B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.

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T A B L E 2 CRS in enrolled patients C R S 0 1 0 2 0 3 0 4 0 5 ABSTRACT Background: In patients with chronic lymphocytic leukemia (CLL) treated with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, intolerance was the most common reason for discontinuation (50% to 63%; Mato AR, et al. Haematologica. 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in ibrutinib-intolerant patients with relapsed/refractory CLL. Methods: Patients with relapsed/refractory CLL (≥1 prior therapy) who discontinued ibrutinib due to Grade 3/4 adverse events or persistent/recurrent Grade 2 adverse events and had progressive disease after ibrutinib discontinuation were eligible. Acalabrutinib was given orally at 100 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate. Results: Sixty patients were treated. The median age was 70 years (range, 43 to 88). Patient characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%), and unmutated IGHV (79%). Fifty-two of 55 patients (95%) with available baseline samples were wild type forBTK and PLCG2. The median number of prior therapies was 2 (range, 1 to 10). The median duration of prior ibrutinib therapy was 6 months (range, <1 to 55); common adverse events that led to ibrutinib discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). At a median follow-up of 19 months (range, 1 to 31), 67% of patients remain on acalabrutinib; discontinuations were mostly due to progressive disease (13%) and adverse events (10%; pneumonia [n=2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n=1]). Efficacy outcomes are in the Table. Common adverse events (any grade) were diarrhea (48%), headache (40%), contusion (35%), and dizziness (32%). Serious adverse events (≥2 patients) were pneumonia (10%), anemia (3%), and syncope (3%). Atrial fibrillation occurred in 3 patients (5%; all Grade 1/2) and major hemorrhage in 2 (3%; Grade 3 hematuria and Grade 2 subdural hematoma). Grade 5 adverse events were pneumonia (n=2), bronchopulmonary aspergillosis (n=1), and ventricular fibrillation (n=1); all were considered not related to treatment. Conclusions: Acalabrutinib is tolerable and effective in ibrutinibintolerant patients, providing a viable strategy for continuing BTK inhibitor therapy. T A B L E 1 N=60 Overall response rate (≥ PRL), n (%) 46 (77) 95% CI 64, 87 CR 1 (2) PR 42 (70) PRL 3 (5) Median PFS Not reached 21-month PFS rate, % (95% CI) 76 (61, 86)Abbreviations: CR, complete response; PFS, progression-free survival; PR, partial response; PRL, partial response with lymphocytosis.ABSTRACT 61

Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP-5862) vs. efficacy and safety responses in patients with B-cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab.Methods: For exposure-efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression-free survival and tumour regression. For exposure-safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B-cell malignancies. Acalabrutinib and ACP-5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP-5862 to overall efficacy/safety.Results: A total of 573 patients were included (exposure-efficacy analyses, n = 274; exposure-safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration-time curve (AUC 24h,ss ) and total active maximal concentration at steady-state (C max,ss ) were Helena Edlund and Núria Buil-Bruna: equal contribution.A principal investigator was not included in the author byline because the reported data are from a pooled exposure-response analysis of data from 8 different studies. The principal investigators of the original studies were not involved in performing these analyses or interpreting the data; therefore, they did not qualify for authorship according to ICMJE criteria.

7530 Background: In CLL pts treated with the Bruton tyrosine kinase (BTK) inhibitor IBR, the most common reason for discontinuation was adverse events (AEs; 50%-63%; Mato et al, 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in IBR-intolerant pts with R/R CLL. Methods: Pts with R/R CLL (≥1 prior therapy) who discontinued IBR due to Gr 3/4 AEs or persistent/recurrent Gr 2 AEs and had progressive disease (PD) after IBR discontinuation were eligible. Acalabrutinib was given at 100 mg BID PO in 28-d cycles until PD or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: 60 pts were treated (median age 70 y [range 43-88]). Pt characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%) and unmutated IGHV (79%). 52/55 (95%) pts with available baseline samples were wild type for BTK and PLCG2. Median number of prior therapies was 2 (range 1-10). Median duration of prior IBR therapy was 6 mo (range <1-55); common AEs that led to IBR discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%) and rash (12%). At a median follow-up of 19 mo (range 1-31), 67% of pts remain on acalabrutinib; discontinuations were mostly due to PD (13%) and AEs (10%; pneumonia [n=2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n=1]). Efficacy outcomes are in the Table. Common AEs (any grade) were diarrhea (48%), headache (40%), contusion (35%) and dizziness (32%). Serious AEs (≥2 pts) were pneumonia (10%), anemia (3%) and syncope (3%). Atrial fibrillation occurred in 3 pts (5%; all Gr 1/2) and major hemorrhage in 2 (3%; Gr 3 hematuria and Gr 2 subdural hematoma). Gr 5 AEs were pneumonia (n=2), bronchopulmonary aspergillosis (n=1) and ventricular fibrillation (n=1), all considered not related to treatment. Conclusions: Acalabrutinib is tolerable and effective in IBR-intolerant pts, providing a viable strategy for continuing BTK inhibitor therapy. Clinical trial information: NCT02717611. [Table: see text]