Acalabrutinib/Venetoclax With or Without Obinutuzumab Earns Positive CHMP Opinion for Untreated CLL

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The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for acalabrutinib (Calquence) plus venetoclax with or without obinutuzumab (Gazyva) for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL).1

The positive opinion was based on findings from the phase 3 AMPLIFY trial (NCT03836261), which were presented at the 2024 ASH Annual Meeting and subsequently published in The New England Journal of Medicine.

At a median follow-up of 40.8 months, the estimated 36-month progression-free survival (PFS) rate was 76.5% with acalabrutinib/venetoclax, 83.1% with acalabrutinib/venetoclax and obinutuzumab, and 66.5% with chemoimmunotherapy (HR for acalabrutinib/venetoclax vs chemoimmunotherapy, 0.65; 95% CI, 0.49-0.87; P = .004).2 The estimated 36-month overall survival (OS) rate was 94.1% with acalabrutinib/venetoclax, 87.7% with acalabrutinib/venetoclax with obinutuzumab, and 85.9% 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,” Wohciech Jurczak, MD, of Maria Sklodowska-Curie National Institute of Oncology in Kraków, Poland, and an investigator for the trial, said in a news release.1 “The fixed duration [acalabrutinib] regimens will allow patients to take breaks from their treatment, reducing the risk of long-term adverse effects [AEs] and drug resistance.”

Background and AMPLIFY Overview

The open-label trial included patients at least 18 years of age with previously untreated CLL, an ECOG performance status of 0 to 2, and the absence of 17p deletions or TP53 mutations.2 Patients were randomly assigned 1:1:1 (n = 867) to be treated with either acalabrutinib from cycles 1 to 14 plus venetoclax from cycles 3 to 14 (n = 291), acalabrutinib/venetoclax in the same respective cycles plus obinutuzumab from cycles 2 to 7 (n = 286), or chemoimmunotherapy (n = 290) with investigator’s choice of fludarabine/cyclophosphamide/rituximab (Rituxan; n = 143) or bendamustine/rituximab from cycles 1 to 6 (n = 147).

The primary end point was PFS in the intention-to-treat population assessed per blinded independent central review.

The median age was 61 years (range, 26-86), and the majority were male (64.5%) with unmutated IGHV (58.9%).

In the 2 investigational arms, patients demonstrated an overall response rate (ORR) of 92.8% for those treated with acalabrutinib/venetoclax (95% CI, 89.4%-95.4%) and 92.7% with acalabrutinib/venetoclax/obinutuzumab (95% CI, 89.2%-95.3%), compared with 75.2% for chemoimmunotherapy (95% CI, 70.0%-79.9%; P < .0001).

Of note, the safety and tolerability of acalabrutinib were consistent with its previously known safety profile, with no new safety signals identified. Grade 3 or greater AEs were reported in 53.6%, 69.4%, and 60.6% of patients from the doublet, triplet, and chemoimmunotherapy groups, respectively. The most common adverse AE of clinical interest that was grade 3 or greater was neutropenia, which was reported in 32.3%, 46.1%, and 43.2% of patients in the doublet, triplet, and chemoimmunotherapy groups, respectively. Death due to COVID-19 was reported in 10, 25, and 21 patients from the respective groups.

AEs that led to the discontinuation of acalabrutinib occurred in 7.6% of patients in the doublet group and 13.7% in the triplet group. Dose reductions due to AEs occurred in 14.2%, 20.8%, and 11.2% in the doublet, triplet, and chemoimmunotherapy groups, respectively.

“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,” Susan Galbraith, executive vice president of Oncology Hematology R&D at AstraZeneca, added in the news release.1 “[Acalabrutinib] has demonstrated efficacy and safety in fixed duration and treat-to-progression regimens, providing patients and their doctors more treatment flexibility.”

References

1. Recommendation based on AMPLIFY phase III trial which showed Calquence combinations demonstrated statistically significant and clinically meaningful improvement in progression-free survival vs chemoimmunotherapy. News release. AstraZeneca. April 29, 2025. Accessed April 29, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/fixed-duration-calquence-recommended-in-eu-for-cll.html
2. 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