Efficacy and Safety of Single-Agent Zandelisib Administered By Intermittent Dosing in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Final Results of the Tidal Phase 2 Study

Introduction: Zandelisib is a novel, highly selective, structurally differentiated, oral PI3Kδ inhibitor. Its on-target residence time (≥5 hours) and high volume of distribution lead to higher tumor exposure relative to plasma over time. In a dose optimization Phase 1b study in various B-cell malignancies, zandelisib was evaluated initially by continuous dosing (CD), and then by intermittent dosing (ID) to allow regulatory T-cell repopulation, thereby reducing immune-related adverse events (AEs) (Pagel et al. Lancet Oncol 2022). The TIDAL trial (NCT03768505) started as a randomized, double-blind, 2-arm study to evaluate the safety and efficacy of zandelisib CD (n=16) vs. ID (n=121) in R/R FL and marginal zone lymphoma (MZL) patients (pts). Here we present results from the final analysis of the FL cohort in the ID arm.

Methods: Eligible pts ≥18 years with FL Grade I-IIIA, ECOG performance status 0-1, progressive disease after ≥2 prior therapies including an anti-CD20 antibody and chemotherapy, and no prior PI3K inhibitor, provided consent and subsequently received zandelisib 60 mg orally once daily for two 28-day cycles, then ID (days 1-7 of 28-day cycles). The study arm evaluating zandelisib 60 mg daily CD closed early to enrollment after maturing data from the Ph 1b study showed pts on ID having fewer discontinuations due to treatment-emergent AEs and a high rate of durable responses. Study treatment was administered until disease progression or intolerance. The primary efficacy endpoint was objective response rate (ORR) as assessed by blinded independent central review (BICR) using modified Lugano Classification. Secondary endpoints were duration of response (DOR), complete response (CR) rate, median progression-free survival (mPFS), safety and tolerability. Prophylaxis for Pneumocystis jirovecii pneumonia was not mandatory in this single agent trial.

Results: Between June 2019 and September 2021, 121 FL pts were enrolled in the ID arm, intent-to-treat (ITT) population, with the initial 91 pts representing the primary efficacy population (PEP). The median number of prior therapies was 3 (range 2-8), 28 pts (23.1%) had prior stem cell transplant, 54 pts (44.6%) were refractory to last therapy, 42 pts (34.7%) had bulky disease (≥5 cm), and 68 pts (56.2%) were POD24. Efficacy data overall and by subgroup (POD24, prior therapy, refractoriness) are shown in the Table. The ORR (CR rate) in the PEP and ITT were 72.5% (36.3%) and 70.2% (34.7%). With median follow-up of 11.3 months in PEP and 9.3 months in ITT, median DOR was estimated at 16.4 and 16.4 months, respectively. Preliminary PFS in the ITT population is shown in the Figure. With a median follow-up of 14.3 months (range: 1.0-30.5) among 121 pts, the most common AEs (all grade/Gr ≥3) were diarrhea (37.2%/5.8%), neutropenia (28.9%/21.5%), nausea (22.3%/0), fatigue (19.0%/0), pyrexia (19.0%/1.7%), and abdominal pain (15.7%/0.8%). 15 pts (12.4%) discontinued therapy due to treatment-related AE. Gr ≥3 AEs of special interest (AESI) in the ID arm were diarrhea in 7 pts (5.8%), lung infection/pneumonia in 6 (5.0%), noninfectious colitis in 4 (3.3%), rash in 4 (3.3 %), stomatitis in 3 (2.5%), and 1 (0.8%) each for ALT and AST increased and noninfectious pneumonitis. In 16 pts in the CD arm, 5 (31.3%) discontinued therapy due to drug-related AE, and 4 (25%) had Gr ≥3 diarrhea/colitis. Gr 5 AEs in the ID arm, excluding COVID-19, were tumor lysis syndrome (1 pt) and pneumonia (1 pt). There were 17 pts with COVID events, fatal in 5.

Conclusions: Single agent zandelisib on ID was associated with high rate of durable responses (72.5% ORR, 36.3% CR rate in PEP) in heavily pretreated R/R FL pts, including those with POD24 and refractory disease, and was associated with a relatively lower incidence of Gr ≥3 AESI and AE-related discontinuations, compared with CD. Based on the safety and efficacy profiles observed in this study, these results support further evaluation of zandelisib ID, alone or in combinations, in various B-cell malignancies. Zandelisib plus rituximab vs. chemoimmunotherapy is being evaluated in the randomized phase 3 study COASTAL in R/R FL and MZL (NCT04745832).