BTK mutation

Finally, current limitations of, and future perspectives on, this research field are discussed. The new chemical labeling techniques offered by NASA/ArNASA chemistry and its derivatives create a valuable molecular toolbox for studying numerous biomolecules in living cells and even in vivo.

One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 co-mutations. While common BTK C481 mutations were observed with both treatments, patterns of mutation and co-mutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W, A428D) in this patient population.

P1/2, N=190, Active, not recruiting, ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. NCT02251548.

New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.

This is the first study to describe the genomic landscape of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib. Here we show that the gene mutational profile of these patients at baseline or at/after disease progression is comparable with patients with relapse/refractory disease who tolerate ibrutinib and, consistent with other studies, patients with mutations in TP53, SF3B1 or ATM genes had less favorable prognosis on BTKi. Further, intolerant patients who progressed on zanubrutinib acquired new BTK mutations and/or had an increase in the frequency of BTK mutations.

Previous treatments comprised chemo-immunotherapies (FC, FCR, BR, CHLR) in 12 cases and ibrutinib in 8 cases (range, 1-3). Richter transformation was present in 2 out of 18 treated patients at 2 and 10 months after the initiation of venetoclax and one patient had progressive disease. Our data show the feasibility of NGS-based MRD assessment in a prospective cohort of patients with CLL treated with venetoclaxbased therapies.

Pts received 1 or more cBTKi: ibrutinib (n=44, 90%), acalabrutinib (n=10, 20%) or zanubrutinib (n=1, 2%). Whether similar resistance patterns would manifest if pirtobrutinib was utilized prior to cBTKi treatment remains uncertain. Figure 1.

In this real-world cross-sectional study, BTK C481 mutations were observed in 21% of BTKi-experienced pts with CLL/SLL, all of whom had a cumulative exposure to BTKis of >36 mo. Because two-thirds of BTKi-experienced pts had <36 mo of BTKi exposure, the prevalence of BTK C481 mutations may be higher in populations with longer BTKi exposure. Further analyses of the natural history of BTK C481 mutations will help identify patients who are at risk of covalent BTKi resistance.

Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.