Background: Zandelisib, a PI3Kδ inhibitor with high target-binding affinity, is administered by intermittent dosing (ID) on days 1-7 of 28-day cycles to potentially enable regulatory T-cell repopulation and lower the risk of immune adverse events (irAEs) seen with continuous PI3Kδ inhibition. In a phase 1b study in 37 patients (pts) with R/R FL, zandelisib daily for two 28-day cycles for tumor debulking then on ID achieved an overall response rate (ORR) of 87% (78% single agent and 95% with rituximab) with < 10% irAEs (Pagel et al. ICML 2021; #113). We conducted the TIDAL study to further evaluate zandelisib in R/R indolent lymphomas (NCT03768505). Methods: Eligible pts ≥18 years with FL Grade I-IIIA, progressive disease after ≥2 prior therapies, and no prior PI3K inhibitor, gave consent and received zandelisib 60 mg daily for 2 cycles then on ID. Not reported here are an arm randomizing pts to zandelisib daily continuously, closed to enrollment early, and an actively enrolling arm in R/R marginal zone lymphoma (MZL). The planned FL sample size was 120 pts on ID, with the primary efficacy population (PEP) pre-defined as the first 91 pts treated. The primary efficacy endpoint was ORR by the Lugano criteria in the PEP as assessed by independent review and analyzed after a minimum 6-month follow-up. Results: 121 FL pts were enrolled. In the PEP (N = 91), the median number of prior therapies was 3 (range 2-8), 21 pts (23%) had received prior stem cell transplant, 42 (46%) had disease refractory to last therapy, 31 (34%) had tumors ≥5 cm, and 51 (56%) were POD24. Overall response rate was 70.3% (n = 64) (95% CI 59.8-79.5%) and complete response rate was 35.2% (n = 32) (95% CI 25.4-45.9%). Responses occurred early with 87.5% (n = 56) of responses observed at the end of Cycle 2 and 75% (n = 24) of CRs at the end of Cycle 4. The data are still immature to estimate accurately the duration of response (DOR). With a median follow-up of 9.4 months (range 0.8-24) for all 121 pts, 12 pts (9.9%) discontinued therapy due to any drug-related AE. Grade 3 AEs of special interest (AESI) were diarrhea in 6 pts (5%), colitis in 2 (1.7%), rash in 4 (3.3%), stomatitis in 3 (2.5%), and 1 (0.8%) each for AST and ALT elevation, and non-infectious pneumonitis. Grade 3 AESIs primarily (15 of 18, 83%) occurred in cycles 1-3, during daily dosing. Conclusions: Zandelisib on ID achieved high ORR and CR rate in heavily pretreated FL pts, and was associated with < 10% of discontinuations due to drug-related AEs and grade 3 AESI, results comparable to the Phase 1b study. Longer follow-up is needed to estimate median DOR. This profile supports evaluation of zandelisib alone and in combination in various B-cell malignancies, both in relapsed disease and earlier lines of therapy. Zandelisib plus rituximab vs chemoimmunotherapy is being studied in the phase 3 trial COASTAL in R/R FL and MZL (NCT 04745832). Clinical trial information: NCT03768505.