Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors

Abstract

Background: The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.

Methods: Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.

Results: Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.

Conclusions: Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.

Trial registration number: NCT02407990.

Keywords: immunotherapy; oncology; programmed cell death 1 receptor; tumors.

Conflict of interest statement

Competing interests: JD has served in a consulting or advisory role for Amgen, BeiGene, Bionomics, Eisai, Eli Lilly and Novartis, and their institution has received research funding from Bionomics, GlaxoSmithKline, Novartis and Roche. SD has received personal fees from Roche; C-CL has served in a consulting or advisory role for Novartis and has received travel, accommodations and expenses from BeiGene; BK has received grants and personal fees from AstraZeneca and MSD Oncology, grants from Ono Pharmaceutical and personal fees from Genexin; MJ's institution has received research funding from BeiGene, Merck Sharp & Dohme, Pfizer and Bristol-Myers Squibb; BM has served in a consultancy or advisory role for Novartis; LH has received grants from Astellas; MF has received honoraria from AstraZeneca, Merck Sharp & Dohme, Lilly, Takeda and Novartis, serves in a consulting or advisory role for AstraZeneca, Merck Sharp & Dohme and has received research funding from BeiGene and AstraZeneca. AH is employed by, has a leadership role in and has stock or other ownership in, Tasman Healthcare/Tasman Oncology Research. SS has received grants from Merck, Britsol-Meyers Squibb, Amgen, Endocyte, AstraZeneca and Roche; PB has received personal fees from Roche; LL, C-YW, JW, VP and YZ are employees of BeiGene; MM serves in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche, and has received travel, accommodations and expenses from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Roche.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study design. CRC, colorectal cancer; Q3W, every 3 weeks.

Figure 2

Concentration of tislelizumab following a single 200 mg dose vs single 2 and 5 mg dose.