Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL)

Background: Ibr, a first‐in‐class, once‐daily BTK inhibitor, is approved in the US and EU for CLL treatment, including del17p. Early studies support synergistic antitumor activity with combined ibr and ven, a BCL‐2 inhibitor approved by FDA for relapsed del17p CLL. Single‐agent ibr lead‐in may lower tumor lysis syndrome (TLS) risk by debulking prior to adding ven. PCYC‐1142 (CAPTIVATE) is a multicenter, phase 2 study of ibr + ven (I+V) in first‐line CLL (NCT02910583) evaluating if remission with undetectable minimal residual disease (MRD(‐)) after I+V can provide pts treatment holidays. Methods: Treatment‐naïve pts <70 y with active CLL/SLL by IWCLL criteria receive single‐agent ibr (420 mg/d PO) lead‐in (3 x 28 d cycles) before initiating ven ramp‐up to 400 mg/d PO. MRD (<0.01% by flow) is assessed in peripheral blood (PB) after 6 cycles I+V. MRD and response in bone marrow (BM) are assessed after 12 cycles I+V with planned randomization and intervention based on MRD status. Results: 163 pts were enrolled (median 58 y; 14% del17p; 15% del11q; 33% longest lymph node diameter [LDi] ≥5 cm). The first 14 pts enrolled for safety run‐in completed ≥6 cycles I+V (median treatment duration, 9.9 mo ibr, 7.2 mo ven). No doselimiting toxicities occurred during safety run‐in; response was seen in 14/14 (CR confirmed in 1/5 early BM; 13/14 PR); PB was MRD(‐) in 9/11 assessed pts. 97 pts (including 14 safety run‐in pts) completed ibr lead‐in plus ≥1 dose of ven (I+V Exposed). AEs in ≥20% of I+V Exposed pts were diarrhea (39%), fatigue (23%), nausea (23%) and arthralgia (21%); grade ≥3 AEs in ≥3% were neutropenia (10%), hypertension (3%) and thrombocytopenia (3%). No clinical TLS occurred; lab TLS was seen in 1/163 pts. In I+V Exposed pts with baseline LDi ≥5 cm, LDi decreased to <5 cm in 19/30 pts (63%) after ibr lead‐in. TLS risk shifted from high to medium/low in 17/22 pts (77%); overall, proportion of high‐risk TLS decreased from 23% at baseline to 3% after ibr lead‐in. Conclusions: Early data show promising activity of I+V oral regimen with MRD(‐) response in 82% in first‐line CLL. Safety was consistent with AE profiles of single‐agent ibr or ven. The protocol‐specified efficacy analysis in the first 30 pts will be presented.