Elsevier

The Lancet

Volume 395, Issue 10232, 18–24 April 2020, Pages 1278-1291
The Lancet

Articles
Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(20)30262-2Get rights and content

Summary

Background

Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia.

Methods

ELEVATE-TN is a global, phase 3, multicentre, open-label study in patients with treatment-naive chronic lymphocytic leukaemia done at 142 academic and community hospitals in 18 countries. Eligible patients had untreated chronic lymphocytic leukaemia and were aged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30–69 mL/min (calculated by use of the Cockcroft-Gault equation) or Cumulative Illness Rating Scale for Geriatrics score greater than 6. Additional criteria included an Eastern Cooperative Oncology Group performance status score of 2 or less and adequate haematologic, hepatic, and renal function. Patients with significant cardiovascular disease were excluded, and concomitant treatment with warfarin or equivalent vitamin K antagonists was prohibited. Patients were randomly assigned (1:1:1) centrally via an interactive voice or web response system to receive acalabrutinib and obinutuzumab, acalabrutinib monotherapy, or obinutuzumab and oral chlorambucil. Treatments were administered in 28-day cycles. To reduce infusion-related reactions, acalabrutinib was administered for one cycle before obinutuzumab administration. Oral acalabrutinib was administered (100 mg) twice a day until progressive disease or unacceptable toxic effects occurred. In the acalabrutinib-obinutuzumab group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3–7. In the obinutuzumab-chlorambucil group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 1 and on day 1 (1000 mg) of cycles 2–6. Oral chlorambucil was given (0·5 mg/kg) on days 1 and 15 of each cycle, for six cycles. The primary endpoint was progression-free survival between the two combination-therapy groups, assessed by independent review committee. Crossover to acalabrutinib was allowed in patients who progressed on obinutuzumab-chlorambucil. Safety was assessed in all patients who received at least one dose of treatment. Enrolment for this trial is complete, and the study is registered at ClinicalTrials.gov, NCT02475681.

Findings

Between Sept 14, 2015, and Feb 8, 2017, we recruited 675 patients for assessment. 140 patients did not meet eligibility criteria, and 535 patients were randomly assigned to treatment. 179 patients were assigned to receive acalabrutinib-obinutuzumab, 179 patients were assigned to receive acalabrutinib monotherapy, and 177 patients were assigned to receive obinutuzumab-chlorambucil. At median follow-up of 28·3 months (IQR 25·6–33·1), median progression-free survival was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil (median not reached with acalabrutinib and obinutuzumab vs 22·6 months with obinutuzumab, hazard ratio [HR] 0·1; 95% CI 0·06–0·17, p<0·0001; and not reached with acalabrutinib monotherapy vs 22·6 months with obinutuzumab, 0·20; 0·13–0·3, p<0·0001). Estimated progression-free survival at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87–96%), 87% with acalabrutinib monotherapy (81–92%), and 47% with obinutuzumab-chlorambucil (39–55%). The most common grade 3 or higher adverse event across groups was neutropenia (53 [30%] of 178 patients in the acalabrutinib-obinutuzumab group, 17 [10%] of 179 patients in the acalabrutinib group, and 70 [41%] of 169 patients in the obinutuzumab-chlorambucil group). All-grade infusion reactions were less frequent with acalabrutinib-obinutuzumab (24 [14%] of 178 patients) than obinutuzumab-chlorambucil (67 [40%] of 169 patients). Grade 3 or higher infections occurred in 37 (21%) patients given acalabrutinib-obinutuzumab, 25 (14%) patients given acalabrutinib monotherapy, and 14 (8%) patients given obinutuzumab-chlorambucil. Deaths occurred in eight (5%) patients given acalabrutinib-obinutuzumab, 12 (7%) patients given acalabrutinib, and 15 (9%) patients given obinutuzumab-chlorambucil.

Interpretation

Acalabrutinib with or without obinutuzumab significantly improved progression-free survival over obinutuzumab-chlorambucil chemoimmunotherapy, providing a chemotherapy-free treatment option with an acceptable side-effect profile that was consistent with previous studies. These data support the use of acalabrutinib in combination with obinutuzumab or alone as a new treatment option for patients with treatment-naive symptomatic chronic lymphocytic leukaemia.

Funding

Acerta Pharma, a member of the AstraZeneca Group, and R35 CA198183 (to JCB).

Introduction

Chronic lymphocytic leukaemia is a B-cell malignancy that is usually considered incurable. This disease usually occurs in older patients and has a widely variable disease course. Although chemoimmunotherapy and CD20 antibodies as first-line treatment have greatly improved outcomes,1, 2, 3, 4, 5 evidence2, 6, 7 indicates a benefit of non-chemotherapeutic approaches targeting Bruton tyrosine-kinase (BTK) with ibrutinib, or BCL-2 with venetoclax, reporting superior outcomes compared with chemoimmunotherapy as first-line therapy. Four randomised studies6, 7, 8, 9 assessed ibrutinib alone or with a CD20 antibody in patients with treatment-naive chronic lymphocytic leukaemia, and reported better progression-free survival than with chemoimmunotherapy (comparator groups given chlorambucil, chlorambucil-obinutuzumab, bendamustine-rituximab, or fludarabine-cyclophosphamide-rituximab).

Studies combining rituximab with ibrutinib did not report improvement in progression-free survival over ibrutinib monotherapy.6, 10 Obinutuzumab mediates superior antibody-dependent cellular cytotoxicity compared with rituximab,11 and was shown to be more efficacious than rituximab among patients with chronic lymphocytic leukaemia in a randomised controlled trial.5 Although obinutuzumab-ibrutinib treatment has shown better efficacy than chlorambucil-obinutuzumab,8 the benefit of adding obinutuzumab to ibrutinib or another BTK inhibitor for patients with untreated chronic lymphocytic leukaemia has not been studied in a trial with BTK inhibitor monotherapy.

Research in context

Evidence before this study

We searched the PubMed database (using the terms “treatment-naive” OR “treatment naive” OR “untreated” AND “Bruton” OR “Bruton's” OR “ibrutinib” OR “acalabrutinib” OR “zanubrutinib” AND “chronic lymphocytic leukemia” OR “chronic lymphocytic leukaemia”) to find research published between Jan 1, 2000, and Oct 3, 2019. No published randomised studies have analysed the efficacy of the Bruton tyrosine-kinase (BTK) inhibitor acalabrutinib either as monotherapy or in combination with an anti-CD20 monoclonal antibody in patients with untreated chronic lymphocytic leukaemia, or compared acalabrutinib (with or without an anti-CD20 antibody) with chemoimmunotherapy. Previous randomised, controlled studies have shown the superior efficacy of the BTK inhibitor ibrutinib with or without an anti-CD20 monoclonal antibody compared with chemoimmunotherapy in chronic lymphocytic leukaemia. These studies reported that adding rituximab to ibrutinib treatment did not increase the likelihood for progression-free survival versus ibrutinib monotherapy in patients with chronic lymphocytic leukaemia. Obinutuzumab, which is a more potent and efficacious anti-CD20 monoclonal antibody compared with rituximab, used in combination with ibrutinib, has been shown to provide greater efficacy than chemoimmunotherapy.

Added value of this study

The results of this study provide new evidence for therapy in patients with treatment-naive chronic lymphocytic leukaemia by showing the efficacy of acalabrutinib used with or without obinutuzumab compared with chemoimmunotherapy. Acalabrutinib with or without obinutuzumab was associated with improved efficacy over obinutuzumab-chlorambucil with a manageable safety profile. After a median follow-up of 28·3 months, the primary endpoint was met at the interim analysis, showing significantly longer progression-free survival with acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil. Similarly, acalabrutinib monotherapy was associated with statistically improved progression-free survival versus obinutuzumab-chlorambucil therapy. Improvements in progression-free survival were consistently observed across prespecified patient subgroups, including age and high-risk genomic features such as del(17)(p13.1), unmutated immunoglobulin heavy-chain variable-region (IGHV), and complex karyotype. A post hoc analysis showed the benefit of adding obinutuzumab therapy to acalabrutinib in treatment-naive patients who have chronic lymphocytic leukaemia, which had not been previously reported in a randomised trial. Indeed, this is the first study to provide insight into the value of a third-generation anti-CD20 antibody plus a BTK inhibitor over a BTK inhibitor alone in chronic lymphocytic leukaemia.

Implications of all the available evidence

These results show the clinical potential of acalabrutinib as first-line therapy, either in combination with obinutuzumab or as monotherapy, to improve clinical outcomes in patients with chronic lymphocytic leukaemia.

Acalabrutinib is a selective, covalent BTK inhibitor with minimal activity against alternative targets, which is approved by the FDA for the treatment of adults with chronic lymphocytic leukaemia.12, 13, 14 Acalabrutinib has shown efficacy alone or in combination with obinutuzumab in phase 1–2 studies15, 16 in patients with untreated chronic lymphocytic leukaemia (proportion of patients with overall response 95–97%), with durable remissions, favourable long-term tolerability, and low discontinuation rates. The phase 3 ELEVATE-TN study was designed to compare the efficacy and safety of acalabrutinib-obinutuzumab or acalabrutinib monotherapy with obinutuzumab-chlorambucil to ascertain if acalabrutinib with or without obinutuzumab had a therapeutic advantage over chemoimmunotherapy in patients with untreated chronic lymphocytic leukaemia.

Section snippets

Study design and participants

ELEVATE-TN is a phase 3, randomised, multicentre, open-label study done at 142 academic and community hospitals in 18 countries (appendix p 3). Eligible patients had untreated chronic lymphocytic leukaemia (also called treatment-naive chronic lymphocytic leukaemia) requiring treatment per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.17 Participants were aged 65 years or older, or older than 18 years and younger than 65 years with comorbidities (creatinine clearance of

Results

From Sept 14, 2015, to Feb 8, 2017, 675 patients were assessed for eligibility. 140 patients did not meet the eligibility criteria, and 535 eligible patients were randomly assigned to receive acalabrutinib-obinutuzumab (179), acalabrutinib monotherapy (179), or obinutuzumab-chlorambucil (177; figure 1). Baseline demographic and disease characteristics were similar between groups (table 1; appendix p 22). Median age was 70 years (IQR 66–75), and 448 (84%) of 535 patients were aged 65 years or

Discussion

Acalabrutinib is a selective, covalent BTK inhibitor developed as a potential alternative to other standard therapies in chronic lymphocytic leukaemia. To our knowledge, ELEVATE-TN is the first randomised, phase 3 study examining the efficacy and safety of acalabrutinib in the first-line treatment setting in chronic lymphocytic leukaemia. In ELEVATE-TN, acalabrutinib plus obinutuzumab or acalabrutinib monotherapy were associated with improved efficacy over obinutuzumab-chlorambucil. After a

Data sharing

Acerta Pharma, a member of the AstraZeneca Group, is committed to data transparency and will consider data sharing requests on a case-by-case basis. Any requests for de-identified patient data can be submitted to Acerta Pharma 3 months post-publication and ending 5 years after Article publication with the intent-to-achieve aims of the original proposal. In addition, Acerta Pharma will provide the study protocol, statistical analysis plan, and informed consent form, and will post results on //ClinicalTrials.gov

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