Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial

Background: In patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL), both continuous Bruton tyrosine kinase inhibitor (BTKi) monotherapy and fixed-duration venetoclax-based combination regimens are highly effective. However, existing fixed-duration regimens using first-generation BTKis have important efficacy and/or safety limitations. AMPLIFY is the first randomized study to evaluate a fixed-duration regimen of venetoclax with a second-generation BTKi. This prespecified interim analysis of AMPLIFY assessed the efficacy and safety of fixed-duration acalabrutinib-venetoclax (±obinutuzumab) vs investigator's choice of chemoimmunotherapy in fit patients with TN CLL. Methods: AMPLIFY (ACE-CL-311; NCT03836261) is an ongoing, randomized, open-label, phase 3 trial in patients with TN CLL aged ≥18 years with Eastern Cooperative Oncology Group performance status ≤2 and without del(17p) or TP53 mutation. Patients were randomized 1:1:1 to receive acalabrutinib-venetoclax (AV; oral acalabrutinib 100 mg BID [cycles 1-14]; oral venetoclax QD [cycles 3-14 with 5-week dose ramp-up [20, 50, 100, 200, 400 mg]), acalabrutinib-venetoclax-obinutuzumab (AVO; AV dosing as above, plus intravenous obinutuzumab 1000 mg cycles 2 [days 1, 8, and 15] and 3−7 [day 1]), or investigator's choice of fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine-rituximab (BR) per standard dosing protocol (cycles 1−6). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) of AV vs FCR/BR in the intent-to-treat population (all randomized patients). Secondary endpoints include BICR-assessed PFS (AVO vs FCR/BR), undetectable minimal residual disease (uMRD; 10-4 cutoff) rate assessed in peripheral blood (AV vs FCR/BR, AVO vs FCR/BR), and overall survival (OS) (AV vs FCR/BR, AVO vs FCR/BR). Results: A total of 867 patients were randomized (AV, n=291; AVO, n=286; FCR/BR, n=290) with median age 61 years (IQR 54.0-66.0), 64.5% male, and 58.6% with unmutated IGHV. At a median follow-up of 41 months, both AV and AVO provided a statistically significant improvement in BICR-assessed PFS over the control arm (hazard ratios [HR] vs FCR/BR: 0.65 and 0.42, P=0.0038 and P<0.0001, respectively); median PFS was not reached in the AV or AVO arms and was 47.6 months for FCR/BR. Estimated 36-month PFS rates were 76.5%, 83.1%, and 66.5%, respectively. BICR-assessed ORR was higher with AV (92.8%, 95% CI 89.4-95.4) and AVO (92.7%, 95% CI 89.2-95.3) vs FCR/BR (75.2%, 95% CI 70.0-79.9; descriptive P<0.0001 for both comparisons). AV demonstrated an OS benefit trend over FCR/BR (HR 0.33, nominal P<0.0001). Deaths that occurred prior to the data cutoff on April 30, 2024 were reported in 18, 37, and 42 patients in the AV, AVO, and FCR/BR groups, respectively, of which COVID-related deaths occurred in 10, 25, and 21 patients. The most common grade ≥3 adverse event (AE) was neutropenia across all arms, reported in 26.8% of patients in the AV group, 35.2% in the AVO group, and 32.4% in the FCR/BR group. Among events of clinical interest, tumor lysis syndrome, atrial fibrillation (any grade), and hypertension (grade ≥3) were reported in 0.3%, 0.7%, and 2.7% (AV); 0.4%, 2.1%, and 2.1% (AVO); and 3.1%, 0.8%, and 0.8% (FCR/BR) of patients, respectively. Serious AEs occurred in 24.7% of patients in the AV group, 38.4% in the AVO group, and 27.4% in the FCR/BR group. MRD data will be presented. Conclusions: AMPLIFY met its primary endpoint, demonstrating superior BICR-assessed PFS with AV vs FCR/BR, with similar findings seen with AVO vs FCR/BR. The combinations of AV and AVO provided deep and durable responses with manageable safety profiles, with AV offering the first all-oral fixed-duration regimen that combines venetoclax with a second-generation BTKi in fit patients with TN CLL.