Safety and Efficacy of the PI3Kδ Inhibitor Zandelisib in Combination with the BTK Inhibitor Zanubrutinib in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) or Mantle Cell Lymphoma (MCL)

Introduction: Dual inhibition of the PI3Kδ and BTK pathways may overcome existing or acquired resistance to single agent therapy. In a global phase 2 study, zandelisib monotherapy achieved an overall response rate (ORR) of 70.3% and a complete response rate (CRR) of 35.2% in 91 patients (pts) with R/R FL and was associated with a low incidence of class-related adverse events (AEs) when administered at 60 mg daily for two 28-day cycles followed by intermittent dosing (ID) in subsequent cycles (Zelenetz et al., J Clin Oncol 40, 2022;#7511). Zanubrutinib is a potent oral BTK inhibitor with a favorable safety profile. We hypothesized the novel combination of zandelisib and zanubrutinib would be well tolerated and improve the depth and durability of responses compared to either agent alone. We evaluated the combination in an ongoing phase 1b trial with initial dose finding safety cohorts followed by histology-specific expansion cohorts (NCT02914938). In the dose finding stage, zandelisib 60 mg on ID from cycle 1 and zanubrutinib 80 mg twice daily was well tolerated (Soumerai et al, J Clin Oncol 39, 2021:#7553), supporting further evaluation of this dose-schedule in histology-specific cohorts.

Methods: Eligible pts ≥18 years with FL Grade I-IIIA or MCL, ≥1 prior therapy, adequate bone marrow and organ function, no prior PI3K or BTK inhibitors, and who signed consent were treated with zandelisib 60 mg on ID (first 7 days of each cycle) and zanubrutinib 80 mg twice daily in 28-day cycles until progression of disease (PD) or intolerance. Imaging was obtained after cycles 2 and 6, and subsequently every 6 months. Response was assessed by investigators using the Lugano criteria. The study has completed enrollment. Herein, we report the FL and MCL cohorts.

Results: 50 pts were treated, 31 with FL (enrolled between Feb 2020 and Oct 2021) and 19 with MCL (enrolled between Jan 2021 and May 2022), with a median age of 67 years (range 40-83). Median number of prior therapies was 2 (range 1-5), 27 pts (54%) had received ≥2 prior therapies, 15 pts (30%) were refractory to last therapy, 14 pts (28%) had a lesion ≥5 cm, and 22 of 31 FL pts (71%) had POD24. As of 23 Jun 2022, the median time on combination therapy is 11.4 months (range 2-29) for FL and 6.5 months (range 1-17) for MCL, with 30 pts (60%) on continued therapy (19 [38%] for ≥12 months). 20 pts (40%) have discontinued therapy (15 [30%] PD; 3 [6%] consent withdrawn; 2 [4%] due to an adverse event (1 neutropenia and 1 DRESS syndrome). In FL the ORR was 80% with a CRR of 20%; in MCL the ORR was 76% with a CR of 35% (Table 1 and Figure 1). In FL with a median follow-up of 11.1 months, the preliminary median progression free survival (PFS) was 22.4 months (95% CI 11.47, NA); in MCL with a median follow-up of 10.8 months, the preliminary median PFS was 10.4 months (95% CI 3.32, NA). Additional follow up is necessary to allow estimates of CRR and duration of responses (DOR). Non-laboratory AEs of any grade (Gr), with Gr 3-4 in parentheses, reported in ≥15% of pts are diarrhea in 32% (2%) of pts, contusion in 20% (0%), headache in 18% (2%), arthralgia in 16% (2%), nausea in 16% (2%) and maculopapular rash in 16% (4%). AEs of special interest include atrial fibrillation, pneumonia, and febrile neutropenia (2 pts [4%] each; all Gr 3), Gr 3 sepsis and Gr 4 DRESS syndrome (1 pt [2%] each). Gr 3-4 laboratory abnormalities include neutropenia in 15 pts (30%), ALT in 6 (12%) and AST in 5 (10%). The only death in the study was a 68-year-old unvaccinated pt with MCL who died of complications of COVID-19.

Conclusions: Zandelisib plus zanubrutinib was well tolerated with no increase in the rate or severity of class-related AEs compared to either agent alone. Few pts (4%) have discontinued due to an AE. We observed high response rates in R/R FL (80%) and MCL (76%). Additionally, responses appear to deepen over time and further follow-up will fully assess the CRR, DOR, and PFS. These results support further evaluation of the combination in B-cell malignancies.