AstraZeneca Announces Positive Top-Line Results from Phase III ELEVATE-TN Trial of Calquence in First-Line Chronic Lymphocytic Leukemia

ELEVATE-TN (ACE-CL-007) is a randomized, multicenter, open-label Phase 3 study conducted in previously untreated (treatment-naïve) patients with chronic lymphocytic leukemia (CLL), designed to evaluate the efficacy and safety of Calquence monotherapy and Calquence plus obinutuzumab combination therapy relative to chlorambucil plus obinutuzumab combination therapy. In this study, 535 patients were randomized in a 1:1:1 ratio into three groups: the first group received chlorambucil plus obinutuzumab; the second group received Calquence (100 mg twice daily until disease progression) plus obinutuzumab; and the third group received Calquence monotherapy (100 mg twice daily until disease progression). The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC) in the Calquence plus obinutuzumab combination arm compared with the chlorambucil plus obinutuzumab combination arm. The key secondary endpoint was PFS assessed by the IRC in the Calquence monotherapy arm compared with the chlorambucil plus obinutuzumab combination arm. Other secondary endpoints included objective response rate (ORR), time to next treatment, and overall survival (OS).

The results demonstrated that the study met its primary endpoint: compared with chlorambucil plus obinutuzumab (a chemotherapy-based regimen), Calquence plus obinutuzumab significantly reduced the risk of disease progression or death by 90% (HR=0.10 [95% CI: 0.06–0.17], p<0.0001), achieving a statistically significant and clinically meaningful improvement in progression-free survival (PFS) (median PFS: not reached vs. 22.6 months). Furthermore, the study also met its key secondary endpoint: compared with chlorambucil plus obinutuzumab, Calquence monotherapy significantly reduced the risk of disease progression or death by 80% (HR=0.20 [95% CI: 0.13–0.30], p<0.0001), achieving a statistically significant and clinically meaningful improvement in PFS (median PFS: not reached vs. 22.6 months). In this study, the safety and tolerability profile of Calquence was consistent with its established profile.

The complete data from this study will be presented at the 2019 American Society of Hematology (ASH) Annual Meeting, held in Orlando from December 7–10.

In June this year, AstraZeneca announced the interim analysis data from ASCEND, its first pivotal Phase III study. The study was conducted in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and compared the efficacy and safety of Calquence versus physician’s choice of treatment, either IdR (rituximab plus idelalisib) or BR (rituximab plus bendamustine). The results showed that the study had already met its primary endpoint at the time of the interim analysis: Calquence significantly prolonged progression-free survival (PFS) in patients with relapsed or refractory CLL compared to physician’s choice of treatment. Specifically, data with a median follow-up of 16.1 months demonstrated that patients receiving Calquence experienced a statistically significant and clinically meaningful improvement in PFS, with a 69% reduction in the risk of disease progression or death compared to those receiving IdR or BR (HR=0.31, 95% CI: 0.20–0.49; p<0.0001). At the time of data analysis, the median PFS had not yet been reached in the Calquence group, whereas it was 16.5 months in the control group. At 12 months, 88% of patients in the Calquence group remained free of disease progression, compared to 68% in the control group. In this study, the safety and tolerability profile of Calquence was consistent with its established characteristics.

The ELEVATE-TN and ASCEND studies confirmed the superiority of Calquence, both as a monotherapy and in combination regimens, over standard-of-care therapies for CLL. Based on data from these two Phase III trials, AstraZeneca has submitted regulatory applications to the U.S. FDA for Calquence for first-line treatment and for relapsed/refractory CLL. In June, the FDA granted Breakthrough Therapy Designation (BTD) for Calquence as a monotherapy for CLL, marking the 10th BTD AstraZeneca has received from the FDA since 2014.

Calquence: A BTK Inhibitor with Annual Sales Expected to Exceed $5 Billion

Calquence received accelerated approval from the U.S. FDA in October 2017 for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who had previously received at least one prior therapy. Currently, the drug is being developed for the treatment of CLL and other hematologic malignancies.

The active pharmaceutical ingredient of Calquence is acalabrutinib, a highly selective, potent, covalent Bruton’s tyrosine kinase (BTK) inhibitor that functions by irreversibly binding to and inhibiting BTK. As a key regulator of the B-cell receptor (BCR) signaling pathway, BTK is widely expressed in various types of hematologic malignancies and plays a role in B-cell proliferation, trafficking, chemotaxis, and adhesion, making it an important therapeutic target for the treatment of hematologic malignancies. In preclinical studies, acalabrutinib demonstrated minimal off-target effects.

Currently, Calquence is being developed for the treatment of various B-cell hematologic malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, Waldenström macroglobulinemia (WM), follicular lymphoma (FL), multiple myeloma, and other hematologic cancers. AstraZeneca has high commercial expectations for Calquence, with peak sales projected to reach $5 billion.