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Clinical Trial
. 2019 Feb 1;5(2):187-194.
doi: 10.1001/jamaoncol.2018.4514.

Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial

Paolo A Ascierto  1 , Georgina V Long  2   3   4 , Caroline Robert  5 , Benjamin Brady  6 , Caroline Dutriaux  7 , Anna Maria Di Giacomo  8 , Laurent Mortier  9 , Jessica C Hassel  10 , Piotr Rutkowski  11 , Catriona McNeil  12   13 , Ewa Kalinka-Warzocha  14 , Kerry J Savage  15 , Micaela M Hernberg  16 , Celeste Lebbé  17 , Julie Charles  18   19 , Catalin Mihalcioiu  20 , Vanna Chiarion-Sileni  21 , Cornelia Mauch  22 , Francesco Cognetti  23 , Lars Ny  24 , Ana Arance  25 , Inge Marie Svane  26   27 , Dirk Schadendorf  28   29 , Helen Gogas  30 , Abdel Saci  31 , Joel Jiang  31 , Jasmine Rizzo  32 , Victoria Atkinson  33   34
Affiliations
Clinical Trial

Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial

Paolo A Ascierto et al. JAMA Oncol. .

Erratum in

Abstract

Importance: This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors.

Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma.

Design, setting, and participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation.

Interventions: Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks).

Main outcome and measure: Overall survival.

Results: At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects.

Conclusions and relevance: Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma.

Trial registration: ClinicalTrials.gov identifier: NCT01721772.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ascierto reported having a consultant/advisory role with Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array, Merck, Pierre-Fabre, Incyte, Genmab, Newlink Genetics, MedImmune, Syndax, and AstraZeneca and reported receiving institutional research funding from Bristol-Myers Squibb, Roche-Genentech, and Array. Dr Long reported receiving honoraria from Merck MSD, Roche, and Bristol-Myers Squibb and reported having a paid consulting role with Merck MSD, Roche, Bristol-Myers Squibb, Amgen, Novartis, and Pierre-Fabre. Dr Robert reported having a paid consulting role with Bristol-Myers Squibb, Merck, Roche, and Amgen and reported receiving honoraria from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Roche, Novartis, and Amgen. Dr Brady reported being paid to participate in speakers’ bureaus for Bristol-Myers Squibb and Merck; reported having a paid consulting role with Merck and Novartis; and reported having travel or other expenses paid or reimbursed by Bristol-Myers Squibb. Dr Di Giacomo reported receiving honoraria from Bristol-Myers Squibb, Roche, and Merck Sharp & Dohme and reported being a consultant for Incyte, Pierre-Fabre, and GlaxoSmithKline. Dr Mortier reported receiving clinical trials funding from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, and Roche and reported participating on an advisory board for Bristol-Myers Squibb. Dr Hassel reported having a paid consulting role with Merck and Amgen and reported receiving honoraria from Bristol-Myers Squibb, Merck, Novartis, Roche, and Pfizer. Dr Rutkowski reported receiving honoraria from Bristol-Myers Squibb, Roche, Novartis, Merck Sharp & Dohme, and GlaxoSmithKline; reported having a paid consulting role with Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, and Amgen; reported being paid to participate in speakers’ bureaus for Novartis and Merck Sharp & Dohme; reported receiving institutional research funding from Bristol-Myers Squibb; and reported having travel or other expenses paid or reimbursed by Novartis. Dr McNeil and members of her department reported having travel or other expenses paid or reimbursed by Merck Sharp & Dohme and Bristol-Myers Squibb; reported participating on advisory boards for Bristol-Myers Squibb and Merck Sharp & Dohme; and reported receiving research funding from Merck Sharp & Dohme for her institution. Dr Kalinka-Warzocha reported receiving payments for trial procedures according to study protocol from Bristol-Myers Squibb; reported receiving honoraria from Bristol-Myers Squibb, Roche, Novartis, Merck Sharp & Dohme, and AstraZeneca; and reported having a paid consultant role with Bristol-Myers Squibb, Merck Sharp & Dohme, and AstraZeneca. Dr Savage reported receiving honoraria from Seattle Genetics, Bristol-Myers Squibb, Celgene, and Takeda; reported having a paid consulting role with Seattle Genetics, Merck, and Bristol-Myers Squibb; reported being paid to participate in a speakers’ bureau for Seattle Genetics; and reported receiving research funding from Roche. Dr Lebbé reported participating on advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, GlaxoSmithKline, and Novartis and reported receiving travel expenses from Bristol-Myers Squibb and Merck Sharp & Dohme. Dr Mihalcioiu reporting having a paid consulting role with Bristol-Myers Squibb, Novartis, and Merck and reported having an issued US patent on circulatory cells. Dr Chiarion-Sileni reported having a paid consulting role with Bristol-Myers Squibb, Roche, GlaxoSmithKline, and Merck Sharp & Dohme; reported being paid to participate in a speakers’ bureau for Bristol-Myers Squibb, Roche, and GlaxoSmithKline; and reported having travel or other expenses paid or reimbursed by Bristol-Myers Squibb, Roche, GlaxoSmithKline, and Merck Sharp & Dohme. Dr Cognetti reported participating on an advisory board for Astellas Oncology. Dr Ny reported receiving clinical institutional funding from Merck Sharpe & Dohme and Syndax; reported receiving payment for participating in advisory boards with Bristol-Myers Squibb and Novartis; and reported having a consulting role with Bristol-Myers Squibb and AstraZeneca. Dr Arance reported having a paid consulting role with GlaxoSmithKline and Roche; reported being paid to participate in speakers’ bureaus for GlaxoSmithKline, Roche, and Bristol-Myers Squibb; and reported having travel or other expenses paid or reimbursed by Bristol-Myers Squibb. Dr Svane reported receiving honoraria from Bristol-Myers Squibb, Merck, and Roche; reported receiving clinical research funding from Bristol-Myers Squibb, Novartis, and Roche; and reported receiving payment for participation in scientific advisory boards from Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr Schadendorf reported receiving honoraria from Merck Sharp & Dohme, Roche, Amgen, Novartis, and Bristol-Myers Squibb; reported having paid consulting roles and being a member of speakers’ bureaus with Merck Sharp & Dohme, Roche, Amgen, Novartis, Bristol-Myers Squibb, Pierre-Fabre, and Merck-Serono; reported having a paid consultant role with Incyte; and reported receiving research funding from Merck Sharp & Dohme and Bristol-Myers Squibb. Dr Gogas reported receiving personal fees from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Amgen. Drs Saci, Jiang, and Rizzo reported being employed by Bristol-Myers Squibb. Dr Atkinson reported receiving honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis; reported having a paid consulting role with Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis; reported being paid to participate in speakers’ bureaus for Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis; and reported having travel or other expenses paid or reimbursed by Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Profile
aReported as sudden death, cause unknown. bSeven patients crossed over to nivolumab; 1 remains on dacarbazine.
Figure 2.
Figure 2.. Survival Outcomes
A, Kaplan-Meier curves of overall survival for the intent-to-treat population. For nivolumab, the overall survival rate at 1 year was 71%; 2 years, 58%; and 3 years, 51%. For dacarbazine, the overall survival rate at 1 year was 46%; 2 years, 26%; and 3 years, 22%. B, Kaplan-Meier curves of investigator-assessed disease progression (in accord with Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) for the intent-to-treat population. For nivolumab, the the progression-free survival rate at 1 year was 43%; 2 years, 35%; and 3 years, 32%. For dacarbazine, the progression-free survival rate at 1 year was 7%; 2 years, 6%; and 3 years, 3%.
See this image and copyright information in PMC

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