Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

Abstract

PURPOSE CAPTIVATE ( NCT02910583 ), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, –1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

“…While the investigated cohort was relatively small ( n = 13), this finding suggests that MEK/Bcl‐2 inhibition is of relevance to both low‐ and high‐risk CLL. This is in agreement with results from the Phase II CAPTIVATE study (NCT02910583), where CLL patients received frontline treatment with the targeted therapies venetoclax plus the BTK inhibitor ibrutinib [ 40 ]. In this study, high undetectable minimal residual disease (uMRD) was observed across patient subgroups, including those with high‐risk disease features [ 40 ].…”

“…This is in agreement with results from the Phase II CAPTIVATE study (NCT02910583), where CLL patients received frontline treatment with the targeted therapies venetoclax plus the BTK inhibitor ibrutinib [ 40 ]. In this study, high undetectable minimal residual disease (uMRD) was observed across patient subgroups, including those with high‐risk disease features [ 40 ]. Clinical data on MEK/Bcl‐2 inhibition in CLL are needed to determine in what setting this combination may be used.…”

Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features

“…Another strategy that is receiving considerable attention in CLL/SLL (in both R/R and treatment-naïve patient settings) is combination therapy involving a BTK inhibitor and venetoclax (± an anti-CD20 mAb). Currently available data from phase II trials show that treatment with ibrutinib [ 85 – 89 ], acalabrutinib [ 90 ] or zanubrutinib [ 91 ] in combination with venetoclax (with [ 88 , 90 , 91 ] or without [ 85 – 89 , 91 ] obinutuzumab) can produce deep responses, with good proportions (38–75% across trials) of patients achieving undetectable MRD. Several phase III trials investigating combinations of a BTK inhibitor and venetoclax (± obinutuzumab or rituximab) are underway (including with fixed-duration regimens), and results will be of particular interest.…”

“…3 ). However, given the potential for ongoing tolerability issues (as well as other factors, including cost), it has been raised whether fixed-duration (or response driven) BTK inhibitor treatment regimens could have an improved risk:benefit ratio [ 81 , 88 , 89 ]. Although deep responses allowing drug discontinuation are generally not rapidly achieved with BTK inhibitor monotherapy, combination therapies (e.g.…”

The three musketeers: uniting against CLL

“…Conversely, recent frontline data from the CAPTIVATE study demonstrate a similar BM MRD-negative rate of 66% with dual ibrutinib and venetoclax in del(17p)/TP53-mutated CLL. 9 Whether triplet therapy is indeed superior to treatment with dual-or single-targeted agents needs to be determined within prospective randomized studies.…”