Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial
Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition...
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| Veröffentlicht in: | The Lancet (British edition) 2023-09, Vol.402 (10404), p.798-808 |
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| creator | Becker, Jürgen C Ugurel, Selma Leiter, Ulrike Meier, Friedegund Gutzmer, Ralf Haferkamp, Sebastian Zimmer, Lisa Livingstone, Elisabeth Eigentler, Thomas K Hauschild, Axel Kiecker, Felix Hassel, Jessica C Mohr, Peter Fluck, Michael Thomas, Ioannis Garzarolli, Marlene Grimmelmann, Imke Drexler, Konstantin Spillner, Alexandra N Eckhardt, Sebastian Schadendorf, Dirk van Akkoi, Alexander van Houdt, Winan Wilhelm, Tabea Farmer, Kimberly Ulrich, Claas Gambichler, Thilo Bluhm, Leonie Schinagl, Heidemarie Kellner, Ivonne Herbst, Rudolf Meiß, Frank Rafei-Shamsabadi, David Sell, Sabine Kaatz, Martin Wulfken, Lena Hartmann, Martin Kähler, Katharina Ziemer, Mirjana Simon, Jan Terheyden, Patrick Thaci, Diamant Loquai, Carmen Mitzel-Rink, Heidrun Grabbe, Stephan Stege, Henner Gaiser, Maria Utikal, Jochen Berking, Carola Heinzerling, Lucie Schlaak, Max Tomsitz, Dirk Dyballa, Jörg Magnolo, Nina Weishaupt, Carsten Berneburg, Mark Garbe, Claus Flatz, Lukas Gesierich, Anja Schilling, Bastian |
| description | Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment).
In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0–1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1–2 vs stages 3–4), age ( |
| doi_str_mv | 10.1016/S0140-6736(23)00769-9 |
| format | Article |
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In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0–1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1–2 vs stages 3–4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78).
Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3–4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2–33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30–1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3–4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported.
Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need.
Bristol Myers Squibb.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(23)00769-9</identifier><identifier>PMID: 37451295</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adjuvants ; Adjuvants, Immunologic - therapeutic use ; Age ; Aged ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Cancer ; Cancer therapies ; Carcinoma ; Carcinoma, Merkel Cell - chemically induced ; Carcinoma, Merkel Cell - drug therapy ; Clinical trials ; Disease ; Disease-Free Survival ; Female ; Health care facilities ; Health services ; Hepatitis ; Humans ; Immune checkpoint inhibitors ; Immunogenicity ; Immunotherapy ; Ipilimumab ; Lymphatic system ; Male ; Melanoma ; Metastasis ; Monoclonal antibodies ; Neoplasm Recurrence, Local - drug therapy ; Nivolumab ; Patients ; PD-1 protein ; PD-L1 protein ; Radiation therapy ; Response rates ; Risk management ; Safety ; Sex ; Skin cancer ; Skin Neoplasms - drug therapy ; Skin Neoplasms - etiology ; Survival ; Targeted cancer therapy</subject><ispartof>The Lancet (British edition), 2023-09, Vol.402 (10404), p.798-808</ispartof><rights>2023 Elsevier Ltd</rights><rights>Copyright © 2023 Elsevier Ltd. All rights reserved.</rights><rights>2023. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-338bb017e63d0a7199d3a5f7c8c86414740b394675603018cc6a861ffe8b61663</citedby><cites>FETCH-LOGICAL-c393t-338bb017e63d0a7199d3a5f7c8c86414740b394675603018cc6a861ffe8b61663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0140673623007699$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37451295$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Becker, Jürgen C</creatorcontrib><creatorcontrib>Ugurel, Selma</creatorcontrib><creatorcontrib>Leiter, Ulrike</creatorcontrib><creatorcontrib>Meier, Friedegund</creatorcontrib><creatorcontrib>Gutzmer, Ralf</creatorcontrib><creatorcontrib>Haferkamp, Sebastian</creatorcontrib><creatorcontrib>Zimmer, Lisa</creatorcontrib><creatorcontrib>Livingstone, Elisabeth</creatorcontrib><creatorcontrib>Eigentler, Thomas K</creatorcontrib><creatorcontrib>Hauschild, Axel</creatorcontrib><creatorcontrib>Kiecker, Felix</creatorcontrib><creatorcontrib>Hassel, Jessica C</creatorcontrib><creatorcontrib>Mohr, Peter</creatorcontrib><creatorcontrib>Fluck, Michael</creatorcontrib><creatorcontrib>Thomas, Ioannis</creatorcontrib><creatorcontrib>Garzarolli, Marlene</creatorcontrib><creatorcontrib>Grimmelmann, Imke</creatorcontrib><creatorcontrib>Drexler, Konstantin</creatorcontrib><creatorcontrib>Spillner, Alexandra N</creatorcontrib><creatorcontrib>Eckhardt, Sebastian</creatorcontrib><creatorcontrib>Schadendorf, Dirk</creatorcontrib><creatorcontrib>van Akkoi, Alexander</creatorcontrib><creatorcontrib>van Houdt, Winan</creatorcontrib><creatorcontrib>Wilhelm, Tabea</creatorcontrib><creatorcontrib>Farmer, Kimberly</creatorcontrib><creatorcontrib>Ulrich, Claas</creatorcontrib><creatorcontrib>Gambichler, Thilo</creatorcontrib><creatorcontrib>Bluhm, Leonie</creatorcontrib><creatorcontrib>Schinagl, Heidemarie</creatorcontrib><creatorcontrib>Kellner, Ivonne</creatorcontrib><creatorcontrib>Herbst, Rudolf</creatorcontrib><creatorcontrib>Meiß, Frank</creatorcontrib><creatorcontrib>Rafei-Shamsabadi, David</creatorcontrib><creatorcontrib>Sell, Sabine</creatorcontrib><creatorcontrib>Kaatz, Martin</creatorcontrib><creatorcontrib>Wulfken, Lena</creatorcontrib><creatorcontrib>Hartmann, Martin</creatorcontrib><creatorcontrib>Kähler, Katharina</creatorcontrib><creatorcontrib>Ziemer, Mirjana</creatorcontrib><creatorcontrib>Simon, Jan</creatorcontrib><creatorcontrib>Terheyden, Patrick</creatorcontrib><creatorcontrib>Thaci, Diamant</creatorcontrib><creatorcontrib>Loquai, Carmen</creatorcontrib><creatorcontrib>Mitzel-Rink, Heidrun</creatorcontrib><creatorcontrib>Grabbe, Stephan</creatorcontrib><creatorcontrib>Stege, Henner</creatorcontrib><creatorcontrib>Gaiser, Maria</creatorcontrib><creatorcontrib>Utikal, Jochen</creatorcontrib><creatorcontrib>Berking, Carola</creatorcontrib><creatorcontrib>Heinzerling, Lucie</creatorcontrib><creatorcontrib>Schlaak, Max</creatorcontrib><creatorcontrib>Tomsitz, Dirk</creatorcontrib><creatorcontrib>Dyballa, Jörg</creatorcontrib><creatorcontrib>Magnolo, Nina</creatorcontrib><creatorcontrib>Weishaupt, Carsten</creatorcontrib><creatorcontrib>Berneburg, Mark</creatorcontrib><creatorcontrib>Garbe, Claus</creatorcontrib><creatorcontrib>Flatz, Lukas</creatorcontrib><creatorcontrib>Gesierich, Anja</creatorcontrib><creatorcontrib>Schilling, Bastian</creatorcontrib><creatorcontrib>DeCOG</creatorcontrib><title>Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment).
In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0–1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1–2 vs stages 3–4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78).
Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3–4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2–33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30–1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3–4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported.
Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need.
Bristol Myers Squibb.</description><subject>Adjuvants</subject><subject>Adjuvants, Immunologic - therapeutic use</subject><subject>Age</subject><subject>Aged</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Carcinoma</subject><subject>Carcinoma, Merkel Cell - chemically induced</subject><subject>Carcinoma, Merkel Cell - drug therapy</subject><subject>Clinical trials</subject><subject>Disease</subject><subject>Disease-Free Survival</subject><subject>Female</subject><subject>Health care facilities</subject><subject>Health services</subject><subject>Hepatitis</subject><subject>Humans</subject><subject>Immune checkpoint inhibitors</subject><subject>Immunogenicity</subject><subject>Immunotherapy</subject><subject>Ipilimumab</subject><subject>Lymphatic system</subject><subject>Male</subject><subject>Melanoma</subject><subject>Metastasis</subject><subject>Monoclonal antibodies</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>Nivolumab</subject><subject>Patients</subject><subject>PD-1 protein</subject><subject>PD-L1 protein</subject><subject>Radiation therapy</subject><subject>Response rates</subject><subject>Risk management</subject><subject>Safety</subject><subject>Sex</subject><subject>Skin cancer</subject><subject>Skin Neoplasms - drug therapy</subject><subject>Skin Neoplasms - etiology</subject><subject>Survival</subject><subject>Targeted cancer 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immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial</title><author>Becker, Jürgen C ; Ugurel, Selma ; Leiter, Ulrike ; Meier, Friedegund ; Gutzmer, Ralf ; Haferkamp, Sebastian ; Zimmer, Lisa ; Livingstone, Elisabeth ; Eigentler, Thomas K ; Hauschild, Axel ; Kiecker, Felix ; Hassel, Jessica C ; Mohr, Peter ; Fluck, Michael ; Thomas, Ioannis ; Garzarolli, Marlene ; Grimmelmann, Imke ; Drexler, Konstantin ; Spillner, Alexandra N ; Eckhardt, Sebastian ; Schadendorf, Dirk ; van Akkoi, Alexander ; van Houdt, Winan ; Wilhelm, Tabea ; Farmer, Kimberly ; Ulrich, Claas ; Gambichler, Thilo ; Bluhm, Leonie ; Schinagl, Heidemarie ; Kellner, Ivonne ; Herbst, Rudolf ; Meiß, Frank ; Rafei-Shamsabadi, David ; Sell, Sabine ; Kaatz, Martin ; Wulfken, Lena ; Hartmann, Martin ; Kähler, Katharina ; Ziemer, Mirjana ; Simon, Jan ; Terheyden, Patrick ; Thaci, Diamant ; Loquai, Carmen ; Mitzel-Rink, Heidrun ; Grabbe, Stephan ; Stege, Henner ; Gaiser, Maria ; Utikal, Jochen ; Berking, Carola ; Heinzerling, Lucie ; Schlaak, Max ; Tomsitz, Dirk ; Dyballa, Jörg ; Magnolo, Nina ; Weishaupt, Carsten ; Berneburg, Mark ; Garbe, Claus ; Flatz, Lukas ; Gesierich, Anja ; Schilling, Bastian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-338bb017e63d0a7199d3a5f7c8c86414740b394675603018cc6a861ffe8b61663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adjuvants</topic><topic>Adjuvants, Immunologic - therapeutic use</topic><topic>Age</topic><topic>Aged</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Carcinoma</topic><topic>Carcinoma, Merkel Cell - chemically induced</topic><topic>Carcinoma, Merkel Cell - drug therapy</topic><topic>Clinical trials</topic><topic>Disease</topic><topic>Disease-Free Survival</topic><topic>Female</topic><topic>Health care facilities</topic><topic>Health services</topic><topic>Hepatitis</topic><topic>Humans</topic><topic>Immune checkpoint inhibitors</topic><topic>Immunogenicity</topic><topic>Immunotherapy</topic><topic>Ipilimumab</topic><topic>Lymphatic system</topic><topic>Male</topic><topic>Melanoma</topic><topic>Metastasis</topic><topic>Monoclonal antibodies</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>Nivolumab</topic><topic>Patients</topic><topic>PD-1 protein</topic><topic>PD-L1 protein</topic><topic>Radiation therapy</topic><topic>Response rates</topic><topic>Risk management</topic><topic>Safety</topic><topic>Sex</topic><topic>Skin cancer</topic><topic>Skin Neoplasms - drug therapy</topic><topic>Skin Neoplasms - etiology</topic><topic>Survival</topic><topic>Targeted cancer therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Becker, Jürgen C</creatorcontrib><creatorcontrib>Ugurel, Selma</creatorcontrib><creatorcontrib>Leiter, Ulrike</creatorcontrib><creatorcontrib>Meier, Friedegund</creatorcontrib><creatorcontrib>Gutzmer, Ralf</creatorcontrib><creatorcontrib>Haferkamp, Sebastian</creatorcontrib><creatorcontrib>Zimmer, Lisa</creatorcontrib><creatorcontrib>Livingstone, Elisabeth</creatorcontrib><creatorcontrib>Eigentler, Thomas K</creatorcontrib><creatorcontrib>Hauschild, Axel</creatorcontrib><creatorcontrib>Kiecker, Felix</creatorcontrib><creatorcontrib>Hassel, Jessica C</creatorcontrib><creatorcontrib>Mohr, Peter</creatorcontrib><creatorcontrib>Fluck, Michael</creatorcontrib><creatorcontrib>Thomas, Ioannis</creatorcontrib><creatorcontrib>Garzarolli, Marlene</creatorcontrib><creatorcontrib>Grimmelmann, Imke</creatorcontrib><creatorcontrib>Drexler, Konstantin</creatorcontrib><creatorcontrib>Spillner, Alexandra N</creatorcontrib><creatorcontrib>Eckhardt, Sebastian</creatorcontrib><creatorcontrib>Schadendorf, Dirk</creatorcontrib><creatorcontrib>van Akkoi, Alexander</creatorcontrib><creatorcontrib>van Houdt, Winan</creatorcontrib><creatorcontrib>Wilhelm, Tabea</creatorcontrib><creatorcontrib>Farmer, Kimberly</creatorcontrib><creatorcontrib>Ulrich, Claas</creatorcontrib><creatorcontrib>Gambichler, Thilo</creatorcontrib><creatorcontrib>Bluhm, Leonie</creatorcontrib><creatorcontrib>Schinagl, Heidemarie</creatorcontrib><creatorcontrib>Kellner, Ivonne</creatorcontrib><creatorcontrib>Herbst, Rudolf</creatorcontrib><creatorcontrib>Meiß, Frank</creatorcontrib><creatorcontrib>Rafei-Shamsabadi, David</creatorcontrib><creatorcontrib>Sell, Sabine</creatorcontrib><creatorcontrib>Kaatz, Martin</creatorcontrib><creatorcontrib>Wulfken, Lena</creatorcontrib><creatorcontrib>Hartmann, Martin</creatorcontrib><creatorcontrib>Kähler, Katharina</creatorcontrib><creatorcontrib>Ziemer, Mirjana</creatorcontrib><creatorcontrib>Simon, Jan</creatorcontrib><creatorcontrib>Terheyden, Patrick</creatorcontrib><creatorcontrib>Thaci, Diamant</creatorcontrib><creatorcontrib>Loquai, Carmen</creatorcontrib><creatorcontrib>Mitzel-Rink, Heidrun</creatorcontrib><creatorcontrib>Grabbe, Stephan</creatorcontrib><creatorcontrib>Stege, Henner</creatorcontrib><creatorcontrib>Gaiser, Maria</creatorcontrib><creatorcontrib>Utikal, Jochen</creatorcontrib><creatorcontrib>Berking, Carola</creatorcontrib><creatorcontrib>Heinzerling, Lucie</creatorcontrib><creatorcontrib>Schlaak, Max</creatorcontrib><creatorcontrib>Tomsitz, Dirk</creatorcontrib><creatorcontrib>Dyballa, Jörg</creatorcontrib><creatorcontrib>Magnolo, Nina</creatorcontrib><creatorcontrib>Weishaupt, Carsten</creatorcontrib><creatorcontrib>Berneburg, Mark</creatorcontrib><creatorcontrib>Garbe, Claus</creatorcontrib><creatorcontrib>Flatz, Lukas</creatorcontrib><creatorcontrib>Gesierich, Anja</creatorcontrib><creatorcontrib>Schilling, Bastian</creatorcontrib><creatorcontrib>DeCOG</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>News PRO</collection><collection>Pharma and Biotech Premium PRO</collection><collection>Global News & ABI/Inform Professional</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni 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Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>The Lancet (British edition)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Becker, Jürgen C</au><au>Ugurel, Selma</au><au>Leiter, Ulrike</au><au>Meier, Friedegund</au><au>Gutzmer, Ralf</au><au>Haferkamp, Sebastian</au><au>Zimmer, Lisa</au><au>Livingstone, Elisabeth</au><au>Eigentler, Thomas K</au><au>Hauschild, Axel</au><au>Kiecker, Felix</au><au>Hassel, Jessica C</au><au>Mohr, Peter</au><au>Fluck, Michael</au><au>Thomas, Ioannis</au><au>Garzarolli, Marlene</au><au>Grimmelmann, Imke</au><au>Drexler, Konstantin</au><au>Spillner, Alexandra N</au><au>Eckhardt, Sebastian</au><au>Schadendorf, Dirk</au><au>van Akkoi, Alexander</au><au>van Houdt, Winan</au><au>Wilhelm, Tabea</au><au>Farmer, Kimberly</au><au>Ulrich, Claas</au><au>Gambichler, Thilo</au><au>Bluhm, Leonie</au><au>Schinagl, Heidemarie</au><au>Kellner, Ivonne</au><au>Herbst, Rudolf</au><au>Meiß, Frank</au><au>Rafei-Shamsabadi, David</au><au>Sell, Sabine</au><au>Kaatz, Martin</au><au>Wulfken, Lena</au><au>Hartmann, Martin</au><au>Kähler, Katharina</au><au>Ziemer, Mirjana</au><au>Simon, Jan</au><au>Terheyden, Patrick</au><au>Thaci, Diamant</au><au>Loquai, Carmen</au><au>Mitzel-Rink, Heidrun</au><au>Grabbe, Stephan</au><au>Stege, Henner</au><au>Gaiser, Maria</au><au>Utikal, Jochen</au><au>Berking, Carola</au><au>Heinzerling, Lucie</au><au>Schlaak, Max</au><au>Tomsitz, Dirk</au><au>Dyballa, Jörg</au><au>Magnolo, Nina</au><au>Weishaupt, Carsten</au><au>Berneburg, Mark</au><au>Garbe, Claus</au><au>Flatz, Lukas</au><au>Gesierich, Anja</au><au>Schilling, Bastian</au><aucorp>DeCOG</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>2023-09-02</date><risdate>2023</risdate><volume>402</volume><issue>10404</issue><spage>798</spage><epage>808</epage><pages>798-808</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><abstract>Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment).
In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0–1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1–2 vs stages 3–4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78).
Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3–4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2–33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30–1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3–4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported.
Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need.
Bristol Myers Squibb.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>37451295</pmid><doi>10.1016/S0140-6736(23)00769-9</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 2023-09, Vol.402 (10404), p.798-808 |
| issn | 0140-6736 1474-547X |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adjuvants Adjuvants, Immunologic - therapeutic use Age Aged Antineoplastic Combined Chemotherapy Protocols - therapeutic use Cancer Cancer therapies Carcinoma Carcinoma, Merkel Cell - chemically induced Carcinoma, Merkel Cell - drug therapy Clinical trials Disease Disease-Free Survival Female Health care facilities Health services Hepatitis Humans Immune checkpoint inhibitors Immunogenicity Immunotherapy Ipilimumab Lymphatic system Male Melanoma Metastasis Monoclonal antibodies Neoplasm Recurrence, Local - drug therapy Nivolumab Patients PD-1 protein PD-L1 protein Radiation therapy Response rates Risk management Safety Sex Skin cancer Skin Neoplasms - drug therapy Skin Neoplasms - etiology Survival Targeted cancer therapy |
| title | Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial |
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