Resistance Spurs Evaluation of Early-Phase BTK Degraders

THE RISE OF Bruton tyrosine kinase (BTK) inhibitors has revolutionized the treatment of multiple hematologic malignancies including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone leukemia (MZL), and other diseases, and their use in solid tumors and autoimmune disorders is undergoing evaluation.¹ Yet, despite the inhibitors’ impressive clinical accomplishments, disease progression can occur as a result of mutations to BTK that lead to widespread resistance. The need for novel treatments to overcome resistance remains paramount.

During the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, investigators revealed early-phase 1 data evaluating various BTK degraders that leverage different strategies to overcome resistance.

BGB-16673

Data spotlighting BGB-16673 across hematologic malignancies were explored. The agent is an orally available bivalent inhibitor that targets the chimeric degradation activation compound designed to induce degradation of wild-type and multiple mutant forms of BTK, including those that commonly confer resistance to BTK inhibitors in patients who experience progressive disease. The advantage of a degradation approach does not require sustained target binding to work, and it can also interrupt the scaffolding function of BTK.

In August 2024, the FDA granted fast track designation to the agent for patients with relapsed/ refractory (R/R) CLL or SLL.²

The phase 1/2 CaDAnCe-101 trial (NCT05006716) is an ongoing open-label, first-in-human study evaluating BGB-16673 monotherapy in patients with R/R B-cell malignancies. Phase 1 results were presented during the 2024 ASH meeting. Investigators evaluated the agent in patients with R/R indolent non-Hodgkin lymphoma (NHL; abstract 1649),³ CLL/SLL (abstract 885),⁴ and Waldenström macroglobulinemia (WM; abstract 860).⁵ Doses at 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, and 600 mg are undergoing evaluation.

“When we consider our clinical experience with BTK inhibitors, it encompasses a whole group of diseases including CLL, Waldenström macroglobulinemia, marginal zone lymphoma [MZL], mantle cell lymphoma [MCL], and to a lesser extent, follicular lymphoma [FL],” Constantine S. Tam, MBBS, MD, told Targeted Therapies in Oncology. “These malignancies are all very BTK responsive.” Tam, lead author of abstract 1649, is the head of the lymphoma service at Alfred Health in Melbourne, Australia, and a professor of hematology at Monash University.

Abstract 1649

Updated results from CaDAnCe-101 focused on patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL) were presented.³ The trial enrolled patients with R/R NHL who were treated with 2 or more prior therapies, an ECOG performance status of 0, 1, or 2, and adequate organ function.

Findings demonstrated that the agent was well tolerated with no dose-limiting toxicities (DLTs) observed in patients with FL or MZL. “Eight patients with FL were enrolled. The median prior lines of therapy was 4.5 and all patients have been previously pretreated with chemotherapy. A quarter of patients with FL were previously treated with a BTK inhibitor and had progressive disease,” Tam said.

Seventeen patients with MZL were enrolled and the median prior lines of therapy was 3 (range, 1-8). The majority of patients (90%) had been previously treated with a BTK inhibitor and 11 out of 15 patients had progressed on a prior BTK inhibitor.

Sixteen patients (80%) reported any-grade treatment-emergent adverse events (TEAEs; grade ≥ 3, 25%), of which, the most common (≥20%) were upper respiratory tract infection (25%; grade ≥3, 5%), fatigue (25%; no grade ≥3), and contusion (20%; no grade ≥3). Five patients (25%) experienced a grade ≥3 TEAE. One patient experienced hypertension (history of hypertension that worsened to grade 3 on study, monitored without treatment), and 1 patient experienced atrial fibrillation (grade 1), both in the MZL group. One patient experienced major hemorrhage. No febrile neutropenia was seen.

No TEAEs led to dose reductions, and 1 patient with MZL had a TEAE that led to treatment discontinuation (pleural effusion related to disease progression). No DLTs occurred, and the maximum tolerated dose was not reached.

In the 14 response-evaluable patients, the overall response rate (partial response or better) was 50% (4/8) for FL (complete response [CR], n = 1; time to CR, 3.3 months) and 67% (4/6) for MZL (CR, n = 2; time to CR, 3.6 and 13.7 months), with 6 of the 8 responses still ongoing at the data cutoff. Median time to first response was 2.7 months (range, 2.6-3.3) for patients with FL and 2.9 months (range, 2.8-3.6) for those with MZL. Responses were seen in patients previously treated with a covalent BTK inhibitor (cBTKi; 2/4 in MZL and 0/1 in FL with prior cBTKi) and a noncovalent BTKi (ncBTKi; 0/1 in MZL and 1/1 in FL with prior ncBTKi).

“The response rate is encouraging, with 50% in FL and 67% in MZL, suggesting that ongoing development for BGB-16673 continues,” Tam said.

Looking ahead, Tam thinks the next steps involve exploring the agent in earlier lines of therapy as well as in other combinations “ because we know for BTK inhibitors, the Achilles’ heel is prolonged therapy, which leads to resistance. If we can combine [this agent] with BCL2 inhibitors or other agents, it could result in fixed-duration therapy. At this point, we don’t know how well this agent combines with others,” Tam said.

Abstract 885

Findings from the CLL/SLL cohort (n = 60)4 from CaDAnCe-101 showed the agent was safe and well-tolerated in this heavily pretreated population, according to a presentation at the 2024 ASH meeting by Meghan C. Thompson, MD, a leukemia specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

Patients were eligible if they met the International Workshop CLL 2018 criteria for treatment; had received 2 or more prior therapies, including treatment with a cBTKi approved for the disease; and had ECOG performance status of 0, 1, or 2. The primary objectives were safety and tolerability, maximum tolerated dose, and the recommended phase 2 dose. Preliminary antitumor activity was a key secondary objective.

The molecular characteristics of the population showed that 82.6% of patients had unmutated IGHV status, 66.7% had deletion 17p and/or TP53 mutation, and 50% had complex karyotypes defined by 3 or more cytogenetic abnormalities.

“The overall response rate for the total cohort was 77.6%. Specifically, in [those patients taking] the 200-mg dose [n = 16], the overall response rate was 93.8% with a median time-to-response of 2.8 months,” Thompson noted during her presentation.

Overall safety demonstrated that the agent had no treatment-related AEs (TRAEs) leading to death; there was 1 dose-limiting toxicity at the 200-mg dose, a grade 3 maculopapular rash.

There were no cases of atrial fibrillation or pancreatitis, but 2 cases of major hemorrhage were reported: 1 case of subarachnoid hemorrhage and 1 case of grade 3 subdural hemorrhage. The most common all-grade AE reported was fatigue (30%), followed by contusion (28.3%), and neutropenia (25.0%). The most common grade 3 or higher AEs were neutropenia (21.7%) and pneumonia (8.3%).

“Overall response rates were observed across multiple biologic subsets as well as multiple prior lines of therapy,” Thompson said. “Looking at prior therapies for double-exposed patients, the overall response rate was 86.7%. In triple- exposed patients, the overall response rate was 58.3%.”

This trial also evaluated patients with Richter transformation. There were 14 safety- evaluable patients and 12 efficacy- evaluable patients. The median age in this population was 64 years (range, 47-80). The overall response rate was 58.3%, and 8.3% of patients had a CR.

Abstract 860

In abstract 860,5 among 27 patients with WM, the objective response rate was 81%, whereas the major response rate (partial response [PR] or better) was 74.1%, and the very good PR rate was 25.9%.

The median time to first response was 1 month (range, 0.9-3.7), with investigators reporting that responses deepened over time; 20 patients were still on treatment with ongoing responses. The median follow- up was 5 months (range, 0.8-24).

Responses were reported among patients receiving the lowest dose (100 mg) as well as in patients previously treated with a cBTKi (22 of 27 patients) and an ncBTKi (4 of 4 patients). In addition, responses were observed in patients with or without BTK mutations (with, 10 of 11; without, 11 of 14; unknown, 1 of 2), MYD88 (with, 20 of 24; without, 1 of 2; unknown, 1 of 1), CXCR4 (with, 11 of 12; without, 10 of 13; unknown 1 of 2), and TP53 (with, 12 of 13; without, 9 of 12; unknown, 1 of 2).

Twenty-seven patients with WM were enrolled and treated as of September 2, 2024. T he median age was 73.0 years (range, 56-81), and patients had undergone a median of 3 (range, 2-11) prior therapies, including prior cBTK inhibitors (27, or 100%), BCL2 inhibitors (5, or 18.5%) and ncBTK inhibitors (4, or 14.8%). A total of 25 patients (92.6%) had previously been treated with chemotherapy. Of those, 11 (44%) had BTK mutations, 24 (92.8%) had MYD88 mutations, and 12 (48%) had CXCR4 mutations.

Treatment-emergent adverse events ( TEAEs) of any grade were reported by 92.6% of patients, with 40.7% reporting grade 3 or higher and 25.9% reporting serious TEAEs. The most common was neutropenia (29.6%; grade 3 or higher, 25.9%).

Investigators reported that no incidents of atrial fibrillation, hypertension, febrile neutropenia, or major hemorrhage occurred; no TEAEs led to treatment discontinuation or dose reduction; no DLTs occurred; and the maximum-tolerated dose was not reached. However, 1 patient died due to a TEAE, specifically septic shock that was considered related to disease progression, and 1 patient died due to disease progression.

NX-5948

The NX-5948-301 trial (NCT05131022) is a multihistology clinical trial of patients with CLL, SLL, NHL, or WM. Nirav N. Shah, MD, associate professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin in Milwaukee, presented data focusing specifically on patients with CLL/SLL during the 2024 ASH meeting.⁶

“There’s an unmet clinical need for those patients who progress after traditional covalent BTK inhibitors and BCL2 inhibitors, with these drugs moving up in the up-front setting and being used in relapsed/refractory disease,” Shah said. “New therapies are indicated for these patients. In particular, with BTK- targeted therapies, we know that mutations develop that lead to resistance to both covalent inhibitors and the recently approved noncovalent BTK inhibitors,” Shah said.

NX-5948 recruits the E3 ligase binder and leads to ubiquitination of the BTK enzyme and proteasome degradation of the molecule. Preclinical data suggest that this mechanism can help overcome BTK resistance and may be agnostic to the presence of BTK mutations that occur in the setting of covalent and noncovalent inhibitors.^6,7

In the study, patients received 50-mg, 100-mg, 200-mg, 300-mg, 450-mg, or 600-mg doses (n = 60). Fourteen patients discontinued treatment, and 46 patients remain on treatment. Median age was 67.0 years (range, 35-88), and the majority (63.3%) were men. Thirty-six patients (60.0%) had an ECOG performance status of 1, and 8.3% had central nervous system involvement.

Regarding previous treatments, the majority of patients were treated with either a BTKi, a BCL2 inhibitor, or both. Mutation status was characterized by TP53 (40.4%), BTK (38.6%), PLCG2 (12.3%), or BCL2 (10.5%).

The safety analysis revealed a tolerable profile that was consistent with prior studies. Investigators reported 1 case of grade 1 atrial fibrillation. Five TEAEs led to drug discontinuation, and 2 grade 5 AEs were deemed not related to the study drug.

“This is a very safe drug with few grade 3 or higher toxicities, and the grade 3 and higher toxicities were largely enriched for cytopenias, most commonly neutropenia in terms of traditional BTK inhibitor–like toxicities,” Shah said.

The objective response rate was 75.5% (95% CI, 61.1%-86.7%) with 73.5% of patients exhibiting a partial response. The median duration of treatment was 3.9 months (range, 0.1-21.0), and the median duration of response was not reached (95% CI, 6.9-not reached), with 13 patients having a duration of response of greater than 6 months.

“As we know, patients can be treated with BTK-type agents for years, so we’ll have to continue monitoring the long-term safety of this agent,” Shah said. “Ongoing studies are being developed to further investigate this agent, with pivotal trials planned in 2025.”

A676

Michael T. Tees, MD, a hematologist at the Colorado Blood Cancer Institute in Denver, Colorado, shared information about an early phase 1 dose-escalation study (NCT05780034) evaluating AC676, a BTK chimeric degrader, during the 2024 ASH meeting.⁸

Tees explained that the agent is a chimeric degrader that uses a proprietary Protein- Protein Interaction Targeting Chimeras (PPI-TAC) platform from Accutar Biotech. By linking a BTK ligand to the cereblon E3-ligase recruiting ligand, AC676 brings BTK in proximity to cereblon, which induces subsequent ubiquitination and degradation of BTK. The trial was initiated in April 2023 with 8 sites in the US that are currently recruiting patients.

The primary trial objective is to determine the safety and tolerability of the agent and secondary objectives are pharmacokinetics and antitumor activity.

Although both cBTK inhibitors and ncBTK inhibitors have demonstrated efficacy, resistance continues to be a clinical challenge. Phase 1 trials that explore the role of BTK degraders across hematologic malignancies look promising and will lead to further evaluation in later- stage trials.

REFERENCES

1. Fares A, Carracedo Uribe C, Martinez D, Rehman T, Silva Rondon C, Sandoval-Sus J. Bruton’s tyrosine kinase inhibitors: recent updates. Int J Mol Sci. 2024;25(4):2208. doi:10.3390/ijms25042208

2. BeiGene’s BGB-16673 receives U.S. FDA fast track designation for CLL/SLL. News release. BeiGene, Ltd. August 26, 2024. Accessed August 26, 2024. https://tinyurl.com/3kskc2vj

3. Tam CS, Frustaci AM, Bijou F, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory (R/R) indolent NHL: results from the phase 1 CaDAnCe-101 study. Blood. 2024;144(suppl 1):1649. doi:10.1182/blood-2024-199154

4. Thompson MC, Parrondo RD, Frustaci AM, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the phase 1 CaDAnCe-101 study. Blood. 2024;144(suppl 1):885. doi:10.1182/blood-2024-199116

5. Seymour JF, Tam CS, Cheah CY, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory Waldenström macroglobulinemia: results from the phase 1 CaDAnCe-101 study. Blood. 2024;144(suppl 1):860. doi:10.1182/blood-2024-199212

6. Shah NN, Omer Z, Collins G, et al. Efficacy and safety of the Bruton’s tyrosine kinase (BTK) degrader NX-5948 in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): updated results from an ongoing phase 1a/1b study. Blood. 2024;144(suppl 1):884. doi:10.1182/blood-2024-194839

7. Montoya S, Bourcier J, Noviski M, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024;383(6682):eadi5798. doi:10.1126/science.adi5798

8. Tees MT, Bond DA, Khan N, et al. A phase 1 study of AC676, a novel BTK chimeric degrader, in patients with B-cell malignancies. Blood. 2024;144(suppl 1):4422. doi:10.1182/blood-2024-194009