Alexander Eggermont, MD of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay explains the ESMO 2020 abstract LBA46 - Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Final results regarding distant metastasis-free survival from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial.
A randomized phase III, double-blind EORTC 1325 / KEYNOTE-054 study was performed to test pembrolizumab versus placebo in patients (pts) with resected stage III high-risk melanoma. Pembrolizumab enhanced recurrence-free survival (RFS) (hazard ratio [HR] 0.57, P<0.0001) relative to placebo at a 1.25-year (yr) median follow-up (Eggermont, NEJM 2018). This resulted in EMA and FDA approval of pembrolizumab adjuvant therapy.
The qualified pts included those aged approximately 18 years with full resection of metastatic cutaneous melanoma to lymph node(s) defined as stage IIIA AJCC-7 (at least one metastatic lymph node > 1 mm), IIIB or IIIC (without in-transit metastasis). 1019 pts were randomized to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks between Aug-2015 and Nov-2016 for a total of 18 doses (about 1 year) or until recurrence of disease or unacceptable toxicity. RFS in the intention-to-treat (ITT) overall population and in pts with PD-L1-positive tumors were the 2 major co-primary endpoints. In these 2 corresponding populations, secondary endpoints included distant metastasis-free survival (DMFS). When approximately 423 DMFS events (distant metastases or deaths) were recorded, the final DMFS analysis was predicted (about 87 percent power to detect an HR of 0.725 in the overall population).
There were 418 DMFS events recorded by April 2020. Pembrolizumab substantially prolonged DMFS in the general 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) at 3.5-yr median follow-up compared with placebo. The effect of pembrolizumab on DMFS was comparable in pts with a PD-L1-negative tumor (N=116; HR 0.49, 99% CI 0.24-0.99) and in other subgroups, with AJCC-7 and -8 staging in particular, and BRAF mutation status. The increase in RFS was verified (HR in the population of ITT 0.59; 95 % CI 0.49-0.70).
Pembrolizumab adjuvant therapy demonstrated clinically significant progress in DMFS in resected high-risk stage III melanoma pts at 3.5-yr median follow-up.
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