TY - JOUR

T1 - Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma

T2 - a randomised, double-blind, multicentre, phase 3 trial

AU - Ascierto, Paolo A

AU - Del Vecchio, Michele

AU - Robert, Caroline

AU - Mackiewicz, Andrzej

AU - Chiarion-Sileni, Vanna

AU - Arance, Ana

AU - Lebbé, Céleste

AU - Bastholt, Lars

AU - Hamid, Omid

AU - Rutkowski, Piotr

AU - McNeil, Catriona

AU - Garbe, Claus

AU - Loquai, Carmen

AU - Dreno, Brigitte

AU - Thomas, Luc

AU - Grob, Jean-Jacques

AU - Liszkay, Gabriella

AU - Nyakas, Marta

AU - Gutzmer, Ralf

AU - Pikiel, Joanna

AU - Grange, Florent

AU - Hoeller, Christoph

AU - Ferraresi, Virginia

AU - Smylie, Michael

AU - Schadendorf, Dirk

AU - Mortier, Laurent

AU - Svane, Inge Marie

AU - Hennicken, Delphine

AU - Qureshi, Anila

AU - Maio, Michele

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2017/5

Y1 - 2017/5

N2 - 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.

AB - 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.

KW - Aged

KW - Alanine Transaminase/blood

KW - Antibodies, Monoclonal/administration & dosage

KW - Antineoplastic Agents/administration & dosage

KW - Colitis/chemically induced

KW - Diarrhea/chemically induced

KW - Double-Blind Method

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Hypophysitis/chemically induced

KW - Intention to Treat Analysis

KW - Ipilimumab

KW - Male

KW - Melanoma/drug therapy

KW - Middle Aged

KW - Survival Rate

KW - Treatment Outcome

U2 - 10.1016/S1470-2045(17)30231-0

DO - 10.1016/S1470-2045(17)30231-0

M3 - Journal article

C2 - 28359784

VL - 18

SP - 611

EP - 622

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 5

ER -