Fixed-Duration Acalabrutinib/Venetoclax Yields PFS Benefit vs SOC in Frontline CLL

Fixed-duration acalabrutinib (Calquence) plus venetoclax (Venclexta) with or without obinutuzumab (Gazyva) in the frontline setting elicited a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs frontline standard-of-care (SOC) chemoimmunotherapy of investigator’s choice in previously untreated adult patients with chronic lymphocytic leukemia (CLL), according to findings from an interim analysis of the phase 3 AMPLIFY trial (NCT03836261).¹

Overall survival (OS) data, although not mature at the time of this analysis, also trended in favor of the acalabrutinib-based regimens compared with SOC chemoimmunotherapy, according to a news release. AMPLIFY will continue to evaluate OS as a key secondary end point.

Findings from AMPLIFY will be presented at an upcoming medical meeting and shared with global regulatory authorities.

“The AMPLIFY results demonstrate the potential of acalabrutinib and venetoclax with or without obinutuzumab to be effective and well-tolerated fixed-duration treatment options for patients with CLL,” Jennifer R. Brown, MD, PhD, said in the news release. “This is an important advance in this setting as fixed-duration regimens allow those living with this chronic disease to take breaks from their treatment, thereby decreasing the possibility of long-term adverse [effects] and drug resistance and improving quality of life.”

Brown is the principal investigator of AMPLIFY, as well as the director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute in Boston, Massachusetts. She is also the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, also in Boston.

“The PFS and OS results from the AMPLIFY phase 3 trial demonstrate the potential of including a BTK inhibitor in a fixed-duration regimen and reinforce our leadership in advancing science for patients with CLL,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, added in the news release. “If approved, [acalabrutinib] would become the only second-generation BTK inhibitor available as both a treat-to-progression and fixed-duration treatment, providing more options for patients and their health care providers.”

The safety and tolerability profile of acalabrutinib plus venetoclax with or without obinutuzumab was consistent with the known safety profiles of each agent. Additionally, investigators identified no new safety signals and observed low rates of cardiac toxicity.

AMPLIFY enrolled patients at least 18 years of age with previously untreated CLL without 17p deletions or TP53 mutations.² Eligible patients needed to have an ECOG performance status of 0 to 2 and active disease requiring treatment per International Workshop on CLL 2018 criteria.

Patients were excluded from enrollment if they had received any prior CLL-specific therapies; detected 17p deletions or TP53 mutations; transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system involvement by leukemia; or a history of confirmed progressive multifocal leukoencephalopathy. Patients could not have received an investigational drug or undergone a major surgical procedure within 30 days prior to their first dose of study drug.

Patients were randomly assigned 1:1:1 to receive acalabrutinib plus venetoclax, acalabrutinib plus venetoclax and obinutuzumab, or investigator’s choice of either fludarabine plus cyclophosphamide and rituximab (Rituxan) or bendamustine plus rituximab.

PFS as assessed by an Independent Review Committee (IRC) in the acalabrutinib plus venetoclax arm served as the trial’s primary end point.¹ Key secondary end points included investigator-assessed PFS in the acalabrutinib plus venetoclax arm, IRC- and investigator-assessed PFS in the acalabrutinib/venetoclax/obinutuzumab arm, OS, event-free survival, overall response rate, duration of response, and time to next treatment.

AMPLIFY included patients from 27 countries across North America, South America, Asia, Europe, and Oceania.

References

1. Fixed-duration Calquence plus venetoclax, with or without obinutuzumab, significantly improved progression-free survival in 1st-line chronic lymphocytic leukaemia in AMPLIFY phase III trial. News Release. AstraZeneca. July 29, 2024. Accessed July 29, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/calquence-fixed-duration-combo-improved-1l-cll-pfs.html
2. Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL (AMPLIFY). ClinicalTrials.gov. Updated May 29, 2024. Accessed July 29, 2024. https://clinicaltrials.gov/study/NCT03836261