At the 65th American Society of Hematology (ASH) Annual Meeting in San Diego, California,  Paolo Ghia, MD, PhD, Università Vita-Salute San Raffaele, Milan, Italy, highlights findings from long-term, up to 5-year follow-up of the phase 2 CAPTIVATE study on the lasting efficacy of Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib plus venetoclax as a first-line treatment among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), which has demonstrated deep remissions with clinically meaningful progression-free survival, including in patients with high-risk genomic features. 

Transcript:

Hello, I'm Paolo Ghia from Università Vita-Salute San Raffaele in Milan, Italy. This year, in San Diego, at the [American Society of Hematology] (ASH) Congress, I presented the follow-up of the CAPTIVATE study. The CAPTIVATE study is one of the first studies that explored the combination of ibrutinib plus venetoclax in treatment-naive patients with chronic lymphocytic leukemia.

This year, we presented [a] follow-up of up to 5 years. In particular, we presented data on the retreatment of patients following the combination of ibrutinib plus venetoclax. The CAPTIVATE study is a complex phase 2 study, where we had 2 different cohorts. One was an [minimal residual disease] MRD-driven cohort. At the end of the treatment, which consisted of 3 months of ibrutinib followed by 12 months of the combination of ibrutinib plus venetoclax, patients were randomized based on the level of undetectable MRD reached.

In particular, those who achieved undetectable MRD were randomized to either stop the treatment–so they were put in a placebo arm–or continued ibrutinib. This is important because the patients who stopped the treatment are the ones [who] we further investigated and presented in this abstract. These patients together with those of the other cohort of the study were patients [who] were treated with 3 months of ibrutinib, 12 months of ibrutinib plus venetoclax, and everybody then stopped regardless of the quality of the response in that so-called fixed duration treatment cohort. 

The combination of all these patients [with] a fixed duration treatment of 15 months [were then] analyzed in this follow-up study. What we first learned is that the vast majority– 2/3 of the patients–progressed [after] more than 2 years after the completion of treatment. This is [a] rather important piece of news because this length is considered, by many physicians, a safe period after which patients could be even retreated with the same treatment that we applied in [the] frontline.

It is true that among the 1/3 of patients [who] progressed earlier than 2 years, we had an enrichment of patients with p53 abnormalities, or a complex karyotype. The other important piece of news is that patients who progressed after ibrutinib plus venetoclax did not show mutations in BTK, [primary sclerosing cholangitis] (PSC) gamma 2, or [B-cell lymphoma 2] (BCL-2) genes, [which] are known to be part of the mechanism of resistance to both [or] either drug. So, this is again reassuring on the possibility of retreating the patient with the same treatment. 

The other important news is that, among the 202 patients who have been treated with this fixed-duration treatment approach, 49 progressed. But, of these 49, 18 did not yet need a subsequent treatment, and indeed that translated [in]to a 4.5-year rate of freedom from next-line treatment that was 82%. So, more than 4 out of 5 patients, still after 4.5 years, did not need a subsequent treatment. Of the patients who received the treatment, 28 in total restarted in ibrutinib-based treatment.

The vast majority, 22, were patients treated only with ibrutinib monotherapy while instead, 6 patients have also retreated with the combination of ibrutinib plus and venetoclax, and 7 patients [who] received [an]other type of treatment. What is very interesting and promising is that the vast majority, if not all, of those who have been retreated with ibrutinib alone, had [a] response, and, in particular, 86% of them responded with the partial or complete response as we would expect with ibrutinib continuous treatment. 1 patient was diagnosed with the Richter transformation 1 month after the restart of treatment, so the disease was [probably] already present the day before. For other patients, we have too short [of a] follow-up so we cannot yet call the response. 

Among the patients who have been retreated with the combination ibrutinib plus venetoclax, 5 out of 6 already responded. In this case, 1/3 with the complete remission, and the remaining with [a] partial response. For 1 patient again, the follow-up was too short. That translated in[to] very interesting and sustained progression-free survival. Indeed, even up to 5 years of follow-up, 70% of the patients are still responding and not progressing.

This is all treated patients, but the same number, 68%, is apparent among patients with unmutated immunoglobulin genes, which we typically consider to be a little bit more difficult to treat particularly with fixed-duration treatment. Patients with p53 aberrations, division 17p, and mutation p53 remain a little bit more difficult to treat because these patients, though they had the sustained response, already reached the median progression-free survival. At 54 months, only 45% of patients are still responding and did not progress. 

Of course, since it is a fixed-duration treatment, we didn't have adverse events in the period following the continuation of the therapy. With that, I think that we can conclude that the combination [of] ibrutinib plus venetoclax is feasible and, in particular, is providing sustained and prolonged progression-free survival, and gives also the opportunity and possibility to retreat the patient using the same drugs that we used in the initial treatment, as the known mutations are occurring and the vast majority, if not all patients, are responding to the subsequent treatment with the same drug. With that, I thank you for your attention.

Source: 

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. Presented at the ASH 65th Annual Meeting & Exposition; December 9-12 2023; San Diego, California. Abstract 633