Acalabrutinib as effective but better tolerated than ibrutinib in CLL

In the first head-to-head trial of BTK inhibitors in previously treated chronic lymphocytic leukaemia (CLL), acalabrutinib demonstrated non-inferior progression-free survival with less cardiotoxicity and fewer discontinuations due to adverse events compared with ibrutinib.

Bruton tyrosine kinase (BTK) is critical for CLL tumour cell proliferation and survival [1]. Ibrutinib, the first BTK inhibitor approved for adults with CLL, is associated with adverse events, particularly cardiovascular toxicities, that can lead to treatment discontinuation [2].

The randomised, non-inferiority, phase 3 ELEVATE-RR trial (NCT02477696) compared ibrutinib and acalabrutinib, a second-generation BTK inhibitor, in previously treated patients with CLL requiring therapy. The study randomised 533 patients 1:1 to receive acalabrutinib (100 mg twice daily) or ibrutinib (420 mg once daily) until progression or unacceptable toxicity. The primary endpoint was progression-free survival; secondary endpoints were incidence of all-grade atrial fibrillation, grade ≥3 infection, Richter transformation, and overall survival. Prof. John Byrd (Ohio State University Comprehensive Cancer Center, OH, USA) presented the first results of this head-to-head trial [3].

At a median follow-up of 40.9 months, progression-free survival was 38.4 months in both arms (HR 1.00; 95% CI 0.79-1.27), so the primary endpoint of non-inferiority was met. Acalabrutinib was statistically superior to ibrutinib in all-grade atrium fibrillation incidence (9.4% vs 16.0%; P=0.023). Among the other secondary endpoints, incidences of grade ≥3 infection and Richter transformation were comparable between arms. Median overall survival was not reached in either arm (HR 0.82; 95% CI 0.59–1.15), with 63 (23.5%) deaths in the acalabrutinib arm and 73 (27.5%) in the ibrutinib arm.

Acalabrutinib was associated with a lower incidence of hypertension (8.6% vs 22.8%), arthralgia (15.8% vs 22.8%), and diarrhoea (34.6% vs 46.0%), but a higher incidence of headache (34.6% vs 20.2%) and cough (28.9% vs 21.3%). Adverse events led to treatment discontinuation in 14.7% of acalabrutinib-treated patients versus 21.3% of ibrutinib-treated patients. Among any-grade events, both cardiac and bleeding events were less frequent with acalabrutinib (24.1% vs 30.0% and 38.0% vs 51.3%, respectively; see Table).

Table: Events of clinical interest [2]

1. Vitale C, Burger JA. Expert Opin Pharmacother. 2016;17:1077-1189.
2. Dickerson T, et al. Blood 2019;134:1919-1928.
3. Byrd, JC, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. Abstract 7500, ASCO 2021 Virtual Meeting, 4–8 June.

Want to read more? Medicom has a featured interview with Dr John Byrd (Ohio State University College of Medicine, OH, USA) about the ELEVATE-RR trial: Acalabrutinib demonstrates similar efficacy and better safety compared with ibrutinib.

 

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Posted on 12 August 202117 August 2021