Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of BTK, is approved in the US for the treatment of various B-cell malignancies. In solid tumors, ibr may inhibit EGFR, HER2, mast cell function, and alter Th1/Th2 polarity. Preclinical data suggest benefit with PD-L1 inhibitors for pancreatic adenocarcinoma (PC), non–small cell lung cancer (NSCLC), HER2+ breast cancer (BC), and triple neg BC (TNBC). These mechanisms may act synergistically. This study assessed the safety and efficacy of ibr plus durvalumab, a PD-L1–targeting antibody, in patients (pts) with R/R solid tumors. Methods: This open-label, multicenter, ph 1b/2 trial enrolled pts with R/R stage III/IV PC, BC (HER2+, TNBC), or NSCLC (adenocarcinoma, squamous). Pts must have failed ≥1 (PC, NSCLC) or ≥2 (BC) prior systemic therapy lines. Ph 1b (6+3 dose de-escalation design) determined the recommended ph 2 dose (RP2D). PD-L1 expression was assessed retrospectively. Results: In ph 1b, 560 mg ibr PO daily and 10 mg/kg durvalumab IV every 2 wk was identified as the RP2D. Of 124 pts enrolled, 122 pts were treated at the RP2D (PC n = 49; BC n = 45; NSCLC n = 28). Median age was 60.5 y; 94% had stage IV disease; median prior radiation/cancer therapies was 4 (range: 1–20); 5 NSCLC pts, but no PC or BC pts, had tumors with high PD-L1 expression. Response rates in evaluable pts were 3% for BC (1 complete response in a TNBC pt; duration of response [DOR]: 23 mo), 2% for PC (1 partial response; DOR: 10 mo), and 0% for NSCLC. Median progression-free survival was 2 mo in each cohort; median overall survival was 4, 4, and 8 mo in the PC, BC, and NSCLC cohorts, respectively. No clinically meaningful differences in the safety profile were observed across tumor types, except differences due to tumor type, location, and prior therapies. Gr ≥3 treatment-emergent adverse events in ≥5% of pts were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). Conclusions: The combination of 560 mg ibr daily and 10 mg/kg durvalumab every 2 wk had an acceptable safety profile, but limited activity in the solid tumors studied, which may be due in part to heavy pretreatment and low PD-L1 expression. Clinical trial information: NCT02401048