Jeff P. Sharman, MD

As reported inThe Lancet by Jeff P. Sharman, MD, of Willamette Valley Cancer Institute/US Oncology, Eugene, Oregon, and colleagues, the phase III ELEVATE-TN trial has shown significantly improved progression-free survival with both acalabrutinib/obinutuzumab and acalabrutinib monotherapy vs chlorambucil/obinutuzumab in treatment-naive chronic lymphocytic leukemia (CLL).¹ The trial supported the November 2019 approval of acalabrutinib with or without obinutuzumab in this setting.

Study Details

In the open-label trial, 535 patients from 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 aged ≥ 65 years or older than 18 years or younger than 65 years 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 the risk of infusion-related reactions. Oral acalabrutinib at 100 mg twice daily was given 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 who experienced disease progression on obinutuzumab/chlorambucil.

In the total study population, the median age was 70 years (84% aged ≥ 65 years); 61% were male; CLL 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 a complex karyotype in 17%.

Outcomes

At a median follow-up of 28.3 months, median progression-free survival was not reached with acalabrutinib/obinutuzumab vs 22.6 months with obinutuzumab/chlorambucil (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% with acalabrutinib/obinutuzumab, 87% with acalabrutinib monotherapy, and 47% with obinutuzumab/chlorambucil. In prespecified subgroup analyses, there was a consistent progression-free survival benefit with acalabrutinib/obinutuzumab and acalabrutinib monotherapy vs obinutuzumab/chlorambucil.

Overall response rates were 94% with acalabrutinib/obinutuzumab vs 79% with obinutuzumab/chlorambucil (P < .0001) and 86% with acalabrutinib monotherapy (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% with acalabrutinib/obinutuzumab, 95% with acalabrutinib monotherapy, and 92% with obinutuzumab/chlorambucil. A total of 45 patients from the obinutuzumab/chlorambucil group crossed over to acalabrutinib monotherapy at disease progression.

Adverse Events

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

Grade ≥ 3 adverse events occurred in 70.2% of 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 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.” 

DISCLOSURE: For full disclosures of the study authors, visit thelancet.com.

REFERENCE

1. Sharman JP, Egyed M, Jurczak W, et al: Acalabrutinib with or without obinutuzumab vs chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): A randomised, controlled, phase 3 trial. Lancet 395:1278-1291, 2020.