Contributions
Abstract: S214
Type: Oral Presentation
Session title: Indolent & mantle cell lymphoma - Clinical
Background
Despite significant improvement in the management of B cell malignancies with targeted therapies, new therapies are still needed in patients with relapsed disease. 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.
Aims
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 patients (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 A: 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 B: 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 A and extended to 56 days for cohort B to include later occurring toxicities in the DLT definition. Response was assessed per iwCLL or Lugano criteria at month 3, 7, 13 and then every 6 months until progression.
Results
20 pts who provided consent and met eligibility criteria were treated, 7 in cohort A and 13 in cohort B: 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). The emergence of Grade 3/4 AE’s in 4/7 patients after the DLT window prompted exploration of a lower dose in cohort B. In cohort B, 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. 15% DLT(2/13) was observed in cohort B which is deemed safe to proceed with disease expansion cohort. 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). None of the 3 evaluable pts with aggressive B-cell lymphomas has responded.
Conclusion
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
Keyword(s): B cell lymphoma, Indolent non-Hodgkin's lymphoma, PI3K, PI3-K/AKT
Abstract: S214
Type: Oral Presentation
Session title: Indolent & mantle cell lymphoma - Clinical
Background
Despite significant improvement in the management of B cell malignancies with targeted therapies, new therapies are still needed in patients with relapsed disease. 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.
Aims
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 patients (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 A: 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 B: 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 A and extended to 56 days for cohort B to include later occurring toxicities in the DLT definition. Response was assessed per iwCLL or Lugano criteria at month 3, 7, 13 and then every 6 months until progression.
Results
20 pts who provided consent and met eligibility criteria were treated, 7 in cohort A and 13 in cohort B: 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). The emergence of Grade 3/4 AE’s in 4/7 patients after the DLT window prompted exploration of a lower dose in cohort B. In cohort B, 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. 15% DLT(2/13) was observed in cohort B which is deemed safe to proceed with disease expansion cohort. 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). None of the 3 evaluable pts with aggressive B-cell lymphomas has responded.
Conclusion
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
Keyword(s): B cell lymphoma, Indolent non-Hodgkin's lymphoma, PI3K, PI3-K/AKT