BTK Degraders and Fixed-Duration Regimens May Represent the Future in CLL

Alexey Danilov, MD, PhD

Treatment with BTK degraders yielded high response rates in patients with chronic lymphocytic leukemia (CLL), and the novel class of therapies targeting BTK are exciting agents under development showing potential to be an effective option, according to Alexey Danilov, MD, PhD.¹

“What’s also important is that BTK degraders work regardless of the BTK mutation that’s present—they work in pirtobrutinib [Jaypirca]-resistant disease. This is a very important and effective emerging new class of agents,” Danilov said in an interview with OncLive®.

Data on the selective BTK degreader NX-5948, which received fast track designation from the FDA in 2024 for the treatment of adult patients with relapsed or refractory (CLL) or small lymphocytic lymphoma (SLL) after at least 2 lines of therapy including a BTK inhibitor and a BCL2 inhibitor, was presented at the 2024 European Hematology Association Congress (EHA).^1,2 Findings from a phase 1a/b trial (NCT05131022) revealed treatment with the agent elicited an objective response rate of 69.2% (95% CI, 48.2%-85.7%) in patients with CLL (n = 26).¹

Danilov noted that in addition to BTK degraders, he is also keeping an eye on the time-limited chemotherapy-free triplet regimen of ibrutinib (Imbruvica), venetoclax (Venclexta), and obinutuzumab (Gazyva) following data from a phase 2 trial (NCT02427451) that showed patients with CLL experienced durable remissions. Findings presented at EHA revealed that the median progression-free survival (PFS) was 81.8 months (95% CI, 57.3-not reached [NR]) for patients who received the triplet with relapsed/refractory disease (n = 25) and 88.5 months (95% CI, 80.6-NR) for patients who were treatment naive (n = 25). The median overall survival was NR in either cohort.³

In the interview with OncLive, Danilov shared insights on the evolution of treatment with BTK inhibitors and touched on the emerging class of BTK degraders. He also emphasized when he uses pirtobrutinib in the treatment of patients with CLL or mantle cell lymphoma (MCL) and highlighted unmet needs within the treatment space. Danilov is associate director of the Toni Stephenson Lymphoma Center, a hematologist-oncologist, and a professor in the Division of Lymphoma at City of Hope in Duarte, California.

OncLive: What is important to note about BTK as a target in NHL and CLL?

Danilov: BTK has been preclinically and clinically validated as a target in B-cell [NHL] for many years now. BTK inhibitors have changed the landscape for the treatment of [various] lymphomas and CLL, and we have 2 classes of drugs approved: covalent and noncovalent BTK inhibitors. The recent data on pirtobrutinib, a noncovalent BTK inhibitor that is approved for the treatment of CLL as well as the treatment of MCL, [in patients who are] refractory to multiple agents, looked very impressive with good safety [findings].

Furthermore, there is an emerging class of proteolysis-targeting chimeras, specifically BTK degraders, [for] which very promising data were recently presented at the 2024 EHA Congress in Madrid. Data on NX-5948, one of the novel BTK degraders, [showed the agent] worked well in patients with [BTK inhibitor]–resistant CLL.

What recent data updates on BTK degraders have stood out to you?

Data presented on BTK degraders [is intriguing]; [at EHA, data showed the agents BGB-16673 and NX-5948 elicited] very impressive response rates of approximately 70% in patients with BTK inhibitor–refractory CLL. The safety was also impressive, with BTK inhibitor–like adverse effects and very few high-grade toxicities [occurring]. These studies will both require longer follow-up to see what the duration of response is, but it’s already very important as promising [efficacy] data [have been seen], which have been life-changing for some of the patients who were treated in the studies.

Which patients would you be more likely to treat with the BTK inhibitor pirtobrutinib?

Pirtobrutinib was investigated in the phase 1/2 BRUIN trial [NCT03740529], which was a large trial that enrolled approximately 700 patients, the majority of whom had CLL or MCL. Pirtobrutinib showed high efficacy in [patients with] CLL who were refractory to covalent BTK inhibitors. A recent update demonstrated that PFS was better in patients who were not also exposed to venetoclax compared with patients who progressed on venetoclax.

The current approval of pirtobrutinib in CLL is for patients who have been exposed to covalent BTK inhibitors and BCL2 inhibitors. However, in real-life [practice], pirtobrutinib is also now used in patients who haven’t seen venetoclax; that is also appropriate. The drug is very safe, even though follow-up is fairly short, and most patients stay on the drug for an average of 2 years, [showing it is a] safe and well tolerated [option]. I have had several patients who have responded to pirtobrutinib treatment following progression on other BTK inhibitors.

Multiple ongoing trials [are] investigating pirtobrutinib in earlier lines of therapy. There were very few patients who were BTK inhibitor naive enrolled in the BRUIN study, [where] very good efficacy data was seen with long-term follow-up, but the number of patients was very small. Therefore, there will be continued investigations in this space.

What additional data have caught your eye in the CLL treatment landscape?

There were very interesting data with long-term follow-up of the chemotherapy-free triplet ibrutinib, venetoclax, and obinutuzumab from [a trial out of] The Ohio State University. It is a time-limited therapy where patients are treated for approximately a year with the triplet, and the long-term follow-up shows a median PFS of approximately 7 years. [Data] were very similar in both patients with treatment-naive and relapsed/refractory CLL. [This] is most likely the first study with a chemotherapy-free triplet approach with the combination of venetoclax and a BTK inhibitor [to] reach a median PFS; that is certainly very impressive.

We will want to see how these patients do with subsequent therapies when they are required. However, I suspect that time to treatment will be even longer than this median PFS of 7 years because patients with CLL don’t immediately need treatment once progression is documented. These novel doublet/triplet regimens have a future in CLL, and it’s very exciting to see many of them being investigated in large trials.

What unmet needs would you like to see addressed within this patient population moving forward?

Patients who have double-refractory disease or who are refractory to BTK inhibitors and BCL2 inhibitors are still [a population where there is] an unmet need. The only agent approved is pirtobrutinib, for which the median PFS is approximately 2 years, and it is a bit shorter for patients who have progressed on both BTK and BCL2 inhibitors.

[Additionally,] younger patients with CLL who are diagnosed at an early age and require therapy are committed to long-term therapy with BTK inhibitors; we need time-limited approaches that will be highly effective [for these patients]. There is also an unmet medical need [for patients who are] immunocompromised, [as immunodeficiency] is one of the main reasons why patients with CLL may die. [These patients] don’t respond to vaccines as well as healthy individuals and are more likely to develop complications of infections, including COVID-19.

Additionally, Richter transformation is still a [difficult disease to treat]—we have some new tools, such as chimeric antigen receptor T-cell therapies and bispecific antibodies, but they’re often not the [final] solution. Many patients are not eligible for allogeneic stem cell transplantation [ASCT] due to age, comorbidities, or inability to make it to ASCT [as a result] of lack of response to therapies.

[The last unmet need is for] patients with [del(17p)] mutations [as they] have less durable responses to current novel agents and don’t [achieve] efficacy with chemotherapy. Overall, there are still quite a few unmet medical needs in this space.

References

1. Linton K, Collins GP, Forconi F, et al. Latest results from an ongoing first-in-human phase 1a/b study of NX-5948, a selective bruton’s tyrosine kinase (BTK) degrader, in patients with relapsed/refractory CLL and other B-cell malignancies. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract: S155.
2. Rogers K, Huang Y, Bhat S, et al. 7-year update on a phase 2 trial of fixed-duration obinutuzumab, ibrutinib, and venetoclax for CLL. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S162.
3. Nurix Therapeutics receives U.S. FDA fast track designation for NX-5948 for the treatment of relapsed or refractory CLL and SLL. News release. Nurix Therapeutics. January 16, 2024. Accessed August 1, 2024. https://finance.yahoo.com/news/nurix-therapeutics-receives-u-fda-210100427.html