Ipilimumab (IPI) vs placebo (PBO) after complete resection of stage III melanoma: final overall survival results from the EORTC 18071 randomized, double-blind, phase 3 trial

Background

IPI has been an approved treatment for stage III melanoma in the US since 2015, based on a significant improvement in recurrence-free survival (RFS; hazard ratio [HR] 0.75; P = 0.0013) (Eggermont et al, Lancet Oncol, 2015). Here, we report the impact of IPI on overall survival (OS) and distant metastasis-free survival (DMFS).

Methods

In this trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis alone). 951 pts (20%/44%/36% who had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement) were randomized, stratified by stage and region, 1:1 to IPI 10 mg/kg (n = 475) or PBO (n = 476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was RFS (updated here). Secondary endpoints included DMFS, OS, and safety.

Results

At 5.3 yrs median follow-up, IPI demonstrated a statistically and clinically significant improvement in OS vs. PBO (HR = 0.72, i.e. 28% risk reduction of death). Similar impact for RFS and DMFS were observed.

CI: Confidence interval, *95%, **95.8% or ***95.1%; NR: not reached; †stratified by stage Among pts who started IPI (n = 471) or PBO (n = 474), 54.1% (IPI) and 26.2% (PBO) experienced grade 3/4 AEs, consistent with previous reports. The most common grade 3/4 immune-related adverse events (AEs) in the IPI-treated pts were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%). 251 (53.3%) pts discontinued IPI due to AEs; 5 (1.1%) died due to drug-related AEs.

Conclusions

IPI as adjuvant therapy provided a clinically and statistically significant improvement in OS with a favorable benefit-risk ratio in high-risk stage III melanoma patients. These data reinforce IPI as an important treatment option for these pts.

Clinical trial identification

NCT00636168

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

A.M.M. Eggermont: Advisory boards for BMS, MSD. V. Chiarion-Sileni: Served in consulting or advisory role for Roche, BMS, GSK, MSD. Participated in speakers' bureau for Roche, BMS, GSK. Travel, accomodations, expenses reimbursed by Roche, GSK, MSD, BMS. J-J. Grob: Served in a consulting or advisory role for BMS, GSK, Novartis, Amgen, Merck Roche. Participated in a speakers' bureau for GSK, Roche, BMS. Conducted research project(s) funded by Roche, BMS. Travel, accomodations, & expenses paid or reimbursed by Roche. R. Dummer: Paid honoraria from Roche, BMS, GSK, MSD, Novartis. Served in consulting or advisory role by Roche, BMS, GSK, MSD, Novartis. Conducted research project(s) funded by Roche, BMS, GSK, MSD, Novartis. J.D. Wolchok: Hon: EMD Serono, Janssen Oncol. Consulting: BMS, Merck, MedImmune, Ziopharm, Polynoma, Polaris, Jounce, GSK. Research funding: BMS, MedImmunce, GSK, Merck. Patent: issued patent for DNA vaccines of cancer in companion animals. Expenses Reimbursed: BMS H. Schmidt: Consultant advisor for Bristol-Myers Squibb, GlaxoSmithKline, Merck, and Roche. He has participated in speakers' bureau for Bristol-Myers Squibb, GlaxoSmithKline, and Roche. O. Hamid: Reports consulting for Amgen, Novartis, Roche, BMS, Merck, Merck Serrano, Pfizer, Genentech. Reports speaker for BMS, Genentech, Novartis, outside the submitted work. C. Robert: Honoraria: BMS, Merck, GSK, Roche, Novartis, Amgen. Consulting or Advisory Role: BMS, Merck, GSK, Roche, Novartis, Amgen. P.A. Ascierto: Honoraria: BMS, Roche-Genentech, GSK. Research Funding: BMS, Roche-Genentech, Ventana. C. Lebbé: Honoraria: BMS, MSD, Roche, Novartis, Amgen. Consulting or Advisory Role: Roche. Research Funding: Roche. Travel, Accomodations, Expenses: BMS, Roche (ASCO, AACR, EADO). M. Smylie: Honoraria: BMS, Roche, GSK, Merck. Consulting or Advisory Role: BMS, Roche, GSK, Merck. Speakers' Bureau: BMS, Roche. J.S. Weber: Stock or Other Ownership: Celldex, Altor, CCAM. Honoraria: BMS, Merck, GSK, Roche, Genentech. Consulting or Advisory Role: BMS, Merck, GSK, Roche, Genentech. Research Funding: BMS, Merck, GSK, Genentech, Roche, Monogenic. C. Taitt: Employee: BMS. Stock or Other Ownership: BMS. V. de Pril: Employee: BMS G. de Schaetzen, S. Suciu: Reports grants from BMS during the conduct of the study. All other authors have declared no conflicts of interest.