Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma

Abstract

Background: We have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.

Methods: This randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.

Results: At a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutant BRAF tumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.

Conclusions: This 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.

Trial registration number: NCT01515189.

Keywords: immunology; oncology; randomized trials.

Conflict of interest statement

Competing interests: PAA has served as a consultant to Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore and 4SC, and received research funding from Array, Bristol-Myers Squibb, Roche-Genentech and MSD. MDV has served as a consultant to Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre and Sanofi. CR has served as a consultant to, or served on the board of directors/advisors of Bristol-Myers Squibb, Pierre Fabre, Novartis, Amgen, Merck, Roche, MSD and Sanofi. AA has received honoraria from Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Amgen, Sanofi and Merck. CLebbé has served on the board of advisors/directors of Merck Serono, Novartis and Sanofi, and has served as a consultant to, received research funding from or served on the board of directors/advisors of Bristol-Myers Squibb, Roche and MSD. IMS has received honoraria from MSD, Novartis, Bristol-Myers Squibb and Pierre Fabre. PR has received honoraria from Bristol-Myers Squibb, Novartis, MSD, Roche, Pierre Fabre, Amgen, Pfizer, Eli Lilly and Blueprint Medicines. CLoquai has served on the board of advisors/directors of Bristol-Myers Squibb, MSD, Pierre Fabre, Roche, Novartis, Sanofi, Biontech and Idera, and received honoraria from Bristol-Myers Squibb, MSD, Pierre Fabre, Roche, Novartis, Sanofi and Kyowa Kirin. LM has served on a medical board for Bristol-Myers Squibb, GlaxoSmithKline, Merck and Roche, and has received travel fees from Bristol-Myers Squibb. OH has received research funding from Amgen, Arcus, Astellas, AstraZeneca, BMS, Celldex, CytomX, Genentech, GSK, Immunocore, Incyte, Iovance, Merck, Merck Serono, MedImmune, NextCure, Novartis, Parker, Pfizer, Polynoma, Regeneron and Roche, served as a consultant to Bristol-Myers Squibb, Amgen, Merck, Novartis and Roche, and received honoraria from Bristol-Myers Squibb, Amgen, Array, Genentech, Novartis and Sanofi. LB has served on the board of advisors/directors of Bristol-Myers Squibb, Novartis, Merck, Roche, Incyte and Bayer, and received research funding from Bristol-Myers Squibb. BD has received research funding from Bristol-Myers Squibb, Roche and Novartis and honoraria from Bristol-Myers Squibb, Pierre Fabre and Roche. DS has received honoraria from Bristol-Myers Squibb, Roche, Novartis, Regeneron, Sanofi, Merck, Amgen, 4SC, Merck-EMD, Array, Pierre Fabre, Philiogen, Incyte and Pfizer, and research funding from Bristol-Myers Squibb and Novartis. CG has has served as a consultant to, or served on the board of directors/advisors of Bristol-Myers Squibb, Amgen, MSD, NeraCare, Novartis, Philogen, Roche and Sanofi, and research funding from Bristol-Myers Squibb, NeraCare, Novartis, Roche and Sanofi. MN has received honoraria from Novartis, Pierre Fabre and Bristol-Myers Squibb. J-JG has received honoraria from Bristol-Myers Squibb, MSD, Roche, Novartis, Amgen, Pierre Fabre, Sun Pharma and Sanofi. LT has received research funding from Bristol-Myers Squibb. GL has received honoraria from and served as a consultant to Roche, MSD, Bristol-Myers Squibb and Novartis. MS has received honoraria from BMS, Merck, Sanofi Genzyme and Novartis. CH has received honoraria from, and served on the board of advisors for Bristol-Myers Squibb, and honoraria from Amgen, MSD, Novartis, Pierre Fabre and Roche. RG has received research funding and honoraria from Amgen, Novartis, Pfizer and Johnson & Johnson, and honoraria from Bristol-Myers Squibb, Roche Pharma, Merck Serono, Pierre Fabre, Sanofi, Merck, Almirall Hermal, LEO, AstraZeneca, Sun Pharma and 4SC. FH and BS are employees of Bristol-Myers Squibb. MM has received honoraria from Bristol-Myers Squibb, AstraZeneca, Roche, MSD, Merck, GlaxoSmithKline and Incyte, and research funding from Bristol-Myers Squibb.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Overall survival in all randomized patients. IPI, ipilimumab.

Figure 2

Overall survival by subgroups. (A) Overall survival in patients with asymptomatic brain metastases at baseline, (B) wild-type BRAF tumors, (C) mutant BRAF tumors, (D) LDH levels ≤ULN and (E) LDH levels >ULN. IPI, ipilimumab; LDH, lactate dehydrogenase; NA, not available; OS, overall survival; ULN, upper limit of normal.

Figure 3

Forest plot of overall survival. ECOG PS, Eastern Cooperative Oncology Group performance status, IPI, ipilimumab; LDH, lactate dehydrogenase; M, metastatic; mOS, median overall survival; ULN, upper limit of normal.