Updated data from the final analysis of the phase 2 CAPTIVATE study (NCT02910583) have reinforced the long-term progression-free survival (PFS) benefit of fixed-duration ibrutinib (Imbruvica) plus venetoclax (Venclexta) for the frontline treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to Paolo Ghia, MD, PhD.
In the overall patient population (n = 202), the PFS rate at 5.5 years was 66% (95% CI, 58%-72%) and the overall survival (OS) rate was 97% (95% CI, 93%-99%).1 Of note, in August 2022,
“The assessment correlates with the durability of the response and with PFS,” Ghia explained in an interview with OncLive®. “The value that you get after 7 months is not associated at all with long-term durability, which really means that we likely cannot shorten the treatment— we need at least all 15 months of treatment to get the best response that we can get to an undetectable minimal residual disease [uMRD].”
In the interview, Ghia discussed the background and design of the CAPTIVATE study, key efficacy data from the final analysis, next steps in research, and the implications of the ibrutinib plus venetoclax regimen in clinical practice.
Ghia is a full professor in medical oncology at Università Vita-Salute San Raffaele, director of the Strategic Research Program on CLL, and head of the Laboratory of B-Cell Neoplasia at the IRCCS Ospedale San Raffaele in Milan, Italy.
OncLive: What was the rationale for conducting the CAPTIVATE study?
Ghia: The CAPTIVATE study was designed a long time ago [and] we aimed to combine a BTK inhibitor like ibrutinib with venetoclax, a BCL2 inhibitor. However, these drugs were, at that time, the best drugs that we had for CLL. The idea was that either drug was shown to be very effective as a continuous treatment, and we wanted to finally be able to provide patients with the possibility of a fixed-duration treatment. There was already the venetoclax plus Obinutuzumab [Gazyva] regimen with 12 months of treatment.
[In the CAPTIVATE study], we wanted to explore what would happen by adding together 2 different drugs, working with 2 different mechanisms, and, in particular, mechanisms that were synergistic. On one hand, ibrutinib was able to [treat] the tissues, lymph nodes, and the bone marrow, and venetoclax was great at killing these cells outside the microenvironment.
What was the design of the study, and what were notable baseline patient characteristics?
The CAPTIVATE study enrolled younger patients with CLL in the frontline, and we had 2 cohorts. The first cohort was a MRD–driven cohort where we treated patients for 3 months with ibrutinib to debulk the patient, and then 12 months of the combination of ibrutinib and venetoclax. At the end of the 15 months, [all patients] were assessed for the level of uMRD and … were [randomly assigned] to either stop the drugs or to continue ibrutinib monotherapy. If they were [MRD-]positive, they would continue with either ibrutinib monotherapy or ibrutinib plus venetoclax. What we saw from the first cohort was that the vast majority of patients were achieving uMRD. It was even difficult then to [randomly assign] patients who were positive for uMRD. Therefore, we decided to design the second cohort with [the same structure as the first cohort, with] 15 months of treatment, but at the end of the treatment, [all patients] stopped [treatment], regardless of the level of undetected MRD, which is the [regimen] that have been approved all over the world, in Europe and in many other countries, as a treatment for patients with frontline CLL.
What were the key efficacy data from both cohorts in the study?
What we have shown in the fixed duration cohort is that after 5.5 years, the PFS was 66%, and we have not yet reached the median PFS. The 5.5-year OS [rate] was 96%. We [also] presented the efficacy in the different genetic subgroups of patients, starting from patients with mutated immunoglobulin genes [n = 78]—those with the best prognosis. [In this subgroup,] we have an astounding [PFS rate of] 79% [95% CI, 68%-87%] at 5.5 years.
When we look at patients with [unmutated IGHV] disease [n = 119], we still have not reached the median PFS at 5.5 years, with 55% [95% CI, 45%-64%] of patients not yet progressing. Finally, patients with TP53 aberrations [n = 29], either deletion 17p or TP53 mutation, [showed] a worse PFS with only 36% [95% CI, 17%-55%] not progressing at 5.5 years. Nevertheless, if we want to look at the half-full glass, here we are talking about patients who typically progress with any therapy. Here, we can give 1/3 of the patients 5 years or more of PFS with only 15 months of therapy, which is quite reassuring.
Of course, in the future, we have to find ways to further identify those who will really benefit from this fixed-duration treatment, and the others who could be treated with continuous ibrutinib. The other results [include] the assessment of uMRD at the end of the therapy.
Were there any new safety signals to note, particularly in patients who finished treatment?
In this final analysis, patients had stopped the treatment a long time ago; therefore, there was not any major concern about the safety itself. Although there were 2 [other] major concerns we had. One is what happens when we retreat the patient [and] is there a cumulative number of adverse [effects]?
There were no new safety signals. When I retreat the patient, I [choose] either ibrutinib alone or ibrutinib plus venetoclax. Also, in terms of other malignancies, which is always something we are afraid of for our patients in the long term, those who develop other malignancies in the vast majority were nonmelanoma skin cancers. The other point is that in this final analysis, we also showed that patients can be retreated, and there is a sustained response. With the treatment, 76% of patients will achieve a response with either ibrutinib or ibrutinib plus venetoclax. Those who do not officially respond still have a stable disease, and we have controlled the disease for at least 1.5 years. Therefore, at the end of the day, the PFS is good, although at the moment, the follow-up is very short: 2 years for patients treated with ibrutinib only, and 1 year for patients treated with ibrutinib plus venetoclax.
Following the CAPTIVATE study, what are the next steps for this research?
The next analysis that we are [planning] will study—at the molecular level—the differences between patients who did achieve uMRD, and those who did not, because that is still the element that is predicting the long-term response. Therefore, it would be nice to identify these patients earlier, so that we could [potentially] increase the quantity of therapy and prolong the time of the therapy. This design [provides] alternative strategies for particular patients who will not achieve and uMRD and not achieve long and durable PFS.
What are the implications regarding treatment sequencing and the use of retreatment strategies in clinical practice?
That remains a major issue in clinical practice, because in many countries, the right treatment is not approved and not reimbursed. At the end of the day, we designed the CAPTIVATE study and many other studies to aim at a fixed-duration treatment because we think it’s an advantage for the patient, the payer, and for the doctors; for everyone involved. Still, it is based on the idea that patients will eventually relapse, we are not curing the patient; we are giving a short period of time so that patients can experience and benefit [from] a longer off-therapy period, and then need to retreat the patient, because that’s the other major point of the fixed-duration treatment that we keep the same bullets for later lines of treatment. If that is not allowed, then the whole idea of the fixed-duration treatment is becoming somewhat weaker.
References
- Ghia P, Allan J, Siddiqi T, et al. Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study. J Clin Oncol. 2025;43(suppl 16):7036. doi:10.1200/JCO.2025.43.16_suppl.7036
- European Commission approves Imbruvica (ibrutinib) in a fixed-duration combination regimen for adult patients with previously untreated chronic lymphocytic leukemia. News release. Johnson & Johnson. August 4, 2022. Accessed September 11, 2025. https://www.jnj.com/media-center/press-releases/european-commission-approves-imbruvica-ibrutinib-in-a-fixed-duration-combination-regimen-for-adult-patients-with-previously-untreated-chronic-lymphocytic-leukaemia-cll