The CHMP Recommends Acalabrutinib Combos For Approval in Untreated CLL

Acalabrutinib plus venetoclax reduced the risk of progression or death by 35% without obinutuzumab and 58% with obinutuzumab in patients with untreated CLL.

The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended acalabrutinib (Calquence) in combination with venetoclax (Venclexta), with or without obinutuzumab (Gazyva), as a fixed-duration regimen, for approval in the European Union in the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL), according to a press release from the developer, AstraZeneca.¹

Supporting results came from the phase 3 AMPLIFY trial (NCT03836261) that evaluated the efficacy and safety of acalabrutinib with venetoclax, with or without obinutuzumab, compared with previously untreated CLL. Prior results showing prolonged PFS with the regimen were presented at the 2024 American Society of Hematology Annual Meeting & Exposition, and shared in the New England Journal of Medicine.^2,3

Acalabrutinib plus venetoclax demonstrated a 35% reduction in the risk of disease progression or death vs standard of care chemoimmunotherapy (HR, 0.65; 95%. CI, 0.49-0.87; P = .0038). Acalabrutinib plus venetoclax and obinutuzumab demonstrated a 58% reduction in the risk of disease progression or death (HR, 0.42; 95% CI, 0.30-0.59; P <.0001).

The median progression-free survival (PFS) was not reached in either of the acalabrutinib groups, though it was 47.6 months in the chemoimmunotherapy group. Additionally, 77% of patients treated with the doublet regimen and 83% of those treated with the triplet regimen were progression-free at 3 years, compared with 67% of patients treated with chemoimmunotherapy.

“CLL is an incurable cancer, which means patients live with the disease and stay on treatment for many years, which can have long-term effects,” Wojciech Jurczak, MD, Maria Sklodowska-Curie National Institute of Oncology, Kraków, Poland, and investigator for the trial, said in the press release. “The fixed duration [acalabrutinib] regimens will allow patients to take breaks from their treatment, reducing the risk of long-term adverse effects and drug resistance.”

AMPLIFY was a randomized, open-label trial that randomly assigned 867 patients, in a 1:1:1 ratio, to receive 100 mg of oral acalabrutinib twice daily from cycles 1 to 14, and oral venetoclax at 20 mg, 50 mg, 100 mg, 200 mg, and 400 mg in a 5-week dose ramp-up from cycles 3 to 14; the triplet group received the same acalabrutinib regimen plus 1000 mg of intravenous obinutuzumab for days 1, 8, and 15 of cycle 2 and then for day 1 of cycles 3 to 7; standard of care was fludarabine plus cyclophosphamide and rituximab (Rituxan) or bendamustine plus rituximab.

Eligible patients were 18 years or older with previously untreated CLL and did not have del(17p) or TP53 mutation. Additionally, patients had an ECOG performance status of 0 to 2, a diagnosis of disease that meets published diagnostic criteria, and active disease per International Workshop on Chronic Lymphocytic Leukemia 2018 criteria.⁴

Exclusion criteria include any prior CLL-specific therapies, transformation of CLL to aggressive non-Hodgkin lymphoma, history of confirmed progressive multifocal leukoencephalopathy, significant cardiovascular disease, history of infection with HIV, major surgical procedure within 30 days of first study drug dose, receipt of any investigational drug within 30 days of first study drug dose, and known history of hypersensitivity or anaphylactic reactions to study drugs or excipients.

The trial’s primary end point was PFS with acalabrutinib and venetoclax per the independent review committee. Secondary end points include PFS with acalabrutinib with venetoclax and obinutuzumab, overall survival, and undetectable measurable residual disease.

No new safety signals were identified with the treatment regimens, and the safety profile was consistent with expectations.

Currently, acalabrutinib is approved by the FDA for previously untreated mantle cell lymphoma.⁵

“With this recommendation, [acalabrutinib] plus venetoclax can potentially be the only all-oral second-generation BTK inhibitor option approved in Europe for patients with previously untreated CLL. [Acalabrutinib] has demonstrated efficacy and safety in fixed-duration and treat-to-progression regimens, providing patients and their doctors more treatment flexibility,” said Susan Galbraith, executive vice president of Oncology Haematology R&D at AstraZeneca.¹

References

1. Fixed-duration calquence-based regimens recommended for approval in the EU by CHMP for 1st-line chronic lymphocytic leukaemia. News release. AstraZeneca. April 29, 2025. Accessed April 29, 2025. https://tinyurl.com/yzy54jbs
2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab Versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Blood. 2024;144(suppl 1):1009. doi:10.1182/blood-2024-200701
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
4. 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 December 27, 2024. Accessed April 29, 2025. https://tinyurl.com/8myakpbw
5. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. January 16, 2025. Accessed April 29, 2025. https://shorturl.at/fTW0O