Adjuvant Pembrolizumab May Improve High-Risk Stage III Melanoma RFS

EORTC 1325/KEYNOTE-054 findings point to a potential survival benefit with adjuvant pembrolizumab treatment for high-risk stage III resectable melanoma

medwireNews:  Patients who receive up to a year of adjuvant pembrolizumab therapy after resection of stage III melanoma with metastatic disease in at least one regional lymph node have a significantly longer time to disease recurrence than those given placebo, research suggests.
The findings of the EORTC 1325/KEYNOTE-054 trial were reported at the American Association of Cancer Research annual meeting 2018, in Chicago, Illinois, USA, and simultaneously published in The New England Journal of Medicine.
Co-chair of the meeting’s Clinical Trials Committee, Louis Weiner, from Georgetown Lombardi Comprehensive Cancer Center in Washington, USA, commented at a press conference that the “remarkable” findings are “ushering in a new era of earlier use of these checkpoint antibodies in the life cycle of these patients”.
“[I]t’s going to change the management of this specific stage and it’s going to inform the future efforts to extend this kind of strategy into other cancers where checkpoint antibodies might be useful”, he emphasized.
The 12-month recurrence-free survival rate (RFS) was 74.5% for the 514 patients who were randomly assigned to receive pembrolizumab 200 mg once every 3 weeks for up to 18 doses, versus 61.0% for the 505 patients instead treated with placebo, giving a significant hazard ratio (HR) of 0.57.
The second co-primary endpoint of 12-month RFS in a subgroup of 852 patients with PD-L1-positive tumours – using a melanoma-specific immunohistochemistry assay, where 2 or higher on a 5-point scale represented positivity in at least 1% of cells –  also significantly favoured use of adjuvant pembrolizumab (HR=0.54). But 12-month RFS was also significantly better with adjuvant pembrolizumab versus placebo for the 116 patients with PD-L1-negative disease (HR=0.47).
Discussing this finding at the press conference, presenting author Alexander Eggermont, from Gustave Roussy Cancer Campus Grand Paris in France, explained that as PD-L1 expression “changes over time”, immunohistochemistry gives only a “snap shot” of expression in a small sentinel node tumour sample. This may explain why the “immune therapy has basically the same outcome in both patient populations”, he said.
During treatment, one patient died from pembrolizumab-related myositis, and the overall rate of drug-related grade 3–5 adverse events was 14.7% with pembrolizuamb versus 3.4% with placebo. 
Immune-related adverse events were mainly grade 1–2, namely endocrine disorders (23.4 vs 5.0%), hypothyroidism (14.3 vs 2.8%), hyperthyroidism (10.4 vs 1.2%) and thyroiditis (3.1 vs 0.2%). Grade 3–4 immune-related events affected 7.1% of pembrolizumab-treated patients and 0.6% of controls, most commonly colitis (2.0 vs 0.2%), pneumonitis (0.8 vs 0%) and hepatitis (1.4 vs 0.2%).
Alexander Eggermont also highlighted in a press release that the trial design which has allowed adjuvant pembrolizumab to be offered for placebo-treated patients with relapse.
“This cross-over design is unique in the world of adjuvant trials in melanoma and will permit us to analyze if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse”, he commented.
The current RFS analysis occurred after patients were followed-up for a median of 1.25 years and a longer duration is required to see if the RFS benefits translate to improved overall survival.
However, Louis Weiner said that these initial results were “compelling” and observed that “when these kinds of large improvements in relapse-free survival have been found in the more metastatic disease settings they have almost always been associated with survival advantages when we’ve waited long enough.”
Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumb versus placebo in resected stage III melanoma . N Engl J Med; Advance online publication 15 April 2018. 
DOI: 10.1056/NEJMoa1802357
Associated press release  

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