Ibrutinib/Venetoclax Shows Potential to Provide Durable Treatment-Free Remissions in CLL With MRD Negativity

Ryan Jacobs, MD

Follow-up data from the phase 2 CAPTIVATE trial (NCT02910583) indicate that the use of first-line ibrutinib (Imbruvica) plus venetoclax (Venclexta) not only leads to deep, sustained responses in younger patients with chronic lymphocytic leukemia (CLL), but may also allow those with minimal residual disease (MRD) negativity to safely achieve durable treatment-free remissions. Further study is required to confirm the durability of these remissions, to understand the tolerability of the regimen’s use in older patients, and to determine how MRD can best be utilized in clinical practice, according to Ryan Jacobs, MD.

Earlier data from the trial showed that the 1-year disease-free survival (DFS) rate following random assignment was not significantly different for those with confirmed uMRD who received placebo vs ibrutinib, at 95% and 100%, respectively (P = .15).¹

Updated data from the MRD cohort presented at the 2022 ASH Annual Meeting demonstrated that at a median of 41 months after stopping treatment, the 3-year DFS rate in the placebo arm was comparable to that achieved in the ibrutinib arm, at 85% and 93%, respectively (HR, 0.435; 95% CI, 0.131-1.446).2 Moreover, the progression-free survival (PFS) rates continued to be high and durable in the placebo and ibrutinib arms, at 88% (95% CI, 74%-95%) and 95% (95% CI, 82%-99%), respectively.

[The data show] that you can have excellent, long-term PFS in a patient who stops a well-tolerated combination after 1 year. Eighty-eight percent of patients are still free of progression with 5 years of follow-up and 4 years off therapy,” Jacobs said. “In the future, I think this [can] be an exciting option for a patient who is interested in an easy, time-limited, oral combination [regimen] that’s [also] well tolerated. We’re excited to continue looking at how durable these remissions [are], and for patients who have recurrence years down the road, [to understand what] their responses to rechallenge of either agent look like.”

In an interview with OncLive^®, Jacobs, a hematologist and medical oncologist and director of the Lymphoma Clinic at Levine Cancer Institute of Atrium Health in Charlotte, North Carolina, highlighted the updated safety and efficacy results from the MRD cohort of the CAPTIVATE trial, discussed unanswered questions regarding MRD as a predictive vs prognostic tool in patients with CLL, and outlined areas that are ripe for further exploration.

OncLive^®: Could you provide background on the CAPTIVATE trial and the key objectives of the MRD cohort? What important questions did this research address?

Jacobs: CAPTIVATE was a very interesting, well-designed phase 2 study that had 2 parts. The first cohort was the MRD cohort. [Data from the MRD cohort] were presented by John N. Allen, MD, of Weill Cornell Medicine, [at the 2022 ASH Annual Meeting]. That cohort specifically looked at [164] patients that were treated with the combination of ibrutinib plus venetoclax. There was a 3-month lead-in with ibrutinib, [followed by] the combination given for 1 year. Previously reported safety results have shown that in this population of patients aged 70 years and younger, [the regimen was] very well tolerated, with very low discontinuation rates due to toxicity.

As we have [moved beyond] that 1-year mark, we have been interested in looking at how the patients do overall if you stop treatment. [More] specifically, how do the patients that obtain MRD negativity do? So, for the patients who seem to get the deepest response, can we stop treatment? [Can we] directly compare that patient group with a group that is getting ibrutinib at 420 mg daily until disease progression? [Ultimately,] the goal is to find a well-tolerated combination that we can give in a time-defined way and will not negatively impact patient outcomes. With more and more time we can answer that question.

What key 5-year follow-up data were presented at the 2022 ASH Annual Meeting?

About half of the initial [164] patients got to a point where they were MRD negative in both the blood and bone marrow. They were [then] randomly assigned to placebo or ibrutinib. [Notably] this was not [an] open-label trial.

[At] 4 years [post-]randomization, 95% of the patients who continued ibrutinib are still progression free, which is an excellent outcome. Of more interest, only 88% of [patients in the] placebo group have gotten to a point without any extra treatment and [have] not had disease progression. Although there is a numeric difference there, it is not yet statistically [significant].

[As such,] we’re getting [increasingly] reassured that these patients who get deep responses to the combination could safely discontinue treatment. That’s a big win for [patients with CLL]. We can reduce toxicity in that way. In fact, it was reported [that] no new, [significant] atrial fibrillation events have occurred post-randomization in these patients who have been able to stop ibrutinib. I bring up that 1 toxicity because it’s one that we talk about with ibrutinib. You’re potentially mitigating other toxicities that could occur as patients continue ibrutinib indefinitely. In addition, there is a lot of quality-of-life benefit of just not having to actively be on a cancer [regimen], and [we should] not overlook the financial toxicity that could really be significant [for these patients].

What are the next steps for this combination?

[This] is still an investigational combination, so it’s not FDA approved yet. This was a phase 2 study. A phase 3 trial [NCT03462719] that is looking at this combination compared [with] obinutuzumab [Gazyva] and chlorambucil in older patients [with CLL] showed an improvement in PFS. We will see if we will ultimately get FDA approval from that data. However, there are questions [pertaining to] how well the combination is tolerated in that older population; I think we need to further tease that [answer] out. [We do know that the regimen was well tolerated] in the younger patients on CAPTIVATE.

We are all interested in how [to] sequence these [effective] treatments that we have for CLL. We don’t know whether [administering] this combination up front [is better than] sequencing 1 drug after the other; it would take a long trial to [determine that answer]. I do think this would be a good option for patients who are interested in [time-defined] oral therapy as opposed to infusion, [which] involves trips to the infusion center, potential infusion reactions with monoclonal antibodies, etc. This combination looks to be a very effective and safe option, particularly in younger patients.

How does this trial help clarify the role of MRD in CLL? What questions still need to be addressed to understand its value in clinical practice?

[Clinical] trials have defined MRD as less than 10-4 or 1 in 10,000 [cancer cells detected with] either high-color flow cytometry or PCR and next-generation sequencing [NGS] [assays like] clonoSEQ. Some institutions have high-level flow [panel] that can detect MRD, but most oncologists don’t have access to in-house MRD testing, so they are sending it out for flow or for NGS/PCR-based testing. We have defined MRD as 10-4, and that is typically the level of information that you get from flow [cytometry], but clonoSEQ, for example, [can detect] sensitivity level down to 10-6.

Some have wondered whether we should look at outcomes at lower levels of detection, [and] move the bar down to 10-5. Some studies are starting to look at the rate at which patients are getting to that deeper level. Those questions remain unanswered, but for now, we are still defining MRD negativity as below 10-4. That is one area that [requires more clarification].

We still don’t know [whether] MRD negativity can [be used] as a predictive tool [and] not just [to] prognosticate. [For example], can we say that because [a patient is] MRD negative, we feel safe stopping the ibrutinib and venetoclax combination, for example, after 1 year as opposed to if [a patient is] MRD positive, where continuing therapy may make more sense?

[According to] prior chemoimmunotherapy data and venetoclax-based data, we can say that obtaining MRD negativity is a prognostic tool, and we can predict that those patients will stay in remission longer and have better outcomes. However, we still don’t have [data from] a trial that [supports] using MRD negativity as a predictive tool and make [treatment] decisions based on it.

I thought we were getting [to that point] until this meeting. [Then, we saw] data from the FLAIR trial [NCT02938520] and some other [trials showed that] a higher number of [patients with] unmutated IGHV are getting to uMRD than [those with] IGHV-mutated [disease]. [Consequently,] a [patient with] unmutated IGHV [is] actually more likely to obtain MRD negativity with the ibrutinib and venetoclax combination than [those harboring the] mutation. Despite that, as they followed these patients after discontinuation, [those with] unmutated [disease] are still having a shorter PFS. As such, we are now questioning whether MRD testing is an accurate way to predict response, because you would think that following the prior prognostic data that we have seen with this testing that those with uMRD and unmutated disease should have a longer PFS than those [with] mutated [disease] who had less MRD negativity.

Now we have more questions to answer. It’s going to be a long time before MRD [testing becomes] standard [for] general oncology practice. It’s certainly used more in high-volume academic centers and is a nice tool to assess response [in] clinical trials, but [the data presented at the meeting raise] more questions.

References

1. Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865. doi:10.1200/JCO.21.00807
2. Allan JN, Siddiqi T, Kipps T, et al: Treatment outcomes after undetectable MRD with first-line ibrutinib (Ibr) plus venetoclax (Ven): fixed duration treatment (placebo) versus continued Ibr with up to 5 years median follow-up in the CAPTIVATE study. Blood. 2022;140 (suppl 1):224-227. doi:10.1182/blood-2022-160338