Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti-programmed death-ligand 1 (PD-L1)) became the first approved treatment for patients with metastatic MCC (mMCC), based on the occurrence of durable responses in a subset of patients. Here, we report long-term efficacy and safety data and exploratory biomarker analyses in patients with mMCC treated with avelumab., Methods: In a cohort of this single-arm, phase 2 trial (JAVELIN Merkel 200), patients with mMCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent review per Response Evaluation Criteria in Solid Tumors V.1.1. Other assessments included duration of response, progression-free survival, overall survival (OS), safety and biomarker analyses., Results: As of 14 September 2018, 88 patients had been followed up for a median of 40.8 months (range 36.4-49.7 months). The ORR was 33.0% (95% CI 23.3% to 43.8%), including a complete response in 11.4% (10 patients), and the median duration of response was 40.5 months (95% CI 18.0 months to not estimable). As of 2 May 2019 (≥44 months of follow-up), the median OS was 12.6 months (95% CI 7.5 to 17.1 months) and the 42-month OS rate was 31% (95% CI 22% to 41%). Of long-term survivors (OS >36 months) evaluable for PD-L1 expression status (n=22), 81.8% had PD-L1+ tumors. In exploratory biomarker analyses, high tumor mutational burden (≥2 non-synonymous somatic variants per megabase) and high major histocompatibility complex class I expression (30% of tumors with highest expression) were associated with trends for improved ORR and OS. In long-term safety assessments (≥36 months of follow-up), no new or unexpected adverse events were reported, and no treatment-related deaths occurred., Conclusions: Avelumab showed continued durable responses and meaningful long-term survival outcomes in patients with mMCC, reinforcing avelumab as a standard-of-care treatment option for this disease., Trial Registration Number: NCT02155647., Competing Interests: Competing interests: SPD reports serving as a consultant or advisor for Amgen, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), GlaxoSmithKline, Immunocore, Immune Design, Incyte, Merck & Co, and Nektar; has received research grants from Amgen, Bristol Myers Squibb, Deciphera, EMD Serono, Incyte, Merck & Co, and Nektar; and has received reimbursement for travel and accommodation expenses from Adaptimmune, EMD Serono, Immunocore and Nektar. SB has received honoraria from and served as a consultant or advisor for Bristol Myers Squibb, EMD Serono, Genentech/Roche, and Sanofi/Regeneron; has received institutional research funding from Bristol Myers Squibb, EMD Serono, Exicure, Immune Design, Merck & Co, NantKwest, Novartis, and OncoSec; and has received reimbursement for travel and accommodation expenses from NantKwest. ASB reports serving as a consultant or advisor for Bayer, Deciphera, EMD Serono, and PierianDx. OH reports serving as a consultant or advisor for Amgen, Bristol Myers Squibb, Merck & Co, Novartis, and Roche; has received honoraria from Amgen, Array BioPharma, Bristol Myers Squibb, Genentech/Roche, Novartis, and Sanofi/Regeneron; is a member of a speakers bureau for Amgen, Array BioPharma, Bristol Myers Squibb, Genentech, Novartis, and Sanofi/Regeneron; and has received institutional research funding from Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Celldex, CytomX Therapeutics, Genentech, GlaxoSmithKline, Immunocore, Incyte, Iovance Biotherapeutics, MedImmune, Merck & Co, Merck Serono, Novartis, Parker Institute for Cancer Immunotherapy, Pfizer, Polynoma, Regeneron, and Roche. JMM has received honoraria from EMD Serono and Pfizer; reports serving as a consultant or advisor for Amgen, Array BioPharma, and Boehringer Ingelheim; has received institutional research funding from Amgen, AstraZeneca, Immunocore, Incyte, MacroGenics, Merck & Co, Novartis, Polynoma, and Sanofi; has received reimbursement for travel and accommodation expenses from EMD Serono and Merck & Co; and has other relationships with Amgen, Array BioPharma, Boehringer Ingelheim, EMD Serono, and Merck & Co. PT has received speakers honoraria from Bristol Myers Squibb, CureVac, Merck & Co, Novartis, Pierre Fabre, and Roche; reports serving as a consultant or advisor for Bristol Myers Squibb, Merck KGaA, Novartis, Pierre Fabre, Sanofi, and Roche; and has received travel support from Bristol Myers Squibb and Pierre Fabre. CL has received honoraria from Amgen, Bristol Myers Squibb, Incyte, Merck & Co, Novartis, Pfizer, Pierre Fabre, and Roche; reports serving as a consultant or advisor for Amgen, Bristol Myers Squibb, Merck & Co, Novartis, and Roche; is a member of a speakers bureau for Amgen, Bristol Myers Squibb, Novartis, and Roche; has received research funding from Bristol Myers Squibb and Roche; has received reimbursement for travel and accommodation expenses from Bristol Myers Squibb; and has other relationships with Avantis Medical Systems. KDL has received honoraria from Array BioPharma and Incyte; has served as a consultant or advisor for Array BioPharma, Merck KGaA, Regeneron, and Roche; and has received research funding from Array BioPharma, Bristol Myers Squibb, Incyte, Iovance Biotherapeutics, Merck KGaA, Nektar, and Roche/Genentech. MM has served as a consultant or advisor for Pfizer and Novartis and has received reimbursement for travel and accommodation expenses from Novartis. SG reports employment at EMD Serono Research & Development Institute; a business of Merck KGaA. PS reports employment at EMD Serono Research & Development Institute; a business of Merck KGaA. BE-L reports employment at Merck KGaA. MB reports employment at EMD Serono Research & Development Institute; a business of Merck KGaA. GG reports employment at Merck KGaA. PTN has received honoraria from EMD Serono and Merck & Co; reports serving as a consultant or advisor for EMD Serono and Pfizer; has received research funding from Bristol Myers Squibb and EMD Serono; and reports a pending patent for high-affinity T-cell receptors that target the Merkel cell polyomavirus. KCS, IB and GPL declare that they have no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)