Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors

Toshio Shimizu, Takashi Seto, Fumihiko Hirai, Mitsuhiro Takenoyama, Kaname Nosaki, Junji Tsurutani, Hiroyasu Kaneda, Tsutomu Iwasa, Hisato Kawakami, Kazuo Noguchi, Takashi Shimamoto, Kazuhiko Nakagawa, Toshio Shimizu, Takashi Seto, Fumihiko Hirai, Mitsuhiro Takenoyama, Kaname Nosaki, Junji Tsurutani, Hiroyasu Kaneda, Tsutomu Iwasa, Hisato Kawakami, Kazuo Noguchi, Takashi Shimamoto, Kazuhiko Nakagawa

Abstract

Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.

Keywords: Anti-PD-1 therapy; PD-L1; Pembrolizumab; Pharmacokinetics; Phase I study.

Figures

Fig. 1
Fig. 1
Serum concentration–time profiles of pembrolizumab following the first administration. Symbols and error bars indicate the mean ± SD
Fig. 2
Fig. 2
PK parameters versus dose following the first administration of pembrolizumab in Japanese and non-Japanese patients with advanced solid tumors. AUC0-∞ total area under the concentration–time curve, Cmax maximum concentration, CL clearance, Vz the terminal phase volume
Fig. 3
Fig. 3
PET-CT images taken before the start of treatment and after cycle 7 show evidence of antitumor activity. A rapid and durable partial response according to irRC was observed in a 91-year-old man with advanced metastatic acral lentiginous melanoma who had active disease in the liver and multiple lymph nodes when treatment with pembrolizumab at 10 mg/kg Q2W was initiated

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Source: PubMed

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