Overall, the phase 3 ELEVATE-RR trial demonstrated efficacy of acalabrutinib and a safety and tolerability profile that with was consistent with that observed in the broader acalabrutinib clinical development program.
Positive high-level results reported from the phase 3 ELEVATE-RR (NCT02477696) trial demonstrated that compared to with ibrutinib (Imbruvica), acalabrutinib (Calquence) met the study’s primary end point of demonstrating non-inferior progression-free survival (PFS) for adults with previously treated, high-risk chronic lymphocytic leukemia (CLL), according to the agent’s developer, AstraZeneca.
Additionally, the trial met its key secondary end point of safety, revealing that patients treated with acalabrutinib experienced a statistically significantly lower incidence of atrial fibrillation compared to with those treated with ibrutinib. Hierarchical testing also revealed no difference regarding grade 3 or higher infections or Richter’s transformation. Moreover, there was a descriptive trend towards a numerically favorable overall survival (OS).
Overall, the safety and tolerability profile observed with acalabrutinib was found to be consistent with that seen in the broader acalabrutinib clinical development program.
“With over forty months of follow-up, today’s results confirm that [acalabrutinib], a selective BTK [Bruton’s tyrosine kinase; BTK] inhibitor, displays superior safety in atrial fibrillation without compromising efficacy,” José Baselga, executive vice president of oncology research and development at AstraZeneca, said in a press release. “The totality of the data confirm our confidence in the favorable benefit-risk profile of [acalabrutinib].”
In the randomized, multicenter, open-label, phase 3 non-inferiority trial, a total of 533 patients with previously treated CLL with high-risk features, including the presence of 17p deletion and/or 11q deletion, were randomized 1:1 to receive either acalabrutinib or ibrutinib. Patients on the acalabrutinib arm were treated with at a dose level of 100 mg acalabrutinib orally twice daily until disease progression or unacceptable toxicity, while those on the ibrutinib arm were treated with a dose of 420 mg ibrutinib orally once daily, with both arms receiving therapy until disease progression or unacceptable toxicity.
The primary endpoint for the trial was PFS tested after 250 events, as determined by an independent review committee for (non-inferiority of acalabrutinib versus ibrutinib). Key secondary end points included incidence of atrial fibrillation, incidence of treatment-emergent grade 3 or higher infections, incidence of Richter’s transformation, and OS.
Notably, ELEVATE-RR is the first phase 3 trial to compare 2 BTK inhibitors in patients with CLL. AstraZeneca indicated that these data will be presented at an upcoming medical meeting and also shared with regulatory health authorities.
Acalabrutinib specifically binds covalently to BTK, thus inhibiting its activity. AstraZeneca, in partnership with Acerta Pharma, is currently evaluating the agent in more than 20 company-sponsored clinical trials as part of an extensive clinical development program. Acalabrutinib is being developed for the treatment of multiple B-cell blood cancers including CLL, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, follicular lymphoma, and other hematologic malignancies.
Acalabrutinib is currently approved for the treatment of CLL and small lymphocytic lymphoma in the United States and for CLL in the European Union and several other countries worldwide. In addition, the agent is under regulatory review in Japan for relapsed or refractory CLL, where a phase I trial is also currently underway for the first-line treatment of CLL.
Further, the next-generation BTK-inhibitor is also approved for the treatment of adult patients with MCL who have received at least 1 prior therapy in the United States and several other countries. The MCL indication in the United States is approved under accelerated approval based on overall response rate, however continued approval for this indication may be dependent upon verification and description of clinical benefit in confirmatory trials.
To date, acalabrutinib is not approved for the treatment of MCL in Europe or Japan.
Calquence met primary efficacy endpoint in head-to-head trial against ibrutinib in chronic lymphocytic leukaemia. News release. AstraZeneca. Published January 25, 2021. Accessed January 25, 2021. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/calquence-met-primary-endpoint-against-ibrutinib.html