Fixed-Duration Approaches Provide Promising Survival Benefit for Select Patients With CLL

Data have suggested that the use of oral doublet and triplet combinations administered at a fixed duration can allow patients with relapsed/refractory chronic lymphocytic leukemia (CLL) to experience prolonged and sustained survival, durable remissions, and reduced toxicities compared with a continuous therapeutic approach; however, more research is needed to inform the proper utilization of this strategy in clinical practice, according to John N. Allan, MD.

In the phase 3 MURANO trial (NCT02005471), treatment with a 2-year fixed-duration of the BCL-2 inhibitor venetoclax (Venclexta) plus rituximab (Rituxan) provided sustained progression-free survival and overall survival benefit at the 7-year follow-up vs bendamustine (Bendeka) plus rituximab in patients with relapsed/refractory CLL.¹ Retreatment with the venetoclax doublet produced a best overall response rate of 72%. Moreover, 8 patients achieved undetectable minimal residual disease status, which was associated with prolonged PFS.

Additional updated data from the phase 3 CLL14 trial (NCT02242942) further demonstrate the potential advantages of fixed-duration BCL-2/BTK inhibitor regimens, with venetoclax plus obinutuzumab (Gazyva) maintaining a PFS benefit vs chlorambucil plus obinutuzumab in patients with previously untreated CLL. A total 53% of patients in the experimental cohort remained in remission after 6 years off therapy, and 65.2% had not required second-line treatment at data cutoff.²

Readouts from ongoing phase 3 trials are eagerly awaited, as they may serve to further elucidate which patients will benefit most from a fixed-duration approach, as well as the optimal duration of therapy and ideal combination partner, Allan adds.

“Oral [fixed-duration] doublet approaches are currently available throughout the world, [although they] are not an FDA-approved approach yet,” said Allan, who is an associate professor of clinical medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine in New York, New York. “These are options provide deep, durable remissions off of therapy. High-risk patients [could] greatly benefit from these approaches as we gain [a deeper] understanding of how to use them best.”

In an interview with OncLive^®, Allan reviewed key takeaways from his presentation at the 41st Annual CFS®, including current data detailing the activity of venetoclax-based, fixed-duration regimens in the frontline setting; the synergy and promising efficacy signals seen with BCL-2 and BTK inhibitor combinations in CLL; and ongoing research efforts exploring triplet regimens vs other continuous approaches in this space.

OncLive: Could you briefly describe the excitement surrounding fixed-duration doublet vs triplet approaches in CLL?

Allan: I spoke at the conference about fixed-duration approaches, particularly looking at doublet and triplet combination approaches with BTK inhibitors and BCL-2 inhibitors. The discussion was really around updates on understanding of the preclinical synergies that have been noted between these agents, and [how we have been] translating those preclinical findings to clinical findings through clinical trials. It was really touching on the expectations, where these drug combination approaches fit in the treatment [paradigm for] CLL and the outcomes data that have been reported to date.

How do long-term data from the phase 3 MURANO trial demonstrate the potential benefits of venetoclax plus rituximab in those with relapsed/refractory disease?

One of the original fixed-duration doublet approaches was venetoclax plus rituximab. That [strategy] was highlighted in the MURANO study, which looked at venetoclax and rituximab against bendamustine and rituximab in relapsed/refractory CLL. At the 2023 EHA Congress, [data from] the 7-year and final data analysis were reported, and showed a PFS benefit with venetoclax and rituximab. In fact, the OS benefit [derived] with venetoclax and rituximab [vs] bendamustine and rituximab was maintained. Of interest in the study update was that there were some retreatment data showing that responses can be attained, although [for] relapsed/refractory patients who have kind of short remissions, retreatment may not [result in] as deep and durable of a remission the second time around.

[Its] limited data; it’s not [reflective of] current patients and how we treat them now, and I’m not sure it translates to frontline treatment and retreatment strategies. However, it’s starting to [improve our] understanding on expectations [for responses to this combination] and [whether we] should retreat patients who have had short remissions. In those types of patients, we probably should be looking at other approaches like continuous therapy, BTK inhibitors, [or others], if they have not seen them [already].

What do long-term findings from the phase 3 CLL14 trial suggest about the benefits of venetoclax plus obinutuzumab in previously untreated patients with CLL?

In the frontline setting, the other study that is [evaluating] a fixed-duration approach is the CLL14 study of venetoclax plus obinutuzumab. This was updated with 6-year follow up and showed impressive results. With that said, we are now seeing a median PFS being met at a little over 6 years for all patients treated there. In comparison with continuous therapy approaches with ibrutinib, 8-years out from [the phase 3 RESONATE trial (NCT01578707)], the median PFS has not yet been met. Clearly there is a difference. Once we stop therapy, patients are likely to relapse sooner. We’ve never shown that effect on OS.

There are clear benefits of fixed-duration approaches and getting off of treatment; [these include] decreased toxicities, [less] financial toxicities, and ease of follow-up for patients. It’s a valuable approach. Patients have remarkable responses, and they can have very durable remissions. There are many patients who are going to go potentially 10 plus years without another prior line of therapy. We’re learning a lot from that study as [the data] continue to mature, [including] who we should treat, who has decreased responses, and maybe who we need to [approach] differently with oral combinations.

What does current research indicate about the synergy of BCL-2 and BTK inhibitor combinations in CLL?

Preclinical synergies have been noted between BCL-2 inhibitors and BTK inhibitors. When all of these preclinical studies were done, it clearly favored BTK/BCL-2 combinations. We are seeing the synergies that are now clinically relevant. We see deep remissions, and an ability to target multiple compartments of a patient’s disease state—whether it’s nodal, bone marrow, peripheral blood niches, etc. These combinations allow us to attack all these different compartments of the disease state. That is seemingly translating into deep remissions as well as [similar] responses to [those achieved with] antibody-based combinations. [This] obviously adds potential complications, logistics, and toxicities…and potentially even prolonged immunosuppression.

Which frontline triplet combinations are currently under investigation in CLL?

[Investigation of] triplet combination approaches against fixed-duration approaches, and oral doublet approaches against continuous therapy and other fixed-duration approaches, are being done currently. We haven’t had any high-level readouts of [these efforts]. The only readouts of doublet and triplet combinations that we’ve seen to date are from phase 2 studies [done] in small numbers of patients. We see great efficacy, tolerable toxicity, manageable safety, and a way to administer the drugs fully and with dose intensity. However, we really are waiting for these phase 3 studies that are accruing and/or [are] enrolled to report out [data]. That’s going to [help us look] at triplets vs oral doublets vs continuous therapy approaches.

It’s not just ibrutinib-based treatments [being evaluated; combination regimens include] zanubrutinib [Brukinsa], acalabrutinib [Calquence], and even reversible BTK inhibitors like pirtobrutinib [Jaypirca].I hope [these trials will help us better] identify the right patient for an oral doublet or triplet, fixed-duration approach, and the optimal duration of therapy. I hope to see [how] these regimens will be clinically relevant in the future.

References

1. Seymour JF, Kater AP, Harrup, et al. Final 7-year follow up and retreatment substudy analysis of MURANO: venetoclax-rituximab-treated patients with relapsed/refractory chronic lymphocytic leukemia. HemaSphere. 2023;7(3):e492813f. doi:10.1097/01.HS9.0000967716.49281.3f
2. Al-Sawaf O, Robrecht S, Zhang C, et al. Ventoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized CLL14 study. Hem Onc. 2023;41: 58-60.doi: 10.1002/hon.3163_25