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Pembrolizumab reduces recurrence risk in stage III melanoma
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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
Reference:
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.
Perspective
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Igor Puzanov, MD, MSCI, FACP
This is another positive trial bringing alternative options to patients with resected stage III malignant melanoma. Results of a similar trial with nivolumab (Opdivo, Bristol-Myers Squibb) were reported at last year’s European Society for Medical Oncology Congress and published in The New England Journal of Medicine.
The important result here is the formal addition of patients with stage IIIA disease with one positive lymph node and tumor of at least 1 mm in a lymph node. These patients were not included in the nivolumab study.
On the other hand, although the nivolumab trial included patients with fully resected stage IV M1a, M1b and M1c disease — for whom nivolumab was effective — the pembrolizumab trial did not include this group. It also is not clear whether — for patients with stage IIIA, B or C disease who have a BRAF mutation — it is better to use dabrafenib (Tafinlar, Novartis) plus trametinib (Mekinist, Novartis), nivolumab (stage IIIB/C disease) or pembrolizumab.
We eagerly await data from the crossover design. That may answer the question of whether starting pembrolizumab early rather than at the time of first detection of metastasis has any effect on ultimate OS outcomes.
Reference:
Weber J, et al. Abstract LBA8_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.
Perspective
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Louis M. Weiner, MD
This study showed adjuvant pembrolizumab is superior to placebo for preventing relapsed melanoma. The benefit persists even when you consider two very important biological barriers — PD-L1 expression and BRAF mutation status. Moreover, the benefit of pembrolizumab was preserved irrespective of stage IIIa, stage IIIb or stage IIIc status. This is remarkable, and it is important. This is really paradigm shifting. One of the reasons I think this is going to be very exciting for our field is because we are really ushering in a new era of using these checkpoint antibodies over the lifecycle of patients with these cancers. It’s going to change the management of this specific stage, and I think it’s going to inform future efforts to extend this kind of strategy into other cancers for which checkpoint inhibitors may be useful. Although the OS data are not yet available, the results are compelling. When these large improvements in RFS have been found in the metastatic setting, they almost always have been associated with improved survival if we wait long enough.
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