New Data Shed Light on the Efficacy of BTK Inhibitors in the CLL Treatment Paradigm

Findings from the 30-month follow-up analysis of the phase 1/2 BRUIN study (NCT03740529) not only confirmed the clinical efficacy of pirtobrutinib (Jaypirca) in patients with chronic lymphocytic leukemia (CLL) following prior treatment with covalent BTK inhibitors but emphasized the potential for high response rates irrespective of prior BCL2 exposure.¹

However, a separate analysis showed a high prevalence of acquired non–BTK mutations, highlighting the ongoing challenges in understanding the full scope of mutations that may contribute to treatment resistance.²

“[The] most frequent mutations were gatekeeper in T474X and kinase impaired in L528W,so we need to continue to find ways to get around some of these obstacles,” David C. Fisher, MD, said in an interview with OncLive^®. “Again, 32% of patients did not have an obvious mutation found on [this] 74-gene panel, so there must be other [mutations] yet to be found.”

In the interview, Fisher, an assistant professor of medicine at Harvard Medical School and an institute physician at Dana-Farber Cancer Institute in Boston, Massachusetts, discussed the evolving role of BTK inhibitors in the CLL treatment paradigm.

OncLive: What were the findings from the 30-month follow-up analysis of the BRUIN study in patients with CLL/SLL who were treated post-BTK inhibitor therapy?

Fisher: Pirtobrutinib is a non-covalent BTK inhibitor, separate from [covalent] BTK inhibitors that’re more commonly used, that inhibits both wild-type and C481S mutated BTK, whereas the [C481S] mutation can get around scanning BTKs of the covalent subtype.

[The BRUIN study evaluated] patients who had C481S mutations vs those who did not. [The] overall response rates [ORRs] were similar in the 70% to 80% range. Patients with the unmutated PLCG2 subtype had an ORR of 80% vs 60% for those with PLCG2 mutations. IGHV status did not affect [responses], with ORRs of 84% and 81% in mutated and non-mutated groups, respectively. Similar outcomes [were observed] for [patients with] complex karyotype, deletion 11q, and deletion 17p.

Overall progression-free survival [PFS] did decrease with time, although the median PFS was about 18 months. [We saw somewhat of] a flattening of the curve around three years at 30%. Overall survival [OS] was very good, as patients still have other options, including BTK degraders and other treatments. The 3-year OS rate was about 70%, and at a median follow-up of 30 months, we saw about an 80% ORR, including in patients with BTK resistance with a C481S mutation. The median PFS [in patients who previously received covalent BTK inhibitors] was 19.4 months, 23 months in the BCL2 inhibitor–naive population, and 15.9 months in those that were exposed to BCL2 inhibitors. [The] drug was well tolerated, with low rates of discontinuation, and drug is approved in the third line after BTK and BCL2 inhibitor exposure.

What resistance mechanisms were observed during pirtobrutinib therapy in patients previously exposed to covalent BTK inhibitors as part of the BRUIN study?

Multiple other mutations become present [in patients who develop disease progression] such as TP53, NOTCH1, PLCG2, and BCL2 mutations.

In patients who did progress, BTK mutations were seen in 44%, non-BTK mutations were seen in 24%, and 32% had no mutations found, suggesting there are other mutations that we have not yet isolated that contribute to resistance non-covalent BTK inhibitors. Some of these [mutations] are present at the beginning of therapy in small amounts that aren’t seen with our standard mutational analysis and expand over time. In this group of patients, 68% had acquired mutations.

What other trials are seeking to combine BTK inhibitors with BCL2 inhibitors and/or monoclonal antibodies?

As part of the BRUIN phase 1b study patients were treated with pirtobrutinib and venetoclax [Venclexta] vs pirtobrutinib, venetoclax, and rituximab [Rituxan]. These were patients who had prior BTK exposure but had not had prior BCL2 exposure. The median time on study was about 25 months. [The] ORR was about 96%, with a 40% complete response [CR] rate. The PFS [rate] was about 80% in both groups.

There’s [another] ongoing study, BRUIN CLL-322 [NCT04965493],which is assessing extended pirtobrutinib, venetoclax, and rituximab vs venetoclax and rituximab, [which is a more standard regimen].

Where does sonrotoclax fit into the treatment paradigm?

[The phase 1 BGB-11417-101 study (NCT04277637)] presented at the 2024 EHA Congress [is assessing] zanubrutinib [Brukinsa] plus sonrotoclax [BGB-11417] in patients with relapsed/refractory CLL. Sonrotoclax is a new BCL2 inhibitor that has a stronger binder than venetoclax [and it’s being evaluated] to see whether it may be an additional BCL2 inhibitor or perhaps an improved one. The median time on the study at this point was 19.3 months, and the ORR was 97%, with a CR rate of 57%. The ongoing phase 3 study, CELESTIAL-TNCLL [NCT06073821], is looking at zanubrutinib and sonrotoclax vs venetoclax and obinutuzumab [Gazyva].

[Another] ongoing phase 3 study, SEQUOIA trial [NCT03336333], is looking at zanubrutinib and venetoclax. This is a study looking at combination therapy with a BTK inhibitor and BCL2 inhibitor in treatment-naive patients with CLL and deletion 17p. The ORR was very good, with a 46% CR rate, so excellent responses.

What is the role of BTK degraders like BGB-16673 in CLL?

The [BTK degrader] BGB-16673 [is being evaluated] for patients with relapsed and refractory CLL. These [agents] are initially being thought of [for] patients who are resistant to BTK and [BCL2] inhibitors, where we do have a lack of good options.

This agent is a bivalent molecule that has a BTK binding moiety, a linker and an E3 ligase binder that induces BTK degradation. In preclinical models this works in both wild-type and BTK-resistant subtypes. In the relapsed/refractory setting the ORR is 72%, 88% in the 200-mg group, which seems to be the dose that will be used moving forward. Disease control was seen somewhere in the range of 70% to 80%. Ongoing studies are looking at prolonged use of the drug and optimized dosing.

References

1. Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the phase 1/2 BRUIN study. Blood. 2023;142(suppl 1):325. doi:10.1182/blood-2023-185852
2. Brown JR, Desikan SP, Nguyen B, et al. Genomic evolution and resistance during pirtobrutinib therapy in covalent BTK-inhibitor (cBTKi) pre-treated chronic lymphocytic leukemia patients: updated analysis from the BRUIN study. Blood. 2023;142(suppl 1):326. doi:10.1182/blood-2023-180143