Promising Data in CLL With Ibrutinib/Venetoclax Doublet

Microscopic images of red blood cells activated platelets and white blood cells are showcased in the photographs as a result of leukemia: © AkuAku - stock.adobe.com

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed potential to restore normal blood immune composition in patients with chronic lymphocytic leukemia (CLL), according to findings from the phase 2 CAPTIVATE study (NCT02910583).¹

Patients in the study were randomized to either placebo or ibrutinib groups if they had confirmed undetectable minimal residual disease (uMRD) or ibrutinib or ibrutinib plus venetoclax if they did not have confirmed uMRD. CLL cells decreased within 3 cycles of initiation of venetoclax treatment. After 16 cycles of treatment, patients with confirmed uMRD had levels similar to healthy donor levels (HDL), and patients without confirmed uMRD had levels which were slightly higher than HDL. Comparatively, patients who received placebo had levels which were comparable with HDL 4 months after 16 cycles.

CD3-positive T-cell counts appeared to normalize within 6 months across all randomized treatment arms in CAPTIVATE. A median decrease of 49% from baseline was observed, and these levels remained consistent, regardless of treatment. Moreover, the ratio of CD4-positive to CD8-positive T-cells, which is normally low in patients with CLL, increased to HDL by cycle 7.

“In conclusion, these findings represent promising evidence for the restoration of important circulating adaptive and innate immune cells with ibrutinib plus venetoclax, particularly in patients receiving an [fixed duration] regimen with previously untreated CLL/[small lymphocytic lymphoma], and support the observed clinical efficacy of this regimen,” study authors wrote.

“Indeed, all [patients] achieved partial responses, at least, or complete responses, with a median follow-up that is now roughly more than 1 year,” said Paolo Ghia, MD, PhD, professor at the Vita-Salute San Raffaele University in Milan, Italy, and researcher on the CAPTIVATE study, in an interview with Targeted Oncology^TM.

Further, findings from the phase 3 GLOW study (NCT03462719)2 showed that patients who received fixed duration ibrutinib plus venetoclax had sustained elimination of CLL cells and recovered normal B cell levels. CLL counts remained at HDL at cycle 28. In contrast, patients who received chlorambucil plus obinutuzumab (Gazvya) experienced elimination of CLL cells following the first treatment, but levels increased following the end of treatment.¹

“The rationale for responding is indeed that we showed that no patient developed mutations in the BTK or PFCγ2 genes that are typically mechanism of resistance to ibrutinib. Also, they did not develop any common and traditional mutation in the BCL2 gene with the exception of a novel mutation that has been described only once, and it’s not clear if and how it has a role in the resistance to venetoclax. The patient anyhow, responded and responded for many years during the initial treatment and also achieved a response during the retreatment,” Ghia explained.

A total of 79 patients were enrolled in CAPTIVATE. The median age was 59 years (range, 28-69), and 61% of patients (n = 48) were male. A 17p deletion or TP53 mutation was observed in 16 patients (20%), while 10 patients (13%) had a deletion of 11q.¹

Regarding safety, 93%-100% of treatment-emergent infections were resolved, and the incidence of infections decreased as treatment time went on.

“We are also keeping an eye on the other malignancies. That's another issue when you treat patients with any therapy and also with targeted therapies. Within the 5 years of follow-up, we had only 8 patients who developed another malignancy in particular skin cancer, like [basal cell carcinoma]. That is known to be more frequent in patients with chronic lymphocytic leukemia,” Ghia said.

The combination of venetoclax and ibrutinib is also being explored in mantle cell lymphoma (MCL), with promising findings emerging from the phase 3 SYMPATICO trial (NCT03112174).

“Ibrutinib or [Bruton tyrosine kinase] monotherapy has been a long-standing standard-of-care in these patients. The question is whether we can do better than monotherapy at providing deeper and more durable responses. Our goal is to develop combination therapy in this context,” said Matthew Matasar, MD, chief of blood disorders at the Rutgers Cancer Institute, New Jersey, in an interview with Targeted Oncology^TM.

“At initiation, there has been an attempt to improve these very clinical endpoints. We see the results are favorable. In terms of activity, we see definite and a marked improvement in response and progression-free survival for the patients treated with the doublets,” said Matasar. “I would say that ibrutinib and venetoclax…is an attractive combination because it is a dual oral program. That's obviously very important both for the patient journey as well as for logistics and operational considerations when we take care of our patients in a variety of health care contexts.”

However, more research is required for the doublet in both the CLL and MCL spaces.

“We may be able to get more benefit out of our line of BTK-inhibiting therapy with this combination approach, deferring the potential toxicities of other later line interventions, such as [chimeric antigen receptor] T-cell therapy and allogeneic stem cell transplantation,” Matasar said regarding the SYMPATICO study. “We need to continue to follow these data and watch them mature. Mantle cell lymphoma is sometimes a marathon and not a sprint. Following these patients to learn their subsequent outcomes, impact of next line of therapy, and responses to the next line of therapy will better clarify the impact of having a doublet in this clinical context.”

“I think that with a longer follow-up, we have been able to show that the use of ibrutinib and venetoclax in frontline data allows [us] to retreat and reuse exactly the same drugs in the patient when they relapse, also because they do not develop mutations in the genes that are inhibited by the by the drugs,” Ghia said regarding the CAPTIVATE study.

REFERENCES:

1. Moreno C, Solman I, Tam C, et al. Immune restoration with ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia: the phase 2 CAPTIVATE study. Blood Adv . 2023;7(18):5294–5303. doi:10.1182/bloodadvances.2023010236

2. Munir T, Moreno C, Owen C, et al. Impact of minimal residual disease on progression-free survival outcomes after fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in the GLOW study. J Clin Oncol. 2023;41(21):3689-3699. doi:10.1200/JCO.22.02283