Unlocking Long-Term Success: Insights From 5-Year Follow-Up of the CAPTIVATE Trial in CLL/SLL


Paolo Ghia, MD, PhD, discusses long-term efficacy data for fixed-duration ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia.

Paolo Ghia, MD, PhD

Paolo Ghia, MD, PhD

First-line, fixed-duration ibrutinib (Imbruvica) plus venetoclax (Venclexta) continued to elicit clinically meaningful progression-free survival (PFS) and deep remissions among patients with chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL) after up to 5 years of follow-up, according to Paolo Ghia, MD, PhD, who adds that responses were also observed with the reintroduction of ibrutinib-based therapy in patients requiring retreatment.1

At the 2023 ASH Annual Meeting, Ghia presented data from the phase 2 CAPTIVATE trial (NCT02910583) of ibrutinib and venetoclax in CLL/SLL. The fixed-duration regimen produced an overall PFS rate of 70% (95% CI, 62%-77%) in this patient population (n = 159). The median time to next treatment has not yet been reached and the estimated 4.5-year rate of freedom from next-line of treatment is 82% (95% CI, 76%-87%).1

“With longer follow-up, we have been able to show that the use of ibrutinib and venetoclax in frontline treatment allows [oncologists] to retreat and reuse the same drugs in the patient when they relapse because they do not develop mutations in the genes that are inhibited by the drugs,” described Ghia, who serves as deputy director of the Division of Experimental Oncology in San Raffaele Scientific Institute in Milan, Italy.

In an interview with OncLive®, Ghia discussed the efficacy of frontline ibrutinib plus venetoclax in patients with CLL, highlighted prolonged responses with the combination in these pretreated patients, and expanded on the potential for retreatment upon relapse in patients who do not develop select resistance mutations.

Ghia is also a 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.

OncLive: What were the design and methodology of the CAPTIVATE trial?

Ghia: At the 2023 ASH Annual Meeting in San Diego, we presented the 5-year follow-up of the CAPTIVATE study, a phase 2 international study where patients with CLL are treated in the front line with a combination of ibrutinib plus venetoclax.

The schema of treatment was 3 cycles of ibrutinib to debulk the patients and decrease the risk of tumor lysis syndrome. This is followed by 12 cycles of the combination therapy.

The study had 2 different cohorts. The first cohort was a minimal residual disease [MRD]–driven cohort, where patients at the end of treatment were randomized based on the level of undetectable MRD. Those who achieved undetectable MRD were randomized to either stop the treatment on the placebo arm or to continue ibrutinib.

The other cohort of the study included patients who all stopped the treatment after [a fixed duration]. Therefore, we combined all the patients who eventually stopped the combination of ibrutinib plus venetoclax because we wanted to see what happened to them. In particular [we wanted to see] if and how we could retreat patients [who experienced] progressive disease.

What was seen regarding progression of disease in these patients?

Out of the 202 patients enrolled, 53 patients progressed during the 56-month median follow-up. Eighteen of those did not yet need [subsequent] treatment. The remaining [patients] were treated again. Seven of them received other treatment, but the vast majority received either ibrutinib alone or ibrutinib in combination with venetoclax. Twenty-two of them received ibrutinib and 6 of them received ibrutinib in combination with venetoclax.

The combination was allowed to be used only if the patient experienced progression more than 2 years after the end of treatment. The good news is that all patients [essentially] responded. The [previous] data that we presented had a shorter follow-up and now there is a longer follow-up for all [patients]. All patients achieved partial responses or complete responses with a medium follow-up [approximately] 1 year [longer than the prior 4-year analysis.]

What were the implications of these results?

We showed that no patient developed mutations in the BTK or the PLCG2 genes that are typically [involved in the] mechanism of resistance to ibrutinib. They also did not develop any common and traditional mutations in the BCL2 gene, except for a novel mutation that has been described only once. It is not clear the role [this mutation plays] in the [development of] resistance to venetoclax.

Patients responded for many years during initial treatment and achieved responses during retreatment. We are also keeping an eye on [second] malignancies. That’s another issue when you treat patients with any therapy and with targeted therapies.

Within the 5 years of follow-up, 8% of patients developed another malignancy, particularly skin cancer, which is known to be more frequently [observed] in patients with CLL.

What would you like your colleagues to take away from this research?

PFS has been studied only in the patients who had the fixed-duration treatment. By design, [within] the first 54 months of follow-up, 70% of patients are still responding or not progressing. That is true for patients with unmutated immunoglobulin genes, as 68% of them are still responding.

Patients with p53 aberrations, [comprising] deletion 17p or TP53 mutations, have a bit shorter PFS, [with] 45% of these patients still responding after 54 months. This is a prolonged response.


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

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