Acalabrutinib Versus Chlorambucil Plus Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia: A Randomized, Multicenter, Open-Label, Phase 3 Study

Introduction: Acalabrutinib is a selective, covalent Bruton tyrosine kinase inhibitor approved in the United States and other countries for the treatment of chronic lymphocytic leukemia (CLL) and was recently approved in China for patients (pts) with CLL who have received ≥1 prior therapy. The global, phase 3 ELEVATE-TN study of pts with treatment-naive (TN) CLL demonstrated that acalabrutinib with or without obinutuzumab (O) had superior progression-free survival (PFS) with a manageable safety profile vs O plus chlorambucil (C). Here we report results from a phase 3 study that evaluated the efficacy and safety of acalabrutinib vs C plus rituximab (C+R) in unfit pts with TN CLL in sites across Asia.

Methods: ChangE (NCT04075292) is a randomized, multicenter, open-label study that included pts with TN CLL aged ≥65 years or aged >18 and <65 years with at least 1 of the following: creatinine clearance 30–69 mL/min or Cumulative Illness Rating Scale-Geriatric score >6. Pts with del(17p) or TP53 mutations were excluded. Pts were randomized 1:1 to either acalabrutinib 100 mg orally twice daily continuously or C+R combination for 6 cycles (C; 0.5 mg/kg orally on days 1 and 15 of C1–6; R, 375 mg/m² intravenously on day 1 of C1 and 500 mg/m² on day 1 of C2–6). Pts in both arms were treated until disease progression or unacceptable toxicity and were followed until death, withdrawal of consent, loss to follow-up, or study termination. The primary endpoint was blinded independent central review (BICR)-assessed PFS. Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to next treatment (TTNT), and overall survival (OS).

Results: At the data cutoff (3 January 2024), 155 pts (acalabrutinib, n=77; C+R, n=78) from 44 sites in mainland China, Taiwan, Vietnam, Thailand, and the Philippines were included in the overall cohort. Of the 155 pts, 103 (acalabrutinib, n=53; C+R, n=50) from 30 sites across mainland China and Taiwan were included in the China cohort. Demographics and baseline characteristics were comparable across the 2 treatment arms in the overall and China cohorts. The study met its primary endpoint. With median follow-up of 23.5 and 18.2 months in the overall and China cohorts, respectively, acalabrutinib demonstrated a 92% risk reduction of BICR-assessed disease progression or death vs C+R (both cohorts: hazard ratio=0.08; P<0.0001). In the overall cohort, acalabrutinib demonstrated improvements in median PFS vs C+R (not reached [NR] vs 15.5 months, respectively) and 24-month PFS rate (92% vs 25%); the PFS benefit of acalabrutinib was consistent across all prespecified subgroups. BICR-assessed ORRs were 76.6% vs 71.8% with median DOR NR vs 11.6 months in the acalabrutinib vs C+R arms, respectively. Median TTNT was NR with acalabrutinib vs 26.2 months with C+R. Median OS was NR in both treatment arms; 2 deaths occurred with acalabrutinib vs 5 with C+R. Efficacy results in the China cohort were consistent with those of the overall cohort. Overall, 150 pts received at least 1 dose of study drug (acalabrutinib, n=77; C+R, n=73) and the median duration of acalabrutinib and C+R exposure was 23.2 and 5.6 months, respectively. Similar rates of any-grade treatment-emergent adverse events (TEAEs; 96.1% vs 93.2%) and treatment-related AEs (TRAEs; 71.4% vs 69.9%) were seen with acalabrutinib and C+R, respectively. Numerically higher rates of grade ≥3 TEAEs (55.8% vs 37.0%) and TRAEs (39.0% vs 27.4%) were seen with acalabrutinib vs C+R. AEs that led to study treatment discontinuation occurred in 10.4% of pts with acalabrutinib (vs 11.0% with C+R) and AEs leading to death occurred in 1 pt in the acalabrutinib arm (unrelated to study drug). In the acalabrutinib arm, no pt reported atrial fibrillation or hypertension (vs 0 and 1 pt, respectively, with C+R); any-grade ventricular tachyarrhythmias and major hemorrhage were reported in 3 (3.9%) and 2 (2.6%) pts, respectively (vs no pts with C+R). The safety profile in the China cohort was consistent with that of the overall cohort and no new safety signals with acalabrutinib were identified.

Conclusion: Acalabrutinib demonstrated a clinically meaningful and statistically significant improvement in PFS vs C+R in the overall and China cohorts. In both cohorts, acalabrutinib was well tolerated with a manageable toxicity profile consistent with the established safety profile of acalabrutinib.