John M. Kirkwood, MD
Adjuvant treatment of patients with intermediate- and high-risk melanoma has changed drastically in the past decade, according to John M. Kirkwood, MD, whose pioneering work helped launch the first therapies in this disease setting more than 20 years ago.
“The goal we want to accomplish with adjuvant therapy in intermediate- and high-risk patients with melanoma is to reduce the risk of relapse [ie, improve relapse-free survival; RFS], improve overall survival [OS], and to provide a tolerable safety profile,” explained Kirkwood, who is the Usher Professor of Medicine, Dermatology & Translational Science at the University of Pittsburgh (UP) School of Medicine, and director of the Melanoma Center at the UP Medical Center’s Hillman Cancer Center. In 2017, he was named a Giants of Cancer Care®
award winner in the melanoma category.
After its approval in 1995, interferon alfa-2b was the most usual go-to regimen offered in the adjuvant setting. Now, however, targeted therapies, checkpoint inhibitors, and novel combination strategies have improved response rates for patients with melanoma.
For example, ipilimumab (Yervoy) was FDA approved in 2015 for the adjuvant treatment of patients with stage III melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, based on the results from the phase III EORTC 19071 study.
In this study, adjuvant ipilimumab, administered at 10 mg/kg, reduced the risk of recurrence by 25% versus placebo (HR, .075; 95% CI, 0.64-0.90; P
The trial included 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes. Patients were randomized to receive ipilimumab or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years.
At a median follow-up of 2.74 years, 324 and 294 RFS events occurred in the ipilimumab and placebo arms, respectively. The 3-year RFS rate was 46.5% in the ipilimumab arm compared with 34.8% in the placebo group. Grade 3 to 5 adverse events (AEs) occurred in 41% of patients who received ipilimumab.
Additionally, the phase III ECOG 1609 study is randomizing patients to adjuvant ipilimumab, at 2 different dose levels, versus high-dose interferon alfa-2b for patients with resected melanoma (NCT01274338).
“The ECOG 1609 study casts doubt upon the need for high-dose ipilimumab as there was no difference between patients treated with 3 mg/kg versus 10 mg/kg of ipilimumab. However, the results of the comparison of the 2 regimens awaits maturation,” Kirkwood said.
Additionally, in December 2017, the FDA approved the PD-1 inhibitor nivolumab (Opdivo) as an adjuvant treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease, based on the findings from the phase III CheckMate-238 trial. In this study, patients were randomized to 1 year of treatment with nivolumab or ipilimumab.
This randomized trial demonstrated that the RFS rate at 18 months with nivolumab was 66.4% (95% CI, 61.8%-70.6%) compared with 52.1% (95% CI, 47.8%-57.4%) for ipilimumab for patients with stage IIIB/C or IV melanoma.2
There was a 35% reduction in the risk of recurrence or death with nivolumab versus ipilimumab (HR, 0.65; 95% CI, 0.53-0.80; P
<.0001). Treatment-related grade 3/4 AEs were much more common in the ipilimumab group compared with the nivolumab arm (14.4% vs 45.9%).
“Nivolumab provides an acceptable benefit-risk ratio as adjuvant therapy for high-risk resected melanoma, reducing the risk of recurrence in resected stage III and IV melanoma,” Kirkwood added, speaking of the immunotherapy trial.
Pembrolizumab (Keytruda), also a PD-1 inhibitor, was investigated in the adjuvant setting for patients with stage III resected high-risk melanoma in the KEYNOTE-054 trial.3
These findings demonstrated that pembrolizumab reduced the risk of recurrence by 43% in this patient population. The hazard ratio for RFS was 0.57 for pembrolizumab versus placebo (98.4% CI, 0.43-0.74; P
<.0001). There were no new safety concerns in this trial compared with outcomes of previous studies investigating the PD-1 inhibitor.
Targeted Therapy Study
According to Kirkwood, another pivotal study for this setting was the COMBI-AD trial, which investigated dabrafenib (Tafinlar) with trametinib (Mekinist) as an adjuvant treatment for patients with BRAF
V600E– or V600K–positive stage III melanoma following complete resection. This combination was granted a priority review designation by the FDA in December 2017.
“This is the first randomized study of a combination of BRAF and MEK inhibition as a melanoma adjuvant therapy, making it a novel adjuvant treatment,” Kirkwood said.
In COMBI-AD, the combination reduced the risk of disease recurrence or death by 53% compared with placebo for patients with BRAF-
mutant stage III melanoma.4
After a median follow-up of 2.8 years, the 3-year RFS rate with dabrafenib and trametinib was 58% compared with 39% for the placebo arm (HR, 0.47; 95% CI, 0.39-0.58; P
This trial randomized 870 patients with BRAF V600E/K stage III melanoma to receive dabrafenib plus trametinib (n = 438) or placebo (n = 432). Early data for OS showed that 86% of patients in the combination arm were still alive at 3 years versus 77% with placebo (HR, 0.57; 95% CI, 0.42-0.79; P
- Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial [published correction appears in Lancet Oncol. 2015;16(6):e262]. Lancet Oncol. 2015;16(5):522-530. doi: 10.1016/S1470-2045(15)70122-1.
- Weber J, Mandala M, Del Vecchio M, et al; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835. doi: 10.1056/NEJMoa1709030.
- Merck’s Keytruda (pembrolizumab) significantly improved recurrence-free survival compared to placebo as adjuvant therapy in patients with stage 3 resected high-risk melanoma (EORTC1325/KEYNOTE-054) [news release]. Kenilworth, NJ: Merck; January 8, 2018. mrknewsroom.com/news-release/oncology/mercks-keytruda-pembrolizumab-significantly-improved-recurrence-free-survival-. Accessed April 12, 2018.
- Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823. doi: 10.1056/NEJMoa1708539.