Investigation of Novel BTK Degrader Continues in CLL

Justin Taylor, MD

In heavily pretreated patients with chronic lymphocytic leukemia (CLL), including those with Bruton's tyrosine kinase (BTK) mutations, clinical responses and benefits were observed when treated with NX-2127, according to findings from a first-in-human, phase 1 study (NCT04830137).

The multicenter, open-label, phase 1 dose-escalation and cohort-expansion NX-2127-001 trial sought to assess the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with relapsed/refractory CLL and B-cell malignancies. Patients were given oral NX-2127 once a day in 28-day cycles starting at 100 mg. Twenty-eight patients were enrolled, including 17 with CLL or small lymphocytic lymphoma, at dose levels 100, 200 and 300 mg.

Among those enrolled in the study, patients were mostly male (64.3%) with a median age of 76 (range, 61-92) years. For the 17 patients with CLL, they had received a median of 6 prior therapies (range, 2-12), all had been previously treated with a BTK inhibitor, and 76.5% had also received venetoclax (Venclexta). Patients had poor prognostic factors, including unmutated IGHV (23.5%) and mutations/deletions in TP53 (17.6%). Mutations observed among the 14 patients with CLL were BTK [C481 (29%), L528 (29%), T474 (14%), V416 (7%)] and BCL2 (14%). Mutations C481, V416 and L528 result in loss of BTK kinase function.

By cycle 1, day 22, all patients had a mean BTK degradation of 86%, with a mean degradation of 83% in patients with CLL. This led to a decrease in BCR signaling as measured by reduction of plasma CCL4. At all dose levels, immunomodulatory activity was observed.

Twelve patients with CLL were response-evaluable, and the best overall response rate (ORR) observed was 33%. There was also evidence that ORR increases with longer follow-up with ORR rates of 16.7% at 2 months, 42.9% at 4 months, and 50% at 6 months. Responses were noted in patients who were BTKi/BCL2 double-refractory, as well as patients who progressed on a ncBTKi.

Data from this trial support further clinical development of NX-2127 in CLL. Investigators will continue to evaluate NX-2127 at the 100 mg dose level and continue dose exploration for other B-cell malignancies.

Red blood cells: © vipman4 - stock.adobe.com

In an interview with Targeted Oncology^TM, Justin Taylor, MD, assistant professor of medicine at the University of Miami, Sylvester Comprehensive Cancer Center, discusses early research on NX-2127, a BTK degrader being evaluated for the treatment of CLL.

Targeted Oncology: Can you discuss the treatment landscape for CLL?

The good thing about CLL is that there are a lot of treatment options. The first-line treatments can differ based on patient's preferences and physicians’ comfort with the drugs. BTK inhibitors are a common frontline treatment. We now have ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, and others still in clinical trials. They're not frontline options, but they may be in the future. The other main frontline option is venetoclax, a BCL2 inhibitor that can be given in combination with the CD20 antibody. Venetoclax is a time-limited therapy, whereas ibrutinib or other BTK inhibitors are continuous therapy. I think it becomes more of a discussion with the patients as to which option they might prefer.

Can you discuss some of your research on NX-2127?

We presented data on a BTK degrader, NX-2127, with some of the first results with this degrader, preclinical results, as well as the clinical results, will be presented later on. Earlier this year, we published some resistance mutations that we're seeing to noncovalent and some covalent BTK inhibitors. These results are looking at BTK degraders to overcome those resistance mutations for CLL.

Our presentation is mainly the preclinical work. We use engineered cell lines that have these mutations and have been shown to be resistant to BTK inhibitors, to show that the degrader would in fact, bind to these mutations in BTK forms as well as degrade them and kill the CLL cells in vitro. We're also presenting some clinical data that degrader has been used in patients in a phase 1 trial. The full results will be presented separately, but we have presented some early results of patients who were treated with CLL, who were treated with an NX-2127 and responded, even if they had these resistance mutations.

What are the key takeaways from this research?

These mutations that cause resistance can still be overcome with a clinical grade degrader. That's now in phase 1 trials. If things continue to go well with this degrader, this may be an option for patients in the future.

What are the next steps for research in this space?

The phase 1 study is ongoing, and as soon as that is complete, they'll move on to the phase 2 study. In terms of the science that we're doing, we're looking at potential other new therapeutics as well, because even though we have a lot of treatment options for CLL, patients can become resistant to multiple lines of therapy, and there's still a need for some patients. Luckily, most patients do not need this, but some patients who are refractory to multiple agents who still need new therapies.

Are there any trials or data that have potential to be practice changing in this space?

These NX-2127 results are not practice changing yet because it's still in clinical trials, but these are exciting data. Some of the more practical things might be the combinations of ibrutinib and venetoclax, or other BTK inhibitors with venetoclax. We reviewed how those are the 2 main agencies in frontline this these studies, and we're looking at combining those in the frontline to get even better responses, deeper remissions, and this will be time limited therapy as well. We're still waiting to see how long these responses are. These are impressive responses with deep responses, but we're still waiting to see how long these last, and whether using both drugs up front is better than, you know, using them sequentially.

REFERENCE:

Mato AR, Wierda WG, Ai WZ, et al. NX-2127-001, a first-in-human trial of NX-2127, a bruton's tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies. Blood:2022;140 (Suppl 1): 2329–2332. doi:10.1182/blood-2022-164772