Tislelizumab, an Anti-PD1 Antibody, in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma in Tirhol Bgb-A317-210: A Prospective Multicenter Lysa Phase 2 Study Conducted in Western Countries

Background: Programmed cell death protein 1 (PD-1) blockade is commonly used to treat relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) but the overall response rates (ORR) and complete response rates (CRR) of approved anti-PD1 antibodies remain suboptimal. Tislelizumab blocks PD-1 with a high specificity and affinity and minimized FcγR binding on macrophages leads to reduced clearance. Results of the initial phase 2 study of tislelizumab in Chinese patients with RR cHL were impressive, with ORR and CRR of 87% and 63%, respectively, and 3-year progression free survival (PFS) of 40%, warranting further evaluation in a Western population with different standard of care, including more frequent use of autologous stem cell transplantation (ASCT) and targeted agents. Methods: TIRHOL (NCT04318080) is an international, prospective phase 2 study for patients with RR cHL conducted in France, Belgium, USA and Australia. Cohort 1 includes patients who previously underwent ASCT; cohort 2 includes patients who were ineligible for ASCT. Prior therapy with brentuximab vedotin (BV) was required in initial design; the protocol was amended to remove this criterion for both cohorts in October 2021. Tislelizumab 200 mg is given intravenously every 3 weeks until progressive disease (PD), unacceptable toxicity, or study withdrawal; tumor assessments are performed every 12 weeks. The primary endpoint is the ORR (best overall response of CR or partial response [PR]), as assessed by investigator, according to PET-CT International Lugano 2014 criteria. Null hypothesis is ORR = 45 % based on previous clinical trials and alternative hypothesis is ORR > 45%. Assuming the observed ORR = 65%, a sample size of 42 patients provides ≥ 80% power of at the one-sided 5% significance level. Secondary endpoints are CRR, time to response (TTR), duration of response (DOR), safety and tolerability of tislelizumab. Main exploratory endpoints are PFS and overall survival (OS). Results: Patients who received at least 1 dose of tislelizumab were included in the analysis. Between August 2020 and September 2022, 45 patients (14 in cohort 1 and 31 in cohort 2) were enrolled and dosed. At inclusion, the median age was 64 years (range 18-87), 67% were male and all had ECOG performance status 0-1; most patients had advanced stage disease (38% III, 42% IV), 11% had bulky disease, 18% had B symptoms and 29% had disease refractory to last therapy. The median prior lines of therapy received was 2 (1 - 4