Acalabrutinib significantly delays disease progression compared to idelalisib-rituximab or bendamustine-rituximab in patients with relapsed/refractory chronic lymphocytic leukaemia
Final results of the phase III ASCEND trial, evaluating acalabrutinib in patients with relapsed/refractory chronic lymphocytic leukaemia (R/R CLL), confirm the previously presented significant improvement in the progression-free survival (PFS) with this second generation Bruton’s Tyrosine Kinase (BTK) inhibitor compared to a combination of rituximab with either idelalisib or bendamustine. After a median follow-up of 22 months, neither the median overall survival (OS) nor the median duration of response (DoR) were reached in the acalabrutinib arm. Finally, fewer patients treated with acalabrutinib than idelalisib plus rituximab discontinued their treatment due to adverse events.
Background
Over the last decade, inhibiting B-cell receptor signalling using the Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib has become one of the standards for the treatment of both newly diagnosed and R/R CLL. In addition to this, combination therapies using the PI3K inhibitor idelalisib plus the anti-CD20 antibody rituximab (IdR) or bendamustine plus rituximab (BR) are also feasible treatment options in patients with R/R CLL. One of the disadvantages of ibrutinib relates to toxicity, which may be treatment-limiting. Acalabrutinib is a next-generation, highly selective, covalent BTK inhibitor with less off-target kinase inhibition than ibrutinib. In theory, this could result in an improved safety profile. In the randomised, phase III ASCEND study, the efficacy and safety of acalabrutinib monotherapy was compared to an investigator’s choice of IdR or BR in patients with R/R CLL. In a pre-planned interim analysis, after a median follow-up of 16 months, it was already shown that acalabrutinib significantly improves the PFS compared to IdR or BR. At EHA 2020, the final results of the trial were presented, with an additional six months of follow-up.
In this trial, a total of 310 patients with R/R CLL were randomised (1:1) to receive oral (PO) acalabrutinib 100 mg twice daily (BID) or investigator’s choice of IdR (idelalisib 150 mg PO BID until progression or toxicity plus rituximab 375 mg/m2 intravenously [IV] on day one of the first cycle, then subsequent doses at 500 mg/m2 every two weeks for four infusions followed by every four weeks for three infusions) or BR (bendamustine 70 mg/m2 IV on day 1 and 2 of cycles 1-6 and rituximab 375 mg/m2 IV on day 1 of the first cycle, then subsequent doses of 500 mg/m2 on day 1 of cycle 2-6) until progression or toxicity.
Results
After a median follow-up of 22 months, the median PFS was not yet reached for acalabrutinib, while this was reported at 18.8 months for IdR/BR (HR [95% CI]: 0.27 [0.18-0.40], p<0.001). The estimated 18-months PFS rates were 82% and 48%, respectively. Interestingly, the PFS benefit of acalabrutinib was observed across all prespecified subgroups, including patients with high-risk features such as patients with a del(17p) or a TP53 mutation (89% reduction in the risk of disease progression or death) and patients with unmutated immunoglobulin heavy chain variables (72% reduction in the risk of disease progression or death). The estimated 18-month OS rate was 88% for both treatment regimens with a median OS that was not yet reached in either arm. The median DoR was significantly longer with acalabrutinib than with IdR/BR with a median that was not reached versus 18.0 months, respectively (HR [95% CI]: 0.19 [0.11-0.33]). The estimated 18-month DoR rate was 85.4% and 49.4%, respectively. The objective response rate (ORR) was 80% with acalabrutinib as compared to 84% with IdR/BR (p=0.35). When also patients with a partial response with lymphocytosis were included, these rates increased to 92% and 88%, respectively.
The median duration of treatment exposure was remarkably longer in the acalabrutinib arm (21.9 months) as compared to the IdR arm (11.5 months) and the BR arm (5.6 months). In total, 27%, 77% and 19% of the patients in the acalabrutinib, IdR and BR arm respectively discontinued treatment, mostly because of adverse events (16%, 56% and 17%, respectively). The incidences of grade ≥3 adverse events (AEs), serious AEs, treatment-related AEs, drug discontinuations and dose modifications were higher with IdR than with acalabrutinib or BR. Serious AEs reported in ≥5% of patients in any subgroup included pneumonia (acalabrutinib: 6%, IdR: 10%, BR: 3%), diarrhoea (acalabrutinib: 1%, IdR: 14%, BR: 0%) and pyrexia (acalabrutinib: 1%, IdR: 7%, BR: 3%). AEs of interest included atrial fibrillation (acalabrutinib: 6%, IdR/BR: 3%), major haemorrhage (all grade; 3% versus 3%), grade ≥3 infections (20% versus 25%), and second primary malignancies excluding non-melanoma skin cancer (5% versus 2%).
Conclusions
Final results from ASCEND confirm the results of the interim analysis and support the favourable efficacy and safety of acalabrutinib compared to IdR and BR in patients with R/R CLL. Overall, these data support the use of acalabrutinib in patients with R/R CLL, including patients with high-risk features.
