Background: FL patients (pts) with POD24 have poorer survival and may benefit from novel therapies at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study for FL demonstrating a high objective response rate (ORR) and well tolerated when given on IS (J Clin Oncol 2020;38:#8016). We report here results based on POD24 status (NCT02914938). Methods: Eligible pts had ≥1 prior therapy, adequate bone marrow and organ function, ECOG performance status ≤2, and no prior PI3K therapy. Zandelisib was administered at 60 mg once daily for 8 weeks followed by IS on days 1-7 of each subsequent 28-day cycle, either as monotherapy or with rituximab at 375 mg/m² for 8 doses in Cycles 1-6. Treatment was continued until disease progression, intolerance, or withdrawal of consent. Imaging scans were obtained after 2 and 6 cycles, and then every 6 cycles. Response was reported based on Lugano criteria. Results: 37 FL pts were enrolled and received zandelisib on IS as monotherapy (N = 18) or in combination with rituximab (N = 19). Median number of prior therapies = 2 (range, 1-5). The ORR was 86.5% (32/37) with 27% CR (complete response). In the monotherapy group the ORR and CR were 77.8 % (14/18) and 27.8% and with rituximab 94.7% (18/19) and 26.3% respectively. Median duration of response (DOR) among all pts was not reached with a median follow-up of 16.9 months (mos) (1.2-33.1+). 22 pts (59%) were POD24, of which 15 (68%) had ≥2 prior lines of therapy. Despite more refractory disease, ORR among the POD24 pts was 81.8% (Table). Zandelisib on IS was well tolerated. 3 pts (8%) discontinued therapy due to an adverse event (AE) for any cause. Grade (Gr) 3 AE of special interest (AESI) were 2 (5.4%) diarrhea, 2 (5.4%) colitis, 3 (8.1%) rash, 3 (8.1%) ALT elevation, 1 (2.7%) AST elevation and no pulmonary infection. Conclusions: Zandelisib administered on IS as monotherapy or with rituximab resulted in a high-rate of durable responses in FL, both in POD24 and non-POD24 groups and therapy was well-tolerated with low rate of Gr 3 class-related AESI and discontinuation rate due to AE’s. Zandelisib as monotherapy is being evaluated in a global Phase 2 study in FL and MZL after failure of 2 prior therapies (NCT03768505). A Phase 3 study of zandelisib plus rituximab in FL and MZL after failure of prior immunochemotherapy will begin enrollment in 2021. Clinical trial information: NCT02914938