Paper Details

ABSTRACT

Background: The phase 3 AMPLIFY trial (NCT03836261) evaluated a fixed-duration (FD) Bruton tyrosine kinase (BTK) inhibitor plus BCL-2 inhibitor ± obinutuzumab combinations in treatment (tx)-naive (TN) chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation. At the prespecified interim analysis, the study met its primary endpoint of independent review committee (IRC)-assessed progression-free survival (PFS) for acalabrutinib + venetoclax (AV) vs chemoimmunotherapy (CIT; fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab); AVO also significantly improved PFS versus CIT (Brown et al, NEJM 2025). At a median follow-up of 5 y, we present prespecified secondary endpoint analyses: overall survival (OS), time to next tx (TTNT), and safety. Investigator-assessed PFS will be presented at the meeting. A final analysis will report IRC-assessed primary and secondary endpoints with longer follow-up.

Methods: Patients (pts) with TN CLL were randomized to AV (A 100 mg BID, cycles [C] 1–14; V ramp-up to 400 mg QD, C3–14), AV+obinutuzumab (AV+O, C2–7), or CIT (C1–6). OS was defined as time from randomization to death from any cause. TTNT was defined as time from randomization to initiation of subsequent anti-CLL tx or death, whichever occurred first. All time-to-event analyses used a Cox proportional-hazards model. As the prespecified testing procedure was completed, all current analyses are descriptive. Serious adverse events (SAEs; tx-emergent and beyond) are reported. Data cutoff was April 30, 2026.

Results: A total of 867 pts were randomized (AV, n=291; AVO, n=286; CIT, n=290). At a median follow-up of 62.8 mo (range 0–85), AV continued to show OS benefit vs CIT (HR 0.47; 95% CI 0.30–0.72); AVO OS HR was 0.71 (0.48–1.06). The estimated OS rates at 60 mo were 90.9% for AV, 85.9% for AVO, and 80.7% for CIT. In a prespecified sensitivity analysis censoring for COVID-19 deaths, the OS HR (95% CI) vs CIT was 0.53 (0.30–0.91) for AV and 0.50 (0.28–0.87) for AVO. Subgroup analyses (without censoring) by IGHV status showed OS benefit for AV vs CIT in both unmutated IGHV (uIGHV) (HR 0.59; 95% CI 0.35–0.99) and mutated IGHV (mIGHV) (0.29; 0.11–0.65); in AVO, values were 0.64 (0.38–1.05) in uIGHV and 0.86 (0.45–1.61) in mIGHV.

TTNT events occurred in 112 (38.5%), 72 (25.2%), and 120 (41.4%) pts in the AV, AVO, and CIT arms, respectively. Median (95% CI) TTNT for AV (77.1 mo [67.3, not calculable (NC)]; HR 0.67 [0.52, 0.87]) and AVO (not reached [79.4, NC]; HR 0.43 [0.32, 0.57]) were longer vs CIT (68.8 mo [57.2, NC]). The estimated cumulative incidence of initiating next line of tx (with censoring for COVID-19 death) at 60 mo was 28.5%, 13.9%, and 41.0% for AV, AVO, and CIT, respectively (HR [95% CI] vs CIT: 0.73 [0.55–0.96] for AV; 0.32 [0.22–0.45] for AVO). Among uIGHV, TTNT benefit was observed for AV (0.69; 0.51–0.93) and AVO (0.35; 0.24–0.50) vs CIT; among mIGHV, values were 0.68 (0.41–1.14) and 0.65 (0.38–1.09), respectively, vs CIT.

Among 834 pts in the safety population, fatal tx-emergent SAEs occurred in 10 (3.4%), 17 (6.0%), and 9 (3.5%) pts in the AV, AVO, and CIT arms, respectively; COVID-19–related events were the most common causes. Fatal SAEs beyond the tx-emergent period occurred in 7 (2.4%), 15 (5.3%), and 22 (8.5%) pts, with infections (predominantly COVID-19) being the most common cause across arms. For SAEs tx-emergent and beyond: infection (any grade [G]) occurred in 42 (14.4%), 87 (30.6%), and 54 (20.8%) pts; infection (G≥3) occurred in 38 (13.1%), 79 (27.8%), and 52 (20.1%) pts. Serious cardiac events (G≥3) occurred in 2 (0.7%), 7 (2.5%), and 3 (1.2%) pts; G5 cardiac events occurred in 1 pt in each arm. Second primary malignancies (SPMs; excluding non-melanoma skin) (any grade) occurred in 18 (6.2%), 16 (5.6%), and 13 (5.0%) pts.

Conclusions: After 5 y of follow-up, AV continued to show an OS benefit vs CIT at both the interim and present analyses across mIGHV and uIGHV subgroups. Notably, both AV and AVO were associated with prolonged TTNT vs CIT, supporting durable disease control and a delay in needing subsequent therapy. No new safety signals were observed, with low incidences of G≥3 infection and G≥3 cardiac events in AV and similar rates of SPMs across arms. AMPLIFY continues to demonstrate efficacy and safety of FD AV regimens, including all-oral AV, for TN CLL.