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Facial Plast Surg 2020; 36(02): 200-210
DOI: 10.1055/s-0040-1709118
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Current Research in Melanoma and Aggressive Nonmelanoma Skin Cancer

Reason Wilken 
1   Department of Dermatology, New York University Langone Health, New York, New York
,
Maressa Criscito
1   Department of Dermatology, New York University Langone Health, New York, New York
,
Anna C. Pavlick
2   Perlmutter Cancer Center, New York University Langone Health, New York, New York
,
Mary L. Stevenson
1   Department of Dermatology, New York University Langone Health, New York, New York
,
John A. Carucci
1   Department of Dermatology, New York University Langone Health, New York, New York
› Author Affiliations
Further Information

Publication History

Publication Date:
15 May 2020 (online)

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Abstract

There have been several significant advances in cancer treatment in the last decade that are applicable to the treatment of melanoma and advanced nonmelanoma skin cancers. Among these are the development of immune checkpoint inhibitors targeting the programmed death protein-1 (PD-1)/programmed death legand-1 (PDL-1) axis, as well as targeted inhibitors of the BRAF/MEK signaling cascade in melanoma, and the hedgehog signaling pathway in basal cell carcinoma (BCC). These immune-based and targeted therapies have dramatically changed the treatment options for locally advanced and metastatic melanoma, Merkel's cell carcinoma, cutaneous squamous cell carcinoma (cSCC), and BCC. In this article, we will briefly review the currently approved targeted and immunotherapy-based treatments for locally advanced and metastatic melanoma, Merkel's cell carcinoma, and cSCC and discuss various combinations of approved therapies, as well as emerging therapeutic candidates that are currently in clinical trials, including novel checkpoint inhibitors in development, intratumoral oncolytic agents (viral and nonviral), and various immune-based therapies such as toll-like receptor (TLR) agonists, adoptive T-cell therapy, T-cell costimulation, and innate immune cell therapy. For advanced BCC, we will discuss trials investigating the currently approved smoothened (SMO) inhibitors for neoadjuvant use, emerging SMO inhibitors in development, topical SMO inhibitors, alternative targets in the hedgehog signaling pathway, and the use of anti-PD-1 agents for advanced BCC both alone and in combination with SMO inhibitors.

Keywords

melanoma - squamous cell carcinoma - basal cell carcinoma - immunotherapy - PD-1
 

  • References

  • 1 Aderhold K, Wilson M, Berger AC, Levi S, Bennett J. Precision medicine in the treatment of melanoma. Surg Oncol Clin N Am 2020; 29 (01) 1-13
    CrossrefPubMedGoogle Scholar
  • 2 Long GV, Hauschild A, Santinami M. , et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017; 377 (19) 1813-1823
    CrossrefPubMedGoogle Scholar
  • 3 Ascierto PA, McArthur GA, Dréno B. , et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016; 17 (09) 1248-1260
    CrossrefPubMedGoogle Scholar
  • 4 Dummer R, Ascierto PA, Gogas HJ. , et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018; 19 (10) 1315-1327
    CrossrefPubMedGoogle Scholar
  • 5 Cohen JV, Buchbinder EI. The evolution of adjuvant therapy for melanoma. Curr Oncol Rep 2019; 21 (12) 106
    CrossrefPubMedGoogle Scholar
  • 6 Eggermont AM, Chiarion-Sileni V, Grob JJ. , et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016; 375 (19) 1845-1855
    CrossrefPubMedGoogle Scholar
  • 7 Snyder A, Makarov V, Merghoub T. , et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371 (23) 2189-2199
    CrossrefPubMedGoogle Scholar
  • 8 Coens C, Suciu S, Chiarion-Sileni V. , et al. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol 2017; 18 (03) 393-403
    CrossrefPubMedGoogle Scholar
  • 9 Tarhini AA. , et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol 2020; 38 (06) 567-575
    PubMedGoogle Scholar
  • 10 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677-704
    CrossrefPubMedGoogle Scholar
  • 11 Dong H, Strome SE, Salomao DR. , et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8 (08) 793-800
    CrossrefPubMedGoogle Scholar
  • 12 Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol 2019; 12 (01) 92
    CrossrefPubMedGoogle Scholar
  • 13 Keilholz U, Mehnert JM, Bauer S. , et al. Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial. J Immunother Cancer 2019; 7 (01) 12
    CrossrefPubMedGoogle Scholar
  • 14 Robert C, Karaszewska B, Schachter J. , et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372 (01) 30-39
    CrossrefPubMedGoogle Scholar
  • 15 Ugurel S, Röhmel J, Ascierto PA. , et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. Eur J Cancer 2017; 83: 247-257
    CrossrefPubMedGoogle Scholar
  • 16 Reddy SM, Reuben A, Wargo JA. Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy. Curr Oncol Rep 2016; 18 (07) 42
    CrossrefPubMedGoogle Scholar
  • 17 Pavlick AC, Fecher L, Ascierto PA, Sullivan RJ. Frontline therapy for BRAF-mutated metastatic melanoma: how do you choose, and is there one correct answer?. Am Soc Clin Oncol Educ Book 2019; 39: 564-571
    PubMedGoogle Scholar
  • 18 Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013; 368 (14) 1365-1366
    CrossrefPubMedGoogle Scholar
  • 19 Hamid O, Hodi S. . Preliminary clinical safety, tolerability, and activity of atezolizumab (anti-PD-L1) combined with vemurafenib in BRAF V600 metastatic melanoma, in Presented at Society for Melanoma research 2015 Congress October 2015 San Francisco CA. 2015
    PubMed
  • 20 Ribas A, Butler M, Lutzky J. , et al. Phase I study combining anti- PDL-1 (MEDI4736) with BRAF (dabrefenib) and.or MEK (trametenib) inhibitors in advanced melanoma. J Clin Oncol 2017; 33 (15, Suppl): 3003-3003
    PubMedGoogle Scholar
  • 21 Ribas A, Hodi FS, Lawrence D. , et al. KEYNOTE-22 update: phase I study of first-line pembrolizumab plus dabrafenib and trametinib for BRAF-mutant advanced melanoma. Ann Oncol 2017; 28 (Suppl. 05) v428-v448
    PubMedGoogle Scholar
  • 22 Ascierto PA, Ferrucci PF, Fisher R. , et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med 2019; 25 (06) 941-946
    CrossrefPubMedGoogle Scholar
  • 23 Rozeman EA, Deken MA, Gadiot J. , et al. Phase II study comparing pembrolizumab (PEM) with intermittent/short-term dual MAPK pathway inhibition (dabrafenib + trametenib) plus pembrolizumab in patients harboring the BRAF V600 mutation (IMPemBra triial). Ann Oncol 2018; 29: LBA46
    PubMedGoogle Scholar
  • 24 Dummer R, Nathan P. The anti-PD-1 antibody spartalizumab (PDR001) in combination with dabrafenib and trametenib in previously untreated patients with advanced BRAF V600-mutant melanoma: first efficacy, safety and biomarker finsings from the part 2 biomarker cohort of COMBI-i. Cancer Res 2018; 78: CT182
    CrossrefPubMedGoogle Scholar
  • 25 Tawbi HAH, Glitza IC. Safety and preliminary activity data from a single center phase II study of nivolumab with dabrafenib and trametenib in patients with BRAF-mutated metastatic melanoma. J Clin Oncol 2018; 36 (15, Suppl): 9560-9650
    CrossrefPubMedGoogle Scholar
  • 26 Sullivan RJ, Hamid O, Gonzalez R. , et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med 2019; 25 (06) 929-935
    CrossrefPubMedGoogle Scholar
  • 27 Sullivan RJ, Lewis KD. Atezolizumab (A) + cobimetanib (C) + vemurafenib (V)in BRAF-mutant metastatic melanoma (mel): updated safety and clinical activity. J Clin Oncol 2017; 35: abstr3063
    CrossrefPubMedGoogle Scholar
  • 28 Ackerman A, Klein O, McDermott DF. , et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014; 120 (11) 1695-1701
    CrossrefPubMedGoogle Scholar
  • 29 Ascierto PA, Simeone E, Sileni VC. , et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest 2014; 32 (04) 144-149
    CrossrefPubMedGoogle Scholar
  • 30 Johnson DB, Pectasides E, Feld E. , et al. Sequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition. J Immunother 2017; 40 (01) 31-35
    CrossrefPubMedGoogle Scholar
  • 31 Hamid O, Ismail R, Puzanov I. Intratumoral Immunotherapy-Update 2019. Oncologist 2019; theoncologist.2019-0438
    PubMedGoogle Scholar
  • 32 Chesney J, Puzanov I, Collichio F. , et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol 2018; 36 (17) 1658-1667
    CrossrefPubMedGoogle Scholar
  • 33 Ribas A, Dummer R, Puzanov I. , et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 2017; 170 (06) 1109-1119.e10
    CrossrefPubMedGoogle Scholar
  • 34 Xiao C, Bator-Kelly CM, Rieder E. , et al. The crystal structure of coxsackievirus A21 and its interaction with ICAM-1. Structure 2005; 13 (07) 1019-1033
    CrossrefPubMedGoogle Scholar
  • 35 Andtbacka RCB, Kaufman H. , et al. Final data from CALM: a phase II study of coxsackie virus A21 (CVA21) oncolytic virus imunotherapy in patients with advanced melanoma. J Clin Oncol 2015; 33: 9030a
    CrossrefPubMedGoogle Scholar
  • 36 Curti BRJ, Hallmeyer S. , et al. The MITCI (Phase Ib) study: a novel immunotherapy combination of intralesional coxsackie virus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint treatment. Presented at the American Association for Cancer Research Annual Meeting April 1–6, 2017 Washington DC, 2017
    PubMed
  • 37 Eissa IR, Naoe Y, Bustos-Villalobos I. , et al. Genomic signature of the natural oncolytic herpes simplex virus hf10 and its therapeutic role in preclinical and clinical trials. Front Oncol 2017; 7: 149
    CrossrefPubMedGoogle Scholar
  • 38 Andtbacka RHI, Agarwala SS. , et al. Final results of a phase II multicenter trial of HF10, areplication-competent oncolytic virus, and ipilimumab combination treatment in patients with stage IIIB-IV unresectable or metastatic melanoma. J Clin Oncol 2017; 35: 9510a
    CrossrefPubMedGoogle Scholar
  • 39 Read TA, Smith A, Thomas J. , et al. Intralesional PV-10 for the treatment of in-transit melanoma metastases-Results of a prospective, non-randomized, single center study. J Surg Oncol 2018; 117 (04) 579-587
    CrossrefPubMedGoogle Scholar
  • 40 Thompson JF, Agarwala SS, Smithers BM. , et al. Phase 2 study of intralesional PV-10 in refractory metastatic melanoma. Ann Surg Oncol 2015; 22 (07) 2135-2142
    CrossrefPubMedGoogle Scholar
  • 41 Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol 2015; 109: 1-10 , 10
    PubMedGoogle Scholar
  • 42 Baines J, Celis E. Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res 2003; 9 (07) 2693-2700
    PubMedGoogle Scholar
  • 43 Carpentier A, Laigle-Donadey F, Zohar S. , et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro-oncol 2006; 8 (01) 60-66
    PubMedGoogle Scholar
  • 44 Ribas A, Medina T, Kummar S. , et al. SD-101 in combination with pembrolizumab in advanced melanoma: results of a phase Ib, multicenter study. Cancer Discov 2018; 8 (10) 1250-1257
    CrossrefPubMedGoogle Scholar
  • 45 Diab A, Benatchez C. , et al. Intratumoral (IT) injection of the tlr9 agonist tilsotolimod (IMO-2125) in combination with ipilumimab triggers durable responses in PD-1 inhibitor refractory metastatic melanoma (rMM): Results from a multicenter, phase I/II study. Ann Oncol 2018; 29: 442-466
    CrossrefPubMedGoogle Scholar
  • 46 Samimi M. Immune checkpoint inhibitors and beyond: an overview of immune-based therapies in merkel cell carcinoma. Am J Clin Dermatol 2019; 20 (03) 391-407
    CrossrefPubMedGoogle Scholar
  • 47 Nghiem PT, Bhatia S, Lipson EJ. , et al. PD-1 Blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016; 374 (26) 2542-2552
    CrossrefPubMedGoogle Scholar
  • 48 Topalian SL, Hollebecque A. , et al. Non-comparitive, open label, multiple cohort, phase 1/2 atudy to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in Merkel cell carcinoma. Cancer Res 2017; 77 (13, Suppl): CT074
    PubMedGoogle Scholar
  • 49 Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 2016; 44 (05) 989-1004
    CrossrefPubMedGoogle Scholar
  • 50 Afanasiev OK, Yelistratova L, Miller N. , et al. Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res 2013; 19 (19) 5351-5360
    CrossrefPubMedGoogle Scholar
  • 51 Solomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 2018; 67 (11) 1659-1667
    CrossrefPubMedGoogle Scholar
  • 52 Chapuis AG, Afanasiev OK, Iyer JG. , et al. Regression of metastatic Merkel cell carcinoma following transfer of polyomavirus-specific T cells and therapies capable of re-inducing HLA class-I. Cancer Immunol Res 2014; 2 (01) 27-36
    CrossrefPubMedGoogle Scholar
  • 53 Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol 2018; 11 (01) 8
    CrossrefPubMedGoogle Scholar
  • 54 Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood 2018; 131 (01) 39-48
    CrossrefPubMedGoogle Scholar
  • 55 Laniosz V, Onajin O, Sominidi-Damodaran S, Meves A, Gibson LE, Baum CL. Natural killer cell response is a predictor of good outcome in MCPyV+ Merkel cell carcinoma: a case series of 23 patients. J Am Acad Dermatol 2017; 77 (01) 31-32
    CrossrefPubMedGoogle Scholar
  • 56 Sadek H, Azli N, Wendling JL. , et al. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer 1990; 66 (08) 1692-1696
    CrossrefPubMedGoogle Scholar
  • 57 Guminski A, Stein B. Immunotherapy and other systemic therapies for cutaneous SCC. Oral Oncol 2019; 99: 104459
    CrossrefPubMedGoogle Scholar
  • 58 Markham A, Duggan S. Cemiplimab: first global approval. Drugs 2018; 78 (17) 1841-1846
    CrossrefPubMedGoogle Scholar
  • 59 Migden MR, Rischin D, Schmults CD. , et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2018; 379 (04) 341-351
    CrossrefPubMedGoogle Scholar
  • 60 Ferris RL, Licitra L, Fayette J. , et al. Nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: efficacy and safety in CheckMate 141 by prior cetuximab use. Clin Cancer Res 2019; 25 (17) 5221-5230
    CrossrefPubMedGoogle Scholar
  • 61 Seiwert TY, Burtness B, Mehra R. , et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016; 17 (07) 956-965
    CrossrefPubMedGoogle Scholar
  • 62 Winkler JK, Schneiderbauer R, Bender C. , et al. Anti-programmed cell death-1 therapy in nonmelanoma skin cancer. Br J Dermatol 2017; 176 (02) 498-502
    CrossrefPubMedGoogle Scholar
  • 63 Tran DC, Colevas AD, Chang AL. Follow-up on programmed cell death 1 inhibitor for cutaneous squamous cell carcinoma. JAMA Dermatol 2017; 153 (01) 92-94
    CrossrefPubMedGoogle Scholar
  • 64 Pol JG, Acuna SA, Yadollahi B. , et al. Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials. OncoImmunology 2018; 8 (01) e1512329
    PubMedGoogle Scholar
  • 65 Leavitt E, Lask G, Martin S. Sonic hedgehog pathway inhibition in the treatment of advanced basal cell carcinoma. Curr Treat Options Oncol 2019; 20 (11) 84
    CrossrefPubMedGoogle Scholar
  • 66 Gutzmer R, Solomon JA. Hedgehog pathway inhibition for the treatment of basal cell carcinoma. Target Oncol 2019; 14 (03) 253-267
    CrossrefPubMedGoogle Scholar
  • 67 Sekulic A, Migden MR, Basset-Seguin N. , et al; ERIVANCE BCC Investigators. 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 (01) 332
    CrossrefPubMedGoogle Scholar
  • 68 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 (03) 372-381
    CrossrefPubMedGoogle Scholar
  • 69 Xie P, Lefrançois P. Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: A systematic review and meta-analysis. J Am Acad Dermatol 2018; 79 (06) 1089-1100.e17
    CrossrefPubMedGoogle Scholar
  • 70 Bendell J, Andre V, Ho A. , et al. Phase I Study of LY2940680, a Smo Antagonist, in Patients with Advanced Cancer Including Treatment-Naïve and Previously Treated Basal Cell Carcinoma. Clin Cancer Res 2018; 24 (09) 2082-2091
    CrossrefPubMedGoogle Scholar
  • 71 Ally MS, Aasi S, Wysong A. , et al. An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol 2014; 71 (05) 904-911.e1
    CrossrefPubMedGoogle Scholar
  • 72 Skvara H, Kalthoff F, Meingassner JG. , et al. Topical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol 2011; 131 (08) 1735-1744
    CrossrefPubMedGoogle Scholar
  • 73 Beauchamp EM, Ringer L, Bulut G. , et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest 2011; 121 (01) 148-160
    CrossrefPubMedGoogle Scholar
  • 74 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 (02) 564-566
    CrossrefPubMedGoogle Scholar
  • 75 Choi FD. , 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 (02) 440-459
    CrossrefPubMedGoogle Scholar
  • 76 Falchook GS, Leidner R, Stankevich E. , et al. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. J Immunother Cancer 2016; 4: 70
    CrossrefPubMedGoogle Scholar
  • 77 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: 1
    PubMedGoogle Scholar