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

Abstract

BackgroundThe 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.MethodsPatients (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.ResultsBetween 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.ConclusionsTislelizumab 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 numberNCT02407990.

Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC)

“…Time-varying clearance was not observed; clearance and volume of distribution of the central compartment were estimated as 0.164 L/day and 2.92 L, respectively [39]. The estimated terminal half-life of tislelizumab 200 mg Q3W was 16.8 ± 5.5 days [40]. Covariate analysis of population pharmacokinetics indicated that dose adjustments were not needed based on age, sex, race, body weight, tumor size, serum albumin level, or immunogenicity status [39].…”

“…Of the 49 evaluable patients with NSCLC treated with tislelizumab 200 mg Q3W in the phase 1B dose-expansion phase, an objective response rate of 12.2% (95% CI: 4.6, 24.8) was observed, despite a high proportion of patients having received prior systemic drug therapy (n = 44, 90%) [40,41]. Clinical benefit was observed in both Asian and non-Asian patients [40], as well in patients with PD-L1-positive (≥25% of tumor cells exhibiting PD-L1 membrane) staining and PD-L1-negative (<25% PD-L1 tumor cell expression) tumors [41]. Across all patients from an openlabel phase 1/2 study conducted in China (BGB-A317-102; NCT04068519), treatment with tislelizumab resulted in a median overall survival of 11.5 months (95% CI: 9.1, 15.0) with a median follow-up of 12.2 months [42].…”

“…1A/1B first-in-human study (BGB-A317-001; NCT02407990), tislelizumab treatment in all patients (n = 451) resulted in a median overall survival of 10.3 months (95% CI: 8.5, 11.6) with a median duration of study follow-up of 8.6 months (range: 0.1, 40.8) [40]. Of the 49 evaluable patients with NSCLC treated with tislelizumab 200 mg Q3W in the phase 1B dose-expansion phase, an objective response rate of 12.2% (95% CI: 4.6, 24.8) was observed, despite a high proportion of patients having received prior systemic drug therapy (n = 44, 90%) [40,41]. Clinical benefit was observed in both Asian and non-Asian patients [40], as well in patients with PD-L1-positive (≥25% of tumor cells exhibiting PD-L1 membrane) staining and PD-L1-negative (<25% PD-L1 tumor cell expression) tumors [41].…”

“…As monotherapy, the adverse events reported in patients treated with tislelizumab were manageable and generally mild-to-moderate in severity [40,42]. In the first-in-human study, median treatment duration of tislelizumab was 2.8 months (range: 0.13-43.7) and 65 patients (14.4%) received treatment for ≥12 months [40].…”

MicroPhenoDB Associates Metagenomic Data with Pathogenic Microbes, Microbial Core Genes, and Human Disease Phenotypes

“…Bear in mind that these phenotypes of SARS-CoV-2 infection might be frequent complications of other diseases and treatments. For example, dyspnea is a frequent complication of chronic respiratory diseases [46], lung cancer [47], and hepatopulmonary syndrome [48]; septic shock is a complication of pneumococcal pneumonia, chronic corticosteroid treatment, and current tobacco smoking [49]; fatigue is a complication of multi-type cancers [50,51] and Parkinson's disease [52]; and lymphopenia is a complication of human immunodeficiency viral infection [53].…”