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This JCO Podcast provides observations and commentary on the JCO article Durable Tumor Regression and Overall Survival in Patients with Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy by Paul Nghiem, MD, PhD et al. My name is Reed Drews, and I am a member of the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center in Boston, MA. My oncologic specialty is non-melanoma skin cancers.

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Merkel cell carcinoma is a rare, aggressive neuroendocrine skin malignancy with high propensity for local recurrence and regional lymph node and systemic metastases. Its incidence rises exponentially with aging and is 10-fold higher in chronically immunosuppressed patients. When Merkel cell carcinoma is advanced and/or unresectable, historical 5-year overall survival rates are low, from 14 to 27%. Cytotoxic chemotherapies, like platinum plus etoposide used in other high-grade neuroendocrine malignancies, have not yielded durable response rates.

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The cutaneous cell (or cells) of origin in Merkel cell carcinoma remains controversial. Nevertheless, scientists have identified 2 pathogenetic pathways leading to Merkel cell carcinoma. In 80% of cases, clonal integration of a polyomavirus leads to Merkel cell polyoma virus-positive Merkel cell carcinoma. In the other 20% of cases, ultraviolet light-induced DNA damage leads to polyoma virus-negative Merkel cell carcinoma. Polyoma virus-negative Merkel cell tumors display predominant cytosine to thymine transitions, a signature of DNA damage from UV light, and they have a 100-fold greater mutational burden than virus-positive Merkel cell cancers. For both subtypes, loss of immune surveillance, as with aging or chronic immunosuppression, contributes to Merkel cell carcinoma development, with diminished non-self-antigen recognition of UV-induced neo-antigens in virus-negative tumors and viral oncoproteins in Merkel cell polyoma virus-positive tumors.

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Given these factors, investigators have recently studied whether immune checkpoint inhibitors might hold promise for managing advanced Merkel cell carcinoma. To date, 3 antibody inhibitors of the programmed cell death-1 pathway (abbreviated PD-1), including anti-PD-ligand-1 avelumab, anti-PD-1 nivolumab and anti-PD-1 pembrolizumab, have been tested in patients with chemotherapy-refractory and/or treatment na\\xefve Merkel cell carcinoma. The 62% objective response rate from avelumab in treatment-na\\xefve Merkel cell carcinoma was nearly twice that observed in chemotherapy-refractory disease. In 2017 avelumab became the first immune checkpoint inhibitor approved by the FDA for advanced Merkel cell carcinoma. Nivolumab yielded similar results, as did pembrolizumab according to a 2016 report from Nghiem and colleagues of a multicenter, phase 2, non-controlled study with 26 patients.

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As reported in this JCO publication, Nghiem and colleagues have now increased their cohort to 50 patients through the multicenter expanded phase 2, Cancer Immunotherapy Trials Network-09/Keynote-017 trial. They administered pembrolizumab 2 mg/kg intravenously every 3 weeks for up to 2 years. Median follow-up time was 14.9 months, with a range from 0.4 to 36.4 months. This represents the longest follow-up to date of any anti-PD-1 pathway inhibitor for first-line treatment of advanced Merkel cell carcinoma. The 50-patient cohort included 43 patients with (stage IV) distant metastatic disease and 7 with stage IIIB recurrent locoregional disease not amenable to definitive surgery or radiation therapy. All patients had normal organ and bone marrow function and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria were previous systemic therapy for unresectable Merkel cell carcinoma, immunodeficiency or systemic immunosuppressive therapy, active autoimmune disease, concurrent second cancer, and active central nervous system metastases.

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The median age of enrolled patients was 70.5 years, with 80% age 65 or older. 64% of patients had Merkel cell polyoma virus-positive tumors. For previous management of their primary Merkel cell carcinoma, 42 patients had had surgery, and 35 patients had had radiation treatment. While no patient had previously received systemic therapy for advanced Merkel cell carcinoma, 3 patients had received adjuvant chemotherapy greater than 6 months prior to study enrollment.

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Patients received a median of 10.5 doses of pembrolizumab \\u2013 range 1 to 35 doses\\u2014and the median treatment duration was 6.6 months \\u2013 range 1 day to 23.6 months. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors, version 1.1. Responses were generally rapid and durable with 2.8 months as the median time to response \\u2013 range 1.5 to 9.7 months. The objective response rate to pembrolizumab was 56%, with complete and partial responses of 24% and 32%, respectively; 10% had stable disease; and 32% had progressive disease.

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At time of data analysis, 20 of 28 responses were on-going, and the median durability of response had not been reached. The Kaplan-Mier estimation of response durability at 24 months was 79.1%. Median progression free survival was 16.8 months, and the Kaplan-Mier estimation of progression free survival at 24 months was 48.3%. Median overall survival had not yet been reached. The Kaplan-Mier estimation of overall survival rate at 24 months was 68.7%.

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Tumor viral status, as determined by small T-antigen specific antibodies in serum or large T-antigen expression in tumor biopsies by immunohistochemistry, did not correlate with any study outcomes, such as progression free survival or overall survival. However, a trend towards improvement of these outcomes appeared in patients with PD-L1-positive tumors, as defined by cell-surface PD-L1 expression on at least 1% of tumor or immune cells.

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The safety profile of pembrolizumab in advanced Merkel cell carcinoma was similar to that in other studies of anti-PD-1 pathway inhibitors: 28% of patients had grade 3 or greater treatment-related adverse events, causing 14% of patients to discontinue treatment. A 73-year old male patient with widely metastatic Merkel cell carcinoma and pre-existing atrial fibrillation died after developing pericardial and pleural effusions 1 day after one infusion of pembrolizumab. Other adverse events were generally manageable and typical of complications of anti-PD-1 pathway inhibitors, including adrenal insufficiency, colitis, hyperthyroidism, hypothyroidism, infusion-related reaction, myocarditis, pancreatitis, pneumonitis, maculopapular rash and thyroiditis.

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With such impressive rates of durable tumor regression and overall survival, on December 19, 2018, the FDA granted accelerated approval to pembrolizumab for treating patients with recurrent locally advanced or metastatic Merkel cell carcinoma. Today\\u2019s standard of care for advanced Merkel cell carcinoma is an anti-PD-1 pathway inhibitor, and the NCCN Clinical Practice Guidelines in Oncology in 2018 recommended avelumab, nivolumab and pembrolizumab as preferred first-line therapy for advanced Merkel cell carcinoma, ahead of cytotoxic chemotherapy.

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Future studies must determine what role anti-PD-1 pathway inhibitors will play in the neo-adjuvant and adjuvant settings when managing early stage Merkel cell carcinoma with high-risk features. Prior to immune check point inhibitors, neo-adjuvant and adjuvant chemotherapy were considered case-by-case, absent strong evidence for benefit.\\xa0 However, now with impressive results from anti-PD-1 pathway inhibitors in advanced Merkel cell carcinoma, adjuvant nivolumab and avelumab are being evaluated in 2 randomized phase II trials. Nivolumab is also undergoing study in the neoadjuvant setting, and researchers presented promising preliminary results of a phase I/II study at the 2018 American Society of Clinical Oncology Annual Meeting. We look to Nghiem, his colleagues and other investigators to keep us informed regarding future advances, including insights into mechanisms of resistance to the immune checkpoint inhibitors.

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This concludes this JCO Podcast. Thank you for listening.