Contribution of Obinutuzumab to Acalabrutinib Therapy in Patients with Treatment-Naive Chronic Lymphocytic Leukemia: Analysis of Survival Outcomes By Genomic Features

Davids, Matthew S.; Sharman, Jeff P.; Eyre, Toby A.; Woyach, Jennifer A.; Miranda, Paulo Andre P. de; Shahkarami, Mina; Butturini, Anna; Emeribe, Ugochinyere; Byrd, John C.

doi:10.1182/blood-2022-157018

Cited by 3 publications

(3 citation statements)

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“…The addition of obinutuzumab in this study provides a 12% improvement in 5-year PFS compared to acalabrutinib monotherapy. Notably, the benefit was seen in TP53-intact patients only, particularly in those with UM-IGHV CLL, replicating the earlier observations with ibrutinib [51]. Patients with mutations in TP53 or del17p also obtained durable disease control with acalabrutinib-based treatment, with a 4-year PFS of 76% and 75%, respectively, for acalabrutinib monotherapy and acalabrutinib-obinutuzumab.…”

Section: Increasing Specificity For Btk: Acalabrutinib and Zanubrutinibsupporting

confidence: 77%

The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives

Eyre

Riches

2023

Cancers

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The development of inhibitors of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) has resulted in a paradigm shift in the treatment of chronic lymphocytic leukaemia (CLL) over the last decade. Observations regarding the importance of B-cell receptor signalling for the survival and proliferation of CLL cells led to the development of the first-in-class BTK inhibitor (BTKi), ibrutinib, for the treatment of CLL. Despite being better tolerated than chemoimmunotherapy, ibrutinib does have side effects, some of which are due to the off-target inhibition of kinases other than BTK. As a result, more specific inhibitors of BTK were developed, such as acalabrutinib and zanubrutinib, which have demonstrated equivalent/enhanced efficacy and improved tolerability in large randomized clinical trials. Despite the increased specificity for BTK, side effects and treatment resistance remain therapeutic challenges. As these drugs all bind covalently to BTK, an alternative approach was to develop noncovalent inhibitors of BTK, including pirtobrutinib and nemtabrutinib. The alternative mechanisms of BTK-binding of these agents has the potential to overcome resistance mutations, something that has been borne out in early clinical trial data. A further step in the clinical development of BTK inhibition has been the introduction of BTK degraders, which remove BTK by ubiquitination and proteasomal degradation, in marked contrast to BTK inhibition. This article will review the evolution of BTK inhibition for CLL and offer future perspectives on the sequencing of an increasing number of different agents, and how this may be impacted on by mutations in BTK itself and other kinases.

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Section: Increasing Specificity For Btk: Acalabrutinib and Zanubrutinibsupporting

confidence: 77%

The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives

Eyre

Riches

2023

Cancers

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“…As yet we do not have robust evidence to suggest that second-generation BTKis can modify the natural course of CLL in specific genetic subgroups, but recent preliminary observations are of interest [63]. A pooled analysis of two clinical studies (ELEVATE-TN and CL-003), designed to compare PFS and OS for acalabrutinib combined with obinutuzumab versus acalabrutinib monotherapy in patients with TN CLL, clearly showed the benefit of adding obinutuzumab to acalabrutinib monotherapy across genomic subgroups, particularly in those with unmutated IGHV or without del(17p)/TP53 mutations or complex karyotype abnormalities [64]. In the ALPINE trial, involving CLL patients with 17p deletion, TP53 mutation, or both, zanu showed improved survival outcomes compared to ibrutinib.…”

Section: Discussionmentioning

confidence: 99%

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

Molica

Tam

Allsup

et al. 2023

Cancers

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Ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu’s advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.

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“…In this respect, zanu may be a better option to use in combination, as it does not inhibit interleukin-2 inducible T-cell kinase (ITK), which is essential for the antibody-dependent cell cytotoxicity (ADCC) that is induced by anti-CD20 antibodies. In a phase I study, by Tam et al, zanu was used in combination with obinutuzumab (ZO) to treat patients with CLL/SLL [62]. The ORR to ZO was 100% (n = 20) in patients with TN and 92% (n = 23) in patients with R/R CLL/SLL.…”

Section: Combining Zanubrutinib With Monoclonal Antibodies or Anti-bc...mentioning

confidence: 99%

Zanubrutinib: Coming of Age for BTK Inhibitors in the Treatment of Chronic Lymphocytic Leukemia?

Molica¹,

Tam²,

Allsup³

et al. 2023

Preprint

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Ibrutinib, a first-in-class Bruton’s Tyrosine Kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated, relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by significant off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab in treatment-naive CLL patients with an acceptable safety profile. More recently, data from the phase III ALPINE trial which directly compared zanu with ibrutinib has demonstrated that zanu’s advantages are both an improved safety profile and enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated National Comprehensive Cancer Network (NCCN) and newly released German CLL practice guidelines, suggest that zanu may replace first-generation BTKi as the preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favourable toxicity profile.

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Contribution of Obinutuzumab to Acalabrutinib Therapy in Patients with Treatment-Naive Chronic Lymphocytic Leukemia: Analysis of Survival Outcomes By Genomic Features

Cited by 3 publications

References 0 publications

The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives

The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

Zanubrutinib: Coming of Age for BTK Inhibitors in the Treatment of Chronic Lymphocytic Leukemia?

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