1-Year DFS Rates Similar Between Ibrutinib and Placebo Following Ibrutinib/Venetoclax in CLL

William G. Wierda, MD, PhD

One-year disease-free survival (DFS) rates in patients with chronic lymphocytic leukemia (CLL) who received ibrutinib (Imbruvica) or placebo after 12 cycles of ibrutinib plus venetoclax (Venclexta) were similar in the minimal residual disease (MRD) cohort in the phase 2 CAPTIVATE trial (NCT02910583), supporting the role of fixed-duration therapy in this patient population.

In this cohort of the multicenter, double-blind, phase 2 CAPTIVATE trial, ​patients with CLL or small lymphocytic lymphoma (SLL) who had confirmed rates of undetectable MRD (uMRD) were randomized to receive ibrutinib or placebo after 12 cycles of ibrutinib plus venetoclax.

Results, which were presented during the 2020 ASH Annual Meeting, showed that the 1-year DFS ​rate in patients who ​had achieved uMRD and received ibrutinib was 100% compared with 95.3% in those who received placebo (P = .1475). Notably, these findings support the role of fixed-duration targeted ​combination strategies in patients who achieve uMRD status.

“Ultimately, ibrutinib and venetoclax are complementary in terms of where they act clinically and how they treat patients with CLL. Moreover, there are mechanistic data in the laboratory that shows synergy between the 2 agents,” lead study author William G. Wierda, MD, PhD. “This has garnered a lot of excitement in the CLL space.”

In an interview with OncLive, Wierda, the D. B. Lane Cancer Research Distinguished Professor, section chief of Chronic Lymphocytic Leukemia, center medical director, Department of Leukemia, Division of Cancer Medicine, and executive medical director at The University of Texas MD Anderson Cancer Center, discussed the latest CAPTIVATE findings in patients with CLL.

OncLive: What was the rationale for the CAPTIVATE trial in patients with CLL/SLL?

Wierda: The rationale was to assess the role of combination targeted therapy, along with the depth of remission, in patients with CLL and SLL. The data that were presented during the 2020 ASH Annual Meeting answered the question of whether a fixed-duration period of treatment is a reasonable approach, along with if patients can expect a reasonable time off treatment, following combined targeted therapy.

What is the synergy between ibrutinib and venetoclax in this patient population?

Ibrutinib is a BTK inhibitor that inhibits a molecule that's downstream of the B-cell receptor–signaling pathway, BTK. It's been approved for several years now, first for relapsed disease and now for frontline treatment. It is broadly approved in CLL. It's very effective and active, including in patients who have been considered high-risk; these patients are defined as those who harbor 17p deletions or TP53 mutations.

Venetoclax is also a small molecule inhibitor; it inhibits BCL-2. When CLL cells are exposed to venetoclax and BCL-2 is inhibited with this agent, it pushes the cells into apoptosis and causes CLL cell death. Ibrutinib is very effective at managing this disease.

Clinically, it works very well in shrinking lymph node size. Many of the patients who are responders are partial responders, meaning that there's still some measurable disease, which is usually in the bone marrow or blood. Venetoclax is highly effective at killing CLL cells and is very potent at killing cells in the blood and bone marrow. However, it’s less active when it comes to shrinking nodal disease.

Please discuss the design of this trial.

Patients received single-agent ibrutinib for the first 3 months. Those 3 months of treatment act to debulk the disease, prior to initiating venetoclax and doing the venetoclax ramp-up. We showed and reported a reduction in the high-risk for tumor lysis syndrome [TLS] group of patients. That population significantly decreased with a 3-month lead-in with ibrutinib monotherapy. Patients get 12 cycles of combined ibrutinib and venetoclax and are evaluated for MRD in blood and bone marrow.

At the end of the combination therapy, they're categorized as either confirmed uMRD or persistent MRD. The confirmed uMRD group are randomized to receive either placebo or continue with ibrutinib. The primary end point is the DFS between those 2 groups at 1 year.

Could you spotlight the key findings from the MRD cohort of CAPTIVATE?

The analysis showed that there wasn’t a difference in 1-year DFS rates between the placebo group versus continued ibrutinib. It was 95% for the placebo group and 100% DFS with ibrutinib at 1 year. With those data, this trial supports a strategy of fixed-duration targeted therapy with the combination. There was a reasonable expectation of DFS and progression-free survival, with no additional treatment, once patients are in an undetectable MRD status. Patients with persistent MRD were also randomized. They were randomized to receive ibrutinib monotherapy versus continued combined therapy.

During the 2020 ASH Annual Meeting & Exposition, we reported the uMRD rate with continued treatment, either with ibrutinib alone or placebo. We also reported the safety and tolerability. Notably, there were no significant safety or tolerability concerns on the study.

What challenges did you face with this research?

We are all interested in knowing who the high-risk patients are, who are more likely to respond, and who's more likely to have MRD-negative disease. Unfortunately, the patient numbers are limited so we can't conduct those subgroup analyses and report on factors that correlate with the likelihood of achieving uMRD or longer DFS. This may be possible with further follow-up data, along with combining the analysis with the other cohorts of the CAPTIVATE trial, which was the fixed-duration cohort.

The fixed-duration cohort was a similarly large group of about 150 patients who received only fixed-duration treatment: 3 months of single-agent ibrutinib, followed by 12 cycles of combined therapy. After this, all the patients stopped treatment. In total, there will be more than 300 patients overall where we can hopefully look at subgroup analyses and identify those who are likely to achieve uMRD with 3 cycles [with ibrutinib] plus 12 cycles of combination therapy.

Reference

Wierda WW, Tam CS, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-9, 2020; virtual. Abstract 123.