The European Medicines Agency Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia.

Abstract

On 5 November 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or in combination with obinutuzumab (AcalaObi) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase 3 multicenter randomized trials. The first trial (007) randomly allocated acalabrutinib vs. AcalaObi vs. chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression-free survival (PFS), as assessed by an independent review committee (IRC), was superior for both the AcalaObi (hazard ratio [HR] 0.1; 95% confidence interval [CI] 0.06-0.17) and acalabrutinib (HR 0.2; 95% CI 0.13-0.3) arms compared to the ChlObi arm. The second trial (309) randomly allocated acalabrutinib vs. rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial the PFS was significantly longer in the acalabrutinib arm (HR 0.31; 95% CI 0.20-0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea and infections. The scientific review concluded that the benefit/risk ratio of acalabrutinib was positive for both indications. The aim of this manuscript was to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before, or for those who have received therapy, but the disease did not respond or relapsed afterwards. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient s death compared to standard therapy. The overall safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.