Clinical impact of immunotherapy in Merkel cell carcinoma patients: A systematic review and meta-analysis

Published:April 19, 2021DOI:


      Immunotherapy is emerging as an alternative treatment for Merkel cell carcinoma, but its long-term effects on response, survival, and safety are not well established. High-quality evidence is needed to estimate the efficacy of this treatment and to review the characteristics of patients and tumors that might improve outcomes.


      To summarize efficacy and safety of immunotherapy in patients with Merkel cell carcinoma.


      A systematic review was performed for studies published in MEDLINE, Web of Science, Scopus, and EMBASE. Two reviewers examined the literature and data extraction in duplicate. We estimated the proportions for objective responses, progression-free survival, overall survival, and treatment-related adverse events. Associations between objective response rate and immunobiologic markers were analyzed.


      Six clinical trials of 201 patients treated with immunotherapy were included. The objective response rate was 51% (95% confidence interval, 0.40-0.62; I2 = 37.1%) and grade ≥3 treatment-related adverse events were observed in 18% (95% confidence interval, 0.11-0.29; I2 = 49.5%) of patients. No significant difference was observed between response rates and immunobiologic characteristics.


      A significantly reduced tumor diameter with durable response rates and a safe profile are obtained with immunotherapy. Similar response rates achieved on either subgroup of viral status or programmed death ligand 1 expression suggests that it might act on multiple, unexplored pathways.

      Key words

      Abbreviations used:

      CI (confidence interval), DOR (duration of response), MCC (Merkel cell carcinoma), MCPyV (Merkel cell polyomavirus), ORR (objective response rate), OS (overall survival), PFS (progression-free survival), TRAE (treatment-related adverse events)
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        • Coggshall K.
        • Tello T.L.
        • North J.P.
        • Yu S.S.
        Merkel cell carcinoma: an update and review: pathogenesis, diagnosis, and staging.
        J Am Acad Dermatol. 2018; 78: 433-442
        • Fitzgerald T.L.
        • Dennis S.
        • Kachare S.D.
        • Vohra N.A.
        • Wong J.H.
        • Zervos E.E.
        Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States.
        Am Surg. 2015; 81: 802-806
        • Paulson K.G.
        • Park S.Y.
        • Vandeven N.A.
        • et al.
        Merkel cell carcinoma: current US incidence and projected increases based on changing demographics.
        J Am Acad Dermatol. 2018; 78: 457-463.e2
        • Afanasiev O.K.
        • 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: 5351-5360
        • Uchi H.
        Merkel cell carcinoma: an update and immunotherapy.
        Front Oncol. 2018; 8: 48
        • Albores-Saavedra J.
        • Batich K.
        • Chable-Montero F.
        • Sagy N.
        • Schwartz A.M.
        • Henson D.E.
        Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study.
        J Cutan Pathol. 2010; 37: 20-27
        • Kaufman H.L.
        • Russell J.
        • Hamid O.
        • et al.
        Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.
        Lancet Oncol. 2016; 17: 1374-1385
        • Nagase K.
        • Narisawa Y.
        Immunotherapy for Merkel cell carcinoma.
        Curr Treat Options Oncol. 2018; 19: 57
        • Nghiem P.
        • Kaufman H.L.
        • Bharmal M.
        • Mahnke L.
        • Phatak H.
        • Becker J.C.
        Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma.
        Future Oncol. 2017; 13: 1263-1279
        • Akinleye A.
        • Rasool Z.
        Immune checkpoint inhibitors of PD-L1 as cancer therapeutics.
        J Hematol Oncol. 2019; 12: 92
        • Bradford D.
        • Demko S.
        • Jin S.
        • et al.
        FDA accelerated approval of pembrolizumab for recurrent locally advanced or metastatic Merkel cell carcinoma.
        Oncologist. 2020; 25: e1077-e1082
        • NIH National Heart, Lung and Blood Institute
        Study quality assessment tools.
        (Available at:)
        • Atkins D.
        • Best D.
        • Briss P.A.
        • et al.
        Grading quality of evidence and strength of recommendations.
        BMJ. 2004; 328: 1490
        • Trikalinos T.A.
        • Trow P.
        • Schmid C.H.
        Simulation-based comparison of methods for meta-analysis of proportions and rates. Agency for Healthcare Research and Quality (US). Report No.: 13(14)-EHC084-EF.
        (Available at:)
        Date: 2013
        Date accessed: May 8, 2021
        • Schwarzer G.
        • Chemaitelly H.
        • Abu-Raddad L.J.
        • Rucker G.
        Seriously misleading results using inverse of Freeman-Tukey double arcsine transformation in meta-analysis of single proportions.
        Res Synth Methods. 2019; 10: 476-483
        • Garza-Davila V.F.
        • Valdespino-Valdes J.
        • Barrera F.J.
        • Ocampo-Candiani J.
        • Garza-Rodriguez V.
        Clinical impact of immunotherapy in Merkel cell carcinoma patients: a systematic review and meta-analysis.
        (Mendeley Data, V1. Accessed May 8, 2021. Available at:)
        • Higgins J.P.T.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Nghiem P.
        • Bhatia S.
        • Lipson E.J.
        • et al.
        PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma.
        N Engl J Med. 2016; 374: 2542-2552
        • Segal N.H.
        • He A.R.
        • Doi T.
        • et al.
        Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer.
        Clin Cancer Res. 2018; 24: 1816-1823
        • D'Angelo S.P.
        • Bhatia S.
        • Brohl A.S.
        • 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: e000674
        • Ferrarotto R.
        • Mata J.
        • Mott F.
        • et al.
        Safety and interim results from a phase II, single-arm study of atezolizumab and bevacizumab in Merkel cell carcinoma (MCC).
        J Clin Oncol. 2019; 37: e21006
        • Topalian S.L.
        • Bhatia S.
        • Hollebecque A.
        • et al.
        Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): efficacy and safety in Merkel cell carcinoma (MCC).
        Cancer Res. 2017; 77 (abstract CT074)
        • Bhatia S.
        • Longino N.V.
        • Miller N.J.
        • et al.
        Intratumoral delivery of plasmid IL12 via electroporation leads to regression of injected and noninjected tumors in Merkel cell carcinoma.
        Clin Cancer Res. 2020; 26: 598-607
        • Wollina U.
        • Koch A.
        • Cardoso J.C.
        Advanced Merkel cell carcinoma - a focus on medical drug therapy.
        Dermatol Ther. 2020; 33: e13675
        • LoPiccolo J.
        • Schollenberger M.D.
        • Dakhil S.
        • et al.
        Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series.
        J ImmunoTher Cancer. 2019; 7: 170
        • Glutsch V.
        • Kneitz H.
        • Goebeler M.
        • Gesierich A.
        • Schilling B.
        Breaking avelumab resistance with combined ipilimumab and nivolumab in metastatic Merkel cell carcinoma?.
        Ann Oncol. 2019; 30: 1667-1668
        • Cowey C.L.
        • Mahnke L.
        • Espirito J.
        • Helwig C.
        • Oksen D.
        • Bharmal M.
        Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA.
        Future Oncol. 2017; 13: 1699-1710
        • Iyer J.G.
        • Blom A.
        • Doumani R.
        • et al.
        Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.
        Cancer Med. 2016; 5: 2294-2301
        • Goodman A.M.
        • Kato S.
        • Bazhenova L.
        • et al.
        Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers.
        Mol Cancer Ther. 2017; 16: 2598-2608
        • Harms P.W.
        • Harms K.L.
        • Moore P.S.
        • et al.
        The biology and treatment of Merkel cell carcinoma: current understanding and research priorities.
        Nat Rev Clin Oncol. 2018; 15: 763-776
        • Lipson E.J.
        • Vincent J.G.
        • Loyo M.
        • et al.
        PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.
        Cancer Immunol Res. 2013; 1: 54-63
        • Archibald W.J.
        • Victor A.I.
        • Strawderman M.S.
        • Maggiore R.J.
        Immune checkpoint inhibitors in older adults with melanoma or cutaneous malignancies: the Wilmot Cancer Institute experience.
        J Geriatr Oncol. 2020; 11: 496-502
        • Marchand A.
        • Kervarrec T.
        • Bhatia S.
        • Samimi M.
        Pembrolizumab and other immune checkpoint inhibitors in locally advanced or metastatic Merkel cell carcinoma: safety and efficacy.
        Expert Rev Anticancer Ther. 2020; 20: 1093-1106
      1. Adjuvant therapy of completely resected Merkel cell carcinoma with immune checkpoint blocking antibodies vs observation (ADMEC-O). identifier NCT02196961.
        (Available at:)
        Date: 2014
        Date accessed: June 15, 2020
      2. Talimogene laherparepvec and nivolumab in treating patients with refractory lymphomas or advanced or refractory non-melanoma skin cancers. identifier NCT02978625.
        (Available at:)
        Date: 2016
        Date accessed: June 15, 2020
      3. Nivolumab and radiation therapy or ipilimumab as adjuvant therapy in treating patients with Merkel cell cancer. identifier NCT03798639.
        (Available at:)
        Date: 2019
        Date accessed: June 15, 2020
      4. Tacrolimus, nivolumab, and ipilimumab in treating kidney transplant recipients with selected unresectable or metastatic cancers. identifier NCT03816332.
        (Available at:)
        Date: 2019
        Date accessed: June 15, 2020
      5. Randomized study of nivolumab+ipilimumab+/- SBRT for metastatic Merkel cell carcinoma. identifier NCT03071406.
        (Available at:)
        Date: 2017
        Date accessed: June 15, 2020
      6. A study of NKTR-262 in combination with NKTR-214 and with NKTR-214 plus nivolumab in patients with locally advanced or metastatic solid tumor malignancies (REVEAL). identifier NCT03435640.
        (Available at:)
        Date: 2018
        Date accessed: June 15, 2020
      7. Phase 1/2 study exploring the safety, tolerability, and efficacy of INCAGN01876 combined with immune therapies in advanced or metastatic malignancies. identifier NCT03126110.
        (Available at:)
        Date: 2017
        Date accessed: June 15, 2020
      8. QUILT-3.009: Patients with stage III (IIIB) or stage (IV) Merkel cell carcinoma (MCC). identifier NCT02465957.
        (Available at:)
        Date: 2015
        Date accessed: June 15, 2020
      9. T-VEC in Non-melanoma Skin Cancer (20139157 T-VEC). identifier NCT03458117.
        (Available at:)
        • Knepper T.C.
        • Russell J.S.
        • Montesion M.
        • et al.
        Comprehensive genomic profiling of advanced Merkel cell carcinoma to reveal insights into immunotherapy response.
        J Clin Oncol. 2018; 36: 9523
        • Colunga A.
        • Pulliam T.
        • Nghiem P.
        Merkel cell carcinoma in the age of immunotherapy: facts and hopes.
        Clin Cancer Res. 2018; 24: 2035-2043
        • Chalmers Z.R.
        • Connelly C.F.
        • Fabrizio D.
        • et al.
        Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
        Genome Med. 2017; 9: 34
        • Paulson K.G.
        • Lewis C.W.
        • Redman M.W.
        • et al.
        Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: a prospective validation study.
        Cancer. 2017; 123: 1464-1474
        • Mahoney K.M.
        • Atkins M.B.
        Prognostic and predictive markers for the new immunotherapies.
        Oncology. 2014; 28: 39-48
        • Tothill R.
        • Estall V.
        • Rischin D.
        Merkel cell carcinoma: emerging biology, current approaches, and future directions.
        Am Soc Clin Oncol Educ Book. 2015; 35: e519-e526
        • Bhatia S.
        • Afanasiev O.
        • Nghiem P.
        Immunobiology of Merkel Cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer.
        Curr Oncol Rep. 2011; 13: 488-497
        • Goh G.
        • Walradt T.
        • Markarov V.
        • et al.
        Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.
        Oncotarget. 2016; 7: 3403-3415
        • Schmults C.
        • Aasi S.
        • Alam M.
        • et al.
        NCCN clinical practice guidelines in oncology: Merkel cell carcinoma, National Comprehensive Cancer Network.
        (Available at:)