Venetoclax Plus BTK Inhibitor–Based Combinations Represent Promising Avenue in CLL/SLL

Supriya Gupta, MD

Venetoclax- (Venclexta) and BTK inhibitor-based combination therapies are a part of the next wave of exciting therapies under investigation in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to Supriya Gupta, MD. Notable advancements in the field also include the addition of lisocabtagene maraleucel (liso-cel; Breyanzi) to the paradigm in 2024 for patients with relapsed/refractory disease as the first and only approved FDA-approved CAR T-cell therapy in this patient population.¹

“The triplet combination of pirtobrutinib [Jaypirca] along with venetoclax and rituximab [(Rituxan) is promising] in the market,” Gupta said in an interview with OncLive®.

Triplet therapies are looking to expand upon the efficacy seen with doublets and monotherapies as the NCCN Clinical Practice Guidelines in Oncology for CLL/SLL currently include venetoclax plus obinutuzumab (Gazyva) and the covalent BTK inhibitor options of acalabrutinib (Calquence) with or without obinutuzumab and zanubrutinib (Brukinsa) as category 1 preferred first-line therapy regimens.²

In the interview, Gupta detailed the pros and cons of various BTK inhibitors, the advantages of venetoclax vs BTK inhibitors, and how CAR T-cell therapy has pushed the CLL field forward. Gupta is a hematologist/oncologist and assistant professor of medicine, hematology, oncology and transplantation at the University of Minnesota Medical School in Minneapolis.

OncLive: What are important considerations when selecting treatments for patients with CLL/SLL?

Gupta: The era of chemotherapy was until the early 2000s; [since then we’ve had] BTK inhibitors, PI3K inhibitors, [and] BCL2 inhibitors, and, more recently, CAR T-cell therapy became available. There have been a lot of advancements in the past few years in terms of targeted therapies that the FDA has approved, so [we’re going] away from chemotherapy, and that plays into the considerations when we’re selecting treatment as well.

Now, the preferred regimens in the frontline setting are usually either covalent BTK inhibitors [with or without obinutuzumab or] a fixed-dose regimen which includes venetoclax and an anti-CD20 antibody. One study that I want to highlight is the phase 1/2 BRUIN study [NCT03740529], which showed the first evidence of activity with pirtobrutinib in CLL; [findings from] it demonstrated promising efficacy and safety in patients with relapsed/refractory CLL who were heavily pretreated, including having received a covalent BTK inhibitor. Thirty-month follow-up [data] that were presented at the [2023] ASH Annual Meeting showed very durable responses with a favorable toxicity profile—[we didn’t] commonly see the toxicities that you would normally see with first generation covalent BTK inhibitors.

How are you selecting between covalent BTK inhibitors for patients?

Ibrutinib [Imbruvica] was the first generation irreversible covalent BTK inhibitor that was approved [by the FDA], and when compared with chlorambucil it demonstrated improved progression-free survival [PFS]. [Further, in] combination with rituximab against fludarabine, cyclophosphamide and rituximab it demonstrated superior PFS and overall survival [OS]. The challenges with ibrutinib are [that] because of the less selective BTK inhibition and the off-target effects and EGFR inhibition, it results in toxicities, [such as] bleeding [and] hypertension. In contrast, the second generation BTK inhibitors like acalabrutinib and zanubrutinib [have less] toxicities because they’re more selective BTK inhibitors. My preference in selecting between the covalent BTK inhibitors [is to reach] for the second generation [agents], either acalabrutinib or zanubrutinib. Acalabrutinib is approved as a monotherapy or as a doublet in combination with obinutuzumab, and zanubrutinib is approved as a monotherapy [in CLL].

What is important to note about pirtobrutinib use following covalent BTK inhibitor use?

Covalent BTK inhibitors bind to the ATP binding side of the BTK and then they inhibit the tyrosine kinase signaling pathway. Patients with CLL who experience disease progression after covalent BTK inhibitor [treatment] tend to have poor outcomes. [Therefore], a new therapeutic modality, using a noncovalent BTK inhibitor, was looked at. Since pirtobrutinib is a highly selective, reversible, noncovalent BTK inhibitor, and it has the ability to overcome this acquired resistance which is at the C481 site of the kinase binding domain, it has the ability to overcome this resistance that covalent BTK inhibitors would experience.

Does venetoclax offer an advantage over BTK inhibitors?

Yes, absolutely. Venetoclax [yields] a high response rate and deep remission, along with prolonged PFS, including for high-risk subgroups and [patients with] MRD-negativity. The other advantage of venetoclax over a BTK inhibitor is it’s a time-limited treatment which a lot of patients prefer. Younger patients who have the potential to be on [treatment] for a very long time may have cumulative toxicity from BTK inhibitors. [Therefore], a venetoclax-based, fixed-duration regimen may be preferred in those patients. Although, there has been complementary activity between the venetoclax and BTK inhibitor combinations, BTK inhibitors are more effective at shrinking nodal disease and BCL2 inhibitors are more effective in clearing bone marrow and peripheral blood lymphocytes. A combination of these two is also being used frequently by physicians.

What combination therapies are most important to keep an eye on that are under investigation?

The triplet of pirtobrutinib combined with venetoclax and rituximab is certainly something that was looked at, and the data are quite promising. The study was presented at the 2023 ASH Annual Meeting and looked at the safety and efficacy of fixed-duration pirtobrutinib in combination with venetoclax and rituximab. The study had a small number of patients [enrolled], but the overall response rate [ORR] was approximately 93% for the doublet looking at pirtobrutinib plus venetoclax and 100% for the triplet. A promising PFS [was observed] as well for both [arms] with a tolerable toxicity profile. This potentially could be something that we’ll be seeing down the road.

What other therapies are changing the treatment landscape of CLL/SLL?

Liso-cel is [one of] the most recently approved drugs for CLL. The phase 1/2 TRANSCEND CLL 004 study [NCT03331198] was the first to report the efficacy of CAR T-cell therapy in patients with relapsed/refractory CLL after progression on BTK inhibitors and venetoclax. These patients had received prior BTK and BCL2 inhibitors, [and] there was a good number of patients who had del(17p) and TP53 [mutations], which is a high-risk subgroup of patients. The complete response [rate] was quite high at [20%] and the ORR was [45%]; 63% of patients had undetectable minimal residual disease in the peripheral blood and 59% in the marrow. Responses were pretty good even in the high-risk patient population. [At a median follow-up of 24 months], the median PFS was 11.9 months and median OS was 30.3 months.

The safety profile was quite tolerable [as well and] the [incidence of] grade 3 cytokine release was less than 10%. It’s a very effective and tolerable drug in a heavily pretreated population.

References

1. U.S. FDA approves Bristol Myers Squibb’s Breyanzi ® as the first and only CAR T cell therapy for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. March 14, 2024. Accessed January 9, 2025. https://news.bms.com/news/details/2024/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Breyanzi--as-the-First-and-Only-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx
2. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2025. Accessed January 8, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf