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4473 Initial Findings from a First-in-Human Phase 1a/b Trial of NX-5948, a Selective Bruton’s Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed/Refractory B Cell Malignancies

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster III
Hematology Disease Topics & Pathways:
Therapies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Emma Searle1*, Francesco Forconi2*, Kim Linton, MD, PhD3*, Alexey Danilov, MD4, Pam McKay5*, David Lewis, MBChB, PHD6*, Dima El-Sharkawi, MBBS, FRCPath, PhD7*, Mary Gleeson8*, John Riches9*, Sarah G. Injac10*, Ted Shih10*, Srinand Nandakumar10*, May Tan10*, Ganesh Cherala10*, Erin Meredith10* and Graham P. Collins, MBBS, DPhil11

1The Christie Hospital and Manchester Cancer Research Centre, Division of Cancer Sciences, Manchester, United Kingdom
2School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
3The Christie Hospital and Manchester Cancer Research Centre, Division of Cancer Sciences, Manchester, GBR
4Department of Hematology and HCT, City of Hope National Medical Center, La Canada Flintridge, CA
5Haematology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
6Derriford Hospital, Plymouth, United Kingdom
7The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
8Sarah Cannon Research Institute and Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
9Barts Cancer Institute, London, United Kingdom
10Nurix Therapeutics, Inc., San Francisco, CA
11Oxford University Hospitals, Oxford, United Kingdom

Introduction: Although BTK inhibitors (BTKi) are effective therapeutics in the treatment of B cell malignancies, emerging BTK resistance mutations in chronic lymphocytic leukemia (CLL), as well as potential growth-promoting kinase-independent scaffolding function of BTK, present a need for improved or new approaches. NX-5948 is a novel, orally administered small molecule that induces specific BTK protein degradation by the cereblon E3 ligase complex without degradation of other cereblon neo-substrates. Importantly, NX-5948 induces degradation of wild-type and mutant forms of BTK in B-cells [Noviski et al. 2023] at sub-nanomolar potencies and exhibits potent tumor growth inhibition in TMD8 xenograft models that contain either wild-type BTK or BTKi-resistant mutations [Robbins 2021]. Here we provide the first disclosure of preliminary safety and efficacy findings from a Phase 1a trial of NX-5948 in patients with relapsed/refractory B cell malignancies.

Methods: NX-5948-301 is a Phase 1, first-in-human, dose-escalation and cohort-expansion trial evaluating the safety, tolerability, and clinical activity of NX-5948 in relapsed/refractory CLL and various subtypes of non-Hodgkin’s lymphoma (NHL). Key eligibility criteria: ≥2 prior lines of therapy; measurable or other evaluable disease per indication-specific response criteria; Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1. Phase 1a (dose escalation) evaluates safety and tolerability of NX-5948 via a standard 3+3 dose escalation in patients with relapsed/refractory B cell malignancies. Approximately 110 patients (30 in Phase 1a, 80 in Phase 1b) may be enrolled and treated until confirmed disease progression or unacceptable toxicity. Endpoints include dose-limiting toxicities (DLTs); treatment-emergent adverse events (TEAEs); deaths; changes in safety parameters; objective response rate per disease-specific response criteria. Phase 1b (dose expansion) will include up to four expansion cohorts.

Results: As of June 9, 2023, 14 patients were enrolled in Phase 1a and received NX-5948 at 50 mg (n=7), 100 mg (n=4), or 200 mg (n=3) orally once daily. Median age was 65 (range 46–79) years; female/male ratio 28.6%/71.4%; white 92.9%; ECOG PS 0/1 21.4%/78.6%; primary diagnoses were CLL (n=4), diffuse large B cell lymphoma (DLBCL, n=4), mantle cell lymphoma (MCL, n=3), marginal zone lymphoma (MZL, n=2), and follicular lymphoma (FL, n=1). Median number of prior therapies was 4.5 (range 2–10), which included: for CLL – BTKi (n=4/4) and BCL2 inhibitor (n=3/4); for NHL – BTKi (n=5/10), bispecific antibody (n=3/10), and CAR-T (n=2/10). NX-5948 was well tolerated with no DLTs and no TEAEs resulting in drug discontinuation or dose reduction. In addition, there were no NX-5948-related grade ≥3 TEAEs or related serious adverse events. The most common TEAEs were purpura/contusion (57.1%, all below grade 3), nausea (35.7%), and thrombocytopenia (35.7%). No atrial fibrillation/flutter or hypertension was reported. Median duration of treatment was 2.8 (range 0.5–9.6) months with 9/14 patients remaining on treatment. Current data indicate that NX-5948 exhibits dose-dependent pharmacokinetics (PK) and a half-life of ~24 hours, supporting once daily dosing (Figure a). Rapid, robust and sustained BTK degradation was observed in all patients, regardless of absolute BTK starting level, tumor type, or NX-5948 dose (Figure b). Of three evaluable patients with CLL receiving the lowest dose of 50 mg, early signs of clinical activity were observed including one confirmed partial response (PR; at 8 and 16 weeks) and 2 patients with stable disease (SD; at 8 weeks). Further treatment responses will be reported at the time of presentation.

Summary/conclusion: Current findings in this heavily pre-treated population of patients with CLL and NHL are encouraging and indicate that NX-5948 is safe and well tolerated and has clinical activity, supporting continuation of its development in CLL and NHL. NX-5948 also exhibits dose-proportional PK, resulting in rapid, robust and sustained BTK degradation. Additional data with higher dose levels and longer treatment duration will be presented at the meeting.

Disclosures: Searle: Janssen: Honoraria, Other: Conference travel; Abbvie: Honoraria, Other: Conference travel; Sanofi: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Forconi: Abbvie: Honoraria, Other: Travel and accommodation, Speakers Bureau; Janssen-cilag: Honoraria, Other: Travel and accommodation, Speakers Bureau; beigene: Honoraria, Other: Travel and accommodation, Speakers Bureau; Astra-Zeneca: Honoraria, Speakers Bureau. Linton: Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hoffman-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Danilov: Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Research Funding; Nurix: Consultancy, Research Funding; MEI: Consultancy, Research Funding; Lilly Oncology: Consultancy, Research Funding; Merck: Consultancy; Cyclacel: Research Funding; Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Genentech: Consultancy; GenMab: Consultancy, Research Funding. McKay: Takeda: Consultancy, Other: Travel to scientific conferences; Roche: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel to scientific conferences; Incyte: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria, Other: Travel to scientific conferences; Celgene/BMS: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy. Lewis: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees. El-Sharkawi: Abbvie, ASTEX, AstraZeneca, BeiGene, Janssen, Kyowa Kiirin: Consultancy; Abbvie, AstraZeneca, BeiGene; Gilead, Janssen, Lily, Novartis, F. Hoffman-La Roche, Takeda: Honoraria; Royal Marsden NHS Foundation trust: Current Employment; Abbvie: Speakers Bureau. Gleeson: Incyte: Other: Speaker Fees. Riches: Janssen: Speakers Bureau. Injac: Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Shih: Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Nandakumar: Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Tan: Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Cherala: Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in private company, Ended employment in the past 24 months; BioMarin: Current equity holder in private company. Meredith: Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins: Daiichi Sankyo: Consultancy, Honoraria; BMS: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau.

OffLabel Disclosure: NX-5948 is a novel, orally administered, small molecule that induces specific BTK protein degradation by the cereblon E3 ligase complex, but not of other cereblon neo-substrates.

*signifies non-member of ASH