Zanubrutinib Plus Obinutuzumab in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Cll/Sll) or Relapsed/Refractory (R/R) Follicular Lymphoma (Fl)

Abstract

14 pts (14/30, 46%) and 18 SAE's occurred in 12 pts (12/30, 40%).Four immune-related adverse events (IRAE) occurred: grade 3 rash, grade 1 hyperthyroidism, grade 2 colitis, and grade 3 pneumonitis (in a 78 y.o. with a history of tobacco use and COPD). One pt. died during cycle 1 from bleed of gastric DLBCL, despite inpatient management, and was not assessed for response or dose intensity.Anthracycline relative dose intensity was 94.7%. 26/29 received all planned P. ORR in 29 assessable pts was 93%: 24 CR (83%), 3 PR (19%) and 2 SD/PD (7%). 19 pts had PET-CR on EOT assessment; 3 had initial PR but a negative biopsy, and 2 had PR converted to CR with repeat PET. Among 8 pts with residual FDG-avid lesions on EOT PET, only 1 relapse occurred.At 16 months follow-up, four relapses and 2 deaths occurred, with PFS/OS of 82/97% at 18 months ( Figure 1). In 22 tested pts to date, 55% had PDL-1 tumor cell ≥ 30%, and PDL H-score (a weighted average) was 0 in 3 pts, 1-99 in 9 pts, and 100 or more in 10 pts. PFS was inferior in PDL1 H score 0 pts (p<.001) and IPI 3-5 pts (p=.07), but no different in GCB vs non-GCB. Conclusions: P + RCHOP did not show toxicity beyond what isexpected with RCHOP, and was associated with a high CR rate in this trial. FDG avid lesions in pts with PR were commonly false positives.Significant PDL-1 tumor staining was seen in most pts tested, and appears to predict PFS; final PDL-1 results will be presented. Our data supports further comparative study of P+RCHOP in DLBCL. Introduction: Bruton Tyrosine Kinase (BTK) plays a critical role in B cell receptor (BCR) signaling. Zanubrutinib is a selective and irreversible BTK inhibitor that has demonstrated potent inhibition of BTK preclinically, with minimal inhibition of other kinases; it has minimal effect on interleukin-2 inducible tyrosine kinase (ITK) and does not inhibit ITK-mediated rituximab-induced antibody-mediated cytotoxicity. Methods: This is a phase 1b study of the combination of zanubrutinib with obinutuzumab in patients with B-cell malignancies. Eligible ABSTRACT 121 patients had ECOG status of 0-2, neutrophil count >1000/μL, platelets >40,000/μL, adequate renal and hepatic function and no significant cardiac disease. Growth factors, transfusion and anticoagulation were allowed. The primary efficacy endpoint was objective response using 2007 International Working Group criteria. Results: As of 16Nov2018, enrollment was complete with 45 CLL/SLL patients (20 treatment-naïve [TN] and 25 R/R) and 36 R/R FL patients. Median follow-up was 25.5 mo (range: 7.9-33.5) for CLL/SLL and 17.8 mo (range: 2.3-33.8) for R/R FL. One fatal adverse event (AE) occurred: squamous cell carcinoma in a CLL patient with prior squamous cell carcinoma. Serious AEs were reported in 22 (49%) CLL/SLL and 12 (33%) R/R FL patients.Common (>20%) any-grade AEs reported in CLL/SLL patients were upper respiratory tract infection (URTI; 49%), neutropenia (42%), contusion (33%), diarrhea (27%), cough (27%), fatigue (27%), and pyrexia (22%); and in FL patients were URTI (39%), con...

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma

“…Zanubrutinib has demonstrated a favorable safety profile and robust activity in several clinical studies treating B-cell malignancies. [10][11][12] On the basis of the safety and efficacy of zanubrutinib in other B-cell malignancies, which showed preliminary data with more favorable pharmacokinetic and pharmacodynamic properties, 13 in the current phase 2 study we aim to evaluate the efficacy and safety of zanubrutinib in patients with relapsed or refractory (R/R) non-GCB DLBCL in China.…”

Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia

“…Second-generation covalent inhibitors of BTK share with ibrutinib the same root designation “brutinib” and also have comparable clinical activity. Among these are acalabrutinib, 15 tirabrutinib (ONO/GS-4059), 16 and zanubrutinib (BGB-3111) 17 . Each is touted to have a potentially higher therapeutic index than ibrutinib due to greater specificity for BTK and/or different mechanisms of action, potentially resulting in fewer “off-target” effects.…”

“…Among these are acalabrutinib, 15 tirabrutinib (ONO/GS-4059), 16 and zanubrutinib (BGB-3111). 17 Each is touted to have a potentially higher therapeutic index than ibrutinib due to greater specificity for BTK and/or different mechanisms of action, potentially resulting in fewer "off-target" effects. One study showed that patients who were intolerant of ibrutinib could tolerate therapy with acalabrutinib.…”

Cytotoxicity of the CD3×CD20 bispecific antibody epcoritamab in CLL is increased by concurrent BTK or BCL-2 targeting

“…Covalent BTKis that do not inhibit ITK include acalabrutinib and zanubrutinib. 5 , 6 Although side effect profiles differ, the 3 BTKis demonstrated potent clinical efficacy. 5 , 6 , 7 , 8 , 9 , 10 Although the depth of response tends to improve with extended therapy, minimal residual disease–negative remissions are uncommon with BTKis.…”

“… 5 , 6 Although side effect profiles differ, the 3 BTKis demonstrated potent clinical efficacy. 5 , 6 , 7 , 8 , 9 , 10 Although the depth of response tends to improve with extended therapy, minimal residual disease–negative remissions are uncommon with BTKis. 11 , 12 , 13 The most common reasons for BTKi discontinuation are disease progression and side effects.…”