We conducted the randomized phase III double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients (pts) with resected high-risk stage III melanoma. At a 1.25-year (yr) median follow-up, pembrolizumab improved recurrence-free survival (RFS) (hazard ratio [HR] 0.57, P<0.0001) as compared to placebo (Eggermont, NEJM 2018). This led to the approval of pembrolizumab adjuvant treatment by EMA and FDA.
Eligible pts included those ≥18 yrs of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as AJCC-7 stage IIIA (at least one lymph node metastasis >1 mm), IIIB or IIIC (without in-transit metastasis). Between Aug-2015 until Nov-2016, 1019 pts were randomized to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (∼1 year) or until disease recurrence or unacceptable toxicity. The 2 main co-primary endpoints were RFS in the intention-to-treat (ITT) overall population and in pts with PD-L1-positive tumors. Secondary endpoints included distant metastasis-free survival (DMFS) in these 2 respective populations. The final DMFS analysis was foreseen when approximately 423 DMFS events (distant metastases or deaths) are reported (∼87% power to detect a HR of 0.725 in the overall population).
By April 2020, 418 DMFS events were reported. At 3.5 yr median follow-up, pembrolizumab compared with placebo significantly prolonged DMFS in the overall population (3.5-yr DMFS rate: 65.3% vs 49.4%; HR 0.60, 95% CI 0.49-0.73; P<0.0001) and in the PD-L1-positive tumor (N=853; HR 0.61; 95% CI 0.49-0.76; P<0.0001). The impact of pembrolizumab on DMFS was similar in pts with a PD-L1-negative tumor (N=116; HR 0.49, 99% CI 0.24-0.99) and in other subgroups, in particular according to AJCC-7 and -8 staging, and BRAF mutation status. The RFS improvement was confirmed (HR in the ITT population 0.59; 95% CI 0.49-0.70).
At 3.5-yr median follow-up, pembrolizumab adjuvant therapy provided a clinically meaningful improvement in DMFS in resected high-risk stage III melanoma pts.
EudraCT: 2014-004944-37.
Merck & Co., Inc.
Merck & Co., Inc.
A.M.M. Eggermont: Honoraria (self): Biocad; Honoraria (self): BioInvent; Honoraria (self): BMS; Honoraria (self): Ellipses Pharma; Honoraria (self): GSK; Honoraria (self): HalioDx; Honoraria (self): IO Biotech; Honoraria (self): MedImmune; Honoraria (self): MSD; Honoraria (self): Nektar Therapeutics; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Regeneron Pharmaceuticals; Honoraria (self): Sanofi; Honoraria (self): Sallas Life Sciences. C.U. Blank: Honoraria (institution): MSD; Honoraria (institution): BMS; Honoraria (institution): Roche; Honoraria (institution): Novartis; Honoraria (institution): Pfizer; Honoraria (institution): Lilly; Honoraria (institution): GSK. M. Mandala': Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Pierre Fabre; Research grant/Funding (institution): Genentech/Roche. G.V. Long: Honoraria (self): Aduro; Honoraria (self): Amgen; Honoraria (self): Array BioPharma; Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): Novartis; Honoraria (self): OncoSec. V. Victoria Atkinson: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Serano; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: OncoSec; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche. S. Dalle: Shareholder/Stockholder/Stock options, Spouse/Financial dependant: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Pierre Fabre. A.M. Haydon: Honoraria (self): Merck. A. Meshcheryakov: Advisory/Consultancy: Lilly Pharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck; Advisory/Consultancy: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Biocad; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Merck Serono; Travel/Accommodation/Expenses: Lilly Pharma. A. Khattak: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD. M. Carlino: Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Ideaya Biosciences; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Roche. S. Sandhu: Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Endocyte; Research grant/Funding (institution): MSD. S. Puig Sarda: Advisory/Consultancy: Isdin; Advisory/Consultancy, Research grant/Funding (institution): Leo Pharma; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Almirall; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Sanofi; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bioderma; Speaker Bureau/Expert testimony: La Roche Posay; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Pierre Fabre; Research grant/Funding (institution): Castle Bioscience; Research grant/Funding (institution): AMLO Bioscience; Research grant/Funding (institution): Melagenics. P.A. Ascierto: Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Array BioPharma; Advisory/Consultancy: Merck Serano; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Newlink Genetics; Advisory/Consultancy: Genmab; Advisory/Consultancy: Incyte; Advisory/Consultancy: MedImmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: Sun Pharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera; Advisory/Consultancy: Ultimovacs; Advisory/Consultancy: Sandoz; Advisory/Consultancy: Immunocore; Advisory/Consultancy: 4SC; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Italfarmaco. A.C.J. van Akkooi: Honoraria (institution), Research grant/Funding (institution): Amgen; Honoraria (institution), Research grant/Funding (institution): BMS; Honoraria (institution), Research grant/Funding (institution): Novartis; Honoraria (institution), Research grant/Funding (institution): MSD; Honoraria (institution), Research grant/Funding (institution): Pfizer; Honoraria (institution), Research grant/Funding (institution): Sanofi; Honoraria (institution), Research grant/Funding (institution): 4SC. C. Krepler: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. N. Ibrahim: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck; Shareholder/Stockholder/Stock options: GSK. M. Kicinski: Research grant/Funding (institution): MSD. S. Suciu: Research grant/Funding (institution): MSD. C. Robert: Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Amgen; Advisory/Consultancy: Biothera; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: CureVac. All other authors have declared no conflicts of interest.