Long-Term Follow-Up of Ibrutinib/Venetoclax Provides Durable Survival in CLL/SLL

Fixed duration ibrutinib (Imbruvica) with venetoclax (Venclexta) led to durable outcomes when used for the treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), even in patients with bulky disease at baseline, according to updated findings from the phase 2 CAPTIVATE study (NCT02910583).¹

In the phase 2 CAPTIVATE study, investigators assessed the combination of ibrutinib and venetoclax as a first-line, all-oral, once-daily regimen for patients with CLL/SLL.² Two cohorts were explored: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and fixed duration (FD cohort).¹

With up to 5.5 years of follow-up, the FD regimen demonstrated durable progression-free survival and overall survival rates, even among high-risk patients with genomic features like del(17p) or mutated TP53. Safety was also manageable, with grade 3 or greater adverse events (AEs) observed in around 60% of patients. Few patients discontinued treatment due to AEs.

“The findings are highly positive for general hematologists because they demonstrate the availability of an easy-to-administer treatment combination. Both ibrutinib and venetoclax are oral therapies, which simplifies administration after the initial debulking phase with ibrutinib,” explained Paolo Ghia, MD, PhD, in an interview with Targeted Oncology^TM.

In the interview, Ghia, deputy director of the Division of Experimental Oncology in San Raffaele Scientific Institute in Milan, Italy, full professor of medical oncology, a group leader in the B-cell Neoplasia Unit, and the head of the Strategic Research Program on CLL at the Università Vita Salute San Raffaele, provided background on the CAPTIVATE trial in CLL/SLL treatment and further discussed data which were presented at the 2024 American Society of Hematology Annual Meeting and Exposition.

Targeted Oncology: Can you provide an overview of the CAPTIVATE trial and what investigators sought to evaluate?

Ghia: The CAPTIVATE trial is a phase 2 international trial where we investigated the combination of ibrutinib, the BTK inhibitor, and venetoclax, a BCL2 inhibitor, in frontline patients with CLL. And in particular, this combination was given with 3 months of debulking with the ibrutinib only, and then 12 months of the combination between ibrutinib and venetoclax. The study involved only young patients below 70 years of age.

There were 2 different cohorts, not arms. They were not randomized to each other. One cohort was MRD driven, so at the end of the 15 months of treatment, patients were randomized based on the level of undetectable MRD. But more importantly, we had the so-called fixed-duration cohort, where patients after 15 months of treatment all stopped the treatment regardless of the level of undetected MRD. And that is actually the regimen that has been approved in Europe, and it can be used now as a standard regimen.

What findings from the trial have been particularly noteworthy?

The study helped us understand the benefits of a combination treatment for patients with chronic lymphocytic leukemia in the frontline setting. This combination has also been explored in a randomized phase 3 study called the GLOW study, which involved elderly patients around 65 years of age. These patients were either treated with venetoclax or chlorambucil, the standard chemotherapy for this patient group.

Microscopic image of CLL cells - Generated with Google Gemini AI

The combination treatment showed significant benefits. At the 5.5-year follow-up, data presented revealed that about two-thirds of patients had not experienced disease progression and were still responding to treatment. Of particular interest, patients with unmutated immunoglobulin genes, but without P53 abnormalities, showed similar progression-free survival outcomes. This suggests that the combination treatment is highly effective in high-risk patients, particularly younger patients with mutated immunoglobulin genes.

From a safety perspective, there was no notable increase in adverse events compared with previous treatments. The exception was diarrhea, which affected more than 50% of patients, but most cases were grade 1 or 2. All other adverse events occurred at frequencies similar to those seen with single-agent therapies, such as ibrutinib or venetoclax.

What from this study was presented at ASH 2024?

We presented another follow-up, but in particular, we wanted to deepen our understanding on the type and quality of response among the different patients who were enrolled in the CAPTIVATE study. In particular, we wanted to understand if the presence of bulky lymphadenopathy defined as more than 5 cm of size might affect the response, in particular, also the durability of the response.

What we have shown is that the starting size of the lymph node, but also the size achieved by the lymph node at the end of the therapy, either more than 1.5 cm or less than 1.5 cm did not affect the PFS of the patient. There was no difference in terms of PFS based on the initial size of the lymph nodes or the resulting size of the lymph nodes at the end of the therapy.

For a community oncologist, what do you believe they should take away from these findings?

The findings are highly positive for general hematologists because they demonstrate the availability of an easy-to-administer treatment combination. Both ibrutinib and venetoclax are oral therapies, which simplifies administration after the initial debulking phase with ibrutinib. Following the 3 months of debulking, the venetoclax ramp-up is easier for patients, as most of the disease is already reduced due to the BTK inhibition. This treatment is highly effective for most patients, with the exception of those with p53 aberrations, who tend to progress earlier.

However, even patients with p53 aberrations have a median progression-free survival of nearly five years, which is still a substantial period, almost 4 years of therapy with only 15 months of treatment. For all other patients, including those with unmutated immunoglobulin genes, responses are very positive with prolonged remissions. Overall, this regimen provides a safe, effective, and easy-to-administer treatment, particularly for younger patients.

What are the implications of these findings for clinical practice and what further research might be needed?

We need a lot of research to optimize treatment, as fixed-duration therapies are a "one-size-fits-all" approach, which is scientifically incorrect. Each disease is different, so treatment duration should be tailored to individual patients. For some, less treatment may be needed, while others may require more treatment, as demonstrated in other studies like [one] which used the same combination. The key takeaway is that we are moving toward fixed-ratio or time-limited treatments for CLL, allowing for a set treatment period followed by years of remission before potentially starting another therapy.

REFERENCES:

1. Wierda WG, Jacobs R, Barr PM, et al. Consistently high 5.5-year progression-free survival (PFS) rates in patients with and without bulky baseline lymphadenopathy ≥5 cm are associated with high undetectable minimal residual disease (uMRD4) rates after first-line treatment with fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study. Blood. 2024;144(suppl 1):1869. doi:10.1182/blood-2024-198104

2. Ghia P, Wierda WG, Barr PM, et al. Relapse after first-line fixed duration ibrutinib + venetoclax: high response rates to ibrutinib retreatment and absence of BTK mutations in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with up to 5 years of follow-up in the phase 2 Captivate study. Blood. 2023;142(suppl 1):642. doi.org/10.1182/blood-2023-187128