Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial
- PMID: 28162999
- PMCID: PMC5636622
- DOI: 10.1016/S1470-2045(17)30015-3
Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial
Abstract
Background: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial.
Methods: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.
Findings: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]).
Interpretation: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events.
Funding: Bristol-Myers Squibb.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Conflict of interest statement
VCS has received personal fees from Bristol-Myers Squibb, GlaxoSmithKline, Roche, Merck, and Amgen for serving on an advisory board; J-JG has received personal fees and non-financial support from Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck, and Novartis for serving on an advisory board, lecturer, travel support, and grants from Bristol-Myers Squibb and GlaxoSmithKline; RD has received personal fees from Bristol-Myers Squibb, MSD, Roche, GlaxoSmithKline, and Novartis for serving on an advisory board; JDW has received other fees from Bristol-Myers Squibb, MSD, and MedImmune for serving as a consultant, and a grant from Bristol-Myers Squibb; OH has received personal fees from Bristol-Myers Squibb for lecturing and grants from Bristol-Myers Squibb; CR has received other fees from GlaxoSmithKline, Roche, Merck, Bristol-Myers Squibb, and Amgen for serving as a consultant; PAA has received personal fees from Bristol-Myers Squibb, Roche, Merck, GlaxoSmithKline, Ventana, Novartis, and Amgen for serving on an advisory board, and grants from Bristol-Myers Squibb, Roche, and Ventana; CL has received personal fees from Bristol-Myers Squibb, GlaxoSmithKline, Roche, Merck, Amgen, and Novartis for serving on an advisory board; MS has received personal fees from Bristol-Myers Squibb and Roche as honoraria and from Merck, Bristol-Myers Squibb, Roche, and GlaxoSmithKline for serving on an advisory board; JSW has received personal fees and grants from Bristol-Myers Squibb; MM has received personal fees from Bristol-Myers Squibb, Roche, MedImmune, and GlaxoSmithKline for serving on an advisory board and lecturing, and grants from Bristol-Myers Squibb and MedImmune; SK and VdP are employees and shareholders of Bristol-Myers Squibb. AE has received personal fees from Bristol-Myers Squibb, Amgen, Merck, and MedImmune for serving on an advisory board, and personal fee from GlaxoSmithKline for serving on a data and safety monitoring board; CC, SS, JMR, VF, HS, and AT have nothing to disclose.
Figures
Comment in
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Adjuvant ipilimumab for stage III melanoma: the patient voice.Lancet Oncol. 2017 Mar;18(3):282-284. doi: 10.1016/S1470-2045(17)30003-7. Epub 2017 Feb 3. Lancet Oncol. 2017. PMID: 28163001 No abstract available.
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Immunotherapy: Does adjuvant ipilimumab have little adverse effect on quality of life?Nat Rev Clin Oncol. 2017 Jul;14(7):395-396. doi: 10.1038/nrclinonc.2017.60. Epub 2017 Apr 25. Nat Rev Clin Oncol. 2017. PMID: 28440331 No abstract available.
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