SEQUOIA 5-YEAR FOLLOW-UP IN ARM C: FRONTLINE ZANUBRUTINIB IN PATIENTS WITH DEL(17P) AND TREATMENT-NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL)

Abstract

Introduction: Zanubrutinib is a next-generation Bruton tyrosine kinase inhibitor that is approved for five indications, including CLL/SLL. Initial results from the SEQUOIA study (NCT03336333), at a median follow-up of 26.2 months, demonstrated superior progression-free survival (PFS) by independent review with zanubrutinib versus bendamustine + rituximab (arms A and B) in patients with treatment-naive CLL/SLL without del(17p) as well as high overall response rate (ORR) and PFS benefit in patients with del(17p) (arm C). Additionally, the 5-year follow-up in arm A demonstrated durable PFS benefit, with estimated 54- and 60-month PFS rates of 80% and 76%, respectively. Here we report updated results in SEQUOIA arm C, in patients with del(17p), after approximately 5 years of follow-up (data cutoff: Apr 30, 2024).

Methods: Arm C is a nonrandomized cohort of SEQUOIA patients with del(17p) that received zanubrutinib monotherapy. Investigator-assessed PFS, overall survival (OS), ORR, and safety/tolerability were evaluated. Adverse events (AEs) were recorded until disease progression or start of next-line therapy.

Results: Between Feb 2018 and Mar 2019, 111 treatment-naive patients with del(17p) were enrolled to receive zanubrutinib. The median age was 71 years (range, 42–87 years), 79 (71%) were male, 67 (60%) were IGHV unmutated, and 47 (42%) had both del(17p) and TP53 mutation. At a median follow-up of 65.8 months (range, 5–75 months), median PFS was not reached. The estimated 60-month PFS rate was 72.2% (62.4%–79.8%) (Figure), or 73.0% (63.3%–80.6%) when adjusted for COVID-19. Median OS was also not reached. The estimated 60-month OS rate was 85.1% (76.9%–90.6%), or 87.0% (79.0%–92.1%) when adjusted for COVID-19. The ORR was 97.3%, and the complete response/complete response with incomplete hematologic recovery rate was 18.2%. Zanubrutinib treatment was ongoing in 62.2% of patients. The most common causes for treatment discontinuation were AEs and progressive disease (in 17.1% and 15.3%, respectively). Key AEs of interest (AEI) included any-grade infection (82%), bleeding (60%), neutropenia (19%), hypertension (18%), anemia (9%), thrombocytopenia (8%), and atrial fibrillation/flutter (7%). Grade ≥ 3 AEI included infection (33%), neutropenia (16%), hypertension (8%), bleeding (6%), atrial fibrillation/flutter (5%), and thrombocytopenia (2%).

Conclusions: With this 5-year follow-up in SEQUOIA, the efficacy of zanubrutinib in treatment-naive higher-risk patients with del(17p) was maintained, and patients continue to demonstrate PFS benefits consistent with the randomized cohort of patients without del(17p) (arm A). Additionally, with longer-term follow-up, no new safety signals were identified. This update, in the largest cohort of uniformly treated patients with del(17p), suggests that zanubrutinib remains a valuable frontline treatment option for patients with or without del(17p) CLL/SLL.

Research funding declaration: This study was sponsored by BeiGene, Ltd.

Encore Abstract: ASCO 2025; EHA 2025

Keyword: chronic lymphocytic leukemia (CLL)

Potential sources of conflict of interest:

C. S. Tam

Honoraria: AbbVie, Janssen, BeiGene, AstraZeneca

P. Ghia

Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Johson & Johnson, Lilly/Loxo Oncology, MSD, Roche

Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Johnson & Johnson, Lilly/Loxo Oncology, MSD, Roche

M. Shadman

Employment or leadership position: BMS (spouse)

Consultant or advisory role: AbbVie, Genentech, AstraZeneca, Genmab, Janssen, BeiGene, BMS, MorphoSys/Incyte, Kite Pharma, Lilly, Fate Therapeutics, Nurix, Merck

Stock ownership: Koi Biotherapeutics

Other remuneration: Research funding: Mustang Bio, Genentech, AbbVie, BeiGene, AstraZeneca, Genmab, Morphosys/Incyte, Vincerx

T. Munir

Consultant or advisory role: AbbVie, BeiGene, Sobi, Alexion, Novartis, Janssen, AstraZeneca, Lilly, Roche

Honoraria: BeiGene, AstraZeneca, Sobi, Roche, Janssen, AbbVie, Lilly

Other remuneration: Research grants: Janssen, AbbVie; Travel, accommodations, or expenses: Alexion, BeiGene, AbbVie, Janssen, AstraZeneca

S. S. Opat

Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Janssen, Novartis

Honoraria: AbbVie, AstraZeneca, BeiGene, Gilead, Janssen, Merck

Other remuneration: Research funding: AbbVie, AstraZeneca, BeiGene, Gilead, Janssen, Novartis, Pharmacyclics, Roche, Takeda; Other relationship: Member of Safety and Data Monitoring Committee (Merck)

M. Lasica

Consultant or advisory role: Janssen, Sobi, AbbVie, Recordati

Honoraria: Janssen, AbbVie

I. W. Flinn

Employment or leadership position: OneOncology

Consultant or advisory role: AbbVie, BeiGene, Genentech, Genmab, KITE, Vincerx, OneOncology, Vincerx Adv Committee

Other remuneration: Research grants (all payments made to institution): AbbVie, AstraZeneca, BeiGene, BMS, Celgene, City of Hope National Medical Center, Epizyme, Fate Therapeutics, Genentech, Gilead Sciences, IGM Biosciences InnoCare Pharma, Incyte, Janssen, Kite Pharma, Loxo, Marker Therapeutics, Merck, MorphoSys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Roche, Seattle Genetics, TG Therapeutics, Vincerx Pharma, 2seventy bio

T. Tian

Employment or leadership position: BeiGene

Stock ownership: BeiGene

S. Agresti

Employment or leadership position: BeiGene

Stock ownership: BeiGene

Other remuneration: Travel, accommodations, or expenses: BeiGene

J. Hirata

Employment or leadership position: BeiGene, Genentech

Stock ownership: BeiGene, Roche

J. R. Brown

Consultant or advisory role: AbbVie, Acerta/AstraZeneca, Alloplex Biotherapeutics, BeiGene, BMS, EcoR1, Galapagos NV, Genentech/Roche, Grifols Worldwide Operations, InnoCare Pharma Inc, Kite Pharma, Loxo/Lilly, Magnet Biomedicine, Merck, Pharmacyclics

Other remuneration: Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics; Royalties: UpToDate; Data Safety Monitoring Board for Grifols Therapeutics