Safety and efficacy of vemurafenib in BRAF^V600E and BRAF^V600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study

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• 作者：Prof Grant A McArthur ; MB BS^a ; ^{grant.mcarthur@petermac.org" class="auth_mail} ; Prof Paul B Chapman ; MD^b ; Caroline Robert ; MD^c ; James Larkin ; MD^d ; John B Haanen ; MD^e ; Prof Reinhard Dummer ; MD^f ; Prof Antoni Ribas ; MD^g ; Prof David Hogg ; MD^h ; Omid Hamid ; MDⁱ ; Paolo A Ascierto ; MD^j ; Prof Claus Garbe ; MD^k ; Alessandro Testori ; MD^l ; Michele Maio ; MD^m ; Paul Lorigan ; MDⁿ ; Prof Celeste Lebbé ; MD^o ; Thomas Jouary ; MD^p ; Prof Dirk Schadendorf ; MD^q ; Stephen J O'Day ; MD^r ; Prof John M. Kirkwood ; MD^s ; Prof Alexander M Eggermont ; MD^t ; Prof Brigitte Dré ; no ; MD^u ; Prof Jeffrey A Sosman ; MD^v ; Keith T Flaherty ; MD^w ; Ming Yin ; PhD^x ; Ivor Caro ; MD^x ; Suzanne Cheng ; PhD^y ; Kerstin Trunzer ; PhD^z ; Prof Axel Hauschild ; MD^aa
• 刊名：Lancet Oncology
• 出版年：March, 2014
• 年：2014
• 卷：15
• 期：3
• 页码：323-332
• 全文大小：396 K

文摘

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Summary

Background

In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF^V600 mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF^V600E and BRAF^V600K mutation subgroups.

Methods

Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF^V600 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/m² 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 , .

Findings

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路5 months (IQR 7路7-16路0) on vemurafenib and 9路5 months (3路1-14路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路6 months [95% CI 12路0-15路2] vs 9路7 months [7路9-12路8]; hazard ratio [HR] 0路70 [95% CI 0路57-0路87]; p=0路0008), as was median progression-free survival (6路9 months [95% CI 6路1-7路0] vs 1路6 months [1路6-2路1]; HR 0路38 [95% CI 0路32-0路46]; p<0路0001). For the 598 (91%) patients with BRAF^V600E disease, median overall survival in the vemurafenib group was 13路3 months (95% CI 11路9-14路9) compared with 10路0 months (8路0-14路0) in the dacarbazine group (HR 0路75 [95% CI 0路60-0路93]; p=0路0085); median progression-free survival was 6路9 months (95% CI 6路2-7路0) and 1路6 months (1路6-2路1), respectively (HR 0路39 [95% CI 0路33-0路47]; p<0路0001). For the 57 (9%) patients with BRAF^V600K disease, median overall survival in the vemurafenib group was 14路5 months (95% CI 11路2-not estimable) compared with 7路6 months (6路1-16路6) in the dacarbazine group (HR 0路43 [95% CI 0路21-0路90]; p=0路024); median progression-free survival was 5路9 months (95% CI 4路4-9路0) and 1路7 months (1路4-2路9), respectively (HR 0路30 [95% CI 0路16-0路56]; p<0路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.

Interpretation

Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF^V600E mutation and in patients with the less common BRAF^V600K mutation.

Funding

F Hoffmann-La Roche-Genentech.