SGR-1505, a potent and selective MALT1 inhibitor with preliminary efficacy in BTKi exposed Waldenström macroglobulinemia (WM) and “double-exposed” CLL/SLL

Abstract Background: MALT1, a core subunit of the CBM complex (CARD11-BCL10-MALT1), plays an essential role in the NF-kB pathway activation downstream of BTK in the B-cell receptor signaling pathway, promoting growth and survival of B-cell malignancies. SGR-1505, a potent and selective MALT1 inhibitor, demonstrates monotherapy and combination activity in B-cell lymphoma models. Translation of single agent clinical activity has been demonstrated in patients with R/R B-cell malignancies, including WM with prior BTKi therapy and CLL/SLL with ≥2 prior lines of therapy (Spurgeon et al. EHA 2025). Initial safety and efficacy data are updated, and pathogenic gene mutations of interest from responding patients are described. Aim: To evaluate the activity of SGR-1505 in overcoming BTK resistance in B-cell malignancies as a single agent or in combination with a BCL-2 inhibitor or BTK degrader preclinically. To characterize the mutational profile and clinical response to SGR-1505 treatment in patients with B-cell malignancies who have relapsed or become refractory to BTKi treatment or who have been double-exposed to BTKi and BCL2i. Methods: SGR-1505 anti-proliferative activity alone or in combination with venetoclax or BTK degrader NX-2127 were evaluated in BTKi-resistant cell lines in vitro and in vivo. OCI-LY3 cell line, a cell line derived from ABC-DLBCL, is primarily resistant to BTKi due to its CARD11 L251P mutation. Cell lines with acquired resistance to BTKi were generated by continuous passage with BTK inhibitors or by introducing BTK C481S or BTK L528W through CRISPR-Cas9 gene editing. Monotherapy clinical activity of SGR-1505 is being evaluated in a phase-1 dose-escalation study in patients with relapsed or refractory B-cell malignancies (NCT05544019). Samples for biomarker analysis were collected at baseline and at scheduled visits. Mutational status of BTK, BCL2 and other genes of interest were taken from medical history, profiled in ctDNA or in biopsies when available. Results: SGR-1505 blocked the caspase mediated cleavage of NF-kB regulators, activation of the downstream NF-kB pathway, and inhibited LY3 cell growth in vitro and in vivo. In B-cell lymphoma lines with acquired BTKi resistance, SGR-1505 exhibited comparable IC50 values as compared to the parental cell lines, and combining SGR-1505 with venetoclax or NX-2127 enhanced growth inhibition. As of 13 May 2025, a total of 49 patients had been treated in study SGR-1505-101, including 6 WM relapsing or refractory to BTKi and 6 CLL/SLL who were double-exposed to prior BTKi and BCL2i. In the 6 WM subjects, median prior lines of therapy was 2 (range: 2-6) and all received prior BTKi as their last line of therapy and were refractory or relapsed due to development of BTK resistance mutations or bypass mechanisms. Four of the 6 had documented MYD88 mutations, and 1 also carried a CXCR4 mutation. SGR-1505 induced rapid IgM decreases. All 6 WM patients have had objective responses (3 minor responses, 3 partial responses, including 1 PR deepening from prior MR and one additional PR following the 13 May 2025 cut-off-date). In the six “double-exposed” CLL/SLL patients, the median prior lines of therapy was 4 (range: 2-7). Two achieved objective partial response (PR or PR-L), including a patient who received 7 lines of prior therapy and carried BCL2 resistance mutation D103Y. During dose escalation, SGR-1505 has also demonstrated activity in other B-cell malignancies, including a complete response in a subject with ABC-DLBCL (deepening from prior PR, confirmed after the data cut), a PR in a subject with MZL who had previously received BTKi, and a PR in a CLL/SLL subject who relapsed following prior chemotherapy. Mutational profiling of BTKi and BCL2 resistance mutations and other genes of interest in SGR-1505 responders is ongoing. Conclusion: Preclinically, SGR-1505 demonstrated the ability to overcome BTKi resistance in multiple in vitro and in vivo models. Clinically, SGR-1505 demonstrated encouraging anti-tumor activity in prior BTKi exposed WM, BTKi/BCL2i double-exposed CLL/SLL and other B-cell malignancies. MALT1 inhibition represents a promising novel therapeutic option with broad activity across multiple tumor types and the potential to overcome BTK and BCL2 resistance.