BACKGROUND: Merkel cell carcinoma is a rare, aggressive skin cancer with poor 
prognosis in patients with advanced disease. Current standard care uses various 
cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour 
oncogenesis is linked to Merkel cell polyomavirus integration and 
ultraviolet-radiation-induced mutations, providing rationale for treatment with 
immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed 
treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with 
stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy.
METHODS: In this multicentre, international, prospective, single-group, 
open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, 
histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled 
from 35 cancer treatment centres and academic hospitals in North America, 
Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance 
status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal 
function, and immune-competent status (patients with HIV, immunosuppression, 
haematological malignancies, and previous organ transplantation were excluded). 
Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus 
status. Collection of biopsy material or use of archival tissue for these 
assessments was mandatory. Avelumab was given intravenously at a dose of 10 
mg/kg every 2 weeks. The primary endpoint was confirmed objective response 
(complete response or partial response) assessed according to RECIST version 1.1 
by an independent review committee. Safety and clinical activity were assessed 
in all patients who received at least one dose of study drug (the modified 
intention-to-treat population). This trial is registered with ClinicalTrials.gov 
as NCT02155647.
FINDINGS: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and 
received at least one dose of avelumab. Patients were followed up for a median 
of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an 
objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including 
eight complete responses and 20 partial responses. Responses were ongoing in 23 
(82%) of 28 patients at the time of analysis. Five grade 3 treatment-related 
adverse events occurred in four (5%) patients: lymphopenia in two patients, 
blood creatine phosphokinase increase in one patient, aminotransferase increase 
in one patient, and blood cholesterol increase in one patient; there were no 
treatment-related grade 4 adverse events or treatment-related deaths. Serious 
treatment-related adverse events were reported in five patients (6%): 
enterocolitis, infusion-related reaction, aminotransferases increased, 
chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each).
INTERPRETATION: Avelumab was associated with durable responses, most of which 
are still ongoing, and was well tolerated; hence, avelumab represents a new 
therapeutic option for advanced Merkel cell carcinoma.
FUNDING: Merck KGaA, Darmstadt, Germany.