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      Tuesday, March 21, 2023
      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Journal of Clinical Oncology

      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

      William G. Wierda, MD, PhD; John N. Allan, MD; Tanya Siddiqi, MD; Thomas J. Kipps, MD, PhD; Stephen Opat, MBBS; Alessandra Tedeschi, MD; Xavier C. Badoux, MBBS; Bryone J. Kuss, MBBS, PhD; Sharon Jackson, MD; Carol Moreno, MD, PhD; Ryan Jacobs, MD; John M. Pagel, MD, PhD; Ian Flinn, MD, PhD; Yvonne Pak, PhD; Cathy Zhou, MS; Edith Szafer-Glusman, PhD; Joi Ninomoto, PharmD; James P. Dean, MD, PhD; Danelle F. James, MD, MAS; Paolo Ghia, MD, PhD; Constantine S. Tam, MBBS, MD

      Disclosures

      J Clin Oncol. 2021;39(33):3853-3865. 

      In This Article

      Abstract and Introduction

      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.

      Introduction

      Targeted therapies that antagonize B-cell receptor signaling by inhibiting the Bruton tyrosine kinase (BTK) pathway and restore apoptosis by inhibiting the antiapoptotic protein B-cell lymphoma 2 (BCL-2) have remarkably improved outcomes for patients with chronic lymphocytic leukemia (CLL).[1] Ibrutinib, a once-daily BTK inhibitor, is the only targeted therapy to demonstrate both improved progression-free survival (PFS) and overall survival (OS) over standard chemotherapy and/or chemoimmunotherapy regimens in randomized phase III studies in previously untreated CLL or small lymphocytic lymphoma (SLL; RESONATE-2; ECOG1912).[2,3] Venetoclax is an oral BCL-2 inhibitor approved for the treatment of CLL and SLL as a single agent or combined with anti-CD20 monoclonal antibodies (rituximab or obinutuzumab).[4] Venetoclax provides deep responses with undetectable minimal residual disease (uMRD) rates in bone marrow (BM) of 16% with single-agent venetoclax in relapsed or refractory CLL[5–8] and 57% with venetoclax plus obinutuzumab in previously untreated CLL.[9] Continuous ibrutinib affords survival benefit, but there is increasing desire for convenient, all-oral, time-limited treatment options that may be safely administered in the outpatient setting.

      Ibrutinib plus venetoclax provides synergistic and complementary antitumor activity beyond peripheral blood (PB) and BM compartments.[10–14] In preclinical CLL models, combined ibrutinib plus venetoclax resulted in greater antitumor activity than either agent alone.[10,11,14] Ibrutinib and venetoclax have complementary mechanisms of action: ibrutinib inhibition of BTK enhances dependence of CLL cells on BCL-2 through reductions in MCL-1 and BCL-XL.[10,11] In addition to inhibiting CLL cell proliferation and survival, ibrutinib mobilizes CLL cells from protective microenvironment niches and disease compartments into circulation by blocking retention signals, rendering cells more susceptible to apoptosis, which is notably accelerated by addition of venetoclax.[10,12,14,15] Recent clinical studies with ibrutinib plus venetoclax demonstrated high uMRD rates in both PB and BM in patients with CLL or SLL.[16–20]

      With time-limited therapies, uMRD is an important end point that appears predictive of durable efficacy outcomes. In patients treated with chemoimmunotherapy, such as fludarabine, cyclophosphamide, and rituximab (FCR), uMRD status correlated with longer PFS and OS, regardless of depth of clinical response per International Workshop on CLL (iwCLL) criteria.[21–23] uMRD at the end of combination venetoclax and rituximab in relapsed or refractory CLL was also predictive of longer PFS.[24] Increasing MRD clearance with targeted combinations is anticipated to lead to longer PFS and potentially OS.

      In CAPTIVATE, we investigated combined ibrutinib plus venetoclax in first-line treatment of CLL or SLL. We report primary analysis results from the CAPTIVATE MRD cohort evaluating disease-free survival (DFS) and treatment-free remission.

      *Relevance section written by JCO Editor-in-Chief Jonathan W. Friedberg, MD.

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