The phase 1/2 KEYMAKER-U02 trial has demonstrated that neoadjuvant pembrolizumab (Keytruda), either as monotherapy or in combination with vibostolimab or gebasaxturev, followed by adjuvant pembrolizumab, shows a manageable safety profile in patients with stage IIIB-D melanoma. The findings, published in Nature Medicine, provide important insights into new treatment approaches for advanced melanoma.
Safety Profile and Adverse Events
The trial, which enrolled 66 patients, reported that 95% of participants experienced at least one adverse event (AE). Treatment-related adverse events (TRAEs) were observed across all treatment arms, with the pembrolizumab/vibostolimab combination showing a 92% TRAE rate, pembrolizumab/gebasaxturev at 84%, and pembrolizumab monotherapy at 80%.
The most frequently reported adverse events included:
- Pruritus (46% in pembrolizumab/vibostolimab arm)
- Fatigue (38% across treatment arms)
- Vitiligo (27% in combination therapy arms)
Grade 3 or 4 adverse events varied among the treatment arms, affecting 15% of patients in the pembrolizumab/vibostolimab arm, 40% in the pembrolizumab/gebasaxturev arm, and 27% in the monotherapy arm. Notably, no treatment-related deaths occurred during the study.
Treatment Protocol and Study Design
The trial randomly assigned patients in a 1:1:1 ratio to three treatment arms:
- Pembrolizumab plus vibostolimab (26 patients)
- Pembrolizumab plus gebasaxturev (25 patients)
- Pembrolizumab monotherapy (15 patients)
The neoadjuvant phase consisted of pembrolizumab administered at 200mg or 400mg intravenously, depending on the treatment arm, with combination therapies administered according to specific protocols. Following six weeks of neoadjuvant treatment, all patients underwent surgical resection and received adjuvant therapy with pembrolizumab.
Efficacy Outcomes
The study demonstrated encouraging efficacy results across all treatment arms. Pathological complete response (pCR) rates were:
- 38% for pembrolizumab/vibostolimab
- 28% for pembrolizumab/gebasaxturev
- 40% for pembrolizumab monotherapy
Major pathologic responses, which include both pCR and near pCR, were observed in 50%, 40%, and 47% of patients in the respective arms. Additionally, pathological partial responses occurred in 31%, 12%, and 27% of patients across the three arms.
Dr. Reinhard Dummer, professor at the University of Zurich and lead investigator, noted that while the efficacy in combination arms was similar to monotherapy, longer follow-up will be necessary to determine any incremental benefits of combining neoadjuvant pembrolizumab with other therapies.
Treatment Completion Rates
The study reported strong treatment completion rates, with the majority of patients completing the neoadjuvant therapy phase. Specifically, 25 patients in the vibostolimab combination arm, 23 in the gebasaxturev combination arm, and 14 in the monotherapy arm completed neoadjuvant treatment. Subsequently, 20, 19, and 11 patients respectively proceeded to receive adjuvant therapy following surgery.
