Acalabrutinib Combo Significantly Improves PFS Vs Chemoimmunotherapy in CLL

"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," according to Jennifer R. Brown, MD, PhD.

Fixed-duration acalabrutinib (Calquence) plus venetoclax (Venclexta) with or without obinutuzumab (Gazyva) elicited a clinically meaningful and statistically significant progression-free survival (PFS) improvement compared with standard chemoimmunotherapy among patients with previously untreated chronic lymphocytic leukemia (CLL), according to a press release on topline results from the phase 3 AMPLIFY trial (NCT03836261).¹

Findings also showed a trend towards improved overall survival (OS) with acalabrutinib plus venetoclax with or without obinutuzumab, although these data were immature at the time of the analysis. Investigators will continue to follow patients for OS as a key secondary end point.

The safety and tolerability of the acalabrutinib-based regimens was comparable with prior reports of each individual agent. Investigators reported low rates of cardiac toxicity; there were no new safety signals.

Investigators plan to present detailed results at a future medical meeting and share their findings with regulatory health authorities across the world.

“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],” lead study investigator Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, said in the press release.¹ “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.”

Investigators of the international, multicenter, open-label AMPLIFY trial are evaluating acalabrutinib-based treatment among adult patients with CLL harboring no 17p deletions or TP53 mutations. Patients were randomly assigned 1:1:1 to receive acalabrutinib plus venetoclax, acalabrutinib plus venetoclax and obinutuzumab, or standard chemoimmunotherapy. Treatment in the comparator arm consisted of fludarabine plus cyclophosphamide and rituximab (Rituxan) as well as bendamustine plus rituximab.²

The trial’s primary end point is PFS in the acalabrutinib/venetoclax arm compared with standard chemoimmunotherapy per independent review committee assessment, with investigator-assessed PFS serving as a secondary end point. Key secondary end points include OS, event-free survival, overall response rate, duration of response, and time to next treatment.

Investigators recruited patients across 27 countries in North America, South America, Europe, Asia, and Oceania. Enrollment took place from 2019 to 2021 through the COVID-19 pandemic.

Patients 18 years and older with active CLL per International Workshop on CLL 2018 criteria requiring treatment were eligible for enrollment on the study. Having an ECOG performance status of 0 to 2 was another requirement for study entry.

Individuals with any prior treatment for CLL, 17p deletions or TP53 mutations, or confirmed progressive multifocal leukoencephalopathy were ineligible for enrollment on the trial. Patients were also unsuitable for enrollment if they had major surgery within 30 days of beginning study treatment, significant cardiovascular disease, active hepatitis B or C infection, stroke or intracranial hemorrhage within 6 months of beginning treatment, or known bleeding disorders. Requiring anticoagulation with warfarin or equivalent vitamin K antagonists was also grounds for exclusion from the trial.

“The [PFS] and [OS] results from the AMPLIFY phase 3 trial demonstrate the potential of including a Bruton tyrosine kinase [BTK] inhibitor in a fixed-duration regimen and reinforce our leadership in advancing science for patients with [CLL]. 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 healthcare providers,” Susan Galbraith, executive vice president of Oncology Research & Development at AstraZeneca, concluded.¹

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://tinyurl.com/273cmc6x
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. Accessed July 29, 2024. https://tinyurl.com/ysju79ym