S224: PRELIMINARY RESULTS OF A PHASE II STUDY OF ORELABRUTINIB IN COMBINATION WITH ANTI-PD-1 MONOCLONAL ANTIBODY IN REFRACTORY OR RELAPSED PRIMARY CNS LYMPHOMA

Abstract

Background: The survival outcomes of patients with relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL) remain extremely poor and there are no approved therapies or widely accepted “standard-of-care” approaches. Previous studies showed that Bruton tyrosine kinase (BTK) inhibitor and anti-programmed death protein-1(PD-1) monoclonal antibody have significant activities in R/R PCNSL, respectively. The combination of BTK inhibitor and anti-PD-1 monoclonal antibody demonstrated synergistic effects both in vivo and in vitro in diffuse large B cell lymphoma, but no clinical data is currently available for PCNSL. Orelabrutinib is a new-generation BTK inhibitor with high CSF concentration and sintilimab is a new-generation anti-PD-1 monoclonal antibody. Aims: To evaluate the safety and efficacy of orelabrutinib combined with sintilimab in patients with R/R PCNSL. Methods: The prospective, multicenter, single-arm phase II study (NCT04899427) enrolled immunocompetent adult patients with R/R PCNSL and eligible organ functions. The patients received once daily orelabrutinib (150mg) in combination with sintilimab (200mg on day 1 of each cycle) every 3 weeks per cycle up to two years or until disease progression, intolerable toxicity, or death. The primary objective was the overall response rate (ORR; defined as partial response [PR] or better) after 4 cycles. Other endpoints mainly included 1-year progression free survival (PFS) rate, time to response (TTR) and safety. Results: The data cut-off date was February 25, 2022. Thirteen patients were enrolled from March 2021 to January 2022, with a median follow-up of 7.0 (1.5-10.5) months. Median age was 61 yr (range 48 to 71) and 6 (46.1%) were male. The median lines of prior treatment were 2 (range 1 to 4). All the patients were high-dose methotrexate treated, seven of those (53.8%) were refractory to the last treatment. Ten patients completed 4 cycles of the experimental regimen while 3 patients ended of treatment in the first 2 cycles due to disease progression. The toxicities were quite mild, with one grade 3 adverse event (AE) of interstitial pneumonitis related pneumocystis carinii infection. No other Grade 3-4 hematological or non-hematological AE was reported. All patients were evaluable for response. The ORR was 61.5%, and 4 patients achieved complete remission (CR), 1 CRu, and 3 PR. The median TTR was 6 weeks (2 to 4 cycles). No relapses were observed in patients who achieved ORR after 4 cycles. Only 1 patient died of disease progression (Fig. 1). The estimated median1-year PFS rate was 67.7% (Fig. 2). Plasma and CSF sample from 4 of 13 patients were collected at 2 h after 15 days orelabrutinib administration. The median CSF concentration of orelabrutinib was 28.7ng/ml (rang 11.8 ng/ml to 52.7 ng/ml). The median CSF/plasma free ratio was 59.8%(rang 46.09% to 86.67%). Image:Summary/Conclusion: The combination of orelabrutinib and sintilimab showed a high ORR and a rapid onset of response in patients with r/r PCNSL with well-tolerated toxicities. Although preliminary, these results supported the use of BTK inhibitor plus anti-PD-1 monoclonal antibody. More clinical data will be updated from this ongoing study.