Adjuvant Immunotherapy Improves Recurrence-Free Survival in Melanoma in KEYNOTE-054

Jeffrey S. Weber, MD, PhD


July 17, 2018

Hello. I'm Dr Jeffrey Weber. I'm a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health. Today I'll discuss a very interesting abstract on the KEYNOTE-054 study. The findings were recently presented at the American Association for Cancer Research annual meeting and published in the New England Journal of Medicine.[1]

This adjuvant immunotherapy trial involved 1019 patients and was conducted by the European Organization for Research and Treatment of Cancer (EORTC). Patients with stage III A, B, and C resected melanoma were randomized 1:1 to receive the programmed death (PD-1) blocking antibody pembrolizumab or placebo. Overall, the two trial arms were well balanced, with a minimal imbalance in patients with macroscopic nodal resected disease. In each arm, 45% of patients had BRAF wild-type melanoma, and a little over 50% were BRAF mutated, which is quite important.

This very impressive, well-conducted, well-powered trial was clearly positive for the pembrolizumab arm. The data clearly show an advantage for pembrolizumab, with a hazard ratio of 0.57 for overall relapse-free survival, with 15 months of follow-up in all patients. The 12-month relapse-free survival was 75% in the pembrolizumab arm and 61% in the placebo arm. At 18 months, those numbers were 71% and 53%, which reflects an 18% absolute difference in relapse-free survival—again, a very impressive number.

The groups were broken down by a number of parameters, including programmed cell death ligand 1 (PD-L1) and BRAF status, as well as by stage, and all subgroups benefited from pembrolizumab adjuvant therapy. Patients with PD-L1-positive tumors had a hazard ratio for recurrence of 0.54. Patients with PD-L1-negative tumors, whom you might think might not benefit as much, had a hazard ratio for recurrence of 0.47. Patients with PD-L1-positive cancer did better, with a 12-month relapse-free survival of 77% compared with 72% for PD-L1- negative patients. Nonetheless, there was clear benefit for both subgroups.

Stage IIIA patients, who generally have a very good outlook, had a hazard ratio of 0.32, which is outstanding. When you break it down by BRAF V600-mutated versus BRAF wild-type, the hazard ratios were still excellent: 0.57 versus 0.64. Again, in the forest plot, virtually all subgroups of patients had clear benefit from pembrolizumab, with superb hazard ratios.

Roughly 10% of patients in the pembrolizumab arm had local regional recurrence compared with 15% in the placebo arm. If distant metastasis [was included] as relapse, either alone or with local regional disease, the recurrence rates were 25% in the placebo arm and 15% in the pembrolizumab arm. Because distant metastasis-free survival is a surrogate for overall survival, I have high hopes that with adequate follow-up we will see a significant benefit in survival. In the data listed, very, very few patients have died thus far, [but this is] with only about 15 months of follow-up in all patients.

In terms of toxicity, as one might expect, pembrolizumab was very well tolerated. About 13% of patients stopped treatment because of an adverse event. The rate of grade III/IV adverse events, immune-related or not, was 14.7%. These data are quite similar to those seen with the use of the FDA-approved nivolumab in a somewhat similar, but worse-risk, patient population.[2]

Overall, the data very definitively both confirm and extend the benefit of adjuvant PD-1 blockade in patients with high-risk, stage III A, B, and C resected melanoma.


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