Long-Term Data for Up-Front Combinations Reaffirm Treatment Options in CLL

Long-term data from clinical trials presented at the 2023 ASH Annual Meeting added further insight to frontline treatment selections for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to Kathleen A. Dorritie, MD, who also noted that the growing list of options could complicate decision-making in the first line and beyond.

“If we use our most potent drugs up-front, will we have options later on for patients as they progress? That also remains a concern,” Dorritie said in an interview with OncLive^®.

In the interview, Dorritie expanded on long-term data from the phase 3 ELEVATE TN (NCT02475681) and FLAIR (ISRCTN01844152) trials, as well as the phase 2 CAPTIVATE study (NCT02910583). She also detailed unmet needs that need to be addressed in future studies for patients with CLL/SLL.

Dorritie is an assistant professor of medicine in the Division of Oncology at the University of Pittsburgh and a hematologist/medical oncologist at University of Pittsburgh Medical Center, Hillman Cancer Center, in Pennsylvania.

OncLive: Considering the 6-year follow-up data from ELEVATE TN, what did these findings show regarding acalabrutinib (Brukinsa) as monotherapy or in combination with obinutuzumab (Gazyva) in patients with treatment-naive CLL?

Dorritie: [ELEVATE TN] was a 1:1:1 randomized study comparing acalabrutinib [with or without] obinutuzumab vs chlorambucil plus obinutuzumab. We've seen a lot of data up to this point showing superiority of the acalabrutinib-containing arms. Importantly, progression-free survival [PFS] was better in both acalabrutinib-containing arms. [The median] PFS was not reached [for acalabrutinib monotherapy and acalabrutinib plus obinutuzumab]. PFS was a little bit better for acalabrutinib plus obinutuzumab vs acalabrutinib alone.¹

That being said, when we look at response rates, they do show that you can use acalabrutinib as a single agent, although you may see a little bit of a deeper response with acalabrutinib plus obinutuzumab, which we saw when we looked at minimal residual disease [MRD] negativity.

Where there any updates regarding the safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy with additional follow-up?

[For] the safety and tolerability of acalabrutinib alone and in combination with obinutuzumab, [data] confirmed what we'd seen in prior studies. There were no unexpected safety signals, which is also reassuring.

What was the importance of the 5-year follow-up data from CAPTIVATE evaluating fixed-duration ibrutinib (Imbruvica) plus venetoclax (Venclexta) in CLL/SLL?

[CAPTIVATE] was an interesting and enlightening study looking at ibrutinib and venetoclax in a fixed-duration format. At the time of the data reporting, [the 54-month PFS rate was 70% (95% CI, 62%-77%)]. Among the patients who had progressed, most progressed beyond the 2-year cutoff after [the fixed-duration] treatment had ended.2

A couple of things were reassuring [with longer-term follow-up]. In patients who went back on therapy, [22 patients] received single-agent ibrutinib, [and 6 patients reinitiated] ibrutinib and venetoclax in combination. At the time of data reporting, 86% of patients [who received single-agent ibrutinib] had responded, which is encouraging in that we may be able to do fixed-duration treatment and not expose patients to toxicity or put them at [higher] risk of developing resistance mutations, knowing that we could retreat them, and they can achieve an excellent response at that time as well.

[During the study], there were low rates of resistance mutations in general. In patients who had progressed, only 1 patient was found to have a BCL-2 mutation; however, no patients developed BTK or a PLCG2 mutations. This is reassuring because we know that patients who stay on BTK inhibitors for a longer period of time are at risk of developing those mutations.

Regarding FLAIR, what did the research reveal about MRD negativity rates when using ibrutinib in combination with venetoclax?

[FLAIR] was another encouraging study for the combination of ibrutinib and venetoclax. In this case, [the combination was] compared to fludarabine, cyclophosphamide, and rituximab [Rituxan; FCR]. This trial had a bit of a different design, as the highest-risk patients [harboring] TP53 mutations were excluded. The study had an adaptive design whereby patients could stop therapy at a certain time point after they achieved MRD negativity.³

There were higher rates of MRD negativity seen with the ibrutinib/venetoclax combination vs FCR. Notably, 90.6% of patients [in the ibrutinib plus venetoclax arm] did achieve MRD negativity in their peripheral blood, which is quite remarkable. And as expected, we saw [improved] overall response rates, PFS, and overall survival.

Interestingly, we saw high rates of PFS in patients [without] IGHV mutations. Those patients tend to do more poorly, but these data suggested that using this combination could put them on par with patients with standard-risk [disease].

What are some of the persisting unmet needs or unresolved questions in CLL that these studies may not have addressed?

One of the big questions we have in mind is: how do we choose an up-front treatment for a patient? We don't know, at this point, whether it's better to use a BTK inhibitor up-front in a fixed-duration manner [in combination] with a CD20 monoclonal antibody vs venetoclax plus a monoclonal antibody. That is a big question a lot of us have. Before these data, most of us were thinking of BTK inhibitors as a continuous therapy option, and so that made it an easier discussion with patients to say, 'Do you want to be on a BTK inhibitor for the long term? Or would you want to be on a potential treatment that's fixed in duration?’ Now that we have these data, it makes things even more complicated, because we have an option where we can combine these 2 targeted, oral agents [ibrutinib plus venetoclax] and get remarkable responses, then potentially be able to stop treatment and reinitiate treatment at the time of progression. That’s a big question.

There have been interesting studies [in later lines of treatment]. [In December 2023], the FDA approved pirtobrutinib [Jaypirca] for patients with CLL/SLL [who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor], based on data from the phase 1/2 BRUIN trial [NCT03740529].⁴

There were also several earlier-phase studies, including a phase 1 trial [NCT04277637] using a novel BCL-2 inhibitor sonrotoclax. Similarly, we had some studies in the relapsed/refractory setting looking at new BTK degraders, which have a whole different mechanism of action [vs BTK inhibitors].

References

1. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± Obinutuzumab Vs Obinutuzumab + Chlorambucil in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-up of Elevate-TN. Blood. 2023; 142(1):636. doi:10.1182/blood-2023-174750
2. 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
3. Munir T, Cairns DA, Bloor A, et al; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063
4. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 1, 2023. Accessed June 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic