Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results

Abstract

Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for patients with chronic lymphocytic leukemia (CLL). ASCEND is the pivotal phase 3 study of acalabrutinib versus investigator's choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) CLL. In the primary ASCEND analysis (median 16.1-month follow-up), acalabrutinib showed superior efficacy with an acceptable tolerability profile versus IdR/BR; here, we report final ~4 year follow-up results. Patients with R/R CLL received oral acalabrutinib 100 mg twice daily until progression or unacceptable toxicity, or investigator's choice of IdR or BR. A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled. At median follow-up of 46.5 months (acalabrutinib) and 45.3 months (IdR/BR), acalabrutinib significantly prolonged investigator-assessed progression-free survival (PFS) versus IdR/BR (median, not reached [NR] vs 16.8 months; P < 0.001); 42-month PFS rates were 62% (acalabrutinib) versus 19% (IdR/BR). Median overall survival (OS) was NR (both arms); 42-month OS rates were 78% (acalabrutinib) versus 65% (IdR/BR). Adverse events led to drug discontinuation in 23%, 67%, and 17% of patients in the acalabrutinib, IdR, and BR arms, respectively. Events of clinical interest (acalabrutinib vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), grade ≥3 infections (29% vs 29%), and second primary malignancies excluding nonmelanoma skin cancer (7% vs 2%). At ~4 years follow-up, acalabrutinib maintained favorable efficacy versus standard-of-care regimens and a consistent tolerability profile in patients with R/R CLL.

Figure 1.

Investigator-assessed progression-free survival. Outcomes are shown for (A) acalabrutinib vs IdR/BR, (B) acalabrutinib vs IdR or BR, (C) acalabrutinib vs IdR/BR by del(17p) and/or TP53 mutation status,^a,b and (D) acalabrutinib vs IdR/BR by IGHV mutation status (ITT population). ^aMutation status for patients with del(17p) were based on values entered manually into IXRS. ^bBecause there were no IdR/BR–treated patients at risk by 42 mo in the del(17p) subgroup based on IXRS data, 42-mo PFS rates were not available for that analysis. ^cHR was based on stratified Cox proportional-hazards model, stratified by randomization stratification factors as recorded in an interactive voice/web response system. ^dP value was based on stratified log-rank test, stratified by randomization stratification factors as recorded in an interactive voice/web response system. ^eHRs were based on unstratified Cox proportional-hazards model. ^fP values were based on unstratified log-rank test. BR = bendamustine plus rituximab; CI = confidence interval; IdR = idelalisib plus rituximab; IGHV = immunoglobulin heavy chain variable region genes; HR = hazard ratio; ITT = intent-to-treat; IXRS = interactive voice/web response system; NR = not reached; mo, months; PFS = progression-free survival; mIGHV = mutated IGHV; TP53m, mutated tumor protein p53; TP53, tumor protein p53; uIGHV = unmutated IGHV.

Figure 2.

Subgroup analysis of investigator-assessed progression-free survival. Forest plot showing progression-free survival analyzed by prespecified subgroups according to baseline demographic and clinical characteristics. Hazard ratios were based on stratified Cox proportional-hazards model, stratified by randomization stratification factors as recorded in interactive voice/web response system. Data for the del(17p) subgroup analysis are based on those recorded in IXRS. BR = bendamustine plus rituximab; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; IdR = idelalisib plus rituximab; IGHV = immunoglobulin heavy chain variable region genes; IXRS = interactive voice/web response system; NE = not estimable; TP53 = tumor protein p53.

Figure 3.

Overall survival. (A) acalabrutinib vs IdR/BR,^a (B) acalabrutinib vs IdR/BR by del(17p) and/or TP53 mutation status, and (C) acalabrutinib vs IdR/BR by IGHV mutation status. ^aEighty patients (52%) in the IdR/BR arm crossed over to the acalabrutinib arm. ^bBased on stratified Cox proportional-hazards model, stratified by randomization stratification factors as recorded in interactive voice/web response system. ^cBased on stratified log-rank test, stratified by randomization stratification factors as recorded in interactive voice/web response system. ^dBased on unstratified Cox proportional-hazards model. ^eBased on unstratified log-rank test. ^fBased on IXRS data. BR = bendamustine plus rituximab; CI = confidence interval; HR = hazard ratio; IdR = idelalisib plus rituximab; IGHV = immunoglobulin heavy chain variable region genes; IXRS = interactive voice/web response system; mIGHV = mutated IGHV; NR = not reached; OS = overall survival; TP53 = tumor protein p53; TP53m = mutated tumor protein p53; uIGHV = unmutated IGHV.

Figure 4.

Investigator-assessed overall response rate with acalabrutinib and IdR/BR. Response assessments were missing in 3 (2%) patients in the acalabrutinib arm and in 6 (4%) patients in the IdR/BR arm. Response rates were based on the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. ^aBased on Cochran-Mantel-Haenszel test with adjustment for randomization stratification factors as recorded in an interactive voice/web response system. ^b95% confidence interval based on normal approximation (with use of Wilson’s score). ^cThe sum of the CR, CRi, and PR rates differs slightly from the ORR due to rounding. BR = bendamustine plus rituximab; CI = confidence interval; CR = complete response; CRi = complete response with incomplete blood count recovery; IdR = idelalisib plus rituximab; nPR = nodular partial response; ORR = overall response rate; PD = progressive disease; PR = partial response; PRL = partial response with lymphocytosis; SD = stable disease.

Figure 5.

Duration of response with acalabrutinib and IdR/BR. ^aBased on stratified Cox proportional hazards model, stratified by randomization stratification factors as recorded in interactive voice/web response system. ^bBased on stratified log-rank test, stratified by randomization stratification factors as recorded in interactive voice/web response system. BR = bendamustine plus rituximab; CI = confidence interval; DOR = duration of response; HR = hazard ratio; IdR = idelalisib plus rituximab; NR = not reached.

Figure 6.

Time to next treatment with acalabrutinib and IdR/BR. ^aBased on stratified Cox proportional hazards model, stratified by randomization stratification factors as recorded in interactive voice/web response system. ^bBased on stratified log-rank test, stratified by randomization stratification factors as recorded in interactive voice/web response system. BR = bendamustine plus rituximab; CI = confidence interval; HR = hazard ratio; IdR = idelalisib plus rituximab; NR = not reached; TTNT = time to next treatment.