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 benefi t in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicityenhanced antibody obinutuzumab yielded durable responses that deepened over time in treatmentnaïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.

Incorporating acalabrutinib, a selective next‐generation Bruton tyrosine kinase inhibitor, into clinical practice for the treatment of haematological malignancies

“…72 At a median follow-up of 39 months in treatment-naive patients and 42 months in patients with R/R CLL, the ORRs were 95% and 92%, respectively. 72 At 36 months, 94% of treatment-naive patients and 88% of patients with R/R CLL were progression-free. ELEVATE-TN assessed the efficacy and safety of obinutuzumab in combination with acalabrutinib in comparison with acalabrutinib monotherapy and with obinutuzumab plus chlorambucil (n = 535 total; n = 179, 179 and 177, respectively).…”

Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

“…While a small percentage of CLL cases will never progress from this indolent disease phase, most patients will maintain a watchful waiting period until worsening cytopenias or disease symptoms emerge, upon which treatment begins. Recent advances in treatment of patients with CLL have dramatically improved patient outcomes, prompted by innovations in drugs targeting B-cell receptor (BCR) signaling pathways including Bruton's tyrosine kinase (BTK) [3][4][5][6][7][8] or phosphoinositide 3-kinases (PI3K) [9][10][11][12][13], or disruption of the B-cell lymphoma 2 (BCL2) [14][15][16][17] inhibitor of apoptosis, among others [18]. Each class of drug yields extended remissions with variable time periods of treatment ranging from intermittent to continuous.…”

Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances

“…Given the success of ibrutinib, several clinical trials were directly conducted both in naive and R/R CLL/SLL patients to determine whether the second-generation irreversible BTK inhibitors acalabrutinib and zanubrutinib would be effective. Byrd, Awan, and Woyach et al reported that acalabrutinib showed an approximate ORR of 90% in ibrutinib-treated or not treated, naive or R/R CLL/SLL, although the longest follow-up time was only 41 months and data maturity requires time [77][78][79][80]. These interim analyses demonstrated favourable safety and durability of the response with acalabrutinib, leading to FDA approval of acalabrutinib as a treatment for R/R CLL/SLL in 2019.…”