Retrospective Data Show Venetoclax-Based Approaches Improve Outcomes in CLL/SLL After Covalent BTK Inhibitor Intolerance

Catherine C. Coombs, MD

Findings from a retrospective, observational study showed that venetoclax (Venclexta)-based regimens improved responses and lowered the risk of progression or death compared with switching to a different BTK inhibitor in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) who were intolerant to a prior covalent BTK inhibitor.

Data presented at the 2023 International Workshop on CLL showed that in the real-world evaluation of 121 patients with BCL-2 inhibitor–naïve CLL/SLL who discontinued their first covalent BTK inhibitor–based regimen, 36.4% of patients (n = 44) switched to another covalent BTK inhibitor and 63.6% of patients (n = 77) changed to a venetoclax-based treatment.

Patients treated with venetoclax-based regimens experienced an overall response rate (ORR) of 83.5% vs 62.5% for patients who received a different covalent BTK inhibitor (unadjusted odds ratio [OR], 3.1; 95% CI, 1.0-9.1; adjusted OR, 4.6; 95% CI, 1.2-18.0). Patients in the venetoclax arm achieved a complete response (CR) rate of 52.7% and a partial response (PR) rate of 30.9%. The CR and PR rates were 25.0% and 37.5%, respectively, in the switched BTK inhibitor arm.

The 12- and 24-month progression-free survival (PFS) rates in the venetoclax arm were 87.3% (95% CI, 79.4%-96.0%) and 78.0% (95% CI, 67.3%-90.3%), respectively. For the switched BTK inhibitor arm, those rates were 79.1% (95% CI, 66.4%-94.3%) and 73.0% (95% CI, 57.7%-92.4%), respectively.

“[These retrospective data] add to the existing wealth of data supporting [the notion] that there are multiple effective strategies in the setting of intolerance to a covalent BTK inhibitor,” Catherine C. Coombs, MD, emphasized. “[We] have to individualize it based on the clinical scenario, the patient's preferences, their own comorbidities, and fitness level.”

In an interview with OncLive®, Coombs, an associate clinical professor at the University of California, Irvine (UCI), UCI School of Medicine, discussed a real-world investigation of switching to a BCL-2 inhibitor-based regimen vs another covalent BTK inhibitor in patients with CLL/SLL who were intolerant to a prior covalent BTK inhibitor and highlighted factors to consider when deciding between these 2 approaches for this patient population.

OncLive: Could you expand on the rationale for investigating real-world treatment approaches for patients with CLL/SLL who were intolerant to a covalent BTK inhibitor?

Coombs: The question that we asked was: what is the efficacy of certain classes of drugs for patients [with CLL] who discontinue a covalent BTK inhibitor for reasons other than progressive disease? This primarily encapsulates patients who had some type of intolerance event, though there were some other patients who discontinued due to other reasons, such as economic reasons or wanting a break from therapy. The 2 major classes of therapy [for patients who switched treatments] were different covalent BTK inhibitors or venetoclax-based approaches.

What was unique about the patient population gathered for this study?

[We collected] data from a number of different clinical sites that actively see patients with CLL on novel therapies. We, of course, recorded data from patients that fit the eligibility criteria of coming off a BTK inhibitor for reasons other than progression.

We had 121 [venetoclax-naïve] patients who met these eligibility criteria, and of these patients, 44 went on to a different covalent BTK inhibitor, whereas 77 went on to a venetoclax-based approach. As a non-prospective and nonrandomized trial, the groups inherently were going to be a bit imbalanced. However, we did find that the baseline clinical and biologic features were largely similar between the groups, with a couple exceptions. Patients who switched to a venetoclax-based approach were less likely to have an ECOG performance status 0, [meaning that] they were perhaps a bit less fit. [Patients who went on to received venetoclax] also had a slightly increased lactate dehydrogenase level compared with the covalent group, which I don't think had a major influence on the results. Otherwise, the groups were well balanced.

The reason for the imbalance in the performance status [could be attributed common practice patterns]. In my own practice—I contributed data for a number of my own patients to the retrospective study—I am nervous about switching [patients with worse ECOG performance statuses] from 1 covalent BTK inhibitor to another covalent inhibitor, since these patients could fall into a more unfit patient group. There are some episodes that happen on covalent BTK inhibitors, primarily cardiac adverse effects, that make me sometimes reluctant to switch within the BTK inhibitor class; I would prefer to switch to a different class. However, that is always up to the discretion of the individual doctor and patient discussion. This may be one explanation for that imbalance.

What were the key findings from this analysis?

What we found is that response rates are actually very good for both patients who switched from 1 covalent BTK inhibitor to another covalent BTK inhibitor, and patients who switched from a covalent BTK inhibitor to venetoclax. However, we did see a higher ORR for patients who switched to a venetoclax-based approach [83.5% vs 62.5%]. Keep in mind that this was a very heterogeneous group, therefore it was not just venetoclax as we use it in 2023 as a time-limited regimen. Rather, a number of these patients were using venetoclax as a continuous monotherapy. [This group featured] a mixture between venetoclax monotherapy, venetoclax plus rituximab [Rituxan], as per the as per the phase 3 MURANO trial [NCT02005471] schedule, and venetoclax/obinutuzumab [Gazyva], which many of us do if that's something that insurance will pay for, even in the relapsed setting. The response rates did favor venetoclax-based regimens, but they were still high for patients who switched to a different covalent BTK inhibitor.

We also explored PFS, which, unadjusted, trended toward favoring venetoclax-based approaches [HR, 0.6; 95% CI, 0.3-1.5]. On the adjusted analysis, PFS did favor the venetoclax-based approach [HR, 0.3; 95% CI, 0.1-0.8; P = .023]. Nonetheless, high efficacy [was observed] with both approaches. This is a fortunate aspect of being a CLL specialist: we have many therapies that can work. However, this does add to the evidence that venetoclax can work quite well following a covalent BTK inhibitor.

As we know, there are limited prospective data in this setting. The MURANO trial, which we [use to inform] our decision to treat most of our patients with venetoclax in the relapsed setting, primarily had a BTK inhibitor-naïve population. There was a phase 2 study [NCT02141282] that looked at venetoclax following ibrutinib, but these patients were extensively pretreated with a median of 4 prior lines of therapy.

Our group [in the retrospective study] was more of therapy-naïve group. Most patients [56.8% in the BTK inhibitor arm and 48.1% in the venetoclax arm] had 1 prior line of therapy. Some patients, of course, had 2 or 3 prior lines of therapy. Once again, these findings support the idea that venetoclax can work quite well following a covalent BTK inhibitor.

How did these results compare to what was expected or hypothesized when you first launched the study?

The results compared similarly to what we would have expected when conducting the study. I don't think anyone had any doubt that either option was an effective option. These are [treatments] that I've used for my own patients, and I have had success with both switching from a covalent BTK inhibitor to a different covalent BTK inhibitor in the setting of intolerance and switching from a covalent BTK inhibitor to venetoclax. [This retrospective study] provides more strength to [these strategies] by pooling a large number of patients from our institutions, and data support what I had already been doing in my own practice.

Looking to the future, how are you hoping that these findings will impact the treatment space of these patients?

Our findings help provide more evidence for our [current] practices that we've been doing with limited evidence. It's always good to get the real-world experience because our patients in the real-world are often not as fit as those who are eligible for trials. [These findings] show that not only is switching from one covalent BTK inhibitor to a different covalent BTK inhibitor is effective, but another highly effective option is switching to a venetoclax-based approach.

Reference

Eyre TA, Coombs CC, Lamanna N, et al. Switching from covalent BTKi to BCL2i is associated with improved clinical outcomes compared to switching to ad different covalent BTKi in patients with CLL/SLL treated in the real-world setting. Presented at: 2023 International Workshop on CLL; October 6-9, 2023; Boston, MA. Poster 1553702.