Authored by Dr. Brian Koffman
Bottom Line:
In heavily treated chronic lymphocytic leukemia patients who have poor prognoses and few options, the BTK degrader, NX-5948, saw 7 of the 10 treated respond.
Who Performed the Research and Where Was it Presented:
Dr. Kim Linton led an international group of researchers to present the oral abstract of these encouraging first results on the last day of the 2024 European Hematology Association (EHA) Annual Meeting in Madrid.
Background:
Treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) was revolutionized when it was understood that the cancer cells depended on their survival and proliferation on signaling through the B-cell receptor (BCR). Several medications have been developed to block this pathway, but the most impactful has been the BTK inhibitors, starting with ibrutinib, followed by acalabrutinib, zanubrutinib, and pirtobrutinib. These oral drugs have proven superior to all prior chemo-immunotherapies therapies (CIT) and have become one of the mainstays of care, prolonging lives and offering patients who were previously out of options new hope. However, CLL / SLL cells can eventually develop mutations that cause these medications to stop working. Finding new ways to block BTK when resistance develops would be highly beneficial to patients.
BTK degraders, such as the experimental NX-5984, work differently. While they are still “small molecules” that can be taken orally, they have a more complex structure. Instead of blocking the activity of BTK, an enzyme or kinase, they tag the whole molecule for destruction or degradation. BTK is completely broken down. Essentially, its component molecules are recycled and used to build new proteins in the cell. This destruction, of course, leads to a full stop of the BCR signaling, which in turn leads to control of the CLL / SLL. Moreover, at least theoretically, resistance to other BTK blockers should not influence its efficacy.
Methods and Participants:
NX-5948-301 is a Phase 1, a first-in-human dose-finding trial evaluating the safety, tolerability, and clinical activity of NX-5948, a novel oral BTK degrader in patients with relapsed or refractory CLL and non-Hodgkin lymphoma or NHL. To be eligible, patients had to have had two or more prior therapies, measurable or other evaluable disease, and be relatively fit (ECOG score of 0-1 or at worst, capable of all but the most strenuous activities). The trial aims to evaluate the safety and tolerability of NX- 5948 and establish the maximum tolerated dose and recommended Phase 2 dose.
Results:
- Enrollees:
- 46 patients (16 CLL, 30 NHL of which 6 had central nervous system or CNS involvement) were enrolled at 6 daily oral dose levels: 50 mg (n=7), 100 mg (n=8), 200 mg (n=9), 300 mg (n=12), 450 mg (n=6), 600 mg (n=4).The median age was 64.67.4% were male.Median prior lines of therapy: 4 (range 2–14), including for CLL: BCL2i such as venetoclax plus a covalent and/or non-covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib) (n=14/16), PI3Ki (duvelisib and idelalisib) (n=5/16)Baseline mutations were common in the patients with CLL: BTK (n=5/12), TP53 (n=5/12), PLCg2 (n=2/12). These were challenging patients to treat.
- In the overall population (n=46), the median duration of follow-up was 3.4 months but ranged up to more than 20 months.
- Adverse Events:
- NX-5948 was well tolerated across all doses with no treatment-related serious adverse events.
- No one dropped out of the trial due to adverse events
- The most common treatment-emergent adverse events or TEAEs were:
- bruises/contusions (39.1%, all mild)
- low platelets or thrombocytopenia (37.0%, 10.9% Grade ≥3 or serious)
- low neutrophils or neutropenia (26.1%, 19.6% Grade ≥3 or serious).
- No atrial fibrillation / flutter was reported.
- Only once was the dose reduced in a lymphoma patient with a rash with the 450 mg. dose that did not recur with rechallenge.
- Efficacy:
- NX-5948 pharmacokinetics (PK) supported once-daily dosing.
- BTK degradation was fast, strong, and sustained in all patients regardless of absolute BTK starting level, tumor type, or dose.
- Out of 10 disease-evaluable patients in CLL, 7 partial remissions (PRs) were documented at doses of 50–200 mg (ORR 70%).
Discussion and Conclusion:
Very early findings from this ongoing first-in-human study of NX-5948 demonstrate an encouraging safety in NHL and chronic lymphocytic leukemia. No patient stopped the drug due to adverse events. Solid responses were observed in a heavily pre-treated, challenging population of patients, some with BTKi resistance mutations, high-risk molecular features, and even central nervous system involvement with NHL. CLL patients’ 70% response rate may improve over time as these were very early results. It would be better if there were more than 10 patients whose results were reported, but that data will be forthcoming. What we already know at this point suggests that NX-5948 will be used in future CLL treatment to extend the success seen with other blockers of BTK. Staying “in class,” in this case blocking BTK as long as possible, is a smart strategy for many patients. Additional research at higher dose levels and longer treatment durations is ongoing, but these early results are encouraging in a group of patients near the end of the line for treatment options.
Links and Resources:
Listen to my monologue below.
Read the abstract at: 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
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
