SUMMARY: The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.
Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and Pirtobrutinib (JAYPIRCA®).
The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. The combination of Ibrutinib as well as Acalabrutinib plus Venetoclax, were noted to be synergistic.
The AMPLIFY trial is a randomized, global, multi-center, open-label Phase III study designed to assess the efficacy and safety of Acalabrutinib in combination with Venetoclax, with or without Obinutuzumab, compared to investigators choice of standard chemoimmunotherapy. In this study, 984 patients (N=984) across 171 locations worldwide with previously untreated CLL were randomized 1:1:1 to receive a fixed-duration regimen of Acalabrutinib and Venetoclax with Obinutuzumab, Acalabrutinib and Venetoclax without Obinutuzumab, or Standard-of-Care chemoimmunotherapy with either Fludarabine plus Cyclophosphamide and Rituximab (FCR) or Bendamustine plus Rituximab (BR). Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and active disease requiring treatment as per the International Workshop on CLL 2018 criteria. Patients with prior CLL-specific treatments, 17p deletions, TP53 mutations, transformation of CLL to aggressive Non-Hodgkin Lymphoma, Central Nervous System involvement, or a history of Progressive Multifocal Leukoencephalopathy were excluded. The Primary endpoint of the trial was Progression Free Survival (PFS) as assessed by an Independent Review Committee (IRC). Key Secondary endpoints included PFS assessed by investigators, Overall Survival (OS), Event-Free Survival (EFS), Overall Response Rate (ORR), Duration of Response, and Time to next treatment.
High-level results from an interim analysis of the AMPLIFY Phase III trial showed that the combination of Acalabrutinib and Venetoclax, with or without Obinutuzumab resulted in a statistically significant and clinically meaningful improvement in PFS compared to standard chemoimmunotherapy, suggesting that patients receiving this combination therapy experienced longer periods without disease progression. The data will be presented at a forthcoming medical meeting and shared with regulatory authorities. Although OS data were not fully mature at the time of the interim analysis, there was a positive trend in favor of the Acalabrutinib-based regimens. The trial will continue to collect and analyze OS data as a key Secondary endpoint.
The safety profile of Acalabrutinib combined with Venetoclax, with or without Obinutuzumab, was consistent with the known safety profiles of these agents. No new safety concerns were identified, and the rates of cardiac toxicity were low, indicating that the treatment is well-tolerated.
In summary, the AMPLIFY trial highlights the potential benefits of fixed-duration treatment regimens. Such regimens allow patients to take breaks from ongoing therapy, reducing the risk of long-term side effects and drug resistance, and potentially improving their quality of life and providing more flexibility for patients. This contrasts with continuous therapies that may carry higher risks of cumulative toxicity and resistance.
Overall, the AMPLIFY trial represents a significant advancement in the treatment of CLL, demonstrating that combining Acalabrutinib with Venetoclax, with or without Obinutuzumab, offers an effective and well-tolerated alternative to standard chemoimmunotherapy, potentially improving patient outcomes and quality of life.
https://www.astrazeneca.com/media-centre/press-releases/2024/calquence-fixed-duration-combo-improved-1l-cll-pfs.html.