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Acalabrutinib plus obinutuzumab induces high rates of durable responses in chronic lymphocytic leukemia
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CHICAGO — Patients with treatment-naive and relapsed or refractory chronic lymphocytic leukemia attained high rates of sustained responses with acalabrutinib plus obinutuzumab, according to results of a phase 1b/phase 2 trial presented at ASCO Annual Meeting.
The combination also appeared safe, and responses deepened over time.
“With evolving preclinical data in which ibrutinib [Imbruvica; Pharmacyclics, Janssen] has shown inhibition of natural killer cell antibody-dependent cell-mediated cytotoxicity due to [interleukin-2-inductible kinase (ITK)] inhibitors, we thought that the combination of ibrutinib plus rituximab [Rituxan; Genentech, Biogen] might not offer advantage over ibrutinib alone,” Jennifer A. Woyach, MD, associate professor in the leukemia research program of the department of internal medicine at The Ohio State University Comprehensive Cancer Center, said in an interview with HemOnc Today. “However, acalabrutinib does not inhibit ITK, so we thought this would be a better Bruton tyrosine kinase inhibitor to combine with antibodies, and hypothesized that this combination would be effective in CLL.”
In the study, Woyach and colleagues evaluated 19 patients with treatment-naive CLL and 26 patients with relapsed or refractory CLL after one or more previous therapies. Median age of all patients was 61 years (range, 42-76).
About half of patients had lymph nodes of 5 cm or greater. A larger proportion of patients with treatment-naive vs. relapsed or refractory CLL had del(17p) (22% vs. 19%), whereas a smaller proportion had del(11q) (28% vs. 35%), complex karyotype (42% vs. 56%), and IGHV unmutated disease (53% vs. 65%). Data were missing on chromosome deletion for one patient with treatment-naive CLL and on IGHV mutation status for two patients in that group.
All patients received oral acalabrutinib (Calquence, AstraZeneca), a highly selective, potent Bruton TKI, in 28-day cycles at 100 mg twice daily — including 15 patients who were switched from 200 mg four times daily— until disease progression. Researchers administered obinutuzumab (Gazyva, Genentech), an anti-CD20 monoclonal antibody, in a standard manner for six cycles starting at cycle 2.
Overall response rate and safety served as the primary endpoints. The researchers used flow cytometry (sensitivity 10-4) to evaluate minimal residual disease.
Median follow-up was 39.4 months (range, 1-44.9) for the treatment-naive group and 42.1 months (range, 19.8-49.1) for the relapsed or refractory group.
Results showed ORRs of 95% (95% CI, 74-100) for the treatment-naive group, including six complete responses (32%) and 12 partial responses (63%), and 92% (95% CI, 75-99) for the relapsed or refractory group, including two complete responses (8%) and 22 partial responses (85%).
Median duration of response and median PFS had not yet been reached in either group. The 33-month rate of duration of response was 94% (95% CI, 67-99) in the treatment-naive group vs. 91% (95% CI, 68-98) in the relapsed or refractory group, with 36-month PFS rates of 94.4% (95% CI, 66.6-99.2) vs. 72.7% (95% CI, 43.8-88.4).
Researchers observed higher minimal residual disease-negativity rates in the bone marrow of treatment-naive (26%) than relapsed/refractory (15%) patients.
Common adverse events of any grade included upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%) and dizziness (47%). Grade 3 and grade 4 adverse events included decreased neutrophil count (24%), syncope (11%), decreased platelet count (9%), increased weight (9%) and cellulitis (9%). Researchers observed two grade 3 bleeding events, including hematuria and muscle hemorrhage, and one case of grade 3 atrial fibrillation.
“We are combining a very effective drug in acalabrutinib with our most effective CD20 antibody, obinutuzumab,” Woyach told HemOnc Today. “The combination is being tested in a phase 3 clinical trial for previously untreated patients vs. acalabrutinib alone vs. chlorambucil/obinutuzumab, so this study will determine whether this should be a standard-of-care regimen for CLL.” – by Jennifer Byrne
Reference:
Woyach JA, et al. Abstract 7500. Presented at: ASCO Annual Meeting; May 31- June 4, 2019; Chicago.
Disclosures: Woyach reports research funding from AbbVie, Janssen, Karyopharm Therapeutics, Loxo Oncology, MorphoSys and Pharmacyclics; and research funding from Janssen and Pharmacyclics. Please see the abstract for all other authors’ relevant financial disclosures.