COMBINATION of ZANUBRUTINIB + VENETOCLAX for TREATMENT-NAIVE (TN) CLL/SLL with DEL(17P) AND/OR TP53: PRELIMINARY RESULTS from SEQUOIA ARM D.

Abstract

Background: Zanubrutinib (zanu) is a next-generation, selective BTK inhibitor designed to have high BTK specificity and minimize offtarget effects. In several recent studies, fixed-duration BCL2/BTK inhibitor combination treatment was tolerable and led to durable responses in patients with CLL/SLL. As monotherapies, zanu and venetoclax (ven), the first-generation BCL2 inhibitor, have achieved high ORRs in patients with del(17p) and/or TP53 mutation. Aim(s): Here, preliminary results in patients with del(17p) and/orT P53 mutation who received zanu + ven combination treatment in the SEQUOIA trial (arm D) are presented. Method(s): SEQUOIA (NCT03336333) is an open-label, global, phase 3 study; arm D is a nonrandomized cohort of patients aged >=65 years old (or 18-64 years old comorbidities) who had TN CLL/SLL with del(17p) and/or TP53 mutation and met iwCLL criteria for treatment. Patients received zanu (160 mg twice daily) lead-in for 3 cycles, then zanu + ven (ramp-up to 400 mg once daily) for 24 cycles, followed by zanu monotherapy until progressive disease, unacceptable toxicity, or meeting early dose-stopping rules for either zanu or ven (simultaneous achievement of CR/CR with incomplete hematopoietic recovery [CRi] and undetectable minimal residual disease [uMRD; <1x10-4 by flow cytometry in peripheral blood (PB) and bone marrow (BM) on 2 consecutive tests >=12 weeks apart]). Responses were investigator assessed per modified iwCLL and Lugano criteria (SLL) with PB MRD assessments every 3 cycles for 2 years and then every 6 cycles. Safety per CTCAE and risk of tumor lysis syndrome (TLS) per Cairo Bishop criteria pre-treatment and prior to ven administration, were also assessed. Patients at high risk for TLS were those with any lymph node >=10 cm or >=5 cm with absolute lymphocyte count >=25x109/L. Result(s): Between Nov 2019 and Jun 2022, 66 patients with centrally assessed del(17p) and/orT P53 mutation were enrolled. Three discontinued treatment during the zanu lead-in period. As of Oct 31, 2023, with a median study follow-up of 28.6 months (range 0.4-47.4), 55 of 63 (87%) patients who initiated zanu + ven remained on treatment (16 on zanu + ven; 39 on zanu monotherapy after completing ven treatment). Among 66 treated patients, 52% were male and the median age was 66 years (range, 26-87). Six patients discontinued the study (4 deaths; 1 withdrawal; 1 lost to follow-up). In 65 response-evaluable patients, the ORR was 100% and the CR+CRi rate was 45% (Table). uMRD was achieved by 48% of patients in >=1 PB sample. Median PFS was not reached and the 36-month estimated PFS was 92% (95% CI, 81%-97%). Ninety-seven percent of patients experienced >=1 TEAE. The most common all-grade non-hematologic TEAEs were COVID-19 (55%), diarrhea (41%), contusion (29%), and nausea (29%). Grade >=3 non-hematologic TEAEs occurred in 44% of patients; the most common were diarrhea (8%) and hypertension (8%). The most common all grade and grade >=3 hematologic toxicity was neutropenia (21% and 17%, respectively). The proportion of patients at high risk for TLS decreased from 35% at screening to 3% after 3 cycles of lead-in zanu and no TLS was reported. Summary/Conclusion: Preliminary data demonstrate promising efficacy and tolerability of zanu + ven combination treatment in patients with highrisk TN CLL/SLL with del(17p) and/or TP53 mutation. The safety profile of zanu + ven was consistent with results of prior zanu studies, and no new safety signals were identified. (Table present).