The Bottom Line:
Tremendous progress over the past decade has been made in managing chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Still, despite all the gains, there is an emerging need for patients who have developed resistant and refractory disease following treatment with covalent Bruton’s tyrosine kinase (cBTK), noncovalent Bruton’s tyrosine kinase (ncBTK) and B-cell lymphoma 2 (BCL-2) inhibitors. Without new therapies, these individuals with the double or triple-refractory disease face a poor prognosis. This first-in-human trial presented at ASH 2022, introduced a new first-in-class agent, NX-2127, that works through a chimeric or dual mechanism to induce actual degradation and breakdown of both the unmutated and mutated Bruton’s tyrosine kinase (BTK) molecules. This Phase 1a trial showed that heavily pretreated CLL / SLL patients with a median of 6 prior therapies and poor prognostic indicators, including mutations causing resistance to covalently binding or cBTKi’s, noncovalently binding or ncBTKi’s and BCL-2 inhibitors responded to treatment without significant safety concerns. The trial results support the continued clinical development and study of NX-2127 for CLL / SLL with a recommendation to move the drug into the second trial stage, Phase 1b, with the expansion of the number of patients enrolled and dosing at the 100 mg level.
Who Performed the Research and Where Was it Presented:
Anthony R. Mato, a hematologist and CLL specialist from Memorial Sloan Kettering Cancer Center in New York, and colleagues presented the results of this Phase 1a trial of NX-2127-001 at the American Society for Hematology (ASH) Annual Meeting in December 2022.
CLL / SLL is a disease of the white blood cells, specifically the B-cell. Survival and proliferation of the B-cell depend upon a complex series of steps along the B-cell receptor signaling pathway which starts with initial stimulation at the B-cell membrane and continues inside the cell through a sequential series of reactions to maintain cell survival and proliferation. A critical step along the pathway involves a protein called BTK that is overexpressed in and maintains the survival of malignant CLL / SLL cells. Over a decade ago, the first Bruton’s tyrosine kinase inhibitor (BTKi), ibrutinib, was introduced and revolutionized the treatment of CLL / SLL, which previously had relied on chemoimmunotherapy. Over time two other BTKi’s, acalabrutinib and zanabrutinib, joined ibrutinib in this subclass of cBTKi’s, which all bind to their target through what is called a covalent bond. Unfortunately, also over the past decade, it was found that drug resistance to cBTKi’s often arises during treatment due to a mutation at the C481 binding site of the BTK molecule where these inhibitors attach. Therefore, a new subclass of BTKi’s called ncBTKi’s, which bind noncovalently at a location other than the C481 binding site, was developed to circumvent this difficulty. Not yet FDA approved for use in CLL / SLL, but far along in clinical trials is the ncBTKi, pirtobrutinib, which in early testing has demonstrated high efficacy for patients who have failed cBTKis. However, just like with cBTKis, despite having an alternate site and mechanism of BTK binding, mutations in BTK causing treatment resistance does occur. The other small molecule inhibitor that has become a mainstay in CLL / SLL treatment is venetoclax, a BCL-2 inhibitor. This drug hastens the death of CLL / SLL cells by blocking the prosurvival BCL-2 protein, which is over-expressed in CLL / SLL cells. Unfortunately, resistance to this BCL-2 inhibitor may also occur. In addition, some patients with aggressive disease may develop resistance to cBTK, ncBTK, and BCL-2 inhibitors following multiple courses of treatment, leaving an unmet need for this group of individuals with relapsed or refractory disease.
This gets complicated. The following paragraph explains that this new therapy tags BTK for destruction.
The trial presented here introduces NX-2127, a novel molecule that works through a dual action pathway to target BTK and Ailos, also known as Ikaros Family Zinc Finger 3 Protein (IKZF3), a transcription factor that plays a critical immodulatory role in the CLL / SLL cell survival. Unlike a BTK inhibitor that blocks the function of BTK, NX-2127 causes degradation, which is the actual breakdown of both the BTK molecule and IKZF3. By temporarily hooking the BTK and IKZF3 targets to a complex called ubiquitin ligase, NX-2127 enables ubiquitin ligase to transfer a ubiquitin molecule to each of these targeted proteins. Our cells contain a natural clearinghouse for removing damaged; unneeded proteins called the proteasome that first recognizes and then degrades proteins tagged with a ubiquitin molecule. Therefore, once complexed with ubiquitin, the BTK and IKZF3 proteins undergo degradation and inactivation by the proteasome. NX-2127 does not have to stay actively bound to the target proteins to inhibit their function. Because of this, far less NX-2127 is required to stop BTK function in contrast to BTKi’s. Furthermore, unlike the cBTKi’s and ncBTKi’s, NX-2127 can target both BTK in its original and mutated forms.
The data presented at ASH 2022 is from a Phase 1 study, which means that this is the first human study with this drug. The initial portion of this trial, Phase 1a, called the dose-escalation phase, is designed to study the safety and tolerability of this drug and determine dosing for the next step of testing. As is usual for Phase 1 studies, only a small number of patients are included. The next stage of this clinical trial is Phase 1b, also known as cohort expansion, in which the efficacy and safety of the drug at a dosing determined in Phase 1a will be studied in additional patients.
Following the presentation at ASH, Dr. Brian Koffman interviewed Dr. Adrian Wiestner, M.D., Ph.D., a hematologist and investigator with the National Institutes of Health, to gain further insights into this research.
Methods and Participants:
- NX-2127-001 is a multicenter, U.S. open-label Phase 1a dose-escalation and Phase 1b cohort-expansion trial.
- This study is designed to evaluate the safety, tolerability, and preliminary efficacy of patients with relapsed or refractory CLL / SLL and other B-cell malignancies.
- Patients receive NX-2127 once daily in 28-day cycles starting at 100 mg.
- 17 of the 28 patients entered in the Phase 1a study had CLL / SLL and were enrolled at dose levels of 100 mg, 200 mg, and 300 mg.
- 64.3% of patients were male, with a median age of 76.
- The patients were heavily pretreated with a median of 6 prior treatments and a range of 2-12 therapies. All patients had previously received a BTKi, and 76.5% had received venetoclax.
- Poor prognostic indicators included unmutated IGHV (23.5%), mutations/deletions in TP53 (17.6%)
- 14 patients were tested for mutations. The following loss of BTK function mutations was found: C481 – 29%, L528 – 29%, and V416- 7%. A BCL2 mutation was found in 14%.
- A mean BTK degradation of 83% was observed in all CLL patients by day 22 of cycle 1
- Immunomodulatory activity, as evidenced by Ikaros (IKZF1) degradation, was observed at all dose levels.
- 12 response evaluable patients with CLL were available for evaluation. The best overall response rate (ORR) was 33%. However, the ORR increased with treatment duration, rising from 16.7% at two months to 50% at six months.
- Responses were noted in BTKi/BCL2 double-refractory patients and those who progressed on a ncBTKi.
- 10 CLL patients remain in the study.
NX-2127, a first-in-class drug with a unique chimeric action mechanism that degrades BTK and IKZF3, was introduced in this first-in-human testing Phase 1a trial. Encouraging initial results were detailed, with the best overall response of 50% reported at six months of treatment duration. Heavily pretreated patients with a median of 6 prior therapies, including BTK and BCL2 inhibitors, and poor prognostic indicators, including mutations to cBTK, ncBTK, and BCL2 inhibitors, showed clinical response without significant safety concerns. The findings support further clinical development and study of NX-2127 for CLL / SLL with progression to Phase 1b of the trial with expanded patient enrollment at a treatment dosing of 100 mg. This is a whole new drug type whose potential is starting to be explored.
Links and Resources:
You can watch our interview with Dr. Adrian Wiestner here:
You can read the actual ASH abstract here:
Similar degraders are being studied that target BCL-2 that is blocked by venetoclax (see ASH 2022: Dr. Jennifer Woyach on Targeting Venetoclax-Resistant Chronic Lymphocytic Leukemia (CLL) with a PROTAC-Based BCL-2/BCL-XL Protein Degrader, so this is an exciting new class of drugs in CLL / SLL and other cancers.
We share in this journey together,
Kim Davidson, MD
CLL patient and physician