Adverse events of interest (AEIs) with zanubrutinib vs fixed-duration combination of venetoclax + obinutuzumab in treatment-naive (TN) chronic lymphocytic leukemia (CLL).

Abstract

e19028 Background: The efficacy and safety of BTKi zanubrutinib (zanu) monotherapy has been evaluated in TN CLL/SLL in SEQUOIA (NCT03336333), while the combination of fixed-duration BCL-2 inhibitor venetoclax + CD20 monoclonal antibody obinutuzumab (VenO) has been evaluated in CLL14 (NCT02242942). This analysis evaluated selective AEIs with zanu vs VenO. Methods: The incidence rates of infections, hematologic events, and treatment-emergent adverse events (TEAEs) leading to treatment (tx) discontinuation of zanu in SEQUOIA (n=351) and VenO in CLL14 (n=212) were compared. In this analysis, data for zanu at median tx duration of 23.9 mo (to match safety follow-up for VenO) and 61.1 mo and data for fixed-duration VenO from available publications (median tx duration, 11.1 mo) were compared for AEIs. Zanu outcomes were adjusted for COVID-19 as SEQUOIA was ongoing during the pandemic while CLL14 was conducted prior to the pandemic. Results: With a median tx duration of 23.9 mo with zanu vs 11.1 mo with VenO (Table), the incidence of grade 3/4 infections (excluding COVID-19), neutropenia, thrombocytopenia, and febrile neutropenia and TEAEs leading to discontinuation was lower with zanu vs VenO (nominal P <.05 for all). With longer zanu exposure at the 61.2-mo median tx duration for zanu, the incidence rate of infection was higher with zanu vs VenO but similar after excluding COVID-19. The rates of neutropenia, thrombocytopenia, and febrile neutropenia remained lower with zanu vs VenO (nominal P ≤.05). COVID-19 was the most common TEAE leading to discontinuation of zanu (1.1% and 1.7% with median tx duration of 23.9 and 61.1 mo, respectively), while neutropenia was the most common TEAE leading to discontinuation of ven (2.4%). Conclusions: Hematologic toxicity rates were lower with zanu vs VenO in the analysis time window. Rates of TEAEs leading to discontinuation and infections excluding COVID-19 were lower with zanu with a median tx duration of 23.9 mo. Continuing zanu monotherapy does not appear to increase the risk of infection, even with much longer tx duration, compared with fixed-duration VenO. Clinical trial information: NCT03336333 , NCT02242942 . AEIs in SEQUOIA vs CLL14. Zanu up to 104 weeks Zanu DCO: April 30, 2024 SEQUOIA zanu (n=351) vs CLL14 VenO (n=212) SEQUOIA zanu (n=351) vs CLL14 VenO (n=212) Median treatment exposure, mo 23.9 vs 11.1 61.2 vs 11.1 Grade 3/4 infections and infestations (system organ class), % 12.5 vs 17.5; P =.109 27.1 vs 17.5; P =.010 Excluding COVID-19 11.1 vs 17.5; P =.034 20.2 vs 17.5; P =.418 Grade 3/4 neutropenia, % 9.1 vs 52.8; P <.001 10.3 vs 52.8; P <.001 Grade 3/4 thrombocytopenia, % 1.1 vs 13.7; P <.001 1.7 vs 13.7; P <.001 Grade 3/4 febrile neutropenia, % 0.6 vs 5.2; P =.004 0.9 vs 5.2; P =.005 Any TEAE leading to discontinuation, % 7.4 vs 15.6; P =.003 18.8 vs 15.6; P =.329 Excluding COVID-19 6.6 vs 15.6; P =.001 16.2 vs 15.6; P =.833 All P values are nominal.