Authored by Dr. Brian Koffman
The Bottom Line:
The CAPTIVATE study results support using ibrutinib combined with venetoclax (I + V) as an all-oral, once-daily fixed-duration regimen for treatment naïve (TN) patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL / SLL). With a four-year follow-up, fixed-duration I + V continues to provide deep, durable remissions with clinically meaningful progression-free survival (PFS) and time off treatment, including in patients with high-risk disease features.
Who Performed the Research and Where Was it Presented:
Dr. Paul Barr of the Wilmot Cancer Center in Rochester, NY, led an international group of researchers in presenting the results of more than four years of data at the American Society of Clinical Oncology (ASCO) 2023 annual meeting.
CAPTIVATE is a large multicenter phase 2 study of first-line I + V in CLL / SLL. Follow-up results from the fixed duration (FD) cohort showed a 3-year PFS rate of 88% overall and rates ≥80% in patients with high-risk features, as presented by Dr. Bill Wierda at ASCO 2022. This is the updated results from the FD cohort with a 4-year follow-up.
Methods and Participants:
Patients aged ≤70 years with previously untreated CLL / SLL received three cycles of ibrutinib and then 12 cycles of I + V (I 420 mg/d orally; V ramp-up to 400 mg/d orally).
- 159 patients were enrolled, including many with high-risk features of
- unmutated IGHV (uIGHV) (56%) or
- del(17p) and/or TP53 mutation (17%).
- The median time of the study was 50 months.
- At four years of follow-up, the best complete response (CR) rate was 58%.
- Overall response rate (ORR) was unchanged at 96%.
- At four years, the PFS rate was 79%.
- The overall survival (OS) rate was 98%.
- 4-year PFS rates were worse in patients with unmutated IGHV (73%) or del(17p) and/or TP53 mutation (63%), but OS rates remained consistently high.
- Four-year PFS rates by measurable (or minimal) residual disease (MRD) status three months after stopping treatment (EOT+3) were significantly higher overall in patients who had achieved undetectable MRD vs. detectable MRD in peripheral blood (90% vs. 66%).
- This difference was minimal at 24 months (100% vs. 91%).
- Median time to next treatment (TTNT) was not reached overall (range 1–53 months).
- The fourth rate of freedom from the next treatment was 84%.
- Second malignancies continue to be noted off treatment; 1 case of prostate cancer occurred during this year of follow-up.
- To date, 19 patients with progressive disease after completing fixed duration I + V in either the FD cohort or treatment to reach MRD cohort placebo arm initiated retreatment with ibrutinib. Responses in 17 patients with available data were 1 CR, 13 partial remission (PR), and 1 each PR with high lymphocyte count, stable disease (SD), and only 1 with progressive disease (PD).
- Median time on retreatment was 11 mo (range 0–39). The most common adverse events (≥10%) with retreatment were diarrhea (n=3), COVID-19 (n=3), and anemia (n=2). In addition, 4 patients have started I + V retreatment to date.
Results of the CAPTIVATE study support I + V as an all-oral, once-daily fixed-duration regimen for previously untreated patients with CLL / SLL. With a four-year follow-up, fixed-duration I + V continues to provide deep, durable remissions with clinically meaningful PFS and time off treatment, including in patients with high-risk disease features. New safety findings off-treatment were expectedly negligible, highlighting the benefits of a fixed-duration regimen. Promising responses were observed upon retreatment with ibrutinib in progressing patients. That said, while this combination has been approved in Canada and across Europe, the FDA has made it clear it is unlikely to be approved in USA, and approval is not being sought.
Links and Resources:
Watch Dr. Brian Koffman’s monologue on the abstract:
To read the original ASCO 2023 article, click on Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 4-y follow-up from the FD cohort of the phase 2 CAPTIVATE study.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-founder, Executive VP and Chief Medical Officer
CLL Society, Inc.