5-Year CAPTIVATE Results Show Promise in CLL/SLL With Ibrutinib/Venetoclax

Paolo Ghia, MD, PhD

Ibrutinib (Imbruvica) given in combination with venetoclax (Venclexta) showed clinically meaningful progression-free survival (PFS) and deep remission rates in chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL), according to 5-year follow-up data from the phase 2 CAPTIVATE trial (NCT02910583).¹

In the study, investigators are assessing the safety and efficacy of ibrutinib in combination with venetoclax in patients with CLL/SLL. Two cohorts make up the trial: a measurable residual disease (MRD)-driven cohort and a fixed duration cohort.

Findings demonstrated that treatment with the fixed-duration regimen led to an overall PFS rate of 70% (95% CI, 62%-77%) among the 159 patients included. The median time to next treatment has not yet been reached. Additionally, the estimated 4.5-year rate of freedom from next line of treatment is 82% (95% CI, 76%-87%).

Overall, these 5-year data show that patients can be retreated safely with either ibrutinib alone or given in combination with venetoclax after relapse.

In an interview with Targeted Oncology^TM, Paolo Ghia, MD, PhD, 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, discussed the 5-year results from the CAPTIVATE study.

White blood cells in leukemia, AI Generative: © Катерина Євтехова - stock.adobe.com

Targeted Oncology: Please provide some background information on the CAPTIVATE study.

Ghia: The CAPTIVATE study is phase 2, international study that includes 2 different cohorts of patients treated in the frontline. Patients with CLL were treated with 3 months of ibrutinib, followed by 12 months of the combination between ibrutinib and the BCL2 inhibitor venetoclax. The 2 cohorts differentiate because there is an MRD cohort that is driven by the assessment of minimal residual disease at the end of the treatment. Those who have achieved undetectable MRD have been randomized to either placebo, so to stop the treatment or to continuous treatment with ibrutinib.

There is a second cohort which is a fixed-duration cohort where every patient at the end of the 15 months of the treatment stops the treatment with ibrutinib and venetoclax. We pulled together all the patients who stopped the treatment, either because they reached undetected MRD in the first cohort, or because by design, they had to stop it in the second cohort, and we analyzed if and how we could retrieve these patients in case of progression.

Out of 202 patients, 53 patients progressed in 5 years. Some of them, not all of them, needed treatment. And in particular, 18 of them did not yet need treatment, though they progressed, and the rest have been treated with either ibrutinib alone continuous therapy, or they have been retreated, 6 of them with ibrutinib plus venetoclax. Seven patients have been treated with other treatment at the discretion of the physician.

Were any of the findings of particular interest to you?

Virtually all patients responded to either ibrutinib monotherapy or ibrutinib and venetoclax. Some patients in the data that we presented have not yet been treated long enough to achieve a response. But now that we have followed them longer, we know that all patients at least achieved a partial response with the exception of 1 patient who had a Richter transformation, and that was diagnosed 1 month after starting the treatment. This is the first point, which is very relevant to know that patients who have received both classes of drugs in the frontline can still be retreated with these drugs. This is also possible because none of these patients developed a mutation in the BTK or PLCgamma2 molecules; that is a typical mechanism of resistance to ibrutinib, and also, nobody developed the classic traditional mutation on the BCL2 gene. That gives the rationale why all patients indeed responded to the treatment with the drugs.

What were the safety findings?

Being off therapy, the patient during the follow-up did not show any adverse events until they started the retreatment. We are following very closely the occurrence of other malignancies. Over 5 years, only 8% of the patients developed a second malignancy, and particularly skin cancer, which is known to be more common in patients with chronic lymphocytic leukemia.

Can you share the progression-free survival data?

Now of course, we all want to know how long patients remain off therapy and they do not progress after a fixed duration of treatment, and at 54 months of follow-up, 70% of the patients are still responding, including patients with unmutated immunoglobulin genes, 68% of them are still responding. Patients with p53 aberration are losing a little bit earlier; the response is still 45% of them, still responding after 54 months of follow-up. So, this is very promising data and appears to be very effective mutually in all patients.

For community oncologists, what would you say are the key points to take home from this research?

This is a treatment that is convenient for community doctors because it is all oral, so we do not need to infuse any antibody, anything [intravenously]. It is convenient and easy. You start with ibrutinib, BTK inhibitors, oral therapy, you do not need to see the patient for many weeks, and that debulks the patient so that when you start venetoclax 3 months later, then the patient is low risk. The vast majority of them become at a low risk of tumor lysis syndrome, which can be a complication when starting venetoclax. But again, with the 3 months of lead-in phase, let's say with ibrutinib, and also if you follow the ramp-up rules and assessment for the biochemical assessment, during the ramp-up, there is no issue of tumor lysis syndrome. In addition, the combination of the 2 drugs showed that it is well-tolerated, particularly in the young and fit patients where we only saw an increase in diarrhea. So more than 50% of the patients do experience diarrhea, but it is typically grade 1 or 2 and resolved after a few days.

REFERENCE:

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