Results of the phase III ASCEND trial demonstrate that the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib significantly reduces the risk of disease progression or death compared to bendamustine or idelalisib in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. After 1 year of therapy 88% of acalabrutinib treated patients were alive and free of progression as compared to 68% in the control arm.
Over the last years, Bruton’s tyrosine kinase (BTK) inhibition became a well-established therapeutic strategy in chronic lymphocytic leukemia (CLL). BTK inhibition first proved its worth in the relapsed/refractory setting and in specific subgroups of patients with high-risk cytogenetic features, but recent data also support the broader use of this strategy in the first-line treatment of CLL patients. Ibrutinib, the first BTK inhibitor that was introduced in clinical practice, dramatically improved both the progression-free (PFS) and overall survival (OS) of CLL patients compared to conventional therapies, both in the first-line and relapsed/refractory setting. However, a subset of patients receiving ibrutinib will experience bothersome adverse events (AEs), including diarrhea, rash, bleeding and atrial fibrillation. These AEs might lead to treatment discontinuations or dose reductions, which potentially compromises the long-term treatment benefit for patients. With the development of more selective BTK inhibitors, such as acalabrutinib, researchers hope to improve the treatment tolerability. In previous phase I/II studies, acalabrutinib demonstrated activity and improved tolerability in patients with CLL. During EHA 2019, the first results of the phase III trial evaluating acalabrutinib in patients with relapsed/refractory CLL were presented.
In the phase III ASCEND trial, 310 patients with relapsed/refractory CLL were randomly assigned to a treatment with acalabrutinib (100 mg PO BID), or rituximab in combination with either idelalisib (150 mg PO BID; IdR) or bendamustine (70 mg/m2; BR). The primary endpoint of the study was PFS, with objective response rate (ORR), duration of response and OS as key secondary objectives. Of note, after confirmed disease progression, patients in the control arm were allowed to cross-over to acalabrutinib.
After a median follow-up of 16.1 months, acalabrutinib was found to be associated with a significant improvement in PFS compared to IdR or BR. In fact, compared to the control arm, patients treated with acalabrutinib had a 69% lower risk of disease progression or death (HR 0.31 [95% CI 0.2-0.49]; p<0.0001). At 12 months, this corresponds to an absolute difference in PFS rate of 20% (88% vs 68%). The PFS improvement with acalabrutinib vs IdR/BR was seen across all investigated subgroups, irrespective of the presence of a del(17p), the TP53 mutation status and the Rai stage. The independently assessed ORR did not differ significantly between acalabrutinib and IdR/BR (81% vs 75%; p<0.22). After one year, 94% of acalabrutinib treated patients were still alive, which is comparable to the 91% OS rate seen with IdR and BR at one year. Of note, 23% of patients randomized to IdR/BR crossed over to receive subsequent acalabrutinib monotherapy.
The most common all-grade adverse events (AEs; ≥15%) with acalabrutinib were headache (22%), neutropenia (19%), diarrhea (18%), anemia and cough (15% each). As such, compared to IdR, acalabrutinib was associated with substantially less diarrhea (18% vs 47% with IdR) and neutropenia (19% vs 45% with IdR). Also with BR the rate of neutropenia was higher than what was observed among acalabrutinib treated patients (19% vs 34%). The most frequently reported high grade AEs (grade 3-4) with acalabrutinib were neutropenia (16%), anemia (12%) and pneumonia (5%). With IdR 40% of patients experienced grade 3-4 neutropenia (40%), while 24% suffered from grade 3/4 diarrhea. With BR, the most common grade 3-4 AE consisted of neutropenia (31%). In total, 5.2% of patients on acalabrutinib developed atrial fibrillation (versus 3.3% on IdR/BR) and 26% experienced a bleeding episode (versus 7.2%. Major bleeding incidence: 1.9% vs 2.6%).
Acalabrutinib monotherapy significantly improved the PFS with a more tolerable safety profile, compared with IdR/BR in patients with relapsed or refractory CLL. As such, the ASCEND trial indicates that acalabrutinib has the potential to change current practice by providing a well-tolerated, highly effective BTK inhibition treatment option.
Ghia P, Pluta A, Wach M, et al. ASCENC phase 3 study of acalabrutinib vs. investigator’s choice of rituximab plus idelalisib or bendamustine in patients with relapsed/refractory CLL. Presented at EHA 2019; abstract LB2606.