Metastatic Merkel cell carcinoma response to nivolumab
© The Author(s). 2016
Received: 22 August 2016
Accepted: 1 November 2016
Published: 15 November 2016
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC.
We report a case of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody.
Immunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents.
KeywordsMerkel cell carcinoma Nivolumab PD-L1 Immunotherapy Polyomavirus Case report
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine malignancy with an annual incidence rate of 0.6 per 100,000 persons . MCC is frequently diagnosed in the elderly in areas of sun-exposed skin and remains a challenging disease to treat. It has a high frequency of local recurrence (30 %) compared to melanoma (3.8 %), and more than 40 % of patients eventually develop distant metastatic disease [2, 3]. Early stage disease is typically managed by surgical excision with or without radiotherapy . Adjuvant radiotherapy may improve locoregional control for some tumors, but it is unclear if it impacts survival [5, 6]. Patients with unresectable locally advanced or metastatic disease are most often treated with chemotherapy . While there are currently no Food and Drug Administration (FDA) approved therapies for advanced MCC, platinum in combination with etoposide has been the standard for advanced stage MCC based on data from small cell lung carcinoma. Cyclophosphamide, doxorubicin and vincristine have also been tried with variable response rates . Unfortunately, responses to chemotherapy are not durable and have not clearly demonstrated a survival advantage . New approaches for the disease are needed.
As our understanding of the oncogenic pathways of MCC evolves, immunotherapy has become a rational and promising treatment option in the advanced or metastatic setting. In 2008, Feng et al. identified a clonally integrated polyomavirus (MCPyV) in the majority (85 %) of human MCCs . Although the oncogenic potential of MCPyV is still being elucidated, the increased risk of MCC in the setting of immunosuppression supports its viral-mediated origin. Circulating antibodies to MCPyV T antigen and MCPyV-specific CD8 and CD4 T-cells have been identified in patients with MCC, but appear unable to eradicate MCPyV positive cells despite immune activation. Several lines of evidence support the expression of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) as a likely contributor to immune evasion in MCC [13, 14]. Lipson et al. analyzed 67 specimens from 49 patients for PD-L1 expression by immunohistochemistry and demonstrated tumor cells and immune infiltrates expressed PD-L1 (49 % and 55 %, respectively) with 97 % of PD-L1-expressing MCC cells geographically associated with immune infiltrates . Afanasiev et al. reported a higher expression of MCPyV specific circulating T-cells with PD-1 expression compared to control Epstein-Barr virus and cytomegalovirus specific T-cells (p < 0.01) . They also found that blocking PD-1 led to augmentation of MCPyV specific T-cell function . Additionally, tumors with high PD-L1 expression were more likely to have CD8 lymphocyte infiltration than tumors with lower PD-L1 expression . Other investigators demonstrated that 50 % of non-activated T cells expressed PD-1, which is thought to be a marker of T cell exhaustion . Taken together, these data strongly support the PD-1/PD-L1 inhibitory axis as an immune evasion strategy for MCC, and targeting this negative signal of T-cell activation could be an important treatment approach against MCC.
Preliminary results of two phase II trials provide additional evidence of PD-1 and PD-L1 inhibition as a valid and promising therapeutic approach [20, 21]. Nghiem and colleagues demonstrated that pembrolizumab (a PD-1 inhibitor) has a 56 % overall response rate in chemotherapy naïve patients with response durations ranging from 2.2 months to at least 9.7 months . Avelumab (a PD-L1 inhibitor) was tested in patients with chemotherapy-refractory MCC and was shown to have a response rate of 31.7 %, with 82 % of respondents having ongoing responses at a median follow-up of 10.4 months . This case highlights the potential therapeutic benefit of nivolumab, including durability of response with immunotherapy for MCC. A clinical trial evaluating nivolumab as a treatment option for virus-associated cancers, including MCC, is currently being conducted (ClinicalTrials.gov. NCT02155647).
Food and Drug Administration
Merkel cell carcinoma
Merkel cell polyomavirus
programmed death-ligand 1
Positron emission tomography
The authors declare that they have no sources of funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
FW contributed to the writing and organization of this manuscript as well as figure production. BS contributed to the writing of this manuscript and figure production. PH contributed to histopathological analysis and figure production. LF contributes to the writing and editing of this manuscript. CL contributed to the writing, organization and editing of this manuscript. All authors read and approved the manuscript.
The authors declare that they have no competing interests.
Consent for publication
Consent for publication has been obtained from the patient for this case report.
Ethics approval and consent to participate
Ethics approval and consent to participate were waived for this study since the case report has been completely de-identified via the Safe Harbor Method.
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