COMBINATION of ZANUBRUTINIB + VENETOCLAX for TREATMENT-NAIVE (TN) CLL/SLL with DEL(17P) AND/OR TP53: PRELIMINARY RESULTS from SEQUOIA ARM D.
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All Authors
Ma, S.
Munir, T.
Lasica, M.
Shadman, M.
Tedeschi, A.
Ferrant, E.
Flinn, I.W.
Janowski, W.
Tani, M.
Robak, T.
LTHT Author
Munir, Talha
LTHT Department
Oncology
Haematology
Haematology
Non Medic
Publication Date
2024
Item Type
Conference Abstract
Language
Subject
ADULT , AGED , COMORBIDITY , CONTUSIONS , COVID-19 , DIARRHOEA , DRUG THERAPY, COMBINATION , DRUG THERAPY , WOMEN , FOLLOW-UP-STUDIES , HYPERTENSION , MEN , NEOPLASM, RESIDUAL , NAUSEA , NEUTROPHILS , CLINICAL TRIALS AS TOPIC , DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS , BLOOD PROTEINS
Subject Headings
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).
Journal
HemaSphere