As reported in The Lancet by Jeff P. Sharman, MD, and colleagues, the phase III ELEVATE-TN trial showed significantly improved progression-free survival with both acalabrutinib/obinutuzumab and acalabrutinib monotherapy vs chlorambucil/obinutuzumab in patients with treatment-naive chronic lymphocytic leukemia.

Jeff P. Sharman, MD

The trial supported the November 2019 U.S. Food and Drug Administration approval of acalabrutinib with or without obinutuzumab in this setting.

Study Details

In the open-label trial, 535 patients from 142 sites in 18 countries were randomly assigned between September 2015 and February 2017 to receive acalabrutinib/obinutuzumab (n = 179), acalabrutinib alone (n = 179), or obinutuzumab/chlorambucil (n = 177). Patients had to be age 65 or older, or older than 18 and younger than 65 with a creatinine clearance of 30 to 69 mL/min. Patients with significant cardiovascular disease were excluded from the trial and concomitant treatment with warfarin or equivalent vitamin K antagonists was not permitted.

Treatment was given in 28-day cycles. Acalabrutinib was administered for one cycle before obinutuzumab administration to reduce risk of infusion-related reactions. Oral acalabrutinib was given at 100 mg twice a day until disease progression or unacceptable toxicity. In the acalabrutinib/obinutuzumab group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1,000 mg), and 15 (1,000 mg) of cycle 2 and on day 1 (1,000 mg) of cycles 3 to 7. In the obinutuzumab/chlorambucil group, obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1,000 mg), and 15 (1,000 mg) of cycle 1 and on day 1 (1,000 mg) of cycles 2 to 6. Oral chlorambucil was given at 0.5 mg/kg on days 1 and 15 of each cycle for six cycles.

The primary endpoint was progression-free survival in the two combination therapy groups as assessed by independent review committee. Crossover to acalabrutinib was allowed in patients whose disease progressed on obinutuzumab/chlorambucil.

In the total study population, median age was 70 years (84% aged ≥ 65 years); 61% were male; chronic lymphocytic leukemia International Prognostic Index score was high-risk in 69% and very high-risk in 12%; and high-risk features included 17p13.1 deletion in 9%, 11q22.3 deletion in 18%, TP53 mutation in 11%, unmutated IGHV in 63%, and complex karyotype in 17%.

Progression-Free Survival

At a median follow-up of 28.3 months, median progression-free survival was not reached in the acalabrutinib/obinutuzumab group vs 22.6 months in the obinutuzumab/chlorambucil group (hazard ratio [HR] = 0.1, P < .0001). Median progression-free survival was not reached in the acalabrutinib monotherapy group (HR vs obinutuzumab/chlorambucil = 0.20, P < .0001). Estimated progression-free survival at 24 months was 93% in the acalabrutinib/obinutuzumab group, 87% in the acalabrutinib monotherapy group, and 47% in the obinutuzumab/chlorambucil group. In prespecified subgroup analyses, there was a consistent progression-free survival benefit for acalabrutinib/obinutuzumab and acalabrutinib monotherapy vs obinutuzumab/chlorambucil.

Overall response rates were 94% in the acalabrutinib/obinutuzumab group vs 79% in the obinutuzumab/chlorambucil group (P < .0001) and 86% in the acalabrutinib monotherapy group (P = .08 vs obinutuzumab/chlorambucil). Complete response rates were 13%, 5%, and 1%, respectively.

Median overall survival was not reached in any group (HR for acalabrutinib/obinutuzumab vs obinutuzumab/chlorambucil = 0.47, P = .06; HR for acalabrutinib monotherapy vs obinutuzumab/chlorambucil = 0.60, P = .16). Estimated overall survival at 24 months was 95% in the acalabrutinib/obinutuzumab group, 95% in the acalabrutinib monotherapy group, and 92% in the obinutuzumab/chlorambucil group. A total of 45 patients from the obinutuzumab/chlorambucil group crossed over to acalabrutinib monotherapy upon disease progression.

Adverse Events

The median durations of treatment exposure were 27.7 months in the acalabrutinib/obinutuzumab group, 27.7 months in the acalabrutinib monotherapy group, and 5.6 months in the obinutuzumab/chlorambucil group.

Grade ≥ 3 adverse events occurred in 70.2% of patients in the acalabrutinib/obinutuzumab group, 49.7% of the acalabrutinib monotherapy group, and 69.8% of the obinutuzumab/chlorambucil group. The most common grade ≥ 3 adverse event reported across groups was neutropenia, which occurred in 30%, 9%, and 41% of patients, respectively. Serious adverse events occurred in 39%, 32%, and 22% of patients. Grade ≥ 3 infections occurred in 21%, 14%, and 8% of patients. Infusion reactions of any grade occurred in 13% of the acalabrutinib/obinutuzumab group and 40% of the obinutuzumab/chlorambucil group. Second primary malignancies—mainly nonmelanoma skin cancers—occurred in 11% of the acalabrutinib/obinutuzumab group, 9% of the acalabrutinib monotherapy group, and 8% of the chlorambucil/obinutuzumab group. Adverse events led to discontinuation of treatment in 11%, 9%, and 14% of patients, respectively. Adverse events led to death in 4, 6, and 11 patients, respectively.

Among adverse events of special interest for acalabrutinib treatment, atrial fibrillation occurred in 3% of the acalabrutinib/obinutuzumab group, 4% of the acalabrutinib monotherapy group, and 1% of the obinutuzumab/chlorambucil group; grade ≥3 hypertension occurred in 3% , 2%, and 3%; and bleeding events occurred in 43% (41% grade 1 or 2), 39% (37% grade 1 or 2), and 12% (all grade 1 or 2). No cases of ventricular tachyarrhythmia were reported.

The investigators concluded, “Acalabrutinib with or without obinutuzumab significantly improved progression-free survival over obinutuzumab/chlorambucil chemoimmunotherapy, providing a chemotherapy-free treatment option with an acceptable side effect profile that was consistent with previous studies. These data support the use of acalabrutinib in combination with obinutuzumab or alone as a new treatment option for patients with treatment-naive symptomatic chronic lymphocytic leukemia.”

John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, Columbus, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Acerta Pharma, a member of the AstraZeneca Group. For full disclosures of the study authors, visit thelancet.com.