The CAPTIVATE study data has been highly anticipated. At ASH 2020, we got important results. Dr. Wierda presented the results of the Minimal (Measurable) Residual Disease (MRD) cohort using MRD status to guide therapy. Undetectable MRD (uMRD) was achieved in >2/3 of patients with 12 cycles of Ibrutinib (I) + Venetoclax (V), and the 30-month progression-free survival (PFS) rate was an impressive 95%.
For more on the design of the CAPTIVATE trial and the results of the MRD cohort, here is the interview with Dr. Wierda that was held soon after ASH 2020. For a patient’s perspective, catch Mark Hoffman’s discussion of his positive experience in the trial.
At the American Society of Clinical Oncology (ASCO) 2021 Annual meeting, which was held virtually, Dr. Paolo Ghia reported the results of the fixed duration (FD) arm.
Patients who were ≤70 years of age with treatment-naive CLL / SLL received 3 cycles of ibrutinib, followed by 12 cycles of I+V. The ibrutinib lead-in was to reduce tumor burden and thus the risk of tumor lysis syndrome that can occur when too much cancer is killed too fast.
- 159 pts were enrolled whose median age was 60
- High-risk features included del(17p) or TP53 mutation in 17%; del(11q) in 18%; complex karyotype in 19%; and unmutated IGHV in 56%
- Most patients were able to complete the planned treatment, with 147 (92%) and 149 (94%) patients completing I+V, respectively
- The median study time was 27.9 months
- With fixed-duration I+V, the complete response (CR) rate was 55% in the overall population and was consistent across high-risk subgroups
- Of the 88 pts who achieved CR, 78 (89%) had durable CR (duration ≥1 year); 1 died 7 months after CR, and 9 with <1 year of follow-up were not evaluable
- The Overall Response Rate (ORR) was 96%
- Undetectable MRD response was found in 77% of patients via peripheral blood (PB), and 60% of patients via bone marrow (BM)
- 24-month PFS was 95%; 24-month Overall Survival (OS) was 98%
- The purpose of the three-month lead-in was to reduce the tumor burden (thus the risk of TLS), which could overwhelm the kidney’s ability to detoxify the blood
- Of the 34 patients with a high baseline TLS risk, 32 (94%) shifted to medium- or low-risk after the ibrutinib lead-in time, and no TLS occurred
- Adverse Events (AEs) were primarily mild with the most common serious AE being neutropenia (dangerously low neutrophil counts) in 33% of patients, hypertension in 6%, and a mildly decreased neutrophil count in 5%
- AEs led to the discontinuation of ibrutinib in 4% of patients, and the discontinuation of venetoclax in 2% of patients
First-line I+V is an oral, once-daily, chemotherapy-free, fixed-duration treatment option that provides deep and durable responses in CLL patients, including those with high-risk features such as del(17p). PFS of 95% at the two-year mark seemed similar to the uMRD arm at 30 months of ≥95%. While it is clearly more simple to have a FD therapy and the two-year results presented at ASCO are encouraging, longer-term data are needed to determine if uMRD guided therapy will improve OS over FD. Another big unanswered question is if sequential drug use or the use of complementary drug combinations up front is the best choice. More research is coming, but one thing we know for sure is that I+V is a potent therapy, even for high-risk patients.
Here is the link to the ASCO 2021 abstract.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.