Background: PI3Kδ inhibitors administered daily in patients (pts) with FL were limited by immune-related adverse events (AEs) due to regulatory T cell (Treg) suppression following continuous on-target inhibition. Zandelisib is a structurally differentiated oral PI3Kδ inhibitor with high specificity and target-binding affinity. We hypothesized that zandelisib administered on an intermittent dosing (ID) schedule (one capsule daily on days 1-7 of a 28-day cycle) would enable Treg repopulation during treatment breaks and improve safety.
Aims: We conducted this analysis to assess the safety and efficacy of zandelisib administered by ID as a single agent or in combination therapy in pts with R/R FL enrolled in a 3-arm phase 1b study in various B-cell malignancies.
Methods: Eligible pts ≥18 years with FL Grade I-IIIA, ECOG PS 0-2, progressive disease after ≥1 prior therapy and no prior PI3Kδ inhibitor, provided consent prior to enrollment (NCT02914938). A dose escalation stage assessed single-agent zandelisib daily continuously and is not reported here (Soumerai et al, J Clin Oncol 2018;36:#7519). Subsequent cohorts evaluated zandelisib 60 mg daily for two 28-day cycles then on ID as a single agent (Group 1) or in combination with rituximab 375 mg/m2 weekly x4 in cycle 1 and on Day 1 of cycles 3-6 (Group 2). Group 3 evaluated zandelisib 60 mg on ID from cycle 1 and zanubrutinib 80 mg twice daily. Treatment was continued until disease progression or intolerance. Imaging scans were obtained after 2 and 6 cycles 6 and then every 6 months. Response was assessed by investigators using the Lugano Criteria.
Results: 69 FL pts were treated: 18 in Group 1, 19 in Group 2, and 32 in Group 3. Enrollment began in September 2017 for Group 1 and 2 and June 2019 for Group 3, and is completed in all 3 groups. Median age was 66 years (range 38-87), median prior therapies was 2 (range 1-5), 40 pts (58%) received ≥2 prior therapies, 45 pts (65%) were POD24, 21 pts (30.4%) were refractory to last therapy, and 28 pts (41%) had tumors ≥5 cm. With a median follow-up of 10.8 months (range 1.8-49.5), 6 pts (8.7%) have discontinued therapy due to an AE. Grade 3 AEs of special interest (AESI) were rash in 6 pts (8.7%), ALT increased in 6 (8.7%), diarrhea in 3 (4.3%), colitis in 2 (2.9%), and AST increased in 3 (4.3%). No grade 4-5 AESI were reported. 1 pt in Group 3 had reversible grade 4 drug rash with eosinophilia and systemic symptoms (DRESSS) syndrome. Grade 3-4 neutropenia was observed in 11 pts (16%). The overall response rate (ORR) in 65 evaluable pts was 84.6% (55/65), 95% CI 73.5-92.4, and the CR rate was 24.6% (16/65), 95% CI 14.8-36.9. The ORR was 77.8% (14/18) in Group 1, 94.7% (18/19) in Group 2, and 82.1% (23/28) in Group 3. The median duration of response (DOR) was 31.1 months in Group 1, 25.8 months in Group 2, and not yet mature in Group 3, with median drug exposure of 17.1, 20.5, and 7.1 months, respectively (Figure).
Image:
Summary/Conclusion: Zandelisib was generally well tolerated when administered by ID as a single agent or in combination with rituximab or zanubrutinib, with a low rate (8.7%) of grade 3 AESI and discontinuations due to AEs. The high ORR and prolonged DOR are encouraging. This profile supports further evaluation of zandelisib on ID as a single agent and in combination in various B-cell malignancies, both in R/R disease and in earlier lines of therapy.