Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas

Summary The combination of the phosphatidylinositol 3‐kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single‐agent therapy. This phase 1 study (NCT02914938) included a dose‐finding stage in patients with relapsed/refractory (R/R) B‐cell malignancies ( n = 20) and disease‐specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1–7 plus zanubrutinib 80 mg twice daily continuously in 28‐day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3–4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression‐free survival (PFS) were not reached in either group. The estimated 1‐year PFS was 72.3% (95% confidence interval [CI], 51.9–85.1) for FL and 56.3% (95% CI, 28.9–76.7) for MCL (median follow‐up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.