Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort

Abstract

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Graphical abstract

Figure 1

Patient flow and disposition. *Hepatitis, erythematous rash, and cerebral hemorrhage in 1 patient each. †Sudden death on study day 23 in a 54-year-old male with a medical history of hypertension, hyperlipidemia, smoking, fatigue, anxiety, depression, insomnia, and gastroesophageal reflux disease. ‡Hemorrhagic cerebral infarction and sinus arrest in 1 patient each. §Pneumonia and neutropenia + pharyngitis in 1 patient each. ǁPatient discontinued venetoclax due to an AE (nausea + vomiting) and subsequently discontinued ibrutinib due to investigator decision.

Figure 2

Best overall response. (A) Best overall response rates as assessed by the investigator in the all-treated population and patients without del(17p) or with del(17p)/mutated TP53. (B) Forest plots of investigator-assessed CR rates across patient subgroups by baseline characteristics in the all-treated population. DOCR, duration of CR; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; ORR, overall response rate; nPR, nodular partial response; PR, partial response. *After achieving CR, 9 patients with <1 year of follow-up were not evaluable; 1 patient died of cardiac arrest 7 months after initial CR and 47 days after completion of therapy. †Per Döhner hierarchy. ‡Proportion of patients with CR or CRi.

Figure 3

Best MRD response. (A) Rates of undetectable MRD in PB and BM in patients without del(17p) or with del(17p) and/or mutated TP53. (B) Forest plot of undetectable MRD in BM across patient subgroups by baseline characteristics in the all-treated population. Error bars represent 95% CIs. *Per Döhner hierarchy.

Figure 4

PFS and OS. Kaplan-Meier curves of (A) PFS as assessed by investigators and (B) OS in the all-treated population and patients without del(17p). Tick marks indicate patients with censored data. Shading indicates time on treatment.

Figure 5

Impact of single-agent ibrutinib lead-in on tumor burden for TLS prophylaxis. (A) Tumor burden categories for TLS prophylaxis at baseline and after ibrutinib lead-in in the all-treated population. (B) Indication for hospitalization (*) for TLS monitoring and prophylaxis at baseline and after ibrutinib lead-in in the all-treated population. *Defined as patients in high tumor burden category for TLS prophylaxis or patients in medium tumor burden category with creatinine clearance (CrCL) <80 mL/min. Of 28 patients who met the criteria for indication for hospitalization after lead-in, 27 had medium tumor burden and a CrCL of <80 mL/min, and 1 had high tumor burden.