Immunotherapy and Its Timing in Advanced Basal Cell Carcinoma Treatment
Keywords:
basal cell carcinoma, advanced, metastatic, anti-PD-1, cemiplimab, nivolumab, pembrolizumab, immunotherapyAbstract
For patients with advanced BCC, including locally advanced or metastatic BCC not amenable to curative surgery or radiotherapy, hedgehog pathway inhibitors (HHI) vismodegib and sonidegib are approved as first-line systemic treatment. Results from clinical trials highlight that the overall discontinuation rate of HHI treatment varies from 88% to 92% with vismodegib and is approximately 92% with sonidegib, and half of patients will discontinue HHI after approximately 8 to 12 months. The main factors weighing in on the decision to discontinue HHI, include efficacy (tumor response), adverse events and patient decision. In clinical practice, some of the patients that stop HHI may be re-evaluated if the tumor becomes amenable to surgery, or restart HHI at a later time, while others will need to switch to immunotherapy, depending on the reasons for HHI discontinuation. In this review, we revisit the therapeutic decisions considering a switch from HHI to immunotherapy with anti-PD-1 agent cemiplimab and we highlight the place of cemiplimab in the therapeutic ladder for patients with advanced BCC. We discuss the evidence on the efficacy and safety of anti-PD-1 agents as second-line systemic monotherapy, or in combination with other treatments, and the emergence of checkpoint immunotherapy as a neoadjuvant treatment.
References
Dessinioti C, Antoniou C, Katsambas A, Stratigos AJ. Basal cell carcinoma: what's new under the sun. Photochem Photobiol. 2010;86(3):481-491.
Laga AC, Schaefer IM, Sholl LM, French CA, Hanna J. Metastatic Basal Cell Carcinoma. Am J Clin Pathol. 2019;152(6):706-717.
Dessinioti C, Tzannis K, Sypsa V, et al. Epidemiologic risk factors of basal cell carcinoma development and age at onset in a Southern European population from Greece. Exp Dermatol. 2011;20(8):622-626.
Krakowski AC, Hafeez F, Westheim A, Pan EY, Wilson M. Advanced basal cell carcinoma: What dermatologists need to know about diagnosis. J Am Acad Dermatol. 2022;86(6S):S1-S13.
Dessinioti C, Stratigos AJ. An Epidemiological Update on Indoor Tanning and the Risk of Skin Cancers. Curr Oncol. 2022;29(11):8886-8903.
Molinaro AM, Ferrucci LM, Cartmel B, et al. Indoor tanning and the MC1R genotype: risk prediction for basal cell carcinoma risk in young people. Am J Epidemiol. 2015;181(11):908-916.
Dessinioti C, Sypsa V, Kypreou K, et al. A case-control study of MC1R variants in Greek patients with basal cell carcinoma: increased risk independently of pigmentary characteristics. Exp Dermatol. 2015;24(6):476-478.
Tagliabue E, Fargnoli MC, Gandini S, et al. MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project. Br J Cancer. 2015;113(2):354-363.
Dessinioti C, Antoniou C, Stratigos AJ. From basal cell carcinoma morphogenesis to the alopecia induced by hedgehog inhibitors: connecting the dots. Br J Dermatol. 2017;177(6):1485-1494.
Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nature reviews Cancer. 2008;8(10):743-754.
Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science (New York, NY). 2020;367(6477).
Neuner RA, Lee J, Rieger KE, Park C, Colevas AD, Chang ALS. Immunotherapy for keratinocyte cancers. Part I: Immune-related epidemiology, risk factors, pathogenesis, and immunotherapy management of keratinocyte cancers. J Am Acad Dermatol. 2023;88(6):1225-1240.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer. 2012;12(4):252-264.
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer cell. 2015;27(4):450-461.
Chang J, Zhu GA, Cheung C, Li S, Kim J, Chang AL. Association Between Programmed Death Ligand 1 Expression in Patients With Basal Cell Carcinomas and the Number of Treatment Modalities. JAMA Dermatol. 2017;153(4):285-290.
Lipson EJ, Lilo MT, Ogurtsova A, et al. Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. Journal for immunotherapy of cancer. 2017;5:23.
Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome medicine. 2017;9(1):34.
Salem P, Hall SW, Benjamin RS, Murphy WK, Wharton JT, Bodey GP. Clinical phase I-II study of cis-dichloro-diammineplatinum(II) given by continuous lv infusion. Cancer Treat Rep. 1978;62(10):1553-1555.
Coker DD, Elias EG, Viravathana T, McCrea E, Hafiz M. Chemotherapy for metastatic basal cell carcinoma. Arch Dermatol. 1983;119(1):44-50.
Moeholt K, Aagaard H, Pfeiffer P, Hansen O. Platinum-based cytotoxic therapy in basal cell carcinoma--a review of the literature. Acta Oncol. 1996;35(6):677-682.
Nasr I, McGrath EJ, Harwood CA, et al. British Association of Dermatologists guidelines for the management of adults with basal cell carcinoma 2021. Br J Dermatol. 2021;185(5):899-920.
Schmults C, Blitzblau R, Aasi SZ, et al. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Basal Cell Skin Cancer. 2023; version 1.2023:https://www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf. Accessed July 3, 2023.
Peris K, Fargnoli MC, Kaufmann R, et al. European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023. Eur J Cancer. 2023;192:113254.
Erivedge. Summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/erivedge-epar-product-information_en.pdf . Accessed on July 3, 2023.
Odomzo. Summary of product characteristics (SPC). Available at: https://www.ema.europa.eu/en/documents/product-information/odomzo-epar-product-information_en.pdf Assessed July 3, 2023. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002839/WC500192970.pdf. .
Barrios DM, Do MH, Phillips GS, et al. Immune checkpoint inhibitors to treat cutaneous malignancies. J Am Acad Dermatol. 2020;83(5):1239-1253.
European Medicines Agency. Libtayo. Summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_en.pdf Access date: July 3, 2023.
Basset-Seguin N, Hauschild A, Kunstfeld R, et al. Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017;86:334-348.
Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017;17(1):332.
Dummer R, Guminksi A, Gutzmer R, et al. Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study. Br J Dermatol. 2020;182(6):1369-1378.
Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716-728.
Dummer R, Guminski A, Gutzmer R, et al. The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2016;75(1):113-125 e115.
Lear JT, Migden MR, Lewis KD, et al. Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. 2018;32(3):372-381.
Mannino M, Piccerillo A, Fabbrocini G, et al. Clinical characteristics of an Italian patient population with advanced BCC and real-life evaluation of HHI safety and effectiveness. Dermatology. 2023.
Atwood SX, Sarin KY, Whitson RJ, et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer cell. 2015;27(3):342-353.
Sharpe HJ, Pau G, Dijkgraaf GJ, et al. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer cell. 2015;27(3):327-341.
Danial C, Sarin KY, Oro AE, Chang AL. An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(6):1325-1329.
Doan HQ, Chen L, Nawas Z, Lee HH, Silapunt S, Migden M. Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma. Oncotarget. 2021;12(20):2089-2100.
Herms F, Lambert J, Grob JJ, et al. Follow-Up of Patients With Complete Remission of Locally Advanced Basal Cell Carcinoma After Vismodegib Discontinuation: A Multicenter French Study of 116 Patients. J Clin Oncol. 2019;37(34):3275-3282.
Bassompierre A, Dalac S, Dreno B, et al. Efficacy of sonic hedgehog inhibitors rechallenge, after initial complete response in recurrent advanced basal cell carcinoma: a retrospective study from the CARADERM database. ESMO Open. 2021;6(6):100284.
Sanchez-Danes A, Larsimont JC, Liagre M, et al. A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Nature. 2018;562(7727):434-438.
Biehs B, Dijkgraaf GJP, Piskol R, et al. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature. 2018;562(7727):429-433.
Dessinioti C, Plaka M, Dimitrakopoulou A, Stratigos AJ. Complete response is reversible upon vismodegib withdrawal and re-inducible upon vismodegib rechallenge in a patient with locally advanced basal cell carcinoma. J Eur Acad Dermatol Venereol. 2019;33(5):e187-e188.
Bower JE, Bak K, Berger A, et al. Screening, assessment, and management of fatigue in adult survivors of cancer: an American Society of Clinical oncology clinical practice guideline adaptation. J Clin Oncol. 2014;32(17):1840-1850.
Lacouture ME, Dreno B, Ascierto PA, et al. Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma. Oncologist. 2016;21(10):1218-1229.
Fife K, Herd R, Lalondrelle S, et al. Managing adverse events associated with vismodegib in the treatment of basal cell carcinoma. Future oncology (London, England). 2017;13(2):175-184.
Sekulic A, Migden MR, Lewis K, et al. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol. 2015;72(6):1021-1026 e1028.
Dessinioti C, Plaka M, Soura E, et al. A Practical Guide for the Follow-Up of Patients with Advanced Basal Cell Carcinoma During Treatment with Hedgehog Pathway Inhibitors. Oncologist. 2019;24(8):e755-e764.
Basset-Seguin N, Hauschild A, Grob JJ, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 2015;16(6):729-736.
Otsuka A, Dreier J, Cheng PF, et al. Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(6):1289-1297.
Falchook GS, Leidner R, Stankevich E, et al. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. Journal for immunotherapy of cancer. 2016;4:70.
Cohen PR, Kato S, Goodman AM, Ikeda S, Kurzrock R. Appearance of New Cutaneous Superficial Basal Cell Carcinomas during Successful Nivolumab Treatment of Refractory Metastatic Disease: Implications for Immunotherapy in Early Versus Late Disease. International journal of molecular sciences. 2017;18(8).
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):1382-1386.
Winkler JK, Schneiderbauer R, Bender C, et al. Anti-programmed cell death-1 therapy in nonmelanoma skin cancer. Br J Dermatol. 2017;176(2):498-502.
Lipson EJ, Bagnasco SM, Moore J, Jr., et al. Tumor Regression and Allograft Rejection after Administration of Anti-PD-1. N Engl J Med. 2016;374(9):896-898.
Cannon JGD, Russell JS, Kim J, Chang ALS. A case of metastatic basal cell carcinoma treated with continuous PD-1 inhibitor exposure even after subsequent initiation of radiotherapy and surgery. JAAD case reports. 2018;4(3):248-250.
Fischer S, Hasan Ali O, Jochum W, Kluckert T, Flatz L, Siano M. Anti-PD-1 Therapy Leads to Near-Complete Remission in a Patient with Metastatic Basal Cell Carcinoma. Oncol Res Treat. 2018;41(6):391-394.
Choi FD, Kraus CN, Elsensohn AN, et al. Programmed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review. J Am Acad Dermatol. 2020;82(2):440-459.
Dumann K, Artz N, Ziemer M. Complete Remission of Basal Cell Carcinoma Following Treatment With Cemiplimab After 2 Years. JAMA Dermatol. 2021;157(8):1004-1006.
Johansson I, Levin M, Akyurek LM, Olofsson Bagge R, Ny L. PD-1 inhibitor therapy of basal cell carcinoma with pulmonary metastasis. J Eur Acad Dermatol Venereol. 2022;36 Suppl 1:70-73.
De Giorgi V, Trane L, Savarese I, et al. Lasting response after discontinuation of cemiplimab in a patient with locally advanced basal cell carcinoma. Clinical and experimental dermatology. 2021;46(8):1612-1614.
Delaitre L, Martins-Hericher J, Truchot E, et al. [Regression of cutaneous basal cell and squamous cell carcinoma under pembrolizumab]. Annales de dermatologie et de venereologie. 2020;147(4):279-284.
Ikeda S, Goodman AM, Cohen PR, et al. Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy. NPJ Genom Med. 2016;1:16037-.
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.
ClinicalTrials.gov. PD-1 in patients with advanced basal cell carcinoma who experienced progression of disease on hedgehog pathway inhibitor therapy, or were intolerant of prior hedgehog pathway inhibitor therapy. 2022; https://clinicaltrials.gov/ct2/show/NCT03132636. Accessed March 3, 2023.
Veron M, Chevret S, Grob JJ, et al. Safety and efficacy of nivolumab, an anti-PD1 immunotherapy, in patients with advanced basal cell carcinoma, after failure or intolerance to sonic Hedgehog inhibitors: UNICANCER AcSe NIVOLUMAB trial. Eur J Cancer. 2022;177:103-111.
Bertrand N, Guerreschi P, Basset-Seguin N, et al. Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: First results of a multicenter, open-label, phase 2 trial (VISMONEO study): Neoadjuvant Vismodegib in Locally Advanced Basal Cell Carcinoma. EClinicalMedicine. 2021;35:100844.
Garbe C, Dummer R, Amaral T, et al. Neoadjuvant immunotherapy for melanoma is now ready for clinical practice. Nat Med. 2023;29(6):1310-1312.
Patel SP, Othus M, Chen Y, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023;388(9):813-823.
Reijers ILM, Menzies AM, van Akkooi ACJ, et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat Med. 2022;28(6):1178-1188.
Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2022;387(17):1557-1568.
Schmults C, Blitzblau R, Aasi SZ, et al. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Squamous cell skin cancer. 2023; version 1.2023:https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf. Accessed April 21, 2023.
Neoadjuvant REGN2810 (Cemiplimab) in Cutaneous Basal Cell Carcinoma of the Head and Neck. ClinicalTrials.gov ID: NCT05929664. Available at: https://www.clinicaltrials.gov/study/NCT05929664?cond=Basal%20Cell%20Carcinoma&term=neoadjuvant&rank=4 . Accessed on July 11, 2023.
A Phase 1B, Single Arm Study of Neoadjuvant-Adjuvant Pembrolizumab in Resectable Advanced Basal Cell Carcinoma of the Head and Neck to Assess for Pathologic Responses in the Tumor Microenvironment. ClinicalTrial.gov ID: NCT04323202. Available at: https://www.clinicaltrials.gov/study/NCT04323202?cond=Basal%20Cell%20Carcinoma&term=neoadjuvant&rank=6 . Accessed on July 11, 2023.
Ligtenberg KG, Hu JK, Damsky W, et al. Neoadjuvant anti-programmed cell death 1 therapy for locally advanced basal cell carcinoma in treatment-naive patients: A case series. JAAD case reports. 2020;6(7):628-633.
Stratigos AJ, Garbe C, Dessinioti C, et al. European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment. Eur J Cancer. 2020;128:83-102.
Keohane SG, Botting J, Budny PG, et al. British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020. Br J Dermatol. 2021;184(3):401-414.
Weis J, Grote C, Weichenthal M, Hauschild A. Complete response of advanced cutaneous squamous cell and basal cell carcinomas with sequential cemiplimab and sonidegib therapy. J Eur Acad Dermatol Venereol. 2022;36 Suppl 1:66-69.
Colombo E, Gurizzan C, Ottini A, et al. The association of cemiplimab plus sonidegib for synchronous cutaneous squamous cell carcinoma and basal cell carcinoma of the head and neck: Two case reports. Frontiers in oncology. 2023;13:1111146.
Sabbatino F, Marra A, Liguori L, et al. Resistance to anti-PD-1-based immunotherapy in basal cell carcinoma: a case report and review of the literature. Journal for immunotherapy of cancer. 2018;6(1):126.
Chang ALS, Tran DC, Cannon JGD, et al. Pembrolizumab for advanced basal cell carcinoma: An investigator-initiated, proof-of-concept study. J Am Acad Dermatol. 2019;80(2):564-566.
A Prospective, Open, Single-arm, Single Center, Phase II Trial to Assess the Efficacy of Anti-PD1 Antibody in Combination With Pulsed Hedgehog Inhibitor in Advanced Basal Cell Carcinoma. ClinicalTrials.gov ID: NCT04679480. Availabe at: https://www.clinicaltrials.gov/study/NCT04679480?cond=basal%20cell%20carcinoma&intr=cemiplimab&rank=4 .Accessed on July 16, 2023.
Nivolumab Alone or Plus Relatlimab or Ipilimumab for Patients With Locally-Advanced Unresectable or Metastatic Basal Cell Carcinoma. ClinicalTrials.gov ID: NCT03521830. Available at: https://www.clinicaltrials.gov/study/NCT03521830?cond=basal%20cell%20carcinoma&intr=nivolumab&rank=1 . Accessed on July 16, 2023.
Ziogas DC, Martinos A, Petsiou DP, Anastasopoulou A, Gogas H. Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers. Cancers (Basel). 2022;14(12).
Ribas A, Dummer R, Puzanov I, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170(6):1109-1119 e1110.
Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10(4):292-303.
A Phase 1 Study of Talimogene Laherparepvec and Panitumumab in Patients With Locally Advanced Squamous Cell Carcinoma of the Skin (SCCS). ClinicalTrials.gov ID NCT04163952. Available at: https://www.clinicaltrials.gov/study/NCT04163952?cond=Squamous%20Cell%20Carcinoma%20of%20the%20Skin&term=talimogene&rank=1 . Accessed on July 20, 2023.
A Phase II Study of Talimogene Laherparepvec Followed by Talimogene Laherparepvec + Nivolumab in Refractory T Cell and NK Cell Lymphomas, Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, and Other Rare Skin Tumors. ClinicalTrials.gov ID: NCT02978625. Available at: https://www.clinicaltrials.gov/study/NCT02978625?cond=NCT02978625&rank=1 . Accessed on July 10, 2023.
Gompertz-Mattar M, Perales J, Sahu A, et al. Differential expression of programmed cell death ligand 1 (PD-L1) and inflammatory cells in basal cell carcinoma subtypes. Archives of dermatological research. 2022;314(8):777-786.
Goodman AM, Kato S, Cohen PR, et al. Genomic landscape of advanced basal cell carcinoma: Implications for precision treatment with targeted and immune therapies. Oncoimmunology. 2018;7(3):e1404217.
Yamakawa K, Ogata D, Hiki K, et al. Metastatic basal cell carcinoma with a high tumor mutational burden that achieved complete response with pembrolizumab. International journal of dermatology. 2023;62(2):e79-e80.
Hall ET, Fernandez-Lopez E, Silk AW, Dummer R, Bhatia S. Immunologic Characteristics of Nonmelanoma Skin Cancers: Implications for Immunotherapy. Am Soc Clin Oncol Educ Book. 2020;40:1-10.
Durante G, Comito F, Lambertini M, Broseghini E, Dika E, Ferracin M. Non-coding RNA dysregulation in skin cancers. Essays Biochem. 2021;65(4):641-655.
Published
Issue
Section
License
Copyright (c) 2023 Clio Dessinioti, Alexander Stratigos

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Dermatology Practical & Conceptual applies a Creative Commons Attribution License (CCAL) to all works we publish (http://creativecommons.org/licenses/by-nc/4.0/). Authors retain the copyright for their published work.

