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Knispel, Sarah; Stang, Andreas; Zimmer, Lisa; Lax, Hildegard; Gutzmer, Ralf; Heinzerling, Lucie; Weishaupt, Carsten; Pfoehler, Claudia; Gesierich, Anja; Herbst, Rudolf; Kaehler, Katharina C.; Weide, Benjamin; Berking, Carola; Loquai, Carmen; Utikal, Jochen; Terheyden, Patrick; Kaatz, Martin; Schlaak, Max; Kreuter, Alexander; Ulrich, Jens; Mohr, Peter; Dippel, Edgar; Livingstone, Elisabeth; Becker, Jürgen C.; Weichenthal, Michael; Chorti, Eleftheria; Gronewold, Janine; Schadendorf, Dirk and Ugurel, Selma (2020): Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: a multicenter retrospective cohort study of the DeCOG. In: Journal for Immunotherapy of Cancer, Vol. 8, No. 1, e000395

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Background: Immune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment. Methods: This multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted for confounders identified by directed acyclic graphs. Adjusted survival curves were calculated using inverse probability treatment weighting. Results: 835 patients who received ICI (anti-CTLA-4, n=596;anti-PD-1, n=239) at 16 centers were analyzed, whereof 235 received a preceding radiotherapy of metastatic lesions in stage IV disease. The most frequent organ sites irradiated prior to ICI therapy were brain (51.1%), lymph nodes (17.9%) and bone (17.9%). After multivariable adjustment for confounders, no relevant differences in ICI therapy outcome were observed between cohorts with and without preceding radiotherapy. BOR was 8.7% vs 13.0% for anti-CTLA-4 (adjusted relative risk (RR)=1.47;95% CI=0.81 to 2.65;p=0.20), and 16.5% vs 25.3% for anti-PD-1 (RR=0.93;95% CI=0.49 to 1.77;p=0.82). Survival probabilities were similar for cohorts with and without preceding radiotherapy, for anti-CTLA-4 (PFS, adjusted HR=1.02, 95% CI=0.86 to 1.25, p=0.74;OS, HR=1.08, 95% CI=0.81 to 1.44, p=0.61) and for anti-PD-1 (PFS, HR=0.84, 95% CI=0.57 to 1.26, p=0.41;OS, HR=0.73, 95% CI=0.43 to 1.25, p=0.26). Patients who received radiation last before ICI (n=137) revealed no better survival than those who had one or more treatment lines between radiation and start of ICI (n=86). In 223 patients with brain metastases, we found no relevant survival differences on ICI with and without preceding radiotherapy. Conclusions: This study detected no evidence for a relevant favorable impact of a preceding radiotherapy on anti-CTLA-4 or anti-PD-1 ICI treatment outcome in metastatic melanoma.

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