Among patients with previously untreated chronic lymphocytic leukemia (CLL), Calquence (acalabrutinib) plus Venclexta (venetoclax) with or without Gazyva (obinutuzumab) significantly prolonged progression-free survival when compared with chemoimmunotherapy, according to study findings published in The New England Journal of Medicine.
After a median follow-up of 40.8 months, the estimated 36-month progression-free survival was 76.5% with Calquence and Venclexta, 83.1% with Calquence plus Venclexta and Gazyva, and 66.5% with chemoimmunotherapy. Estimated 36-month overall survival was 94.1% with Calquence plus Venclexta, 87.7% with the Calquence combination and 85.9% with chemoimmunotherapy.
“Results for progression-free survival suggest that the benefit of adding [Gazyva to Calquence and Venclexta] was most apparent in the subgroup with unmutated IGHV, which had results that were similar to those in the subgroup with mutated IGHV,” Dr. Jennifer R. Brown and colleagues wrote in the study. “In addition, overall survival was significantly prolonged with [Calquence plus Venclexta] as compared with chemoimmunotherapy.”
Brown is the director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston.
Side effects leading to discontinuation of Calquence occurred in 7.6% and 13.7% of patients in the Calquence plus Venclexta, and Calquence plus Venclexta and Gazyva groups, respectively. Dose reduction occurred in 14.1%, 20.8% and 11.2% in the three groups. Infections and neutropenia were the most common reasons for treatment interruption and dose reduction.
Serious side effects were reported in 24.7%, 38.4% and 27.4% of patients in the three groups. Cardiac events and second primary cancers were more common in the Calquence plus Venclexta (9.3% and 5.2%) and Calquence plus Venclexta and Gazyva (12% and 4.2%) groups compared to the chemoimmunotherapy group (3.5% and 0.8%). Basal cell and squamous cell carcinomas occurred more often in the Calquence plus Venclexta group.
Hypertension occurred in 4.1%, 3.9% and 2.7%, and grade 3 (severe) or higher neutropenia was reported in 32.3%, 46.1% and 43.2%. Tumor lysis syndrome was observed in 0.3%, 0.4% and 3.1% of patients.
Deaths from any cause were reported in 18, 37 and 42 patients in the three groups, with COVID-19-related deaths occurring in 10, 25 and 21 patients, respectively. Of the 56 COVID-19-related deaths, 48 occurred in 2020 and 2021.
“The safety profile of fixed-duration [Calquence plus Venclexta] in this trial aligned with that in previous studies of [Calquence],” study authors wrote.
A total of 867 patients were randomized with 291 assigned to Calquence plus Venclexta, 286 to Calquence plus Venclexta and Gazyva and 290 to chemoimmunotherapy. Of those in the chemoimmunotherapy group, 143 received fludarabine and cyclophosphamide and rituximab and 147 received bendamustine-rituximab. The median patient age was 61 years, and 58.6% had unmutated IGHV.
This phase 3 open-label trial enrolled patients 18 or older with an Eastern Cooperative Oncology Group performance-status score of 0 to 2 and no 17p deletion or TP53 mutation. Participants were randomly assigned to receive either Calquence plus Venclexta (Calquence in cycles 1 to 14; Venclexta in cycles 3 to 14), Calquence plus Venclexta and Gazyva (same regimen with Gazyva in cycles 2 to 7) or chemoimmunotherapy with fludarabine and cyclophosphamide and rituximab or bendamustine and rituximab (cycles 1 to 6), as chosen by investigators.
Reference:
“Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia,” by Dr. J. R. Brown, et al., The New England Journal of Medicine.
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