{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:41:16Z","timestamp":1791438076964,"version":"4.3.3"},"reference-count":25,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"unspecified","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,10,27]]},"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1\/programmed cell death 1 ligand 1 (PD-1\/PD-L1) inhibition of up to 62%. However, primary and secondary resistance to PD-1\/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.<\/jats:p>\n               <jats:p>Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI\/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.<\/jats:p>\n               <jats:p>All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI\/NIVO. In total, 7 patients responded to IPI\/NIVO (overall response rate 50%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95% CI 2.43\u2014not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9% and 26.8 %, respectively. The OS rate at 36 months was 64.3%. Only 3 (21%) patients did not receive all 4 cycles of IPI\/NIVO due to immune-related adverse events.<\/jats:p>\n               <jats:p>In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI\/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI\/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.<\/jats:p>","DOI":"10.1136\/jitc-2022-005930","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T10:16:07Z","timestamp":1669803367000},"page":"e005930","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":31,"title":["Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG"],"prefix":"10.1136","volume":"10","author":[{"given":"Valerie","family":"Glutsch","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Universit\u00e4tsklinikum W\u00fcrzburg, Wurzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Schummer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Universit\u00e4tsklinikum W\u00fcrzburg, Wurzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Kneitz","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Universit\u00e4tsklinikum W\u00fcrzburg, Wurzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Gesierich","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Universit\u00e4tsklinikum W\u00fcrzburg, Wurzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Goebeler","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Universit\u00e4tsklinikum 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