Emerging BTK-based Combination Approaches for CLL: Ibrutinib Plus Venetoclax

As the treatment paradigm for chronic lymphocytic leukemia (CLL) expands beyond continuous treatment with Bruton's tyrosine kinase (BTK) inhibitors, investigators are exploring novel combinations of BTK inhibitors with other agents (eg, BCL2 and CD20 inhibitors) that have complementary activities, synergistic interactions, and nonoverlapping toxicities.

A key focus of current combination therapy trials is whether BTK inhibitors in combination with other agents as part of a time-limited regimen can lead to enduring remissions, as well as improved progression-free and overall survival.

In April 2020, the FDA expanded ibrutinib’s indication to include its combination with rituximab as a front-line treatment for adult patients with CLL.¹ More clinical trials studying the safety of ibrutinib in combination with other agents are currently underway. One of these combination regimens is ibrutinib plus venetoclax, a BCL2 inhibitor. Venetoclax causes CLL cell apoptosis and death; however, myeloid-cell leukemia 1 (MCL1) proteins could protect CLL cells from mitochondria-mediated death. Ibrutinib-mediated BTK inhibition reduces MCL1 protein levels. Consequently, preliminary clinical trial results of this combination have shown complementary activities, synergistic interactions, and nonoverlapping toxicities.²

In an open-label, phase 2 study from July 2016 through June 2018, investigators examined the efficacy of ibrutinib plus venetoclax in treatment-inexperienced adult patients with CLL (N = 80).⁹ The primary end point was the best response (complete remission [CR], or complete remission with incomplete count recovery [CRi]) at any time during the treatment for up to 2 months after combined therapy completion.⁹ The median age was 65 years (range, 26 to 83); 30% of the patients were 70 years of age or older, and 92% had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. The median time to follow-up was 14.8 months.²

Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles.2 Eleven patients (14%) discontinued the study—5 during the monotherapy phase and 6 during the combination phase.²

After 12 cycles of combined treatment, 88% of patients (29 of 33) obtained CR or CRi, and 61% (20 of 33) obtained undetectable minimal residual disease (uMRD). Responses were observed in all high-risk subgroups;in particular, 94% of patients aged 65 years or older obtained CR or CRi, and 76% obtained uMRD by cycle 12.²

The combination’s toxicity and adverse event (AE) profile was similar to ibrutinib and venetoclax monotherapies; no new safety concerns were observed. Atrial fibrillation, probably related to ibrutinib, occurred in 15% of the patients. Grade 3 or 4 neutropenia was noted in 48% of the patients and was managed by G-CSF support and either dose interruptions or dose reductions of study drugs. The risk of neutropenic fever was 5%.²

The appropriate duration of ibrutinib plus venetoclax for CLL treatment is unclear and is currently being explored in other ongoing trials. In the phase 2 CAPTIVATE (NCT02910583) trial, investigators are assessing both MRD-guided discontinuation and fixed duration therapy for ibrutinib plus venetoclax in treatment-inexperienced adult patients with CLL or SLL.^3,4

The MRD-guided randomization phase of the MRD cohort examined whether this combination obtained treatment-free remission in patients who reached uMRD.3 Among the 149 patients in this cohort (median age, 58 years; range, 28 to 69), 58% obtained confirmed uMRD and were randomized to either continue ibrutinib alone (n = 43) or placebo (n = 43). The remaining 63 patients who did not reach confirmed uMRD were randomized to continue receiving ibrutinib (n = 31) or the combination (n = 32).³

The CAPTIVATE trial is ongoing, but primary end point results showed similar 1-year disease-free survival among patients with confirmed uMRD who continued treatment with ibrutinib (100%) or placebo (95.3%) and those without confirmed uMRD who continued treatment with ibrutinib (95.2%) or ibrutinib with venetoclax (96.7%).⁴

Most AEs were grade 1 or 2 and occurred most frequently in early cycles of the combination arm. The most common grade 3 or 4 AEs were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%). No new safety concerns were observed.⁴

There are several other ongoing trials underway assessing the ibrutinib-venetoclax combination. NEXT STEP (NCT04639362) is a single-arm, phase 2 trial evaluating first-line treatment with venetoclax plus ibrutinib induction, followed by obinutuzumab intensification in treatment-inexperienced adult patients (N = 85) with CLL/SLL who have a WHO performance status of 0-3.^5,6 Investigators noted that the aim of the trial is “to help personalize CLL treatment by selecting sequential time-limited therapies guided by MRD.”

Patients will receive 3 lead-in cycles of ibrutinib 420 mg per day, followed by 12 induction cycles and 1 bridging cycle of ibrutinib combined with venetoclax. There will be a 5-week ramp up starting on the first day of cycle 4. Patients with MRD and/or no CR after their cycle 15 evaluation will continue ibrutinib and proceed to intensification cycles 17 through 22. During the first intensification cycle, obinutuzumab will be added to ibrutinib on days 1, 2, 8, and 15. During the remaining cycles, obinutuzumab will be added to ibrutinib on day 1 only.⁶

The primary end point is CR with uMRD 3 months after the end of intensification with ibrutinib plus obinutuzumab in patients who are not in CR and/or uMRD on combination ibrutinib and venetoclax. Primary study completion is expected on December 1, 2025.^5,6

Ibrutinib is also being investigated in combination with obinutuzumab with or without venetoclax.⁷ Regarding the ibrutinib plus venetoclax combination, specifically, other notable studies are exploring the regimen’s potential in relapsed/refractory CLL and patients with high-risk disease.^8,9 Finally, a head-to-head study is underway to evaluate ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab.10 The results of these studies and others may shed further light on the potential of this regimen in the treatment of CLL.

1. Imbruvica. Prescribing information. Janssen Biotech, Inc.; 2020.
2. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103. doi: 10.1056/NEJMoa1900574
3. U.S. National Library of Medicine. Ibrutinib plus venetoclax in subjects with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CAPTIVATE)(NCT02910583). Last updated October 9, 2020. Accessed April 9, 2021. https://clinicaltrials.gov/ct2/show/NCT02910583
4. Wierda WG, 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: The 62nd Annual Meeting and Exposition of the American Society for Hematology; December 5-8, 2020; Virtual. Presentation 123.
5. U.S. National Library of Medicine. CLL induction treatment with venetoclax and ibrutinib, followed by ibrutinib and obinutuzumab in patients with MRD (NCT04639362). Last updated December 30, 2020. Accessed April 9, 2021. https://clinicaltrials.gov/ct2/show/record/ NCT04639362
6. Kersting S, Levin MD, Niemann CU, Norden Y, Kater AP. First line treatment with venetoclax and ibrutinib induction followed by obinutuzumab intensification exclusively in CLL/SLL patients not in complete remission and/or with detectable bone marrow minimal residual disease (NEXT STEP trial). Blood. 2019;13(Supp1):1753. doi: 10.1182/blood-2019-124550
7. U.S. National Library of Medicine. Ibrutinib and obinutuzumab with or without venetoclax in treating patients with chronic lymphocytic leukemia (NCT03701282). Last updated April 6, 2021. Accessed April 9, 2021. https://clinicaltrials.gov/ct2/show/record/ NCT03701282
8. U.S. National Library of Medicine. Venetoclax and ibrutinib in patients with relapsed/refractory CLL or SLL (NCT03045328). Last updated July 7, 2020. Accessed April 9, 2021. https://clinicaltrials.gov/ct2/show/NCT03045328
9. U.S. National Library of Medicine. Venetoclax and ibrutinib in treating participants with high-risk chronic lymphocytic leukemia/small lymphocytic lymphoma (NCT03128879). Last updated March 31, 2021. Accessed April 9, 2021. https://clinicaltrials.gov/ct2/show/NCT03128879
10. U.S. National Library of Medicine. A study of the combination of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab for the first-line treatment of participants with chronic lymphocytic leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)(NCT03462719). Last updated March 5, 2021. Accessed April 9, 2021. https://clinicaltrials.gov/ct2/show/record/NCT03462719