapointe R, Hudson M, Johnson NA, et al. Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation. Nat Commun. 2019;10(1):4712. DOI: 10.1038/s41467-019-12628-1. PMID: 31624262. PMCID: PMC6797722.

Rzeniewicz K, Larkin J, Menzies AM, Turajlic S. Immunotherapy use outside clinical trial populations: never say never? Annals of Oncology. 2021;32(7):866–80. DOI: 10.1016/j.annonc.2021.03.199. PMID: 33771665.

Luan FL, Hojo M, Maluccio M, Yamaji K, Suthanthiran M. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy1. Transplantation. 2002;73(10):1565-1572. DOI: 10.1097/00007890-200205270-00008. PMID: 12042641.

Karia PS, Azzi JR, Heher EC, Hills VM, Schmults CD. Association of Sirolimus Use With Risk for Skin Cancer in a Mixed-Organ Cohort of Solid-Organ Transplant Recipients With a History of Cancer. JAMA Dermatol. 2016;152(5):533. DOI: 10.1001/jamadermatol.2015.5548. PMID: 26792250.

Delanoy N, Michot J-M, Comont T, Kramkimel N, Lazarovici J, Dupont R, et al. Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study. The Lancet Haematology. 2019;6(1):e48–57. DOI: 10.1016/S2352-3026(18)30175-3.

Haverkos BM, Abbott D, Hamadani M, Armand P, Flowers ME, Merryman R, et al. PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130(2):221–8. DOI: 10.1182/blood-2017-01-761346. PMID: 28468799. PMCID: PMC5510790.

Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med. 2016;375(2):143–53.

Ijaz A, Khan AY, Malik SU, Faridi W, Fraz MA, Usman M, et al. Significant Risk of Graft-versus-Host Disease with Exposure to Checkpoint Inhibitors before and after Allogeneic Transplantation. Biology of Blood and Marrow Transplantation. 2019;25(1):94–9. DOI: 10.1016/j.bbmt.2018.08.028. PMID: 30195074. PMCID: PMC6310648.

Klocke K, Sakaguchi S, Holmdahl R, Wing K. Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Proc Natl Acad Sci USA. 2016;113(17):E2383–92. DOI: 10.1073/pnas.1603892113. PMID: 27071130. PMCID: PMC4855592.

Khan SA, Pruitt SL, Xuan L, Gerber DE. Prevalence of Autoimmune Disease Among Patients With Lung Cancer: Implications for Immunotherapy Treatment Options. JAMA Oncol. 2016;2(11):1507. DOI: 10.1001/jamaoncol.2016.2238. PMID: 27262099. PMCID: PMC5656433.

Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Oncology. 2016;2(2):234–40. DOI: 10.1001/jamaoncol.2015.4368. PMID: 26633184.

Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Annals of Oncology. 2017;28(2):368–76. DOI: 10.1093/annonc/mdw443. PMID: 27687304.

Weinstock C, Singh H, Maher VE, Kim G, Pazdur R. FDA analysis of patients with baseline autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents. JCO. 2017;35(15_suppl):3018–3018. DOI: 10.1200/JCO.2017.35.15_suppl.3018.

Danlos F-X, Voisin A-L, Dyevre V, et al. Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. European Journal of Cancer. 2018;91:21–9. DOI: 10.1016/j.ejca.2017.12.008. PMID: 29331748.

Leonardi GC, Gainor JF, Altan M, et al. Safety of Programmed Death–1 Pathway Inhibitors Among Patients With Non–Small-Cell Lung Cancer and Preexisting Autoimmune Disorders. JCO. 2018;36(19):1905–12. DOI: 10.1200/JCO.2017.77.0305. PMID: 29746230.

Toi Y, Sugawara S, Kawashima Y, et al. Association of Immune‐Related Adverse Events with Clinical Benefit in Patients with Advanced Non‐Small‐Cell Lung Cancer Treated with Nivolumab. The Oncol. 2018;23(11):1358–65. DOI: 10.1634/theoncologist.2017-0384. PMID: 29934411. PMCID: PMC6291330.

Cortellini A, Buti S, Santini D, et al. Clinical Outcomes of Patients with Advanced Cancer and Pre‐Existing Autoimmune Diseases Treated with Anti‐Programmed Death‐1 Immunotherapy: A Real‐World Transverse Study. The Oncol. 2019;24(6):e327-e337. DOI: 10.1634/theoncologist.2018-0618. PMID: 30796151. PMCID: PMC6656514.

Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. The Lancet Oncology. 2015;16(8):908–18.

Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncology. 2015;16(4):375–84. DOI: 10.1016/S1470-2045(15)70076-8.

Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. The Lancet Oncology. 2012;13(5):459–65. DOI: 10.1016/S1470-2045(12)70090-6.

Maslov DV, Tawagi K, Kc M, Simenson V, et al. Timing of steroid initiation and response rates to immune checkpoint inhibitors in metastatic cancer. J Immunother Cancer. 2021;9(7):e002261. DOI. 10.1136/jitc-2020-002261. PMID: 34226279. PMCID:PMC8258666.

Sylvie E, Jean K, Alain C. Skin Cancers after Organ Transplantation. The New England Journal of Medicine. 2003;11.

Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2018;78(2):237–47. DOI: 10.1016/j.jaad.2017.08.059. PMID: 29332704.

Garrett GL, Lowenstein SE, Singer JP, He SY, Arron ST. Trends of skin cancer mortality after transplantation in the United States: 1987 to 2013. J Am Acad Dermatol. 2016;75(1):106–12. DOI: 10.1016/j.jaad.2016.02.1155. PMID: 27067869.

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. Annals of Oncology. 2021;S0923753421021864. DOI: 10.1016/j.annonc.2021.07.008. PMID: 34293460.

https://www.ema.europa.eu/en/documents/product-information/entyvio-epar-product-information_it.pdf. Accessed date September 30, 2021.

Jarkowski A, Hare R, Loud P, et al. Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): The Roswell Park Experience and a Review of the Literature. American Journal of Clinical Oncology. 2016;39(6):545–8. DOI: 10.1097/COC.0000000000000088. PMID: 24879468.

Maubec E, Petrow P, Scheer-Senyarich I, Duvillard P, Lacroix L, Gelly J, et al. Phase II Study of Cetuximab As First-Line Single-Drug Therapy in Patients With Unresectable Squamous Cell Carcinoma of the Skin. JCO. 2011;29(25):3419–26. DOI. 10.1200/JCO.2010.34.1735. PMID: 21810686.

Borradori L, Sutton B, Shayesteh P, Daniels GA. Rescue therapy with anti-programmed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases. Br J Dermatol. 2016;175(6):1382–6. DOI: 10.1111/bjd.14642. PMID: 27059424.

Miller DM, Faulkner-Jones BE, Stone JR, Drews RE. Complete pathologic response of metastatic cutaneous squamous cell carcinoma and allograft rejection after treatment with combination immune checkpoint blockade. JAAD Case Reports. 2017;3(5):412–5. DOI: 10.1016/j.jdcr.2017.06.005. PMID: 28932782.

Paoluzzi L, Ow TJ. Safe Administration of Cemiplimab to a Kidney Transplant Patient with Locally Advanced Squamous Cell Carcinoma of the Scalp. Current Oncology. 2021;28(1):574–80. DOI: 10.3390/curroncol28010057. PMID: 33477979. PMCID: PMC7903284.

Ali SA, Arman HE, Patel AA, Birhiray RE. Successful Administration of Cemiplimab to a Patient With Advanced Cutaneous Squamous Cell Carcinoma After Renal Transplantation. JCO Oncology Practice. 2020;16(3):137–8. DOI: 10.1200/JOP.19.00567. PMID: 31770056.

Hanna GJ, Ruiz ES, LeBoeuf NR, et al. Real-world outcomes treating patients with advanced cutaneous squamous cell carcinoma with immune checkpoint inhibitors (CPI). Br J Cancer. 2020;123(10):1535–42. DOI: 10.1038/s41416-020-01044-8. PMID: 32868898. PMCID: PMC7653959.

Valentin J, Gérard E, Ferte T, Prey S, Dousset L, Dutriaux C, et al. Real world safety outcomes using cemiplimab for cutaneous squamous cell carcinoma. Journal of Geriatric Oncology. 2021;S1879406821000527. DOI: 10.1016/j.jgo.2021.02.026. PMID: 33736973.

Rabinowits G, Park SJ, Ellison DM, et al. Checkpoint inhibition in immunosuppressed or immunocompromised patients with advanced cutaneous squamous cell carcinoma (CSCC): Data from prospective CemiplimAb-rwlc Survivorship and Epidemiology (C.A.S.E.) study. JCO. 2021;39(15_suppl):9547–9547. DOI: 10.1200/JCO.2021.39.15_suppl.9547.