Proof of concept of NX‐2127, a first‐in‐class Bruton's Tyrosine Kinase (BTK) dual‐targeted protein degrader with immunomodulatory activity, in patients with DLBCL

Introduction: Despite advances in cell- and immune-based therapies, relapsed diffuse large B cell lymphoma (DLBCL) remains a high unmet medical need. Preclinical data suggest that drugs modulating E3 ligases may synergize with BTK inhibition in certain subtypes of DLBCL [Yang et al. 2012]. Combination therapy with ibrutinib, lenalidomide and rituximab demonstrated clinical activity in recurrent DLBCL [Goy et al. 2019], and ibrutinib + lenalidomide + R-CHOP was effective in de novo DLBCL [Westin et al. 2023]. BTK degradation may further potentiate anti-tumor activity by modulating protein non-kinase function (e.g., scaffolding). NX-2127 is an oral, first-in-class, dual-function small molecule degrader that combines the activity of a targeted BTK degrader with the immunomodulatory activity of an Ikaros and Aiolos degrader. Preliminary safety of NX-2127 in all patients and efficacy in patients with chronic lymphocytic leukemia (CLL) have been presented [Mato et al. 2022]. Here we report overall safety and initial findings of activity in patients with non-germinal center B cell (non-GCB) DLBCL. Methods: NX-2127-001 (NCT04830137) is a first-in-human, multicenter, US-based, open-label, phase 1 dose-escalation (phase 1a) and cohort-expansion (phase 1b) trial, evaluating the safety, tolerability, and preliminary efficacy of NX-2127 in adults with relapsed/refractory B cell malignancies, including CLL, DLBCL, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom’s macroglobulinemia. NX-2127 is administered orally once daily in 28-day cycles starting at 100 mg. Results: As of 21 September 2022, 36 patients have been enrolled at 100, 200 and 300 mg dose levels. Patients were predominantly male (63.9%) with a median age of 75 (range 50–92) years and a median of 4 (range 2–11) prior lines of therapy. The most common all-grade adverse events were fatigue (52.8%), neutropenia (38.9%), and contusion (27.8%). Adverse events resulting in treatment discontinuation included: atrial fibrillation (n = 3), cognitive disorder (n = 2), anemia (n = 1), confusional state (n = 1), fatigue (n = 1), pain in extremity (n = 1), and ventricular tachycardia (n = 1). NX-2127 led to robust BTK degradation of >80% across dose levels and degradation of cereblon neosubstrates. Two patients with non-GCB DLBCL were enrolled: one patient experienced stable disease followed by progressive disease at the 100 mg dose; a second patient with four prior lines of therapy experienced complete response at the 300 mg dose at the time of first response assessment (week 8), which was maintained at week 16. Conclusions: In this first-in-human, first-in-class study of a BTK degrader, NX-2127 was well tolerated and showed promising activity in a patient with non-GCB DLBCL. These data support further clinical development of NX-2127 in B cell lymphoid malignancies including DLBCL. The research was funded by: Nurix Therapeutics, Inc. Keyword: Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. A. Danilov Consultant or advisory role: Abbvie, AstraZeneca, Bayer Oncology, BeiGene, Bristol Myers Squibb, Genentech, Incyte, Lilly Oncology, Morphposys, Nurix, Oncovalent, Pharmacyclics and TG Therapeutics Research funding: Abbvie, AstraZeneca, Bayer Oncology, Bristol Myers Squibb, Cyclacel, Lilly Oncology, MEI Pharma, Nurix and Takeda Oncology K. Patel Consultant or advisory role: ADC Therapeutics, Abbvie, AstraZeneca, Caribou, Epizyme, Fate Therapeutics, Genentech, Lilly, MEI, Merck, Morphosys Pharmacyclics/Janssen, Xencor Research funding: (Institutional) - Abbvie, AstraZeneca, CRISPR, Curis Epizyme, Fate Therapeutics, Genentech/Roche, Lilly, MEI, Merck, Nurix Therapeutics, Pharmacyclics/Janssen, Xencor M. Wang Consultant or advisory role: AbbVie, Acerta Pharma, ADC Therapeutics America, Amphista Therapeutics Limited, AstraZeneca, Be Biopharma, BeiGene, BioInvent, Deciphera, DTRM Biopharma (Cayman) Limited, Genentech, InnoCare, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Lilly, Merck, Miltenyi Biomedicine, Milken Institute, Oncternal, Parexel, Pepromene Bio, Pharmacyclics, VelosBi Honoraria: AbbVie, Acerta Pharma, AstraZeneca, Bantam Pharmaceutical, BeiGene, BioInvent, Bristol Myers Squibb, CAhon, Dava Oncology, Eastern Virginia Medical School, Genmab, i3Health, IDEOlogy Health, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Medscape, Meeting Minds Experts, MD Education, MJH Life Sciences, Merck, Moffit Cancer Center, Nurix Therapeutics, Oncology Specialty Group, OncLive, Pharmacyclics, Physicians Education Resources (PER), Practice Point Communications (PPC), Scripps, Studio ER Congressi, WebMD Research funding: Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio, Vincerx C. Sun Research funding: Genmab P. O’Connor Employment or leadership position: Nurix Therapeutics, Inc. Stock ownership: Nurix Therapeutics, Inc. A. Schwab Employment or leadership position: Nurix Therapeutics, Inc. Stock ownership: Nurix Therapeutics, Inc. M. Tan Employment or leadership position: Nurix Therapeutics, Inc. Stock ownership: Nurix Therapeutics, Inc. A. Wiestner Honoraria: Elsevier Research funding: Nurix Therapeutics, Pharmacyclics/Abbvie, Acerta,/Astra Zeneca Merck, Genmab