A phase 1 study of the anti-CC chemokine receptor 4 antibody, mogamulizumab, in combination with nivolumab in patients with advanced or metastatic solid tumors.

Doi, Toshihiko; Muro, Kei; Ishii, Hiroshi; Kato, Terufumi; Tsushima, Takahiro; Takenoyama, Mitsuhiro; Oizumi, Satoshi; Gemmoto, Kazuto; Suna, Hideaki; Enokitani, Kouki; Kawakami, Tetsuyoshi; Nishikawa, Hiroyoshi; Yamamoto, Noboru

PURPOSE Regulatory T-cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab (anti-programmed death-1 [PD-1] antibody) in immunotherapy-naive patients with advanced/metastatic solid tumors. EXPERIMENTAL DESIGN This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose-escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted. RESULTS 96 patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculo-papular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T-cells in tumor-infiltrating lymphocytes increased. CONCLUSIONS Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.