Objective response rate of 83% with two complete responses and a median progression-free survival of 22.1 months were reported in Phase 1a for bexobrutideg (NX-5948) across doses in relapsed/refractory CLL/SLL. Median duration of response reached 20.1 months. In a randomized Phase 1b cohort, the 600 mg dose produced an 83.3% ORR versus 73.7% at 200 mg, with early PFS curves favoring 600 mg. Safety remained consistent across doses with no dose-limiting toxicities, no Grade 4 infections, and the most common events being purpura/contusion, neutropenia, and petechiae.
The news: Nurix presented updated Phase 1a/1b data at ASH and confirmed 600 mg once-daily as the recommended Phase 2 dose, now being advanced in a global, single‑arm pivotal Phase 2 trial (DAYBreak‑CLL‑201) for relapsed/refractory CLL. The dataset spans 126 treated patients, with Phase 1a efficacy based on 47 evaluable patients and a randomized Phase 1b dose-optimization cohort of 42 patients conducted under FDA’s Project Optimus framework. The program enrolled a heavily pretreated population, including prior covalent and non-covalent BTK inhibitor exposure and a high prevalence of TP53 and BTK pathway resistance mutations.
Strategically, this is a bid for accelerated approval in a post‑BTK/post‑BCL‑2 setting where options remain constrained and durability is the differentiator. Nurix is leaning into two regulatory priorities at once: a degrader mechanism designed to address kinase-dead and non‑C481 BTK mutations that blunt both covalent and non‑covalent inhibitor activity, and Optimus‑aligned randomized dose selection that de‑risks the RP2D choice prior to pivotal work. The clean safety signal and absence of dose-limiting toxicities create room to push the 600 mg dose, which early randomized data suggest may confer a PFS edge. The brain‑penetrant profile could also extend relevance to the small subset with CNS involvement, although CNS efficacy was not detailed here.
For trial operators, the single‑arm pivotal design lowers operational complexity but intensifies the enrollment challenge in a crowded third‑line CLL landscape now populated by non‑covalent BTK inhibitors, emerging cell therapies, and combination studies. The eligibility breadth—responses across BTK‑resistant genotypes and TP53‑mutated disease—may help sites recruit without extensive biomarker gating. An oral, once‑daily regimen with limited infectious complications should reduce infusion chair pressure and supportive‑care overhead, though vigilance for cytopenias and bleeding remains standard. CROs and data teams should anticipate regulator scrutiny on dose justification, exposure‑response, and durability, with DOR and PFS analyses in double‑exposed subgroups likely to carry the most weight. For regulators, a single‑arm CLL filing will hinge on the depth and persistence of responses against the backdrop of available non‑covalent BTK options; the randomized dose work helps, but a clearly articulated confirmatory strategy will be expected.
Next, watch for maturation of the randomized 200 mg versus 600 mg cohort to confirm a PFS separation, expanded durability metrics at the RP2D, and any signal in patients with CNS disease. The pivotal study’s enrollment velocity will be an early read on differentiation versus approved non‑covalent BTK inhibitors and investigational bispecifics and cellular therapies competing for the same patient pool. Key open questions include resistance mechanisms under degrader pressure, the potential for MRD‑guided treatment strategies, and where bexobrutideg fits in earlier lines or in combination with BCL‑2 inhibitors or anti‑CD20 backbones. The pivotal path looks viable if current durability holds; the risk is that cross‑trial comparisons against entrenched BTK options may compress the perceived margin, making confirmatory design and real‑world performance decisive.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
