NX-5948 Shows Early Promise in CLL After BTKi Failure

Treatment with NX-5948 demonstrated tolerable safety and induced promising responses in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), according to data from a phase Ia study presented at the 2024 Pan Pacific Lymphoma Conference.

“Deep clinical responses were observed in a heavily pretreated population of patients with CLL and NHL, some with Bruton’s tyrosine kinase inhibitor (BTKi) resistance mutations, high-risk molecular features, and central nervous system [(CNS)] involvement,” wrote the study’s authors.

NX-5948 in Treatment of CLL After BTKi

This first-in-human, dose-escalation trial enrolled patients with two or more prior lines of therapy, evaluable disease, and Eastern Cooperative Oncology Group performance scores of zero or one. The primary objectives were to evaluate the safety and efficacy of NX-5948, establish a maximum tolerated dose, and identify a recommended phase II dose.

The study enrolled 46 patients, of whom 16 had CLL and 30 had NHL, including six with CNS involvement. The median age was 64 years (range, 42-88 years), and 67.4% were male. Participants received once-daily doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, or 600 mg.

After an overall median duration of follow-up of 3.4 months (range, 0.2-20.1 months), NX-5948 was reportedly well tolerated at all doses, with no treatment-related serious adverse events (AEs) and no patients discontinuing due to treatment-emergent AEs (TEAEs). The most common TEAEs were purpura or contusion, thrombocytopenia, and neutropenia.

Among 10 patients with evaluable CLL, seven had a partial response at doses of 50 mg to 200 mg. Among 24 patients with evaluable NHL, eight patients responded at doses of 50 mg to 600 mg. Notably, all four patients who received the 450-mg dose had a response, including three complete responses and one partial response.

“These data suggest a role for NX-5948 in the CLL treatment landscape and warrant its continued investigation in NHL, including subtypes where BTKi may not be sufficient,” the researchers concluded.

Reference

Shah N, Linton K, Collins P. Latest results from an ongoing first-in-human phase 1a/b study of NX-5948, a selective Bruton’s tyrosine kinase (BTK) degrader, in patients with relapsed/refractory CLL and other B-cell malignancies. 2024 Pan Pacific Lymphoma Conference; July 15-19, 2024; Lahaina, Hawaii.