The second-generation Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib, alone, or in combination with obinutuzumab significantly improved progression-free survival compared with a standard combination of obinutuzumab/chlorambucil in treatment-naive patients with chronic lympocytic leukemia (CLL), according to results of the phase III ELEVATE TN trial. In June 2019, AstraZeneca, maker of acalabrutinib, announced positive results of the study. In December 2019, lead author Jeff P. Sharman, MD, presented detailed results of the ELEVATE TN trial at the 2019 ASH Annual Meeting & Exhibition.¹

Jeff P. Sharman, MD

Ibrutinib was the first BTK inhibitor to transform the treatment of patients with CLL and other hematologic malignancies. The second-generation BTK inhibitor acalabrutinib is a more selective BTK inhibitor designed to have an improved side-effect profile.

Phase III ELEVATE TN

At a median follow-up of 28.3 months, acalabrutinib/obinutuzumab achieved a 90% reduction in the risk of disease progression or death compared with obinutuzumab/chlorambucil (P < .0001). Single-agent acalabrutinib also led to an 80% reduction in risk of disease progression or death vs standard obinutuzumab/chlorambucil (P < .0001). The study was not designed to directly compare the two acalabrutinib arms.

“Acalabrutinib is a more selective BTK inhibitor, with less off-target kinase inhibition in vitro compared with ibrutinib and a favorable safety profile, prompting this evaluation as a front-line therapy with or without obinutuzumab,” said Dr. Sharman, Director of Research at Willamette Valley Cancer Institute in Eugene, Oregon, and Medical Director of Hematology Research at The US Oncology Network.

The combination of obinutuzumab and chlorambucil was considered a standard front-line option for patients with CLL before the approval of ibrutinib.

Study Details

The randomized, multicenter, open-label, phase III ELEVATE TN trial compared acalabrutinib as a single agent or in combination with obinutuzumab vs chlorambucil/obinutuzumab in 535 treatment-naive patients with CLL. Patients were randomly assigned 1:1:1 to three arms: chlorambucil plus obinutuzumab (n = 177); acalabrutinib in combination with obinutuzumab until disease progression or unacceptable toxicity (n = 179); or single-agent acalabrutinib at 100 mg twice daily until disease progression or unacceptable toxicity (n = 179). Crossover from the control arm was allowed at disease progression. Participants were stratified according to 17p deletion status, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 or 2, and geographic region.

Baseline characteristics were similar across all three treatment arms. The median age was 70.5 years, 63% had an unmutated IGHV, 47% had Rai stage III or IV disease, 18% had 11q deletion, and 14% had 17p deletion or TP53 mutation. Most patients (93.6%) had an ECOG performance status between 0 and 1. High-risk features were evenly distributed across the three treatment arms.

The median treatment duration was 27.7 months in the acalabrutinib arms and 5.6 months in the chlorambucil/obinutuzumab arm. The median progression-free survival, as assessed by independent review committee (the primary endpoint), was not reached in the acalabrutinib arms vs 22.6 months in the obinutuzumab/chlorambucil arm. Two-year progression-free survival rates were 93% for acalabrutinib/obinutuzumab, 87% for single-agent acalabrutinib, and 47% for obinutuzumab/chlorambucil. The benefit of the combination of acalabrutinib/obinutuzumab was consistent across subgroups, including all risk groups and with or without mutated IGHV.

Although not designed to compare both acalabrutinib arms, an exploratory analysis of progression-free survival suggested that acalabrutinib/obinutuzumab was superior to single-agent acalabrutinib, Dr. Sharman noted.

Response Rates and Survival

Overall survival was comparable to the control group for both acalabrutinib-containing arms, but this difference was not statistically significant at the time the data were reported. Longer follow-up is needed to show a survival benefit, Dr. Sharman said. Estimated 2-year rates of overall survival were 95%, 95%, and 92% with acalabrutinib/obinutuzumab, acalabrutinib alone, and obinutuzumab/chlorambucil, respectively.

“Acalabrutinib is a more selective BTK inhibitor, with less off-target kinase inhibition in vitro compared with ibrutinib and a favorable safety profile, prompting this evaluation as a front-line therapy with or without obinutuzumab.”

— Jeff P. Sharman, MD

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The objective response rate was 93.9% for acalabrutinib/obinutuzumab vs 78.5% for the control arm (P < .0001). In addition, the acalabrutinib/obinutuzumab group had a complete response rate of 13%, partial response rate of 81%, and stable disease rate of 2%. In the single-agent acalabrutinib arm, the objective response rate was 85.5%, which was not significantly different from the obinutuzumab/chlorambucil arm.

FDA Approval

On November 21, 2019, acalabrutinib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of CLL or small lymphocytic lymphoma as front-line therapy and in relapsed or refractory patients. Approval was based on the results of the ELEVATE TN trial and the ASCEND trial, which compared acalabrutinib vs investigator’s choice of rituximab/idelalisib or rituximab/bendamustine in patients with previously treated CLL. Results of the phase III ASCEND clinical trial were presented in June at the 2019 European Hematology Association Annual Congress (LBA2606).

Zanubrutinib, another BTK inhibitor, is currently in phase III trials.

Safety

In the ELEVATE TN study, continuous acalabrutinib therapy was compared with fixed-duration obinutuzumab/chlorambucil, leading to an imbalance in adverse events that occurred within 30 days of the last dose.

Treatment discontinuation rates were 20.7%, 20.1%, and 18.1% in the acalabrutinib/obinutuzumab, acalabrutinib monotherapy, and obinutuzumab/chlorambucil arms, respectively. The most common reason for treatment discontinuation was toxicity. Two deaths were reported on the acalabrutinib combination arm, three deaths on the single-agent acalabrutinib arm, and one death in the chemoimmunotherapy group.

No new or unexpected adverse events were reported. More serious adverse events were reported in the acalabrutinib/obinutuzumab arm (38.8%), compared with acalabrutinib alone (31.8%) and obinutuzumab/chlorambucil (21.9%).

Grade 3 or higher adverse events were reported in 70.2%, 49.7%, and 69.8% of the three groups, respectively. The most common adverse events of any grade occurring in 15% or more of patients (in descending order) were headache, diarrhea, neutropenia, fatigue, contusion, arthralgia, cough, upper respiratory tract infection, nausea, and dizziness. Grade 3 or higher neutropenia was reported in 41.4% of the obinutuzumab/chlorambucil arm vs 9.5% with acalabrutinib alone and 29.8% with acalabrutinib/obinutuzumab.

Serious adverse events were consistent with previous safety reports of acalabrutinib. The most common serious adverse events with acalabrutinib/obinutuzumab, acalabrutinib monotherapy, and obinutuzumab/chlorambucil were pneumonia (6.7%, 2.8%, and 1.8%, respectively), infusion-related events (2.2%, 0%, and 1.2%), anemia (1.7%, 2.2%, and  0%), febrile neutropenia (1.7%, 1.1%, and  4.1%), and tumor-lysis syndrome (0.6%,  0%, and 4.7%).

Adverse events of importance for acalabrutinib included atrial fibrillation and hypertension, which are a concern with ibrutinib, but rates for these cardiac events were low with acalabrutinib; any-grade atrial fibrillation occurred in 6 patients on acalabrutinib/obinutuzumab and in 7 patients on single-agent  acalabrutinib. 

DISCLOSURE: Dr. Sharman has served in a consulting or advisory role for and has received honoraria or research funding from Acerta, Pharmacyclics, TG Therapeutics, Genentech, AbbVie, Pfizer, Juno, Celgene, and AstraZeneca.

REFERENCE

1. Sharman JP, Banerji V, Fogliatto LM, et al: ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab or alone vs obinutuzumab plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia. 2019 ASH Annual Meeting. Abstract 31. Presented December 7, 2019.