Acalabrutinib/Venetoclax sNDA Under FDA Review for Previously Untreated CLL

A supplemental new drug application seeking the approval of the fixed-duration, all-oral combination of venetoclax (Venclexta) plus acalabrutinib (Calquence) for previously untreated patients with chronic lymphocytic leukemia (CLL) has been submitted to the FDA.¹

The application is supported by data from the phase 3 AMPLIFY trial (NCT03836261), which showed a statistically significant improvement in progression-free survival (PFS) with the combination vs standard chemoimmunotherapy in this patient population.¹

Findings published in the New England Journal of Medicine showed that the median PFS was not reached with either acalabrutinib plus venetoclax or acalabrutinib plus venetoclax and obinutuzumab (Gazyva) vs 47.6 months with chemoimmunotherapy.² This translated to a 35% reduction in the risk of disease progression or death with acalabrutinib plus venetoclax (HR, 0.65; 95% CI, 0.49-0.87; P = .0004) and 58% reduction in the risk of disease progression or death with acalabrutinib plus venetoclax and obinutuzumab (HR 0.42; 95% CI, 0.30-0.59; P < .0001).^1,2

“This FDA submission marks a milestone for CLL treatment with the potential approval for the first oral combination regimen of venetoclax and acalabrutinib for previously untreated patients with chronic blood cancer,” Svetlana Kobina, vice president of global medical affairs and oncology at AbbVie stated in a news release.¹ “This new fixed-treatment duration approach could allow patients the opportunity for time off treatment, if approved, and be potentially practice-changing in frontline CLL care.”

Notably, data from AMPLIFY also supported the European approval of fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab for patients with treatment-naive CLL in June 2025.²

AMPLIFY Trial Overview

AMPLIFY was a global, multi-center, open-label trial evaluating venetoclax plus acalabrutinib alone or in combination with obinutuzumab vs chemoimmunotherapy in patients with previously untreated CLL without 17p deletion or TP53 mutation.¹ Upon enrollment, patients were randomly assigned 1:1:1 to receive either acalabrutinib-based regimen for 14, 28-day cycles, or standard-of-care chemoimmunotherapy for 6 cycles.

The study’s primary end point was PFS per independent review committee assessment in the acalabrutinib plus venetoclax arm. Secondary end points comprised PFS in the acalabrutinib plus venetoclax and obinutuzumab arm, overall survival (OS), and undetectable measurable residual disease.

Additional Efficacy and Safety Data

Additional efficacy data from AMPLIFY showed that, at a median follow-up of 40.8 months, the estimated 36-month PFS rate was 76.5% with acalabrutinib plus venetoclax, 83.1% with acalabrutinib plus venetoclax and obinutuzumab, and 66.5% with chemoimmunotherapy (HR, 0.65; 95% CI, 0.49-0.87; P = 0.004).³ The estimated 36-month OS rates were 94.1%, 87.7%, and 85.9% for these respective regimens.

The safety and tolerability profile of the combination regimen was also consistent with the known profiles of each individual agent, and no new safety signals were identified.¹ The most common any-grade adverse effects (AE) with the acalabrutinib plus venetoclax regimen were neutropenia, hemorrhage, and COVID-19.

Regarding adverse effects (AE) of clinical interest, the most frequently observed grade 3 or higher event was neutropenia; this was reported in 32.3%, 46.1%, and 43.2% in the acalabrutinib plus venetoclax, acalabrutinib plus venetoclax and obinutuzumab, and chemoimmunotherapy groups, respectively.³ The incidence of any-grade tumor lysis syndrome was low, with an incidence of 0.3% in patients treated with acalabrutinib plus venetoclax compared with 3.1% in patients treated with chemoimmunotherapy. ¹

References

1. AbbVie submits for U.S. FDA approval of combination treatment of Venclexta (venetoclax) and acalabrutinib for previously untreated patients with chronic lymphocytic leukemia (CLL).News release. AbbVie. July 29, 2025. Accessed July 29, 2025. https://news.abbvie.com/2025-07-29-AbbVie-Submits-for-U-S-FDA-Approval-of-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-with-Chronic-Lymphocytic-Leukemia-CLL
2. Fixed-duration Calquence-based regimens approved in EU for patients with chronic lymphocytic leukaemia in the 1st-line setting. News release. AstraZeneca. June 6, 2025. Accessed July 29, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/fixed-duration-calquence-approved-in-eu-for-1l-cll.html
3. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804