Phase III AMPLIFY Trial Shows Calquence Plus Venetoclax Significantly Improves Survival in Untreated CLL

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A regimen of fixed-duration Calquence (acalabrutinib; AstraZeneca) plus venetoclax, with or without Gazyva (obinutuzumab), was found to significantly improve progression-free survival (PFS) compared to chemoimmunotherapy in fit patients with previously untreated chronic lymphocytic leukemia (CLL), according to an interim analysis of the Phase III AMPLIFY trial (NCT03836261) published in The New England Journal of Medicine.^1,2

Further, patients administered Calquence, a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, in combination with venetoclax were found to have significantly longer overall survival (OS) compared to chemoimmunotherapy; however, investigators noted that long-term follow-up is necessary to analyze the durability of the survival benefits of fixed-duration combination therapy with a second-generation BTK inhibitor plus venetoclax with or without Gazyva.

“Although fixed-duration chemoimmunotherapy can lead to durable remission in some patients, continuous treatment with a Bruton’s tyrosine kinase inhibitor (with or without an anti-CD20 antibody) has shown superior efficacy in patients with previously untreated CLL,” the study authors wrote. “Fixed-duration venetoclax combinations with obinutuzumab, ibrutinib, or both have led to high rates of undetectable measurable residual disease (MRD) and prolonged progression-free survival in patients with previously untreated CLL, findings that show the clinical usefulness of these therapies.”¹

Calquence was initially approved by the FDA in October 2017 to treat patients with MCL previously administered at least one prior therapy.³ In November 2019, the BTK inhibitor was also approved for adults with CLL and small lymphocytic lymphoma (SLL).⁴ Calquence was most recently approved in combination with bendamustine and rituximab for the first-line treatment of adult patients with previously untreated mantle cell lymphoma who are ineligible for autologous hematopoietic stem cell transplantation.⁵

Gazyva is a CD20-directed cytolytic antibody that is currently approved in more than 100 countries for the treatment of lymphoma, including in combination with chlorambucil for the treatment of patients with previously untreated CLL; in combination with chemotherapy followed by Gazyva monotherapy in patients with stage II bulky, III, or IV follicular lymphoma (FL); and combined with (Bendeka) bendamustine followed by Gazyva monotherapy for FL in adults who did not respond to a rituximab-containing regimen, or whose FL returned.⁶ Venetoclax is a B-cell lymphoma-2 inhibitor indicated for CLL, SLL, and acute myeloid leukemia.

Trial Design

The open-label AMPLIFY trial enrolled patients aged 18 years and older with an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and without a 17p deletion or TP53 mutation. A total of 867 patients were randomly assigned in a 1:1:1 ratio to receive Calquence–venetoclax (n = 291), Calquence–venetoclax–Gazyva (n = 286), or chemoimmunotherapy (n = 290) with investigator’s choice of fludarabine–cyclophosphamide–rituximab (n = 143) or bendamustine–rituximab (n = 147). The trial’s primary endpoint was a comparison of PFS between Calquence-venetoclax vs. chemoimmunotherapy in the intention-to-treat population, as assessed by blinded independent central review.

The results showed that at a median follow-up of 40.8 months, the estimated 36-month PFS was 76.5% in the Calquence-venetoclax cohort, 83.1% in the Calquence-venetoclax-Gazyva cohort, and 66.5% in the chemoimmunotherapy (hazard ratio for disease progression or death with Calquence-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P=0.004; for the comparison of Calquence–venetoclax–Gazyva with chemoimmunotherapy, P<0.001). Estimated 36-month OS was 94.1% in the Calquence-venetoclax cohort, 87.7% in the Calquence-venetoclax-Gazyva cohort, and 85.9% with chemoimmunotherapy.

In terms of safety, the most frequently reported adverse event of clinical interest of grade 3 or higher was neutropenia, which was reported by 32.3% of patients in the Calquence-venetoclax cohort, 46.1% in the Calquence-venetoclax-Gazyva cohort, and 43.2% in the chemoimmunotherapy cohort.

“In this interim analysis of the AMPLIFY trial in fit patients with previously untreated CLL, fixed-duration acalabrutinib–venetoclax (with or without obinutuzumab) significantly prolonged progression-free survival as compared with chemoimmunotherapy,” the study authors concluded. “Results for progression-free survival suggest that the benefit of adding obinutuzumab to acalabrutinib–venetoclax was most apparent in the subgroup with unmutated IGHV, which had results that were similar to those in the subgroup with mutated IGHV. In addition, overall survival was significantly prolonged with acalabrutinib–venetoclax as compared with chemoimmunotherapy.”¹

References

1. Brown J., et al. Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. N Engl J Med. 2025;392:748-762. DOI: 10.1056/NEJMoa2409804. Vol. 392 No. 8.

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. Updated December 27, 2024. Accessed February 20, 2025. https://clinicaltrials.gov/study/NCT03836261

3. FDA approves new treatment for adults with mantle cell lymphoma. News release. FDA. October 31, 2017. Accessed February 20, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-mantle-cell-lymphoma

4. Calquence approved in the US for adult patients with chronic lymphocytic leukaemia. News release. AstraZeneca. November 21, 2019. Accessed February 20, 2025. https://www.astrazeneca.com/media-centre/press-releases/2019/calquence-approved-in-the-us-for-adult-patients-with-chronic-lymphocytic-leukaemia-21112019.html#

5. CALQUENCE® (acalabrutinib) plus chemoimmunotherapy approved in the US for patients with previously untreated mantle cell lymphoma. Yahoo!finance. January 17, 2025. Accessed February 20, 2025. https://finance.yahoo.com/news/calquence-acalabrutinib-plus-chemoimmunotherapy-approved-120000864.html

6. Furie R. et al. Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis. N Engl J Med 2025; DOI/full/10.1056/NEJMoa2410965.