2898 - Adjuvant immunotherapy with nivolumab (NIVO) alone or in combination with ipilimumab (IPI) versus placebo in stage IV melanoma patients with no evidence of disease (NED): A randomized, double-blind phase 2 trial (IMMUNED)

Background

The PD1 inhibitor NIVO has been approved for the adjuvant treatment of high-risk stage III and IV resected melanoma based on a phase III trial demonstrating improved recurrence-free survival (RFS) compared to IPI. We conducted a phase II double-blind, randomized, multicenter trial to determine the efficacy of NIVO alone or in combination with IPI vs. placebo for adjuvant therapy in stage IV melanoma pts with NED.

Methods

Pts ≥18 yrs of age with stage IV cutaneous or unknown primary melanoma and NED after surgery or radiation therapy were eligible (IMMUNED; CA209-184, NCT02523313, supported by BMS). They were randomly assigned 1:1:1 (stratified by trial site, site of metastasis and PD-L1 status) to receive either NIVO 3 mg/kg Q2W (n = 59) or NIVO 1 mg/kg plus IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W (n = 56) or placebo (n = 52) for a period of up to 1 year, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS in the intent-to-treat population.

Results

Between September 2015 and September 2018, 167 pts were randomized at 20 German centers and 162 pts received at least one infusion. At a median follow-up of 28.4 months, the RFS was significantly longer for NIVO compared to placebo (hazard ratio (HR) 0.56, 95% CI 0.36 to 0.88), and for NIVO plus IPI compared to placebo (HR 0.23, 95% CI, 0.13 to 0.41). Results from prespecified subgroup analyses demonstrated consistent HR favoring NIVO and NIVO plus IPI over placebo. Treatment-related grade 3/4 adverse events (AE) were reported in 27% pts of the NIVO group and in 71% of the NIVO plus IPI group. Treatment-related AEs of any grade led to treatment discontinuation in 13%, 62% and 2% of the NIVO, NIVO plus IPI and placebo group, respectively. No treatment-related deaths were reported.

Conclusions

Among stage IV melanoma pts with NED adjuvant therapy with NIVO alone or in combination with IPI resulted in significantly longer RFS compared to placebo. The rate of grade 3/4 treatment-related AEs in the NIVO and in the NIVO plus IPI group was higher than the rate reported in the CheckMate 067 trial in pts with unresectable melanoma.

Clinical trial identification

IMMUNED; CA209-184, NCT02523313.

Editorial acknowledgement

Legal entity responsible for the study

University Hospital Essen, Prof. Dirk Schadendorf.

Funding

Funding in part by Bristol-Myers Squibb.

Disclosure

D. Schadendorf: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Amgen; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Leo Pharma; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (self): Incyte; Honoraria (self), Honoraria (institution): Regeneron; Honoraria (self), Honoraria (institution): 4SC; Honoraria (self): AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Honoraria (institution): Merck-EMD; Honoraria (self): Pfizer; Honoraria (self), Honoraria (institution): Philogen; Honoraria (self): Array. J.C. Hassel: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Payments to institution for treating patients within clinical trials: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Pierre Fabre. M. Fluck: Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Pierre-Fabre. T. Eigentler: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Sanofi Genzyme; Advisory / Consultancy: Leo Pharma; Honoraria (self), Advisory / Consultancy: MSD. C. Loquai: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sun Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Biontech; Advisory / Consultancy, Travel / Accommodation / Expenses: Almirall; Travel / Accommodation / Expenses: Kyowa Kirin. R. Gutzmer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Serono; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Sanofi; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: Novartis; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Almirall Hermal; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Leo; Honoraria (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: SunPharma; Advisory / Consultancy: 4SC; Research grant / Funding (institution): Johnson & Johnson. P. Mohr: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: GSK; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Sanofi. A. Hauschild: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Philogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Provectus; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Regeneron; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: OncoSec; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi-Genzyme; Advisory / Consultancy: Sun Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis. J.C. Becker: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (institution): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC; Advisory / Consultancy: CureVac; Advisory / Consultancy: eTheRNA; Advisory / Consultancy: Lytix; Advisory / Consultancy: Novartis; Advisory / Consultancy: ReProTHer; Advisory / Consultancy: Rigontec; Research grant / Funding (institution): Alcedis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): IQVIA; Travel / Accommodation / Expenses: Incyte. F. Kiecker: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Pierre Fabre. C. Garbe: Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): NeraCare; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Philogen; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi. E. Livingstone: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Medac; Honoraria (self): Janssen; Advisory / Consultancy: Actelion; Travel / Accommodation / Expenses: Pierre Fabre. L. Zimmer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.