LBA3_PR - Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial

Background

Current standard of care for patients (pts) after resection of high-risk stage II melanoma is observation. In the phase 3 double-blind KEYNOTE-716 trial we evaluated pembrolizumab (pembro) versus placebo in pts with resected AJCC-8 stage IIB or IIC melanoma. We present results of the first recurrence-free survival (RFS) interim analysis.

Methods

Eligible pts aged ≥12 years with complete resection of cutaneous stage IIB or IIC melanoma with negative sentinel lymph node biopsy were randomized 1:1 to pembro 200 mg (2 mg/kg for pediatric pts) or placebo Q3W for 17 cycles (up to 1 year). Randomization was stratified by T category 3b, 4a, 4b (adults) with a separate stratum for pediatric pts. Treatment continued until disease recurrence or unacceptable toxicity. The primary endpoint was RFS per investigator assessment. Safety was also evaluated. The data cutoff date for the interim analysis was December 4, 2020.

Results

Overall, 976 pts (64% stage IIB; 34.8% stage IIC) were randomized (487 pembro; 489 placebo). At median follow-up of 14.4 months, pembro significantly prolonged RFS vs placebo (HR 0.65, 95% CI 0.46-0.92; P=0.00658; median not reached for both). 54 (11.1%) vs 82 (16.8%) pts had a recurrence with almost halving of distant recurrence events in the pembro (23) vs placebo (38) group. The 12-month RFS rate was 90.5% vs 83.1%. Grade ≥3 any-cause AEs occurred in 125 (25.9%) vs 83 (17.1%) pts in the pembro vs placebo group. Grade ≥3 drug-related AEs occurred in 78 (16.1%) vs 21 (4.3%) pts; 74 (15.3%) vs 12 (2.5%) discontinued due to a drug-related AE. No deaths due to any-cause AE or drug-related AEs occurred with pembro; four deaths due to any-cause AEs occurred with placebo. Immune-mediated AEs occurred in 36.2% vs 8.4%, most commonly hypothyroidism (15.7% vs 3.5%) and hyperthyroidism (10.4% vs 0.6%). Most were grade 1-2 in severity.

Conclusions

Adjuvant pembrolizumab for resected stage IIB and IIC melanoma decreased the risk of disease recurrence or death by 35% compared with placebo and was associated with significantly prolonged RFS and a favorable benefit-risk profile.

Clinical trial identification

NCT03553836; EudraCT 2018-000669-35; First posted: June 12, 2018.

Editorial acknowledgement

Editoral assistance was provided by Luana Atherly-Henderson, PhD, CMPP an employee of Merck Sharp & Dohme, Corp.

Legal entity responsible for the study

Merck Sharp & Dohme Corp.

Funding

Merck Sharp & Dohme Corp.

Disclosure

J.J. Luke: Financial Interests, Personal, Advisory Board: 7 Hills; Financial Interests, Personal, Advisory Board: Fstar; Financial Interests, Personal, Advisory Board: RefleXion; Financial Interests, Personal, Advisory Board: Alphamab Oncology; Financial Interests, Personal, Advisory Board: Arch Oncology; Financial Interests, Personal, Advisory Board: Kanaph; Financial Interests, Personal, Advisory Board: Onc.AI; Financial Interests, Personal, Advisory Board: Pyxis; Financial Interests, Personal, Advisory Board: Tempest; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Alnylam; Financial Interests, Personal, Advisory Board: Array; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Checkmate; Financial Interests, Personal, Advisory Board: Cstone; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Flame; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Kadmon; Financial Interests, Personal, Advisory Board: KSQ; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Immunocore; Financial Interests, Personal, Advisory Board: Inzen; Financial Interests, Personal, Advisory Board: Crown; Financial Interests, Personal, Advisory Board: Macrogenics; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: Nektar; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Regeneron; Financial Interests, Personal, Advisory Board: Ribon; Financial Interests, Personal, Advisory Board: Rubius; Financial Interests, Personal, Advisory Board: Silicon; Financial Interests, Personal, Advisory Board: Synlogic; Financial Interests, Personal, Advisory Board: TRex; Financial Interests, Personal, Advisory Board: Werewolf; Financial Interests, Personal, Advisory Board: Xilio; Financial Interests, Personal, Advisory Board: Xencor; Financial Interests, Personal, Ownership Interest: Actym; Financial Interests, Personal, Ownership Interest: Alphamab Oncology; Financial Interests, Personal, Ownership Interest: Arch Oncology; Financial Interests, Personal, Ownership Interest: Kanaph; Financial Interests, Personal, Ownership Interest: Mavu; Financial Interests, Personal, Ownership Interest: Onc.AI; Financial Interests, Personal, Ownership Interest: Pyxis; Financial Interests, Personal, Ownership Interest: Tempest; Financial Interests, Institutional, Invited Speaker: AbbVie; Financial Interests, Institutional, Research Grant: Agios; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Invited Speaker: Astellas; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Corvus; Financial Interests, Institutional, Invited Speaker: EMD Serono; Financial Interests, Institutional, Invited Speaker: Genmab; Financial Interests, Institutional, Invited Speaker: Ikena; Financial Interests, Institutional, Invited Speaker: Immatics; Financial Interests, Institutional, Invited Speaker: Incyte; Financial Interests, Institutional, Invited Speaker: Kadmon; Financial Interests, Institutional, Invited Speaker: KAHR; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Moderna; Financial Interests, Institutional, Invited Speaker: Nektar; Financial Interests, Institutional, Invited Speaker: Numab; Financial Interests, Institutional, Invited Speaker: Replimmune; Financial Interests, Institutional, Invited Speaker: Rubius; Financial Interests, Institutional, Invited Speaker: Fstar; Financial Interests, Institutional, Invited Speaker: Synlogic; Financial Interests, Institutional, Invited Speaker: Takeda; Financial Interests, Institutional, Invited Speaker: Trishula; Financial Interests, Institutional, Invited Speaker: Tizona; Financial Interests, Institutional, Invited Speaker: Xencor. P. Rutkowski: Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Blueprint Medicines; Financial Interests, Personal, Invited Speaker: Philogen. P. Queirolo: Financial Interests, Advisory Role: Bristol Myers Squibb; Financial Interests, Advisory Role: MSD; Financial Interests, Advisory Role: Merck; Financial Interests, Advisory Role: Novartis; Financial Interests, Advisory Role: Pierre Fabre; Financial Interests, Advisory Role: Sun Pharma; Financial Interests, Advisory Role: Sanofi-Regeneron; Financial Interests, Advisory Role: Roche. M. Del Vecchio: Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Advisory Role: Sanofi. J. Mackiewicz: Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: MSD. V. 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G.V. Long: Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Personal, Advisory Role: Aduro Biotech Inc; Financial Interests, Personal, Advisory Role: Amgen Inc; Financial Interests, Personal, Advisory Role: Array Biopharma Inc; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Evaxion Biotech A/S; Financial Interests, Personal, Advisory Role: Hexel AG; Financial Interests, Personal, Advisory Role: Highlight Therapeutics SL; Financial Interests, Personal, Advisory Role: Merck Sharp Dohme; Financial Interests, Personal, Advisory Role: Novartis Pharma AG; Financial Interests, Personal, Advisory Role: OncoSec; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: QBiotics Group Limited; Financial Interests, Personal, Advisory Role: Regeneron Pharmaceutical Inc; Financial Interests, Personal, Advisory Role: SkylineDX BV; Financial Interests, Personal, Advisory Role: Specialised Therapeutics Australia Pty Ltd. 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