Alexander M.M. Eggermont
CHICAGO — Patients with stage III melanoma at high risk for recurrence after surgery demonstrated significantly reduced risk for recurrence after 1 year of treatment with pembrolizumab, according to results from the KEYNOTE-054/EORTC 1325 trial presented at American Association for Cancer Research Annual Meeting.
“Over the course of 15 years, from 1996 to 2009, three type of regimens of interferon were approved by the FDA, but all basically — whether it was high-dose, low-dose or pegylated interferon — had a very marginal impact on stage III melanoma,” Alexander M.M. Eggermont, MD, PhD, director general of Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, said during a press conference. “Now we have a new era where, in a very short amount of time, we’ve seen the new drugs one by one establish their activity in advanced melanoma. They have also been shown to [have a significant impact] in the adjuvant setting.”
Patients with stage IIIa melanoma have a high risk for recurrence. Five-year relapses rates are 37% among those with stage IIIa disease, 68% among those with stage IIIb disease, and 89% among those with stage IIIc disease.
In the double-blind, phase 3 KEYNOTE-054/EORTC 1325 trial, Eggermont and colleagues assessed the efficacy of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) for 1,019 patients with stage III melanoma at high risk for recurrence after complete tumor resection.
All patients underwent complete and adequate resection and had at least one positive sentinel node.
Researchers randomly assigned patients 1:1 to 200 mg pembrolizumab or placebo every 3 weeks for a total of 18 doses, or until disease recurrence or unacceptable toxicity.
At Median follow-up of 1.25 years, 135 of 514 (26.2%) patients assigned pembrolizumab and 216 of 505 patients (42.7%) assigned placebo developed recurrent disease or died.
The results — published simultaneously in The New England Journal of Medicine — showed patients assigned pembrolizumab demonstrated a 43% reduced risk for recurrence than those assigned placebo (18-month RFS, 71.4% vs. 53.2%; HR = 0.57; 98.4% CI, 0.43-0.74).
Researchers observed the reduced recurrence risk among pembrolizumab-treated patients with PD-L1-positive tumors (HR = 0.54; 95% CI, 0.42-0.69) and those with PD-L1-negative tumors (HR = 0.47; 95% CI, 0.26-0.85).
“PD-L1 expression modulates and changes over time. It’s just a snapshot on a very small tumor load; therefore, you may not always assess PD-L1 expression in this context,” Eggermont said.
This may explain why pembrolizumab appeared effective even in PD-L1-negative tumors, he added.
Results of a subgroup analysis showed persistent RFS benefit with pembrolizumab, including among patients with:
- Stage IIIa melanoma (HR = 0.32; 99% CI, 0.09-1.23);
- Stage IIIb melanoma (HR = 0.56; 99% CI, 0.37-0.86);
- Stage IIIc melanoma (HR = 0.58; 99% CI, 0.39-0.88);
BRAF 600E/V mutations (HR = 0.57; 99% CI, 0.37-0.89); and
BRAF wild-type disease (HR = 0.64; 99% CI, 0.42-0.96).
A higher percentage of patients assigned pembrolizumab experienced grade 3 to grade 5 drug-related adverse events (14.7% vs. 3.4%).
Pembrolizumab-treated patients experienced a higher rate of endocrine disorders (23.4% vs. 5%), most of which were grade 1 or grade 2. The most common immune-related adverse events in the pembrolizumab group included hypothyroidism (14.3% vs. 2.8%), hyperthyroidism (10.4% vs. 1.2%) and thyroiditis (3.1% vs. 0.2%). Most were grade 1 or grade 2.
Overall, 39 patients out of 514 patients experienced grade 3 adverse events. The most common grade 3 to grade 4 immune-related adverse events in the pembrolizumab group included colitis (2% for pembrolizumab vs. 0.2% for placebo), hepatitis (1.4% vs. 0.2%) and pneumonitis (0.8% vs. 0%).
One patient assigned pembrolizumab died due to myositis.
Researchers acknowledged limitations of the study, including limited follow-up and inability to determine treatment effect on OS.
“It’s convincingly demonstrated that pembrolizumab does have a significant impact on recurrence free survival, both in the overall population and in the PD-L1-positive patient population, and it’s true across all subgroups,” Eggermont said. “It also had a very favorable safety profile.” – by Cassie Homer
Eggermont AMM, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosures: Merck sponsored the study. Eggermont reports honorarium from Actelion, Agenus, Amgen, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, HalioDx, Incyte, ISA Pharmaceuticals, MedImmune, Merck, Merck Serono, Nektar, Novartis, Pfizer and Sanofi. Please see the abstract for all other authors’ relevant financial disclosures.