Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia

Abstract

Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2-6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL. SIGNIFICANCE: Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity-enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.This article is highlighted in the In This Issue feature, p. 327.

©2020 American Association for Cancer Research.

Figures

Figure 1.

Pharmacodynamics of acalabrutinib. A, The percentage of BTK occupancy by acalabrutinib at each timepoint for patients with a signal to noise ≥5 for the day 1 presample. B, The pBTK fold change over control (C1D1 pre + 1 μmol/L exogenous acalabrutinib) for each timepoint. C, The BTK fold change over control (C1D1 pre + 1 μmol/L exogenous acalabrutinib) for each timepoint. For each figure, the horizontal line in the center of the box represents the median. Significance was determined using a paired two-tailed parametric t test: *, P < 0.5; ****, P < 0.0001. BID, twice a day; C, cycle; D, day; pBTK, phosphorylated BTK; pre, predose; QD, once a day.

Figure 2.

T cells, monocytes, and NK cell counts in peripheral blood from all acalabrutinib-treated patients over time. Absolute counts of CD4+ (A) and CD8+ (B) T cells, CD14+ monocytes (C), and NK cells (CD16+CD56+; D). Cells were measured by flow cytometry. The normal reference range for each subset is shown with dashed lines. All plots include patients being assessed at baseline assessment and the respective visit. P values are from the Wilcoxon signed-rank test. NK, natural killer.

Figure 3.

Kaplan–Meier curves for progression-free survival (A) and overall survival (B). mo, months; OS, overall survival; PFS, progression-free survival; R/R, relapsed/refractory; TN, treatment-naïve.

Figure 4.

A, Response and MRD status by baseline genomic alterations. B and C, MRD in bone marrow (B) and peripheral blood (C). LOH, loss of heterozygosity; mut, mutated; TN, treatment-naïve; R/R, relapsed/refractory.