(Update) Venetoclax in CLL

Commentary by Jennifer R. Brown, MD, PhD, CLL Site Editor for JNCCN 360

Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School

Venetoclax¹ has been developed primarily for use in combination regimens with the intent of achieving deep remission with fixed-duration therapy in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Recent long-term follow-up reports from both the MURANO^2,3and CLL14⁴ studies have demonstrated that a fixed-duration regimen of venetoclax with an anti-CD20 antibody can result in prolonged remission after discontinuation of therapy. After 2 years of therapy in the relapsed setting, median progression-free survival in the MURANO trial was 53.6 months, and in the front-line setting, 74% of patients were in remission at 4 years after just 1 year of therapy. These results are certainly encouraging. Early data also suggest that patients can be potentially re-treated with the same regimen on relapse. Data are also starting to emerge on the combination of a Bruton’s tyrosine kinase (BTK) inhibitor with venetoclax, albeit with shorter follow-up.^5,6 As yet, comparative data for these two approaches are lacking, and it is unclear which patients should be considered for the combination of a BTK inhibitor and venetoclax rather than venetoclax plus a monoclonal antibody. The use of minimal residual disease measurements to guide therapeutic decisions with these regimens is another intense area of research, where new data may emerge in the next several years.

DISCLOSURES

Jennifer R. Brown, MD, PhD, has received clinical research support/data safety monitoring board from Acerta Pharma, BeiGene, Catapult, Eli Lilly and Company, and MEI Pharma.

She has also served on a scientific advisory board or as a consultant or expert witness for AbbVie, Acerta Pharma, BeiGene, Catapult, Celgene, Juno Therapeutics, MEI Pharma, MorphoSys AG, Novartis, and Pfizer.

Long-Term Data Confirm Benefit

The introduction of novel targeted agents for use in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) has resulted in a shift away from chemotherapy-containing regimens and expanded the evolving treatment landscape. Since venetoclax was first highlighted in 2019 (See Original Venetoclax Spotlight), long-term data from key clinical trials have confirmed a sustained benefit for patients with CLL/SLL—both in relapsed or refractory disease and as first-line therapy. A growing body of data supporting the use of an all-oral, fixed-duration regimen of venetoclax/ibrutinib in treatment-naive patients has also been reported and described, albeit with shorter follow-up.

Anti-CD20 Monoclonal Antibody Combinations

Two key clinical trials on which the approval of venetoclax by the U.S. Food and Drug Administration was based released long-term data demonstrating durable responses in the treatment of patients with CLL/SLL. Both studies compared the effectiveness of venetoclax plus an anti-CD20 monoclonal antibody with standard-of-care chemoimmunotherapy.

Relapsed or Refractory CLL

Based on previous findings from the MURANO study, venetoclax plus rituximab was approved as a 24-month combination treatment regimen for patients with relapsed or refractory CLL/SLL. In the subsequent 5-year long-term follow-up, the improvement in median progression-free survival with venetoclax/rituximab compared with bendamustine/rituximab was sustained at 53.6 versus 17.0 months, respectively—corresponding to an 81% reduction in the risk of disease progression.^2,3 Overall survival was also improved with the venetoclax/rituximab combination, with an estimated 5-year overall survival rate of 82.1% compared with 62.2%, respectively, resulting in a 60% reduction in the risk of mortality. However, the baseline presence of del(17p), genomic complexity, and unmutated immunoglobulin heavy chain gene (IGHV) were associated with an increased risk of minimal residual disease (MRD) conversion and subsequent disease progression after the end of treatment.

Newly Diagnosed CLL/SLL

The other study, the phase III CLL14 trial, evaluated the use of venetoclax combination therapy in patients with previously untreated CLL and coexisting conditions.⁴ Participants received either 1 year of venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab (fixed duration). In a 3-year follow-up—after at least 24 months off treatment—progression-free survival was 81.9% with venetoclax/obinutuzumab versus 49.5% with chlorambucil/obinutuzumab. Undetectable MRD was achieved in 76% versus 35%, respectively, at 3 months after treatment completion and in 47% versus 7% at 18 months after treatment completion (P < .0001).

BTK Inhibitor Combinations

Several clinical trials are currently underway to investigate the combination of venetoclax with a BTK inhibitor as a fixed-duration, first-line treatment for CLL, a regimen hypothesized to have a synergistic effect. Although initial study results are encouraging, the U.S. Food and Drug Administration has not yet approved a BTK inhibitor/venetoclax combination.¹

CAPTIVATE Study

The phase II CAPTIVATE trial is a two-part study evaluating the use of 3 cycles of ibrutinib lead-in followed by 12 cycles of ibrutinib plus venetoclax (total, 15 cycles). The primary analysis of the first part of the study, the MRD cohort, was presented at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.⁵ At the end of the initial 15 cycles, MRD was evaluated; if patients had confirmed undetectable MRD, they were randomly assigned to receive either placebo or ibrutinib.

Undetectable MRD—75% in peripheral blood and 72% in bone marrow—was achieved with 12 cycles of ibrutinib plus venetoclax in more than two-thirds of patients, although only 58% met the criteria for confirmed undetectable MRD per the study protocol. Subsequent 30-month progression-free survival rates were at least 95% in both the placebo and ibrutinib arms. In this group with confirmed undetectable MRD, the 1-year disease-free survival rate did not significantly differ for patients randomly assigned to receive placebo versus ibrutinib (95.3% vs. 100%, P = .1475). These results (ie, similar 1-year disease-free survival rates in both groups) are considered to be supportive of a fixed-duration dosing regimen.

The primary analysis of the second part of the study, the fixed-duration cohort, was presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.⁶ This group of patients also completed 15 cycles, but no further treatment was given as follow-up or maintenance therapy. The complete response rate was 55% in the overall population and was consistent across high-risk subgroups. Of the patients who achieved a complete response, 89% had a durable complete response of at least 1 year.

Similar to results seen in the MRD cohort, undetectable MRD was achieved in 77% of patients in peripheral blood and in 60% of patients in bone marrow. The objective response rate was 96%, and the 24-month progression-free survival was 95%.

As for toxicity, the safety profile of the combination regimen was consistent with known adverse events for each component agent. One major concern when venetoclax is initiated is the risk of tumor-lysis syndrome (TLS). In the CAPTIVATE study, 3 months of lead-in ibrutinib monotherapy served to debulk disease, thereby decreasing the risk for TLS when venetoclax is added to the regimen. Of the patients with high baseline risk for TLS based on tumor burden, 94% had shifted to medium or low risk after the ibrutinib lead-in. No incidents of clinical TLS were reported.

Additional Ongoing Studies

In addition to the CAPTIVATE trial, several other studies are also underway to evaluate BTK inhibitors in combination with venetoclax and other novel targeted agents (ClinicalTrials.gov identifiers NCT03701282, NCT03737981, NCT03836261, NCT03824483). Two phase III studies, for example, are investigating the use of ibrutinib, venetoclax, and an anti-CD20 monoclonal antibody as first-line therapy: the Eastern Cooperative Oncology Group (ECOG) EA9161 study includes young, fit patients, whereas its sister study, the ALLIANCE A041702 study, is enrolling older patients. Other ongoing research includes phase II studies of either acalabrutinib or zanubrutinib with venetoclax and obinutuzumab as well as a phase III study comparing acalabrutinib plus venetoclax—with and without obinutuzumab—with chemoimmunotherapy as first-line therapy.

References

1. Venclexta (venetoclax) FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208573s023lbl.pdf. Accessed July 2, 2021.
2. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol 2020;38:4042–4054.
3. Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease in a subset of relapsed/refractory chronic lymphocytic leukemia patients following fixed-duration venetoclax-rituximab therapy. Blood 2020;136(suppl):19–21.
4. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized phase 3 CLL14 trial. EHA 2021 Virtual Congress. Abstract S155.
5. Wierda WG, Tam CS, Allan JN, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: 1-year disease-free survival results from the minimal residual disease cohort of the phase 2 CAPTIVATE study. Blood 2020;136(suppl 1):16–17.
6. Ghia P, Allan JN, Siddiqi T, et al. Fixed-duration first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia/small lymphocytic lymphoma: primary analysis of the fixed-duration cohort of the phase 2 captivate study. J Clin Oncol 2021;39(15 suppl). Abstract 7501.