Lasica, Masa

Abstract Introduction: The first-generation BCL2 inhibitor,venetoclax, is an effective treatment for CLL/SLL, but its usage may be limited by toxicity. Sonrotoclax, a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-101 (NCT04277637) is an ongoing, phase 1/1b, dose-escalation/expansion study in patients with B-cell malignancies. Presented here are preliminary data for sonrotoclax + obinutuzumab in patients with treatment-naive (TN) CLL/SLL in BGB-11417-101. Methods: Obinutuzumab is administered intravenously at 100 mg on day (D) 1, 900 mg on D2, 1,000 mg on D8 and D15 of cycle (C) 1, and then 1,000 mg on D1 of C2-6 of each 28-day cycle. Beginning on C2D1, sonrotoclax is administered orally once daily with ramp-up to the target doses, 160 or 320 mg. Patients can continue treatment until progressive disease (PD), unacceptable toxicity, or undetectable minimal residual disease (uMRD4; <1 CLL cell per 10,000 leukocytes [<0.01%]) in peripheral blood (PB) by next-generation sequencing (NGS; ClonoSEQ) after 15 treatment cycles. Study endpoints include safety per NCI-CTCAE v5.0, overall response rate (ORR) per iwCLL guidelines, and MRD status in PB per modified ERIC flow cytometry (FC) assay or NGS, depending on the timepoint. Tumor lysis syndrome (TLS) is assessed per Howard (2011) criteria. Results: As of May 16, 2025, 55 patients with TN CLL/SLL were enrolled (160 mg, n=20; 320 mg, n=35), and 21 patients (all 320 mg) have discontinued sonrotoclax + obinutuzumab (due to uMRD4 per NGS as protocol-mandated [n=17], PI decision uMRD4 per FC [n=2], and PD [n=2]). Four patients discontinued obinutuzumab only per PI decision (160 mg, n=1), thrombocytopenia (320 mg, n=2), and prostate cancer prior to starting sonrotoclax (160 mg, n=1). For all patients, the median age was 62 y, 65% were male, and 89% were White. At baseline, 14% of patients (8/55) had high tumor burden and 58% (31/53) had unmutated IGHV. Median study follow-up was 8.9 months (range, 0.4-25.4 months) for all patients; 6.4 months (range, 0.4-9.0 months) for 160 mg; and 16.0 months (range, 2.9-25.4 months) for 320 mg. Maximum tolerated dose was not reached. The most common any-grade treatment-emergent AEs (TEAEs) were thrombocytopenia (56%), infusion-related reaction (56%), and neutropenia (49%). Neutropenia was the most common grade ≥3 TEAE (38%). No deaths due to TEAEs occurred, and no TEAEs led to sonrotoclax discontinuation. Two cases of laboratory TLS occurred after C1D1 of obinutuzumab prior to starting sonrotoclax; no clinical or laboratory TLS occurred during sonrotoclax ramp up. No meaningful safety differences were observed among sonrotoclax dose cohorts. In 37 efficacy-evaluable patients (160 mg, n=7; 320 mg, n=30), the ORR was 89%; for the 320-mg cohort, ORR was 93% (28/30). Complete response (CR) rates (CR + CR with incomplete marrow recovery [CRi]) were 46% (all patients) and 43% (320 mg). For 23 patients in the 320 mg cohort who reached the C15 MRD assessment, the best C15 uMRD4 rate per FC was 87% (20/23; 2 not evaluable; 1 missing); per NGS, the uMRD4 rate at C15 was 78% (18/23; 5 missing). All patients with an available C15 MRD assessment achieved uMRD4 and remain in remission as of the data cutoff date. The median time from reaching sonrotoclax target dose to uMRD4 was 2.3 months (range, 1.4-5.6 months) in the 320-mg cohort. Three patients experienced PFS events: 1 died from an indeterminate cause (160 mg, discontinued treatment after C1D9 of obinutuzumab) and 2 had PD (320 mg; both Richter's transformation at C6 and C2). Conclusions: Sonrotoclax + obinutuzumab was generally well tolerated in patients with TN CLL/SLL, with no sonrotoclax discontinuations or deaths due to TEAEs. No laboratory or clinical TLS events occurred during sonrotoclax ramp-up. Encouraging antitumor activity was observed with sonrotoclax 320 mg. High rates of blood uMRD4 occurred early and deepened over time. All patients with an available C15 MRD assessment by NGS or FC achieved uMRD4 and remain in remission. A registrational phase 3 study (CELESTIAL-RRCLL, BGB-11417-303) assessing this combination with sonrotoclax 320 mg is currently recruiting.

Introduction: Bruton tyrosine kinase (BTK) inhibitors are highly effective against Waldenström macroglobulinemia (WM). Their effectiveness can be limited by resistance caused by BTK mutations and intolerance. BGB-16673 is a bivalent small molecule that induces BTK degradation by binding specifically to BTK and the E3 ligase. The E3 ligase catalyzes the transfer of ubiquitin molecules to BTK, which marks BTK for destruction by the proteasome. Preclinically, BGB-16673 degraded wild-type and mutant BTK associated with covalentand noncovalent BTK inhibitors (ncBTKis), leading to tumor suppression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing, open-label, first-in-human, phase 1/2 study evaluating BGB-16673 monotherapy in patients with a range of B-cell malignancies. Here, early results in patients with WM enrolled in the phase 1 portion are presented. Methods: Eligiblepatients must have confirmed R/R WM (≥2 prior therapies), an ECOG performance status of 0-2, and adequate organ function. Patients must have previously received an anti-CD20 antibody and, in the US and EU, a covalent BTK inhibitor (cBTKi). BGB-16673 was orally dosed once daily in 28-day cycles. Dose escalation used a Bayesian optimal interval design (6 planned dose levels, 50-600 mg once daily). Primary objectives were to evaluate safety/tolerability (CTCAE v5.0) and to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks (cycle 1). A secondary objective was to evaluate the overall response rate (ORR, IWWM-6 consensus criteria), with the first assessment occurring after 4 weeks of treatment. Results: As of May 24, 2024, 22 patients with WM were enrolled and treated (100 mg, n=4; 200 mg, n=10; 350 mg, n=8). The median age was 73.0 (range, 56-81) years, and the median number of prior therapies was 3.5 (range, 2-11), including prior cBTKis (n=22 [100%]), BCL2 inhibitors (n=4 [18%]), and ncBTKis (n=3 [14%]). Twenty patients (91%) had previously received chemotherapy. According to the International Prognostic Scoring System for WM, 6 patients (27%) had low-risk disease, 7 (32%) had intermediate-risk disease, and 8 (36%) had high-risk disease (missing/unknown data, n=1). Five patients (23%) had BTK mutations, 20 (91%) had MYD88 mutations, and 8 (36%) had CXCR4 mutations. The median follow-up was 4.3 (range, 0.3-21.3) months. Ninety-five percent of patients reported any-grade treatment-emergent adverse events (TEAEs; grade ≥3, 45%; serious, 23%), the most common (≥20%) of which were neutropenia/neutrophil count decreased (32%; grade ≥3, 23%), contusion (23%; no grade ≥3), and diarrhea (23%; no grade ≥3). The most common grade ≥3 TEAE (≥20%) was neutropenia/neutrophil count decreased. No atrial fibrillation, hypertension, febrile neutropenia, or major hemorrhage occurred. Three patients (14%) had a grade ≥3 infection (bronchopulmonary/cerebral aspergillosis, septic shock, and pseudomonal bacteremia/sinusitis). No patients had a TEAE that led to treatment discontinuation or dose reduction. No DLTs occurred, and the MTD was not reached. One patient (5%) died due to a TEAE (septic shock, considered related to disease progression). One patient died due to disease progression. In 21 response-evaluable patients (1 too early), the ORR (minor response or better) was 90%, the major response rate (partial response [PR] or better) was 81%, and the very good PR or better rate was 14%. Median time to first response was 0.95 (range, 0.9-3.7) months, with responses deepening over time. Seventeen patients remain on treatment and have ongoing responses. Responses were seen at the lowest dose (100 mg, 4/4), in patients previously treated with a cBTKi (19/21) and an ncBTKi (3/3), and in patients discontinued from prior BTKi due to disease progression (15/17). In addition, responses were observed in patients with and without mutations in BTK (with, 5/5; without, 6/8; unknown, 8/8), MYD88 (with, 18/20; without, 1/1), and CXCR4 (with, 8/8; without, 11/13). One patient had IgM flare at initial response assessment and went on to develop PR. Conclusions: Early data from this ongoing, first-in-human study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows promising antitumor activity in heavily pretreated patients with BTK inhibitor-exposed R/R WM, including those with BTK and CXCR4 mutations.

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3). No significant difference was observed between pts with/without CXCR4mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]

Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria). Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent. Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash). BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks. Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

7569 Background: B-cell lymphoma 2 inhibitors (BCL-2i) are well tolerated and effective in treating B-cell lymphoproliferative disorders such as CLL. Investigational agent lisaftoclax is a novel, oral, highly selective and potent BCL-2i. Preclinical data show a strong synergistic effect of lisaftoclax plus ibrutinib in an ibrutinib-insensitive PDXWM1 model. Methods: This global, open-label, multicenter study evaluates the safety and efficacy of lisaftoclax alone and combined with ibrutinib or rituximab in pts with WM. Pts were enrolled in 3 arms: Arm A (lisaftoclax), BTKi-resistant/intolerant pts; Arm B (lisaftoclax plus ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax plus rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high TLS risk. Primary objectives were pharmacokinetics (PK), safety, and efficacy assessments; responses were assessed per IWWM criteria. Results: As of January 25, 2023, 46 pts were enrolled (Arm A [n = 14]; up to 1,000 mg; Arm B [n = 24]; up to 1,200 mg; Arm C [n = 8]; up to 800 mg). Baseline characteristics are shown in the table. Median (range) treatment duration was 6 (1-18; Arm A), 14 (1-27; B), and 8 (2-26; C) months. Overall response rates (ORRs) were: Arm A, 25% (median time to response [MTTR], 4.3 months); Arm B, 90.9% (MTTR, 1.9); Arm C, 37.5% (MTTR, 4.4). No significant difference was observed between pts with and without CXCR4-mut. At 1,200 mg, 1 DLT (grade 3 clinical TLS), due to pre-existing renal impairment, was reported. At 1,000 mg, 1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic therapies; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (13%), leukocytopenia (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmias were not observed. Only 1 pt required dose reduction (due to neutropenia). MTD has not been reached. A total of 14 pts discontinued study treatment because of disease progression (n = 5) and AE (n = 1). Lisaftoclax plus ibrutinib showed a PK exposure comparable to ibrutinib alone, indicating no potential DDI. Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. Internal study identifier: APG2575WU101. *SA and ML are co-first authors. Clinical trial information: NCT04260217 . [Table: see text]

Abstract Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

7502 Background: The BCL-2i venetoclax is active in certain HMs but can increase the risk of tumor lysis syndrome (TLS), requiring a 5-week dose ramp-up for CLL patients. Cases of severe neutropenia with venetoclax treatment have also been reported. Lisaftoclax is a novel, potent, selective BCL-2i that is active against HMs and is under clinical development. Methods: This first-in-human global phase I dose study assessed the safety, PK, PD, efficacy, and MTD/RP2D of lisaftoclax in patients with R/R CLL and other HMs. Lisaftoclax was orally administered daily in a 28-day cycle. Patients with CLL or intermediate-high TLS risk were initiated on a daily ramp-up schedule until the assigned dose before the study cycles. Results: On January 7, 2021, 35 pts had been enrolled and treated with lisaftoclax at doses ranging from 20 to 1,200 mg, with a median (range) of 2 (1-13) prior lines of treatment, and had diagnoses of R/R CLL or SLL (n = 15), MM (n = 6), FL (n = 5), WM (n = 4), and either AML, MCL, DLBCL, MDS, or HCL (n = 1 each). No DLT has been observed, even though 1,200 mg was considered as the highest dose treated. The MTD has not been reached, and no laboratory or clinical TLS has been reported. Any grade TRAEs in > 10% of pts included neutropenia (22.9%) and anemia (17.1%; hematologic), and fatigue (28.6%), diarrhea (17.1%), and nausea (11.4%; nonhematologic). Grade >3 TRAEs were neutropenia (14.3%) and thrombocytopenia, leukopenia, lymphopenia, fatigue, and nausea (2.9% of pts each). In CLL/SLL pts, grade 3-4 TRAEs included neutropenia (13.3%) and thrombocytopenia (6.7%), which did not cause treatment-related discontinuation. In all, 12 of 35 pts (34.3%) had non-treatment-related SAEs, and only two pts experienced > 1 SAE. With a median (range) treatment of 7 (3-20) cycles, 12 of 14 evaluable R/R CLL/SLL pts achieved PR, for an ORR of 85.7% and a median (range) time to response of 3 (2-7) cycles. Absolute lymphocyte counts (ALCs) were reduced at lisaftoclax doses as low as 20 mg/day. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 20 to 1,200 mg (average half-life: 4-5 hours). On BH3 profiling, lisaftoclax rapidly triggered changes in BCL-2 complex in CLL/SLL pt samples, which were consistent with rapid clinical reductions in ALCs. Conclusions: Lisaftoclax was well tolerated up to 1,200 mg/day. No TLS was observed, even with the daily ramp-up schedule. There were no significant new or unmanageable safety findings, and the ORR in R/R CLL/SLL pts was 85.7%. Grade 3-4 TRAEs were infrequent, even at dose levels of 800 mg and above. BCL-2i lisaftoclax offers a treatment alternative for patients with R/R CLL/SLL and other HMs, with a daily ramp-up schedule that may be more pt “user friendly” and a favorable preliminary safety profile. Internal study identifier APG2575-001. Clinical trial information: NCT03537482.