Jeff P. Sharman, MD
Acalabrutinib (Calquence) as a single agent or in combination with obinutuzumab (Gazyva) led to a statistically significant improvement in progression-free survival (PFS) compared with obinutuzumab plus chlorambucil in treatment-naïve patients with chronic lymphocytic leukemia (CLL), according to results from the phase III ELEVATE-TN trial presented at the 2019 ASH Annual Meeting.
At a median follow-up of 28.3 months, the combination of the BTK inhibitor with obinutuzumab led to a 90% reduction in the risk of disease progression or death compared with obinutuzumab/chlorambucil (HR, 0.10; 95% CI, 0.06-0.17; P
<.0001). When used as monotherapy, acalabrutinib also showed a statistically significant benefit in PFS (HR, 0.20; 95% CI, 0.13-0.30; P
“Acalabrutinib has demonstrated efficacy and a consistent safety profile in treatment-naïve and relapsed/refractory patients, and is now an approved treatment option for patients with CLL,” said lead study author Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, in a presentation during the meeting.
Obinutuzumab combined with chlorambucil was a standard frontline option for patients with CLL prior to the introduction of the BTK inhibitor ibrutinib (Imbruvica). In November 2019, the FDA granted approval to acalabrutinib for the treatment of patients with CLL or small lymphocytic lymphoma, partly based on data from the ELEVATE-TN trial, as well as the ASCEND trial, which evaluated the BTK inhibitor compared with either rituximab (Rituxan) or idelalisib (Zydelig) in previously treated patients with CLL.
“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 frontline therapy with or without obinutuzumab,” Sharman said.
In the randomized, multicenter, open-label, phase III ELEVATE-TN (ACE-CL-007) trial, investigators evaluated the safety and efficacy of acalabrutinib
alone or in combination with obinutuzumab versus chlorambucil/obinutuzumab in 535 treatment-naïve patients with CLL. Patients were randomized 1:1:1 into 3 arms: chlorambucil plus obinutuzumab (n = 177); 100 mg of acalabrutinib twice daily 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). Patients were stratified by 17p deletion status, ECOG performance status of 0 to 1 or 2, and geographic region.
Crossover from the obinutuzumab/chlorambucil arm was permitted after independent review committee (IRC)-confirmed disease progression; therefore, these patients were not included in the PFS data that were presented during the 2019 ASH Annual Meeting.
An interim analysis was planned based on events, which was after the occurrence of ~111 IRC-assessed PFS in the combination arms, or after 24 months if the required number of events was not met by this time.
Baseline characteristics were similar across the 3 treatment arms. The median patient age for the trial was 70.5 years, 63% of patients had an unmutated IGVH
, 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.
The treatment discontinuation rates were 20.7%, 20.1%, and 18.1% in the acalabrutinib/obinutuzumab, acalabrutinib-alone, and obinutuzumab/chlorambucil arms, respectively. The most common reason patients discontinued treatment was due to adverse events (AEs), which occurred in 11.2%, 8.9%, and 14.1% of patients, respectively. Two deaths were reported on the acalabrutinib combination arm, 3 deaths on the single-agent acalabrutinib arm, and 1 death in the chemoimmunotherapy group. The median duration of treatment in the acalabrutinib arms was 27.7 months and 5.6 months in the chlorambucil/obinutuzumab arm, and 79.3% of patients were still continuing on treatment.
The primary endpoint was PFS in the acalabrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm, as assessed by IRC. Secondary endpoints included IRC-assessed PFS in the acalabrutinib-alone arm versus chlorambucil/obinutuzumab, as well as objective response rate (ORR), time to next treatment, overall survival (OS), and safety.
Results by IRC assessment showed that the median PFS was not reached with either acalabrutinib arm, compared with 22.6 months (95% CI, 20.2-27.6) with chlorambucil/obinutuzumab. The 2-year PFS rates were 93%, 87%, and 47% for acalabrutinib/obinutuzumab, single-agent acalabrutinib, and chemoimmunotherapy, respectively.