Acalabrutinib Shows Superior PFS, Safety Over Other Treatments in Relapsed/Refractory CLL

John F. Seymour, AM

Acalabrutinib (Calquence) demonstrated an advantage in quality-adjusted survival compared with other standard treatments for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), according to findings from a post-hoc risk-benefit analysis that were presented during the 2021 ASH Annual Meeting and Exposition.¹

Acalabrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor, showed progression-free survival (PFS) benefit in phase 3 trials versus previous approved treatments for CLL as well as tolerable toxicity.^2,3 Investigators applied Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) analysis, a quality-adjusted life-year (QALY) method that assesses the risks and benefits of treatment based on drug efficacy and toxicity profile, to the results of these studies. The findings demonstrated that acalabrutinib offers significant quality-adjusted survival gains compared with immunotherapy or a PI3K inhibitor, as well as clear benefit over ibrutinib (Imbruvica), a first-generation BTK inhibitor.

The Q-TWiST analysis focused on a pair of phase 3 studies, the ASCEND trial (NCT02970318) and ELEVATE-RR trial (NCT02477696). The ASCEND trial compared acalabrutinib with either bendamustine (Bendeka) plus rituximab (Rituxan) or idelalisib (Zydelig) plus rituximab in patients with R/R CLL. The ELEVATE-RR trial compared acalabrutinib with ibrutinib in patients with R/R CLL with high-risk genomics.

For this analysis, investigators looked at patients from the trials in 3 states: duration with toxicity before disease progression, duration without progression or toxicity, and duration from disease progression to death or end of follow-up. Toxicity was defined based on grade 3 and 4 adverse events (AEs), and when comparing acalabrutinib to ibrutinib, it was also measured by grade 2 to 4 AEs and the occurrence of AEs of any grade that occurred frequently.

“We also applied definitions of grade 2 to 4 AEs and any-grade AEs occurring in 10% or more patients because a significant clinical burden is associated with persistent low-grade adverse events in BTK inhibitor treatment,” John F. Seymour, AM, from the Peter MacCallum Centre and the Royal Melbourne Hospital in Melbourne, Australia, said in his presentation.

Investigators created Kaplan-Meier survival curves for time from toxicity to disease progression, PFS, and overall survival. The Q-TWiST analysis was based on the total of the weighted restricted mean durations of each of the 3 states.

When comparing acalabrutinib with bendamustine/rituximab or idelalisib/rituximab, patients spent an average 3.58 more months without progression or toxicity with acalabrutinib (95% CI, 2.42-4.74) and 2.51 fewer months between disease progression and death (95% CI, −3.50 to −1.60) and 0.73 fewer months with toxicity but before disease progression. The Q-TWiST with acalabrutinib was 17.48 months compared with 15.52 months with immunotherapy or PI3K inhibitors, a difference of 1.96 months (95% CI, 1.13-2.81).

In the acalabrutinib versus ibrutinib comparison, patients who received acalabrutinib had an average 0.37 months more between disease progression and death or relapse (95% CI, −1.82 to 2.60; P = .749). When analyzing toxicity by counting all AEs that affected at least 10% of patients, their Q-TWiST was 33.02 months with acalabrutinib versus 30.46 months with ibrutinib, an increase of 2.56 months (95% CI, 0.19-4.83). When considering grade 2, 3, and 4 AEs, the Q-TWiST difference was 2.58 months (95% CI, 0.22-4.89). When only considering grade 3 and 4 AEs, the difference was 1.28 months, which was not statistically significant (95% CI, −1.34 to 3.80).

A sensitivity analysis based on utility measures from the study did not find statistically significant improvement in Q-TWiST for acalabrutinib in either study population regardless of toxicity definition; however, the investigators noted in their presentation that the 2 studies were not designed to collect EuroQol-5 Dimension quality of life data from patients after treatment discontinuation.

“Overall, acalabrutinib demonstrated a favorable benefit-risk profile compared with idelalisib or B/R [bendamustine plus rituximab] in ASCEND or ibrutinib in ELEVATE-RR among patients with relapsed/refractory CLL,” Seymour concluded.

References

1. Seymour JF, Gaitonde P, Emeribe U, Cai L, Mato AR. A quality-adjusted survival (Q-TWiST) analysis to assess benefit-risk of acalabrutinib versus idelalisib/bendamustine plus rituximab or ibrutinib among relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3722.
2. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355
3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210