Initial results of the combination of PI3Kδ inhibitor zandelisib (ME-401) and the BTK inhibitor zanubrutinib in patients (pts) with relapsed or refractory (R/R) B-cell malignancies.

7553 Background: Dual inhibition of PI3Kδ and BTK pathways may overcome existing or acquired monotherapy resistance. Dual inhibition of these pathways displays synergistic activity in cell lines that is evident even at suboptimal concentrations [Blood 2015;125(14):2306-09]. Zandelisib is a potent, selective, and structurally differentiated oral PI3Kδ inhibitor (i), and zanubrutinib is an oral BTKi. Based on their efficacy as monotherapy, we hypothesized that the combination of zandelisib and zanubrutinib can be well tolerated and may improve the depth and durability of responses. We evaluated this combination therapy in pts with R/R B-cell malignancies to determine the optimal dose and schedule for further evaluation in disease-specific expansion cohorts (NCT02914938). Methods: This is a multi-cohort Phase 1b study enrolling pts with FL, CLL, MZL, MCL, DLBCL, or high grade B-cell lymphoma (HGBCL), ≥1 prior therapy, adequate bone marrow and organ function, ECOG performance status ≤2, and no prior PI3Ki or BTKi therapy. For this combination therapy, two dose levels were evaluated in 28-day cycles: Cohort 10A: zandelisib 60 mg once daily for 2 cycles followed by an intermittent schedule (IS) on days 1-7 of subsequent 28-day cycles and zanubrutinib 160 mg twice daily (bid). Cohort 10C: zandelisib 60 mg on days 1-7 starting in Cycle 1 and zanubrutinib at 80 mg bid. Dose limiting toxicity (DLT) observation period was 28 days for cohort 10A and extended to 56 days for cohort 10C. Response was assessed at month 3, 7, 13 and then every 6 months until progression. Results: 20 pts treated, 7 in cohort 10A and 13 in cohort 10C: 8 FL, 5 CLL, 2 DLBCL, 2 HGBCL, 2 MZL, and 1 MCL. Median age 70 years (range, 44-85) and median prior therapies 2 (1-8). Median follow-up of 2.9 months (0.5-17.4+). There were no DLT in cohort 10A, grade (Gr) ≥3 adverse events (AE) occurred after day 28 in 4 pts, including Gr 4 neutropenia (1 pt), Gr 3 neutropenia, fatigue and CMV colitis (1 pt), Gr 3 AST/ALT and rash (1 pt) and Gr 3 AST/ALT (1 pt). In cohort 10C, 2 pts had DLT with Gr 3 AST/ALT in Cycle 2, with 1 pt successfully resuming both drugs and 1 discontinued treatment due to recurrence of Gr 3 AST/ALT upon rechallenge.. Other Gr 3 AE were all laboratory findings: 1 pt (CLL) had laboratory TLS, neutropenia and thrombocytopenia and 2 pts (FL, DLBCL) had neutropenia. Response rate was 100% (2 CR 14 PR) in the following 16 pts with indolent NHL and MCL evaluable for response: FL (2 CR, 6 PR), CLL (5 PR), MCL (1 PR) and MZL (2 PR). No pt with aggressive B-cell lymphomas has responded. Conclusions: The combination of zandelisib 60 mg on IS from Cycle 1 and zanubrutinib 80 mg bid is well tolerated and achieves a high ORR in R/R indolent B-cell malignancies. This schedule is being evaluated in expansion cohorts in R/R FL and MCL. Clinical trial information: NCT02914938.