Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study
Identifieur interne : 003522 ( Main/Exploration ); précédent : 003521; suivant : 003523Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study
Auteurs : Grant A. Mcarthur ; Paul B. Chapman ; Caroline Robert ; James Larkin ; John B. Haanen ; Reinhard Dummer ; Antoni Ribas ; David Hogg ; Omid Hamid ; Paolo A. Ascierto ; Claus Garbe ; Alessandro Testori ; Michele Maio ; Paul Lorigan ; Celeste Lebbé ; Thomas Jouary ; Dirk Schadendorf ; Stephen J. O Ay ; John M. Kirkwood ; Alexander M. Eggermont ; Brigitte Dréno ; Jeffrey A. Sosman ; Keith T. Flaherty ; Ming Yin ; Ivor Caro ; Suzanne Cheng ; Kerstin Trunzer ; Axel HauschildSource :
- The Lancet. Oncology [ 1470-2045 ] ; 2014.
Descripteurs français
- KwdFr :
- Adulte, Adulte d'âge moyen, Dacarbazine (usage thérapeutique), Femelle, Humains, Indoles (effets indésirables), Indoles (usage thérapeutique), Inhibiteurs de protéines kinases (usage thérapeutique), Mutation, Mâle, Mélanome (génétique), Mélanome (mortalité), Mélanome (traitement médicamenteux), Protéines proto-oncogènes B-raf (antagonistes et inhibiteurs), Protéines proto-oncogènes B-raf (génétique), Sujet âgé, Sulfonamides (effets indésirables), Sulfonamides (usage thérapeutique), Survie sans rechute, Études de suivi.
- MESH :
- antagonistes et inhibiteurs : Protéines proto-oncogènes B-raf.
- effets indésirables : Indoles, Sulfonamides.
- génétique : Mélanome, Protéines proto-oncogènes B-raf.
- mortalité : Mélanome.
- traitement médicamenteux : Mélanome.
- usage thérapeutique : Dacarbazine, Indoles, Inhibiteurs de protéines kinases, Sulfonamides.
- Adulte, Adulte d'âge moyen, Femelle, Humains, Mutation, Mâle, Sujet âgé, Survie sans rechute, Études de suivi.
English descriptors
- KwdEn :
- Adult, Aged, Dacarbazine (therapeutic use), Disease-Free Survival, Female, Follow-Up Studies, Humans, Indoles (adverse effects), Indoles (therapeutic use), Male, Melanoma (drug therapy), Melanoma (genetics), Melanoma (mortality), Middle Aged, Mutation, Protein Kinase Inhibitors (therapeutic use), Proto-Oncogene Proteins B-raf (antagonists & inhibitors), Proto-Oncogene Proteins B-raf (genetics), Sulfonamides (adverse effects), Sulfonamides (therapeutic use).
- MESH :
- chemical , adverse effects : Indoles, Sulfonamides.
- chemical , antagonists & inhibitors : Proto-Oncogene Proteins B-raf.
- chemical , genetics : Proto-Oncogene Proteins B-raf.
- chemical , therapeutic use : Dacarbazine, Indoles, Protein Kinase Inhibitors, Sulfonamides.
- drug therapy : Melanoma.
- genetics : Melanoma.
- mortality : Melanoma.
- Adult, Aged, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mutation.
Abstract
In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced
Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for
675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7–16·0) on vemurafenib and 9·5 months (3·1–14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0–15·2]
Inhibition of BRAF with vemurafenib improves survival in patients with the most common
F Hoffmann-La Roche-Genentech.
Url:
DOI: 10.1016/S1470-2045(14)70012-9
PubMed: 24508103
PubMed Central: 4382632
Affiliations:
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Le document en format XML
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Mcarthur</name></author><author><name sortKey="Chapman, Paul B" sort="Chapman, Paul B" uniqKey="Chapman P" first="Paul B" last="Chapman">Paul B. Chapman</name></author><author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name></author><author><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name></author><author><name sortKey="Haanen, John B" sort="Haanen, John B" uniqKey="Haanen J" first="John B" last="Haanen">John B. Haanen</name></author><author><name sortKey="Dummer, Reinhard" sort="Dummer, Reinhard" uniqKey="Dummer R" first="Reinhard" last="Dummer">Reinhard Dummer</name></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name></author><author><name sortKey="Hogg, David" sort="Hogg, David" uniqKey="Hogg D" first="David" last="Hogg">David Hogg</name></author><author><name sortKey="Hamid, Omid" sort="Hamid, Omid" uniqKey="Hamid O" first="Omid" last="Hamid">Omid Hamid</name></author><author><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name></author><author><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name></author><author><name sortKey="Testori, Alessandro" sort="Testori, Alessandro" uniqKey="Testori A" first="Alessandro" last="Testori">Alessandro Testori</name></author><author><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name></author><author><name sortKey="Lorigan, Paul" sort="Lorigan, Paul" uniqKey="Lorigan P" first="Paul" last="Lorigan">Paul Lorigan</name></author><author><name sortKey="Lebbe, Celeste" sort="Lebbe, Celeste" uniqKey="Lebbe C" first="Celeste" last="Lebbé">Celeste Lebbé</name></author><author><name sortKey="Jouary, Thomas" sort="Jouary, Thomas" uniqKey="Jouary T" first="Thomas" last="Jouary">Thomas Jouary</name></author><author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name></author><author><name sortKey="O Ay, Stephen J" sort="O Ay, Stephen J" uniqKey="O Ay S" first="Stephen J" last="O Ay">Stephen J. O Ay</name></author><author><name sortKey="Kirkwood, John M" sort="Kirkwood, John M" uniqKey="Kirkwood J" first="John M." last="Kirkwood">John M. Kirkwood</name></author><author><name sortKey="Eggermont, Alexander M" sort="Eggermont, Alexander M" uniqKey="Eggermont A" first="Alexander M" last="Eggermont">Alexander M. Eggermont</name></author><author><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name></author><author><name sortKey="Sosman, Jeffrey A" sort="Sosman, Jeffrey A" uniqKey="Sosman J" first="Jeffrey A" last="Sosman">Jeffrey A. Sosman</name></author><author><name sortKey="Flaherty, Keith T" sort="Flaherty, Keith T" uniqKey="Flaherty K" first="Keith T" last="Flaherty">Keith T. Flaherty</name></author><author><name sortKey="Yin, Ming" sort="Yin, Ming" uniqKey="Yin M" first="Ming" last="Yin">Ming Yin</name></author><author><name sortKey="Caro, Ivor" sort="Caro, Ivor" uniqKey="Caro I" first="Ivor" last="Caro">Ivor Caro</name></author><author><name sortKey="Cheng, Suzanne" sort="Cheng, Suzanne" uniqKey="Cheng S" first="Suzanne" last="Cheng">Suzanne Cheng</name></author><author><name sortKey="Trunzer, Kerstin" sort="Trunzer, Kerstin" uniqKey="Trunzer K" first="Kerstin" last="Trunzer">Kerstin Trunzer</name></author><author><name sortKey="Hauschild, Axel" sort="Hauschild, Axel" uniqKey="Hauschild A" first="Axel" last="Hauschild">Axel Hauschild</name></author></analytic><series><title level="j">The Lancet. Oncology</title><idno type="ISSN">1470-2045</idno><idno type="eISSN">1474-5488</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Aged</term><term>Dacarbazine (therapeutic use)</term><term>Disease-Free Survival</term><term>Female</term><term>Follow-Up Studies</term><term>Humans</term><term>Indoles (adverse effects)</term><term>Indoles (therapeutic use)</term><term>Male</term><term>Melanoma (drug therapy)</term><term>Melanoma (genetics)</term><term>Melanoma (mortality)</term><term>Middle Aged</term><term>Mutation</term><term>Protein Kinase Inhibitors (therapeutic use)</term><term>Proto-Oncogene Proteins B-raf (antagonists & inhibitors)</term><term>Proto-Oncogene Proteins B-raf (genetics)</term><term>Sulfonamides (adverse effects)</term><term>Sulfonamides (therapeutic use)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Dacarbazine (usage thérapeutique)</term><term>Femelle</term><term>Humains</term><term>Indoles (effets indésirables)</term><term>Indoles (usage thérapeutique)</term><term>Inhibiteurs de protéines kinases (usage thérapeutique)</term><term>Mutation</term><term>Mâle</term><term>Mélanome (génétique)</term><term>Mélanome (mortalité)</term><term>Mélanome (traitement médicamenteux)</term><term>Protéines proto-oncogènes B-raf (antagonistes et inhibiteurs)</term><term>Protéines proto-oncogènes B-raf (génétique)</term><term>Sujet âgé</term><term>Sulfonamides (effets indésirables)</term><term>Sulfonamides (usage thérapeutique)</term><term>Survie sans rechute</term><term>Études de suivi</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Indoles</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Proto-Oncogene Proteins B-raf</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Proto-Oncogene Proteins B-raf</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Dacarbazine</term><term>Indoles</term><term>Protein Kinase Inhibitors</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines proto-oncogènes B-raf</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Melanoma</term></keywords><keywords scheme="MESH" qualifier="effets indésirables" xml:lang="fr"><term>Indoles</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Melanoma</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Mélanome</term><term>Protéines proto-oncogènes B-raf</term></keywords><keywords scheme="MESH" qualifier="mortality" xml:lang="en"><term>Melanoma</term></keywords><keywords scheme="MESH" qualifier="mortalité" xml:lang="fr"><term>Mélanome</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Mélanome</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Dacarbazine</term><term>Indoles</term><term>Inhibiteurs de protéines kinases</term><term>Sulfonamides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Disease-Free Survival</term><term>Female</term><term>Follow-Up Studies</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Mutation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Femelle</term><term>Humains</term><term>Mutation</term><term>Mâle</term><term>Sujet âgé</term><term>Survie sans rechute</term><term>Études de suivi</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><sec id="S1"><title>Background</title><p id="P1">In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced <italic>BRAF</italic><sup>V600</sup> mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the <italic>BRAF</italic><sup>V600E</sup> and <italic>BRAF</italic><sup>V600K</sup> mutation subgroups.</p></sec><sec id="S2"><title>Methods</title><p id="P2">Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for <italic>BRAF</italic><sup>V600</sup> mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m<sup>2</sup> of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.</p></sec><sec id="S3"><title>Findings</title><p id="P3">675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7–16·0) on vemurafenib and 9·5 months (3·1–14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0–15·2] <italic>vs</italic> 9·7 months [7·9–12·8]; hazard ratio [HR] 0·70 [95% CI 0·57–0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1–7·0] <italic>vs</italic> 1·6 months [1·6–2·1]; HR 0·38 [95% CI 0·32–0·46]; p<0·0001). For the 598 (91%) patients with <italic>BRAF</italic><sup>V600E</sup> disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9–14·9) compared with 10·0 months (8·0–14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60–0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2–7·0) and 1·6 months (1·6–2·1), respectively (HR 0·39 [95% CI 0·33–0·47]; p<0·0001). For the 57 (9%) patients with <italic>BRAF</italic><sup>V600K</sup> disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2–not estimable) compared with 7·6 months (6·1–16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21–0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4–9·0) and 1·7 months (1·4–2·9), respectively (HR 0·30 [95% CI 0·16–0·56]; p<0·0001). The most frequent grade 3–4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.</p></sec><sec id="S4"><title>Interpretation</title><p id="P4">Inhibition of BRAF with vemurafenib improves survival in patients with the most common <italic>BRAF</italic><sup>V600E</sup> mutation and in patients with the less common <italic>BRAF</italic><sup>V600K</sup> mutation.</p></sec><sec id="S5"><title>Funding</title><p id="P5">F Hoffmann-La Roche-Genentech.</p></sec></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name><name sortKey="Caro, Ivor" sort="Caro, Ivor" uniqKey="Caro I" first="Ivor" last="Caro">Ivor Caro</name><name sortKey="Chapman, Paul B" sort="Chapman, Paul B" uniqKey="Chapman P" first="Paul B" last="Chapman">Paul B. Chapman</name><name sortKey="Cheng, Suzanne" sort="Cheng, Suzanne" uniqKey="Cheng S" first="Suzanne" last="Cheng">Suzanne Cheng</name><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name><name sortKey="Dummer, Reinhard" sort="Dummer, Reinhard" uniqKey="Dummer R" first="Reinhard" last="Dummer">Reinhard Dummer</name><name sortKey="Eggermont, Alexander M" sort="Eggermont, Alexander M" uniqKey="Eggermont A" first="Alexander M" last="Eggermont">Alexander M. Eggermont</name><name sortKey="Flaherty, Keith T" sort="Flaherty, Keith T" uniqKey="Flaherty K" first="Keith T" last="Flaherty">Keith T. Flaherty</name><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name><name sortKey="Haanen, John B" sort="Haanen, John B" uniqKey="Haanen J" first="John B" last="Haanen">John B. Haanen</name><name sortKey="Hamid, Omid" sort="Hamid, Omid" uniqKey="Hamid O" first="Omid" last="Hamid">Omid Hamid</name><name sortKey="Hauschild, Axel" sort="Hauschild, Axel" uniqKey="Hauschild A" first="Axel" last="Hauschild">Axel Hauschild</name><name sortKey="Hogg, David" sort="Hogg, David" uniqKey="Hogg D" first="David" last="Hogg">David Hogg</name><name sortKey="Jouary, Thomas" sort="Jouary, Thomas" uniqKey="Jouary T" first="Thomas" last="Jouary">Thomas Jouary</name><name sortKey="Kirkwood, John M" sort="Kirkwood, John M" uniqKey="Kirkwood J" first="John M." last="Kirkwood">John M. Kirkwood</name><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name><name sortKey="Lebbe, Celeste" sort="Lebbe, Celeste" uniqKey="Lebbe C" first="Celeste" last="Lebbé">Celeste Lebbé</name><name sortKey="Lorigan, Paul" sort="Lorigan, Paul" uniqKey="Lorigan P" first="Paul" last="Lorigan">Paul Lorigan</name><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name><name sortKey="O Ay, Stephen J" sort="O Ay, Stephen J" uniqKey="O Ay S" first="Stephen J" last="O Ay">Stephen J. O Ay</name><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name><name sortKey="Sosman, Jeffrey A" sort="Sosman, Jeffrey A" uniqKey="Sosman J" first="Jeffrey A" last="Sosman">Jeffrey A. Sosman</name><name sortKey="Testori, Alessandro" sort="Testori, Alessandro" uniqKey="Testori A" first="Alessandro" last="Testori">Alessandro Testori</name><name sortKey="Trunzer, Kerstin" sort="Trunzer, Kerstin" uniqKey="Trunzer K" first="Kerstin" last="Trunzer">Kerstin Trunzer</name><name sortKey="Yin, Ming" sort="Yin, Ming" uniqKey="Yin M" first="Ming" last="Yin">Ming Yin</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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