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MATCHING-ADJUSTED INDIRECT COMPARISONS OF EFFICACY AND SAFETY OF ACALABRUTINIB VERSUS IBRUTINIB IN TREATMENT-NAÏVE CHRONIC LYMPHOCYTIC LEUKEMIA
Author(s): ,
Matthew Davids
Affiliations:
Medical Oncology,Dana-Farber Cancer Institute,Boston,United States
,
Claire Telford
Affiliations:
AstraZeneca,Gaithersburg,United States
,
Sarang Abhyankar
Affiliations:
Acerta Pharma,San Francisco,United States
,
Catherine Waweru
Affiliations:
AstraZeneca,Gaithersburg,United States
Ingo Ringshausen
Affiliations:
Haematology,University of Cambridge,Cambridge,United Kingdom
(Abstract release date: 05/14/20) EHA Library. S Davids M. 06/12/20; 294642; EP724
Dr. Matthew S Davids
Dr. Matthew S Davids
Contributions
Abstract

Abstract: EP724

Type: e-Poster

Background
Bruton tyrosine kinase (BTK) inhibition is an established therapeutic strategy for the treatment of chronic lymphocytic leukemia (CLL). Ibrutinib (ibr), a first-generation BTK inhibitor, is considered a standard frontline treatment option. Whilst ibr is generally well tolerated, significant cardiovascular and bleeding complications can occur, and additionally persistent lower grade toxicities can limit long-term use in clinical practice. Acalabrutinib (acala) is a highly selective, potent, next-generation, covalent BTK inhibitor with minimal off-target kinase inhibition, approved in Australia, Canada and the USA for CLL. In the absence of head-to-head randomized controlled trial data, indirect approaches provide an alternative method for comparing the relative treatment effects of these different approved therapies.

Aims
To compare indirectly the efficacy and safety of acala with ibr, either as monotherapies or in combination with anti-CD20 monoclonal antibody obinutuzumab (GA-101; G).

Methods
Matching-adjusted indirect comparisons use individual patient data (IPD) from one trial to match baseline characteristics with those of another trial, by applying weights to the IPD dataset equal to the odds of being in the comparator trial. After matching, treatment outcomes are compared across balanced trial populations. IPD from 179 patients treated with acala monotherapy and 179 patients treated with acala + G in the ELEVATE-TN trial (NCT02475681) were adjusted to match average baseline characteristics of 136 patients treated with ibr monotherapy in the RESONATE-2 trial and 113 patients treated with ibr + G in the ILLUMINATE trial. Outcomes were compared at similar median follow-up duration (28.5, 29 and 31.3 months for ELEVATE-TN, RESONATE-2 and ILLUMINATE, respectively) to reduce heterogeneity. After matching, progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) and adverse event (AE) rate differences for acala versus ibr (both with or without G) with their 95% confidence intervals (CI) and p values were assessed.

Results
OS and PFS were similar for acala mono- and combination therapy versus ibr mono- and combination therapy, except for a reduction in the risk of death with acala versus ibr + G. AE rates with statistical differences between comparators after matching are reported in the Table. Acala monotherapy was associated with (AEs grade 3-4) lower rates of atrial fibrillation (–4.0%), infections (–11.6%), and major hemorrhage (–5.2%) compared with ibr monotherapy. Acala monotherapy was associated with lower rates of any grade 3–4 AE (–23.9%), peripheral edema (–12.0%), atrial fibrillation (–5.0%), neutropenia (–26.8%), thrombocytopenia (–17.3%) and pneumonia (–5.7%) compared with ibr + G. Acala + G was associated with lower rates of peripheral edema (–11.4%) and febrile neutropenia (–4.5%) compared to ibr + G. Conversely, acala + G was associated with higher rates of neutropenia (20.7%) compared with ibr monotherapy.

Conclusion
In this indirect comparison, acala (with or without G) demonstrated lower rates of several clinically important AEs than ibr (with or without G) in treatment-naïve patients with CLL, without compromising efficacy. Although indirect comparisons have limitations, such as the baseline characteristics that can be controlled for and low power to detect differences, these data provide initial insight into potential differences between these two approved BTK inhibitors as we await more definitive comparative data from an ongoing randomized trial (ELEVATE R/R: NCT02477696). 

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Chronic lymphocytic leukemia, Ibrutinib, Treatment

Abstract: EP724

Type: e-Poster

Background
Bruton tyrosine kinase (BTK) inhibition is an established therapeutic strategy for the treatment of chronic lymphocytic leukemia (CLL). Ibrutinib (ibr), a first-generation BTK inhibitor, is considered a standard frontline treatment option. Whilst ibr is generally well tolerated, significant cardiovascular and bleeding complications can occur, and additionally persistent lower grade toxicities can limit long-term use in clinical practice. Acalabrutinib (acala) is a highly selective, potent, next-generation, covalent BTK inhibitor with minimal off-target kinase inhibition, approved in Australia, Canada and the USA for CLL. In the absence of head-to-head randomized controlled trial data, indirect approaches provide an alternative method for comparing the relative treatment effects of these different approved therapies.

Aims
To compare indirectly the efficacy and safety of acala with ibr, either as monotherapies or in combination with anti-CD20 monoclonal antibody obinutuzumab (GA-101; G).

Methods
Matching-adjusted indirect comparisons use individual patient data (IPD) from one trial to match baseline characteristics with those of another trial, by applying weights to the IPD dataset equal to the odds of being in the comparator trial. After matching, treatment outcomes are compared across balanced trial populations. IPD from 179 patients treated with acala monotherapy and 179 patients treated with acala + G in the ELEVATE-TN trial (NCT02475681) were adjusted to match average baseline characteristics of 136 patients treated with ibr monotherapy in the RESONATE-2 trial and 113 patients treated with ibr + G in the ILLUMINATE trial. Outcomes were compared at similar median follow-up duration (28.5, 29 and 31.3 months for ELEVATE-TN, RESONATE-2 and ILLUMINATE, respectively) to reduce heterogeneity. After matching, progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) and adverse event (AE) rate differences for acala versus ibr (both with or without G) with their 95% confidence intervals (CI) and p values were assessed.

Results
OS and PFS were similar for acala mono- and combination therapy versus ibr mono- and combination therapy, except for a reduction in the risk of death with acala versus ibr + G. AE rates with statistical differences between comparators after matching are reported in the Table. Acala monotherapy was associated with (AEs grade 3-4) lower rates of atrial fibrillation (–4.0%), infections (–11.6%), and major hemorrhage (–5.2%) compared with ibr monotherapy. Acala monotherapy was associated with lower rates of any grade 3–4 AE (–23.9%), peripheral edema (–12.0%), atrial fibrillation (–5.0%), neutropenia (–26.8%), thrombocytopenia (–17.3%) and pneumonia (–5.7%) compared with ibr + G. Acala + G was associated with lower rates of peripheral edema (–11.4%) and febrile neutropenia (–4.5%) compared to ibr + G. Conversely, acala + G was associated with higher rates of neutropenia (20.7%) compared with ibr monotherapy.

Conclusion
In this indirect comparison, acala (with or without G) demonstrated lower rates of several clinically important AEs than ibr (with or without G) in treatment-naïve patients with CLL, without compromising efficacy. Although indirect comparisons have limitations, such as the baseline characteristics that can be controlled for and low power to detect differences, these data provide initial insight into potential differences between these two approved BTK inhibitors as we await more definitive comparative data from an ongoing randomized trial (ELEVATE R/R: NCT02477696). 

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Chronic lymphocytic leukemia, Ibrutinib, Treatment

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