BTK degraders: emerging activity in various B-cell malignancies

The new class of BTK degraders is being developed in response to emerging patterns of resistance that limit the utility of BTK and BCL2 inhibitors. On one hand, BTK mutations decrease the efficacy of both covalent and non-covalent BTK inhibitors; on the other hand, some mutations lead to “kinase dead” or “kinase bypassing” BTK mutants with intact B-cell receptor signaling through a scaffolding function of BTK [1, 2].

This raises the need for a new treatment modality that targets both emerging resistance mutations and the BTK scaffolding activity. These two mechanisms are potentially addressed by BTK degraders such as NX-5948, which is a chimeric targeting molecule that works by catalyzing ubiquitylation and proteasomal degradation of BTK [3].

Responses to NX-5948 despite poor-prognosis mutations

NX-5948 is being evaluated in an ongoing phase IA/IB trial conducted in adults with relapsed/refractory B-cell malignancies. At EHA 2024, Linton et al. presented the latest results for 31 patients with chronic lymphocytic leukemia (CLL) and 48 patients with mantle cell lymphoma, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma, primary CNS lymphoma, and Waldenström macroglobulinemia (WM) [4]. All of them had relapsed/refractory disease and were pretreated with ≥ 2 lines of therapy (≥ 1 for CNS lymphoma). The average age in the total population was 67.0 years. A median of 4.0 prior lines had been administered before study entry, with BTK and BCL2 inhibitors having been used in 74.7 % and 44.3 %, respectively. Forty-three percent of patients had received both drug classes. Almost 50 % of the CLL cohort were carriers of TP53 mutations, and 43.3 % showed BTK mutations. These alterations indicate a hard-to-treat and genetically diverse population.

According to the safety analysis across the CLL and non-Hodgkin lymphoma (NHL) groups, NX-5948 was well tolerated in this elderly and heavily pretreated patient group. Common treatment-emergent adverse events (TEAEs) included purpura/contusion (35.4 %), thrombocytopenia (26.6 %), neutropenia (20.3 %), fatigue (17.7 %), anemia (16.5 %), petechiae (16.5 %), rash (16.5 %), and headache (15.2 %). Neutropenia constituted the most frequent grade 3 TEAE (15.2 %). One dose-limiting toxicity occurred, and two TEAEs resulted in drug discontinuation in the NHL cohort. No additional safety signals were observed at higher doses. In particular, the treatment did not give rise to cardiac TEAEs.

The efficacy findings reported at EHA focused on the CLL cohort. In response-evaluable patients (n = 26), NX-5948 induced a high ORR of 69.2 %, with all of the responses being partial remissions (PR) and PR with lymphocytosis. Responses occurred across the entire dose range; they were already evident at the time of the first scan after 8 weeks in most responders and were ongoing in all of them at data cut-off. No significant pattern of response was observed in patients with treatment-resistance and poor-prognosis mutations, which implies that the poor prognosis associated with these mutations may be overcome by the treatment. The analysis revealed no distinct genotypic profile linked to intrinsic NX-5948 resistance. In 30 individuals with CLL, NX-5948 caused rapid and robust degradation of wild-type and mutant BTK (­Figure).

These results support the continued development of NX-5948 in the setting of CLL, where phase IB dose expansion is planned. The dose escalation part of the study is still ongoing. According to the authors, BTK degraders have the potential to replace BTK inhibitors, particularly in patients with many mutations.

Figure: Rapid and robust degradation of wild-type and mutant BTK with NX-5948

Figure: Rapid and robust degradation of wild-type and mutant BTK with NX-5948

Promising efficacy of BGB-16673

The chimeric degradation activating compound BGB-16673 has been designed to induce BTK degradation via polyubiquitination [5]. In the first-in-human phase I/II CaDAnCe-101 study, BGB-16673 is being assessed in adults with relapsed/refractory B-cell malignancies after ≥ 2 prior therapies including covalent BTK inhibition, if approved for the respective disease. Preliminary data have shown a tolerable safety profile of BGB-16673 and clinical responses even in the presence of resistance to covalent and non-covalent BTK inhibitor therapy, along with substantial reductions in BTK protein levels in peripheral blood and tumor tissue [6]. Parrondo et al. presented updated safety and efficacy results for patients with relapsed/refractory CLL and small lymphocytic lymphoma (SLL) [7]. Forty-nine individuals were included in the analysis with a median follow-up of 4.6 months. They had received a median of 4 prior lines of treatment, with 89 % having discontinued BTK inhibitor treatment due to disease progression. Many showed high-risk features such as unmutated IGHV status (82 %), del(17p) or TP53 mutation (60 %), or complex karyotype (47 %). BGB-16673 is being tested within a dose range from 50 mg to 500 mg/d.

Among any-grade AEs, the most common were fatigue (33 %), contusion (29 %), anemia (22 %), diarrhea (22 %) and neutropenia/decreased neutrophil count (22 %). Grade ≥ 3 neutropenia occurred in 20 %. The maximum tolerated dose had not been reached at the time of the analysis. One dose-limiting toxicity was noted at the 200 mg dose, which was grade 3 maculopapular rash that resolved after a 5-day dose hold and did not reappear on resumed treatment. To date, no cases of atrial fibrillation or grade ≥ 3 hypertension have been observed, and no treatment-related fatal AEs were reported. Dose interruptions and reductions were called for in 37 % and 6 %, respectively.

BGB-16673 demonstrated promising anti-tumor activity, including in patients with covalent and non-covalent BTK-inhibitor–resistant mutations and those previously exposed to BCL2 and BTK inhibitors. Overall, 72 % of 43 response-evaluable patients responded (Table). The ORR for the 200 mg group was 88 %, with two individuals obtaining complete remission. After data cut-off, an additional patient in the 200 mg dose cohort experienced deepening of response from stable disease to PR, which increased the ORR in this cohort to 94 %. Also, in patients after prior covalent BTK and BCL2 inhibitor treatment, the ORR was as high as 70 %; patients with del(17p) or TP53 mutation responded in 68 % and those with complex karyotype in 67 %. Responses were observed irrespective of the presence of PLCG2 mutations and C481S, T474I and/or L528S BTK mutations. A phase II cohort of patients with CLL/SLL exposed to both covalent BTK and BCL2 inhibition is currently enrolling.

Table CaDAnCe-101 study: responses achieved with BGB-16673 in CLL patients

Findings for BGB-16673 in indolent NHL

Another analysis from the CaDAnCe-101 study reported at EHA 2024 relates to updated findings in the setting of FL, MZL and WM [8]. Twenty-five patients included in the data set were treated with BGB-16673 100 mg, 200 mg, or 350 mg/d. Sixty-four percent of them remained on treatment at a median follow-up of 5.85 months. They were heavily pretreated, with a median of 4 prior lines of therapy.

BGB-16673 appeared to be safe and tolerable, with no dose-limiting toxicities seen to date. The most common TEAEs across dose groups were contusion (32 %) followed by fatigue, neutropenia/decreased neutrophil count, asymptomatic transient elevation of amylase levels, and upper respiratory tract infection (each 24 %). Grade ≥ 3 TEAEs mainly included neutropenia/decreased neutrophil count (20 %) and anemia (8 %). None of the BGB-16673–related TEAEs led to death or treatment discontinuation. The ORRs were 57 % in patients with FL, 60 % in those with MZL, and 92 % in the group with WM. Disease control resulted in 86 %, 80 % and 100 %, respectively. All patients with WM showed numerical reductions in IgM levels from baseline. Ongoing anti-tumor activity with a short time to response was noted, which also applied to patients who had BTK-inhibitor–resistant disease.

Overall, these data support further investigation of the clinical activity of BGB-16673 in patients with NHL. Dose finding and additional safety expansion are ongoing, and enrollment is continuing in the CaDAnCe-101 study.

REFERENCES

  1. Noviski et al., XX International Workshop on CLL, October 6-9 2023, Boston, USA, poster 2020
  2. Montoya S et al., Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science 2024; 383(6682): eadi5798
  3. Robbins DW et al., Nx-5948, a selective degrader of BTK with activity in preclinical models of hematologic and brain malignancies. Blood 2021; 138(Supplement 1): 2251
  4. Linton K et al., Latest results from an ongoing first-in-human phase 1a/b study of NX-5948, a selective Bruton’s tyrosine kinase degrader, in patients with relapsed/refractory CLL and other B-cell malignancies. EHA 2024, abstract S155
  5. Feng X et al., Bruton tyrosine kinase protein degrader BGB-16673 is less apt to cause, and able to overcome variable BTK resistance mutations compared to other BTK inhibitors. EHA 2023, abstract P1239
  6. Seymour JF et al., First results from a phase 1, first-in-human study of the Bruton’s tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory B-cell malignancies. Blood 2023; 142 (Supplement 1): 4401
  7. Parrondo RD et al., Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory CLL/SLL: Results from the phase 1 BGB-16673-101 study. EHA 2024, abstract S157
  8. Cheah CY et al., Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory indolent NHL: Results from the phase 1 BGB-16673-101 study. EHA 2024, abstract P1119

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