LBA3 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

Abstract

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; P¼0.00658; 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. Immunemediated 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 Significance of Distant Metastasis-Free Survival (DMFS) in Melanoma: A Narrative Review from Adjuvant Clinical Trials

“…At the ESMO congress in September 2021, the CheckMate 716 interim analysis on pembrolizumab in the adjuvant setting for resected stage IIB-IIC melanoma reported that the risk of disease recurrence or death decreased by 35% compared with placebo, with prolonged RFS and a favorable benefit–risk profile. These promising results may indicate that these stage II patients could also benefit from adjuvant immunotherapy, making its approval likely in the near future [ 59 ]. Another study with the targeted therapy encorafenib/binimetinib is currently ongoing [ 60 ].…”

A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance

“…Given the improved toxicity profile compared with that of ipilimumab, PD-1 blockade has become a standard of care for adjuvant therapy. Recently, adjuvant pembrolizumab received Food & Drug Administration approval for stage-IIb/c melanoma on the basis of its improved RFS compared with that of placebo 104 .…”

Die Systemtherapie des malignen Melanoms

“…Im September 2021 wurde auf dem ESMO-Kongress die erste Interimsanalyse der adjuvanten Phase-3-Studie KEYNOTE-716 vorgestellt 14 , welche den Einsatz von Pembrolizumab im Stadium IIB und IIC gegenüber Placebo überprüft. Dabei zeigte sich das Rezidiv-freie Überleben im Therapiearm signifikant verbessert.…”

“…Im September 2021 wurde auf dem ESMO-Kongress die erste Interimsanalyse der adjuvanten Phase-3-Studie KEYNOTE-716 vorgestellt [14]…”