Acalabrutinib-Based Regimens Receive European Approval in Frontline CLL

Chronic Lymphocytic Leukemia |
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The European Commission has approved a fixed-duration regimen of acalabrutinib (Calquence) for use in combination with venetoclax (Venclexta), with or without obinutuzumab (Gazyva), for the treatment of patients with treatment-naive chronic lymphocytic leukemia (CLL).1

The approval is based on data from the phase 3 AMPLIFY trial (NCT03836261), which were published in the New England Journal of Medicine and showed a substantial improvement in progression-free survival (PFS) with the acalabrutinib-based regimens vs investigator’s choice of chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab (Rituxan) or bendamustine plus rituximab (BR).

The median PFS was not reached with either acalabrutinib regimen vs 47.6 months with chemoimmunotherapy, resulting in 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 = .0038) 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).

The safety and tolerability profile of acalabrutinib was also consistent with past reports, and no new signals were identified.

“For patients diagnosed with [CLL], this approval provides a new option in the first-line setting that may help to minimize long-term [adverse] effects [AEs] and reduce drug resistance as they may occur with continuous treatment,” Barbara Eichhorst, MD, an associate professor and attending physician at the University Hospital Cologne in Germany and investigator for the AMPLIFY trial, said in a news release. “A fixed-duration regimen is appealing to patients and helps with adherence during the treatment period.”

AMPLIFY was a randomized, global, multi-center, open-label trial that enrolled patients with previously untreated CLL without 17p deletion or TP53 mutation. Patients were randomly assigned 1:1:1 to receive either acalabrutinib plus venetoclax or acalabrutinib plus venetoclax with obinutuzumab for 14, 28-day cycles, or standard-of-care chemoimmunotherapy for 6 cycles.

The primary end point was PFS in the acalabrutinib plus venetoclax arm according to independent review committee assessment. PFS in the acalabrutinib plus venetoclax and obinutuzumab arm was a key secondary end point, along with overall survival (OS) and undetectable measurable residual disease.

At a median follow-up of 40.8 months (range, 0-59), the estimated 36-month PFS rates were 76.5% (95% CI, 71.0%-81.1%) with acalabrutinib plus venetoclax, 83.1% (95% CI, 78.1%-87.1%) with acalabrutinib plus venetoclax and obinutuzumab, and 66.5% (95% CI, 59.8%-72.3%) with chemoimmunotherapy.2

The median OS was 57.8 months with acalabrutinib and venetoclax (HR vs chemoimmunotherapy, 0.33; 95% CI, 0.18-0.56; P < .001) and not calculable with acalabrutinib plus venetoclax and obinutuzumab (HR vs chemoimmunotherapy, 0.76; 95% CI, 0.49-1.18). The estimated 36-month OS rates were 94.1% (95% CI, 90.7%-96.3%) with acalabrutinib plus venetoclax, 87.7% (95% CI, 83.2%-91.0%) with acalabrutinib plus venetoclax and obinutuzumab, and 85.9% (95% CI, 81.0%-89.6%) with chemoimmunotherapy.

Additional findings indicated that the estimated 36-month event-free survival rate according to blinded independent central review (BICR) was 75.9% with acalabrutinib plus venetoclax, 82.8% with acalabrutinib plus venetoclax and obinutuzumab, and 64.5% with chemoimmunotherapy.

The BICR-assessed overall response rates were 92.8% (95% CI, 89.4%-95.4%) with acalabrutinib and venetoclax, 92.7% (95% CI, 89.2%-95.3%) with acalabrutinib, venetoclax, and obinutuzumab, and 75.2% (95% CI, 70.0%-79.9%) with chemoimmunotherapy.

With respect to safety, neutropenia was the most common grade 3 or higher AE of clinical interest, occurring in 32.3%, 46.1%, and 43.2% of patients in the acalabrutinib plus venetoclax; acalabrutinib, venetoclax, and obinutuzumab; and chemoimmunotherapy arms, respectively.

Other AEs in the respective three arms included cardiac events (9.3%; 12.0%; 3.5%), hypertension (4.1%; 3.9%; 2.7%), hemorrhage (32.3%; 30.3%; 4.2%), infection (50.9%; 53.9%; 31.7%), second primary cancer (5.2%; 4.2%; 0.8%), and tumor lysis syndrome (0.3%; 0.4%; 3.1%).

“[This] approval brings a new fixed-duration treatment option to patients with previously untreated chronic lymphocytic leukemia across Europe,” Dave Fredrickson, executive vice president of the Oncology Haematology Business Unit at AstraZeneca, said.1 “[Acalabrutinib] plus venetoclax is the first and only all-oral combination treatment option with a second-generation BTK inhibitor approved in the EU and provides patients and their physicians more flexibility in managing this incurable blood cancer.”

References

1. 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 June 6, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/fixed-duration-calquence-approved-in-eu-for-1l-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