In prior studies, acalabrutinib, a selective, covalent irreversible Bruton’s tyrosine kinase inhibitor, has shown durable responses as a single agent or combined with obinutuzumab in treatment-naïve chronic lymphocytic leukemia (CLL). Here, interim results are presented for the multicenter, open-label phase 3 ELEVATE-TN study, which evaluated the efficacy and safety of acalabrutinib + obinutuzumab and acalabrutinib monotherapy versus obinutuzumab + chlorambucil in the frontline treatment of CLL. Eligible patients were randomized 1:1:1 to each of the 3 study arms. Patients were stratified by del(17p) status, Eastern Cooperative Oncology Group status (≤1 vs 2), and geography. The study allowed for crossover to acalabrutinib monotherapy for patients in the obinutuzumab + chlorambucil arm with independent review committee (IRC)-confirmed progression.
The primary end point was IRC-assessed progression-free survival (PFS) with acalabrutinib + obinutuzumab versus obinutuzumab + chlorambucil. Key secondary end points included IRC-assessed PFS with acalabrutinib monotherapy versus obinutuzumab + chlorambucil, IRC-assessed overall response rate (ORR), overall survival (OS), and safety. Minimal residual disease in peripheral blood or bone marrow was assessed in patients with investigator-assessed complete response with incomplete bone marrow recovery.
A total of 535 patients were randomized to the 3 study arms: acalabrutinib + obinutuzumab (n = 179), acalabrutinib monotherapy (n = 179), and obinutuzumab + chlorambucil (n = 177); del(17p) was noted in 9.5%, 8.9%, and 9.0% of patients.
At a median follow-up of 28.3 months, patients in the acalabrutinib + obinutuzumab arm had significantly longer PFS versus those in the obinutuzumab + chlorambucil arm (median not reached vs 22.6 months; hazard ratio [HR], 0.10; P <.0001), reducing the risk for progression or death by 90%. A similar PFS advantage was seen for patients in the acalabrutinib monotherapy arm (HR, 0.20; P <.0001). PFS improvement with acalabrutinib + obinutuzumab or acalabrutinib versus obinutuzumab + chlorambucil was consistent across high-risk subgroups. Median OS was not reached in any arm of the study. A total of 45 of 177 patients (82%) in the obinutuzumab + chlorambucil arm crossed over to the acalabrutinib monotherapy arm. IRC-assessed ORR in the 3 arms was as follows: acalabrutinib + obinutuzumab, 94%; acalabrutinib monotherapy, 85.5%; and chlorambucil + acalabrutinib, 78.5%. Complete response rates were higher with acalabrutinib + obinutuzumab (13%) than with obinutuzumab + chlorambucil (5%).
In terms of safety, adverse events (AEs) led to treatment discontinuation in 20 patients (11%) who received acalabrutinib + obinutuzumab, in 16 patients (9%) who received acalabrutinib, and in 25 patients (14%) who received obinutuzumab + chlorambucil. Grade ≥3 AEs occurred in 70% of patients who received acalabrutinib + obinutuzumab, in 50% who received acalabrutinib, and in 70% who received obinutuzumab + chlorambucil; deaths were reported in 3%, 4%, and 7% of patients, respectively. In terms of AEs of particular interest, atrial fibrillation (any grade) was reported in 3% of patients in the acalabrutinib + obinutuzumab group, in 4% of patients in the acalabrutinib group, and in 1% of the obinutuzumab + chlorambucil group; bleeding (grade ≥3) in 2%, 2%, and 0% of patients, respectively; and grade ≥3 hypertension in 3%, 2%, and 3% of patients, respectively.
The researchers concluded that acalabrutinib given alone or in combination with obinutuzumab significantly improved PFS versus obinutuzumab + chlorambucil, with an acceptable safety profile in patients with treatment-naïve CLL.
Sharman J, et al. ASH Abstract 31. Session 642.