The combination of acalabrutinib (Calquence) and obinutuzumab (Gazyva) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with obinutuzumab/chlorambucil in patients with previously untreated chronic lymphocytic leukemia, meeting the primary endpoint of the phase III ELEVATE-TN trial.
José Baselga, MD
The combination of acalabrutinib (Calquence) and obinutuzumab (Gazyva) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with obinutuzumab/chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL), meeting the primary endpoint of the phase III ELEVATE-TN trial.1
Additionally, single-agent acalabrutinib showed a statistically significant and clinically meaningful improvement in PFS compared with obinutuzumab combined with chlorambucil, which was a key secondary endpoint. Acalabrutinib also demonstrated safety and tolerability data that were consistent with prior findings of the BTK inhibitor, which is developed by AstraZeneca. Due to these positive data, the company stated that it will end the trial early.
“These findings confirm the superiority of Calquence as a monotherapy and also in combination over standard-of-care treatments for chronic lymphocytic leukemia,” José Baselga, executive vice president, Oncology R&D, AstraZeneca, said in a press release. “The positive results from both the ELEVATE-TN and ASCEND trials will serve as the foundation for regulatory submissions later this year.”
Full findings of ELEVATE-TN will be presented at an upcoming medical meeting.
The multicenter, open-label, phase III ELEVATE-TN (ACE-CL-007) trial randomized 535 treatment-naïve patients with CLL in a 1:1:1 ratio to receive acalabrutinib alone or in combination with obinutuzumab, or chlorambucil plus obinutuzumab. In both acalabrutinib arms, the BTK inhibitor was administered at 100 mg twice daily until disease progression.
The primary endpoint is PFS in the acalabrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm as assessed by an independent review committee (IRC). A key secondary endpoint is IRC-assessed PFS with single-agent acalabrutinib compared with chlorambucil plus obinutuzumab. Objective response rate, time to next treatment, and overall survival are additional secondary endpoints of the study.
This is the second pivotal trial with acalabrutinib in CLL to meet its primary endpoint early. In May 2019, results of the phase III ASCEND trial showed that single-agent acalabrutinib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with the combination of rituximab (Rituxan) and either idelalisib (Zydelig) or bendamustine in patients with treatment-naïve CLL.2 It was decided that, due to these interim data, the trial would end early.
Detailed data from ASCEND will be presented at the 2019 European Hematology Association Annual Congress.
At the 2019 ASCO Annual Meeting, 3-year follow-up findings of a single-arm trial of acalabrutinib plus obinutuzumab in both treatment-naïve and relapsed/refractory patients with CLL were presented. Results demonstrated a 95% ORR in the previously untreated population, and a 92% ORR in those with relapsed/refractory CLL.3 The median duration of response had yet to be reached.
The longer follow-up of this single-arm study comprised 45 patients with CLL; 19 had untreated CLL and 26 had relapsed/refractory disease. In those with relapsed/refractory disease, prior treatment with a BTK inhibitor was permitted except in the case of discontinuation for on-treatment disease progression.
In the study population, the median age was approximately 62; half of the patients had bulky disease, and 1 patient had small lymphocytic lymphoma. An estimated 20% had deletion 17p, one-third had del(11q), most patients had unmutated IGHV. Approximately half of the patients had complex karyotype.
After a median follow-up of about 3.5 years, 78% of the patients remained on treatment. Moreover, 10 patients discontinued treatment with acalabrutinib, 5 because of adverse events, 4 due to Richter transformation, 1 because of disease progression, and 1 patient died. All but 2 patients completed therapy with obinutuzumab.
Additional findings showed that patients with no prior therapy had a 39-month PFS rate of 94.4%; those with relapsed/refractory disease had a 42-month PFS rate of 72.7%.
Acalabrutinib is currently FDA approved for the treatment of adult patients with relapsed/refractory mantle cell lymphoma.