Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial
Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of...
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| Veröffentlicht in: | The lancet oncology 2017-05, Vol.18 (5), p.611-622 |
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| creator | Ascierto, Paolo A, Dr Del Vecchio, Michele, MD Robert, Caroline, Prof Mackiewicz, Andrzej, Prof Chiarion-Sileni, Vanna, MD Arance, Ana, MD Lebbé, Céleste, Prof Bastholt, Lars, MD Hamid, Omid, MD Rutkowski, Piotr, Prof McNeil, Catriona, MD Garbe, Claus, Prof Loquai, Carmen, MD Dreno, Brigitte, Prof Thomas, Luc, Prof Grob, Jean-Jacques, Prof Liszkay, Gabriella, Prof Nyakas, Marta, MD Gutzmer, Ralf, Prof Pikiel, Joanna, MD Grange, Florent, MD Hoeller, Christoph, MD Ferraresi, Virginia, MD Smylie, Michael, MD Schadendorf, Dirk, Prof Mortier, Laurent, Prof Svane, Inge Marie, MD Hennicken, Delphine, MSc Qureshi, Anila, MD Maio, Michele, MD |
| description | Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov , number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two ( |
| doi_str_mv | 10.1016/S1470-2045(17)30231-0 |
| format | Article |
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We report a phase 3 trial comparing the benefit–risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov , number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. Interpretation In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(17)30231-0</identifier><identifier>PMID: 28359784</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Aged ; Alanine ; Alanine transaminase ; Alanine Transaminase - blood ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Cancer ; Cancer therapies ; Clinical trials ; Colitis ; Colitis - chemically induced ; Diarrhea ; Diarrhea - chemically induced ; Double-Blind Method ; Double-blind studies ; Failure analysis ; Female ; Follow-Up Studies ; Hematology, Oncology and Palliative Medicine ; Humans ; Hypophysitis - chemically induced ; Immune checkpoint inhibitors ; Immunotherapy ; Intention to Treat Analysis ; Intravenous administration ; Ipilimumab ; Life Sciences ; Male ; Melanoma ; Melanoma - drug therapy ; Melanoma - secondary ; Metastases ; Metastasis ; Middle Aged ; Monoclonal antibodies ; Motivation ; Oncology ; Quality of life ; Statistical analysis ; Studies ; Survival ; Survival Rate ; Targeted cancer therapy ; Treatment Outcome</subject><ispartof>The lancet oncology, 2017-05, Vol.18 (5), p.611-622</ispartof><rights>Elsevier Ltd</rights><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited May 1, 2017</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c537t-b4087bf557e314124a60dff4ba9a325aeb1282e46bced93b4ab175a242c56e573</citedby><cites>FETCH-LOGICAL-c537t-b4087bf557e314124a60dff4ba9a325aeb1282e46bced93b4ab175a242c56e573</cites><orcidid>0000-0001-5478-9826 ; 0000-0002-9493-0238 ; 0000-0002-1014-4062 ; 0000-0001-5574-5825 ; 0000-0001-8530-780X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1470204517302310$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28359784$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-01807340$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Ascierto, Paolo A, Dr</creatorcontrib><creatorcontrib>Del Vecchio, Michele, MD</creatorcontrib><creatorcontrib>Robert, Caroline, Prof</creatorcontrib><creatorcontrib>Mackiewicz, Andrzej, Prof</creatorcontrib><creatorcontrib>Chiarion-Sileni, Vanna, MD</creatorcontrib><creatorcontrib>Arance, Ana, MD</creatorcontrib><creatorcontrib>Lebbé, Céleste, Prof</creatorcontrib><creatorcontrib>Bastholt, Lars, MD</creatorcontrib><creatorcontrib>Hamid, Omid, MD</creatorcontrib><creatorcontrib>Rutkowski, Piotr, Prof</creatorcontrib><creatorcontrib>McNeil, Catriona, MD</creatorcontrib><creatorcontrib>Garbe, Claus, Prof</creatorcontrib><creatorcontrib>Loquai, Carmen, MD</creatorcontrib><creatorcontrib>Dreno, Brigitte, Prof</creatorcontrib><creatorcontrib>Thomas, Luc, Prof</creatorcontrib><creatorcontrib>Grob, Jean-Jacques, Prof</creatorcontrib><creatorcontrib>Liszkay, Gabriella, Prof</creatorcontrib><creatorcontrib>Nyakas, Marta, MD</creatorcontrib><creatorcontrib>Gutzmer, Ralf, Prof</creatorcontrib><creatorcontrib>Pikiel, Joanna, MD</creatorcontrib><creatorcontrib>Grange, Florent, MD</creatorcontrib><creatorcontrib>Hoeller, Christoph, MD</creatorcontrib><creatorcontrib>Ferraresi, Virginia, MD</creatorcontrib><creatorcontrib>Smylie, Michael, MD</creatorcontrib><creatorcontrib>Schadendorf, Dirk, Prof</creatorcontrib><creatorcontrib>Mortier, Laurent, Prof</creatorcontrib><creatorcontrib>Svane, Inge Marie, MD</creatorcontrib><creatorcontrib>Hennicken, Delphine, MSc</creatorcontrib><creatorcontrib>Qureshi, Anila, MD</creatorcontrib><creatorcontrib>Maio, Michele, MD</creatorcontrib><title>Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov , number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. Interpretation In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.</description><subject>Aged</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Alanine Transaminase - blood</subject><subject>Antibodies, Monoclonal - administration & dosage</subject><subject>Antibodies, Monoclonal - adverse effects</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Clinical trials</subject><subject>Colitis</subject><subject>Colitis - chemically induced</subject><subject>Diarrhea</subject><subject>Diarrhea - chemically induced</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Failure analysis</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Hypophysitis - chemically induced</subject><subject>Immune checkpoint inhibitors</subject><subject>Immunotherapy</subject><subject>Intention to Treat Analysis</subject><subject>Intravenous administration</subject><subject>Ipilimumab</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Melanoma</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - secondary</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Motivation</subject><subject>Oncology</subject><subject>Quality of life</subject><subject>Statistical analysis</subject><subject>Studies</subject><subject>Survival</subject><subject>Survival Rate</subject><subject>Targeted cancer therapy</subject><subject>Treatment Outcome</subject><issn>1470-2045</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkU1v1DAQhiMEoqXwE0CWuBRpQ8df64QDqKqAVlqJA3C27GTSdZuPxU4W9a_wa5ndLK3UCyePPc-845k3y15zeM-BL8--c2UgF6D0KTfvJAjJc3iSHdOzyrUqiqf7eEaOshcp3QBww0E_z45EIXVpCnWc_bnahDZ0U-c848C667Pba7bFmKbEwkNKHjKhZxs3BuzHxH6Hcc2mPmLCanS-RTZE1uHo0khIRWHr-qFzH5hj0fX10IWE9YLVw0Rw7tvQ062bWoJJMOKCbdYuITUbY3Dty-xZ49qErw7nSfbzy-cfF5f56tvXq4vzVV5pacbcKyiMb7Q2KLniQrkl1E2jvCudFNqh56IQqJa-wrqUXjnPjXZCiUovURt5ki1m3bVr7SaGzsU7O7hgL89XNvQJY2eBF2Ckgi0n_HTGN3H4NWEaLc1VYUvD4jAly4tCclOqUhD69hF6M0yxp2GIKrUGAK2I0jNVxSGliM39JzjYndd277XdGWm5sXuvLVDdm4P65Dus76v-mUvApxlA2t42YLSpIutoDSGSZbYewn9bfHykUJFroXLtLd5hepjGJmFhFtlpcLNXAPkXhC3NQw</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Ascierto, Paolo A, Dr</creator><creator>Del Vecchio, Michele, MD</creator><creator>Robert, Caroline, Prof</creator><creator>Mackiewicz, Andrzej, Prof</creator><creator>Chiarion-Sileni, Vanna, MD</creator><creator>Arance, Ana, MD</creator><creator>Lebbé, Céleste, Prof</creator><creator>Bastholt, Lars, MD</creator><creator>Hamid, Omid, MD</creator><creator>Rutkowski, Piotr, Prof</creator><creator>McNeil, Catriona, MD</creator><creator>Garbe, Claus, Prof</creator><creator>Loquai, Carmen, MD</creator><creator>Dreno, Brigitte, Prof</creator><creator>Thomas, Luc, Prof</creator><creator>Grob, Jean-Jacques, Prof</creator><creator>Liszkay, Gabriella, Prof</creator><creator>Nyakas, Marta, MD</creator><creator>Gutzmer, Ralf, Prof</creator><creator>Pikiel, Joanna, MD</creator><creator>Grange, Florent, MD</creator><creator>Hoeller, Christoph, MD</creator><creator>Ferraresi, Virginia, MD</creator><creator>Smylie, Michael, MD</creator><creator>Schadendorf, Dirk, Prof</creator><creator>Mortier, Laurent, Prof</creator><creator>Svane, Inge Marie, MD</creator><creator>Hennicken, Delphine, MSc</creator><creator>Qureshi, Anila, MD</creator><creator>Maio, Michele, MD</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><general>Elsevier</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0001-5478-9826</orcidid><orcidid>https://orcid.org/0000-0002-9493-0238</orcidid><orcidid>https://orcid.org/0000-0002-1014-4062</orcidid><orcidid>https://orcid.org/0000-0001-5574-5825</orcidid><orcidid>https://orcid.org/0000-0001-8530-780X</orcidid></search><sort><creationdate>20170501</creationdate><title>Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial</title><author>Ascierto, Paolo A, Dr ; Del Vecchio, Michele, MD ; Robert, Caroline, Prof ; Mackiewicz, Andrzej, Prof ; Chiarion-Sileni, Vanna, MD ; Arance, Ana, MD ; Lebbé, Céleste, Prof ; Bastholt, Lars, MD ; Hamid, Omid, MD ; Rutkowski, Piotr, Prof ; McNeil, Catriona, MD ; Garbe, Claus, Prof ; Loquai, Carmen, MD ; Dreno, Brigitte, Prof ; Thomas, Luc, Prof ; Grob, Jean-Jacques, Prof ; Liszkay, Gabriella, Prof ; Nyakas, Marta, MD ; Gutzmer, Ralf, Prof ; Pikiel, Joanna, MD ; Grange, Florent, MD ; Hoeller, Christoph, MD ; Ferraresi, Virginia, MD ; Smylie, Michael, MD ; Schadendorf, Dirk, Prof ; Mortier, Laurent, Prof ; Svane, Inge Marie, MD ; Hennicken, Delphine, MSc ; Qureshi, Anila, MD ; Maio, Michele, MD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c537t-b4087bf557e314124a60dff4ba9a325aeb1282e46bced93b4ab175a242c56e573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Aged</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>Alanine Transaminase - blood</topic><topic>Antibodies, Monoclonal - administration & dosage</topic><topic>Antibodies, Monoclonal - adverse effects</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Clinical trials</topic><topic>Colitis</topic><topic>Colitis - chemically induced</topic><topic>Diarrhea</topic><topic>Diarrhea - chemically induced</topic><topic>Double-Blind Method</topic><topic>Double-blind studies</topic><topic>Failure analysis</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Hypophysitis - chemically induced</topic><topic>Immune checkpoint inhibitors</topic><topic>Immunotherapy</topic><topic>Intention to Treat Analysis</topic><topic>Intravenous administration</topic><topic>Ipilimumab</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Melanoma</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - secondary</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>Motivation</topic><topic>Oncology</topic><topic>Quality of life</topic><topic>Statistical analysis</topic><topic>Studies</topic><topic>Survival</topic><topic>Survival Rate</topic><topic>Targeted cancer therapy</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ascierto, Paolo A, Dr</creatorcontrib><creatorcontrib>Del Vecchio, Michele, MD</creatorcontrib><creatorcontrib>Robert, Caroline, Prof</creatorcontrib><creatorcontrib>Mackiewicz, Andrzej, Prof</creatorcontrib><creatorcontrib>Chiarion-Sileni, Vanna, MD</creatorcontrib><creatorcontrib>Arance, Ana, MD</creatorcontrib><creatorcontrib>Lebbé, Céleste, Prof</creatorcontrib><creatorcontrib>Bastholt, Lars, MD</creatorcontrib><creatorcontrib>Hamid, Omid, MD</creatorcontrib><creatorcontrib>Rutkowski, Piotr, Prof</creatorcontrib><creatorcontrib>McNeil, Catriona, MD</creatorcontrib><creatorcontrib>Garbe, Claus, Prof</creatorcontrib><creatorcontrib>Loquai, Carmen, MD</creatorcontrib><creatorcontrib>Dreno, Brigitte, Prof</creatorcontrib><creatorcontrib>Thomas, Luc, Prof</creatorcontrib><creatorcontrib>Grob, Jean-Jacques, Prof</creatorcontrib><creatorcontrib>Liszkay, Gabriella, Prof</creatorcontrib><creatorcontrib>Nyakas, Marta, MD</creatorcontrib><creatorcontrib>Gutzmer, Ralf, Prof</creatorcontrib><creatorcontrib>Pikiel, Joanna, MD</creatorcontrib><creatorcontrib>Grange, Florent, MD</creatorcontrib><creatorcontrib>Hoeller, Christoph, MD</creatorcontrib><creatorcontrib>Ferraresi, Virginia, MD</creatorcontrib><creatorcontrib>Smylie, Michael, MD</creatorcontrib><creatorcontrib>Schadendorf, Dirk, Prof</creatorcontrib><creatorcontrib>Mortier, Laurent, Prof</creatorcontrib><creatorcontrib>Svane, Inge Marie, MD</creatorcontrib><creatorcontrib>Hennicken, Delphine, MSc</creatorcontrib><creatorcontrib>Qureshi, Anila, MD</creatorcontrib><creatorcontrib>Maio, Michele, MD</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ascierto, Paolo A, Dr</au><au>Del Vecchio, Michele, MD</au><au>Robert, Caroline, Prof</au><au>Mackiewicz, Andrzej, Prof</au><au>Chiarion-Sileni, Vanna, MD</au><au>Arance, Ana, MD</au><au>Lebbé, Céleste, Prof</au><au>Bastholt, Lars, MD</au><au>Hamid, Omid, MD</au><au>Rutkowski, Piotr, Prof</au><au>McNeil, Catriona, MD</au><au>Garbe, Claus, Prof</au><au>Loquai, Carmen, MD</au><au>Dreno, Brigitte, Prof</au><au>Thomas, Luc, Prof</au><au>Grob, Jean-Jacques, Prof</au><au>Liszkay, Gabriella, Prof</au><au>Nyakas, Marta, MD</au><au>Gutzmer, Ralf, Prof</au><au>Pikiel, Joanna, MD</au><au>Grange, Florent, MD</au><au>Hoeller, Christoph, MD</au><au>Ferraresi, Virginia, MD</au><au>Smylie, Michael, MD</au><au>Schadendorf, Dirk, Prof</au><au>Mortier, Laurent, Prof</au><au>Svane, Inge Marie, MD</au><au>Hennicken, Delphine, MSc</au><au>Qureshi, Anila, MD</au><au>Maio, Michele, MD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>18</volume><issue>5</issue><spage>611</spage><epage>622</epage><pages>611-622</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><abstract>Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov , number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. Interpretation In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28359784</pmid><doi>10.1016/S1470-2045(17)30231-0</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-5478-9826</orcidid><orcidid>https://orcid.org/0000-0002-9493-0238</orcidid><orcidid>https://orcid.org/0000-0002-1014-4062</orcidid><orcidid>https://orcid.org/0000-0001-5574-5825</orcidid><orcidid>https://orcid.org/0000-0001-8530-780X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2017-05, Vol.18 (5), p.611-622 |
| issn | 1470-2045 1474-5488 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_inserm_01807340v1 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Aged Alanine Alanine transaminase Alanine Transaminase - blood Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - adverse effects Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Cancer Cancer therapies Clinical trials Colitis Colitis - chemically induced Diarrhea Diarrhea - chemically induced Double-Blind Method Double-blind studies Failure analysis Female Follow-Up Studies Hematology, Oncology and Palliative Medicine Humans Hypophysitis - chemically induced Immune checkpoint inhibitors Immunotherapy Intention to Treat Analysis Intravenous administration Ipilimumab Life Sciences Male Melanoma Melanoma - drug therapy Melanoma - secondary Metastases Metastasis Middle Aged Monoclonal antibodies Motivation Oncology Quality of life Statistical analysis Studies Survival Survival Rate Targeted cancer therapy Treatment Outcome |
| title | Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial |
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