Background: Acalabrutinib, a highly selective, potent, covalent BTK inhibitor, was assessed as monotherapy in pts with R/R de novo DLBCL. Methods: Eligible pts aged ≥18 y, with ECOG PS ≤2 and confirmed R/R non-germinal center (GCB) type DLBCL assessed by local IHC received oral acalabrutinib 100 mg bid until progressive disease (PD) or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics and investigator-assessed overall response rate (ORR; per Lugano criteria), duration of response (DOR) and progression-free survival (PFS). Results: 21 pts enrolled. To most recent prior therapy, 11 were relapsed (rel; partial response or better [≥PR], then PD), 10 were refractory (ref; no response/stable disease). Median age was 64 y (range 32-84); 86% had ECOG PS ≤1; 57% had extranodal disease; 81% had Ann Arbor stage III/IV; median no. of prior therapies was 3 (range 1-5). Median time on study was 3.9 mo (range 0.8-22.5); 1 pt continues therapy. Pts discontinued treatment primarily for PD (81%); 2 pts discontinued due to AEs (considered unrelated). PK was similar to prior studies, with rapid absorption and clearance; median steady-state BTK target occupancy was 97%-99% (n=5). ORR (≥PR) for all pts was 24% (5/21; 19% complete response [CR]). NanoString subtyping conducted on 15 pts revealed 5 GCB, 9 activated B-cell (ABC), and 1 unclassified DLBCL. The Table lists characteristics of the 5 responders. Common AEs (any grade) were diarrhea (43%), fatigue (43%), anemia (29%), cough (29%) and dizziness (29%); common Grade 3/4 AEs were anemia (24%), fatigue (10%) and abdominal pain (10%). Three pts had Grade 5 AEs (respiratory failure, meningeal progression, and sepsis); none were drug related. No atrial fibrillation, hypertension, TLS or Grade ≥3 bleeding AEs occurred. Conclusions: Acalabrutinib monotherapy was tolerable and had activity in difficult-to-treat DLBCL pts, including ref pts, supporting further studies in DLBCL. Clinical trial information: NCT02112526

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