Linear Clinical Research

Abstract Background: HR+/HER2− tumors account for ∼70% of all breast cancers (BCs)1 and are responsible for most BC-related deaths. CDK4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) have improved outcomes for HR+/HER2− BC2; however, patients eventually experience progressive disease and require new therapies. B-cell lymphoma 2 (BCL2) is an anti-apoptotic protein involved in regulation of the intrinsic apoptosis pathway that is often dysregulated in tumors. In BC, estrogen receptor signaling leads to upregulation of BCL2, which is overexpressed in 70-80% of HR+ BC.3-5 When administered in rational combinations with other anticancer agents, BCL2 inhibitors (BCL2i) are likely to enhance potential antitumor effects.5 In HR+ BC mouse xenograft models, the addition of a BCL2i to ET enhanced antitumor activity relative to single agent ET.6 Furthermore, the addition of a CDK4i or CDK4/6i to BCL2i + ET significantly augmented this antitumor activity, suggesting further exploration of the triplet is warranted.6-9 BGB-21447 is a novel, orally bioavailable, next-generation BH3 mimetic that was designed to be a highly potent inhibitor of both wild-type and mutant BCL2, which is also active against BCL-xL and is currently in clinical trials for hematologic cancers and BC. BGB-43395 is a selective CDK4i with improved CDK4 coverage and greater selectivity for CDK4 over CDK6, thus minimizing off-target toxicities. BGB-43395 is currently under development with ET in HR+ BC and other selected solid tumors (NCT06120283, NCT06253195). Here, we describe an ongoing phase 1 study of BGB-21447 + fulvestrant with and without BGB-43395 (NCT06756932). Methods: This is an open-label, international, multicenter, phase 1 dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of BGB-21447 in combination with fulvestrant without (Part A) or with BGB-43395 (Part B) in patients with previously treated HR+/HER2− metastatic BC. Sequential cohorts will receive ascending doses of BGB-21447 and fulvestrant. BGB-43395 will be added to the doublet combination dose-escalation component. Key eligibility criteria include patients ≥18 years with histologically or cytologically confirmed HR+HER2− metastatic BC, previous treatment in the advanced/metastatic setting, including prior treatment with CDK4/6i and ET in any setting, Eastern Cooperative Oncology Group Performance Status ≤1, and adequate organ function. Patients with prior BCL2i exposure are excluded. Primary objectives are to assess the safety and tolerability of BGB-21447 in combination with fulvestrant, with or without BGB-43395, and to determine the maximum tolerated dose, maximum administered dose, and recommended dose for expansion of both the doublet and triplet combination. Secondary objectives are preliminary antitumor activity (objective response rate, duration of response, and time to response per Response Evaluation Criteria in Solid Tumors v1.1), characterization of the PK (single dose and steady state), and the preliminary effect of food on PK. This study is currently recruiting patients, with sites open across Australia, China, and the United States (Part A only). Citation Format: 1. Burstein HJ. N Engl J Med. 2020;383:2557-2570. 2. Thill M and Schmidt M. Ther Adv Med Oncol. 2018;3:1758835918793326. 3. Kawiak A, Kostecka A. Cancers (Basel). 2022;14:279. 4. Dawson SJ et al. Br J Cancer. 2010;103 :668-675. 5. Lok SW, et al. Cancer Discov. 2019;9:354-369. 6. Vaillant F, et al. Cancer Cell. 2013;24:120-129. 7. Whittle JR, et al. Clin Cancer Res. 2020;26:4120-4134. 8. Lindeman G, et al. Clin Cancer Res. 2025;31(12_Supplement):P2-07-18. 9. BeOne Medicines. Data on file. Citation Format: G. Lindeman, C. Muttiah, P. Lau, N. Hunter, J. Zhang, Y. Liu, Y. Dong, P. Zhou, A. Kavi, K. Keyvanjah, Z. Shao. Trial in progress: a phase 1 dose-escalation study evaluating BGB-21447 (BCL2 inhibitor) in combination with fulvestrant with and without BGB-43395 (CDK4 inhibitor) in patients with previously treated HR+/HER2− metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-29.

355 Background: IKS014 is an ADC targeting HER2 that comprises a humanized IgG1 antibody conjugated to the monomethyl auristatin F payload, via a novel β-glucuronidase-cleavable linker. IKS014 has been evaluated by a separate sponsor in trials conducted exclusively in China. Preliminary signs of anti-tumor activity, including objective responses in various tumor types, were previously noted at doses ≥ 1.0 mg/kg (≥ 40 mg/m 2 ). Methods: IKS014-01 is a non-randomized, open-label, multicenter trial of IKS014 in participants with advanced solid tumors that express HER2 (NCT05872295). The trial is divided into two parts: Part I, a dose-escalation portion (DE) and Part II which includes 4 disease-specific Expansion Cohorts. Data from the DE portion is presented. The DE portion is intended to establish the MTD and/or a recommended dose for IKS014 monotherapy to be evaluated in Part II and to provide initial safety, efficacy, PK, PD, and immunogenicity data. Key exclusion criteria include clinically significant cardiovascular, pulmonary, or hepatic disease; or active central nervous system involvement. Participants in the DE portion must have HER2+ (IHC3+, IHC2+/ISH+) or HER2 low (IHC2+/ISH- or IHC1+) expressing solid tumors. IKS014 is infused once every 3 weeks. Participants were enrolled into cohorts of increasing dose levels using a standard 3+3 design and monitored for DLTs during Cycle 1. Results: As of July 2025, 62 patients have been treated with IKS014 across five dose levels (40, 60, 90, 120 and 105 mg/m 2 ) including 4 enrichment cohorts, during Part I DE. Among the safety population (across all dose levels and tumor indications); the most common treatment-related adverse events in descending order were dry eye, hypokalemia, keratitis, dry mouth, nausea, pneumonitis, fatigue, alopecia, decreased appetite, and aminotransferase increased. Per protocol, the MTD has not been achieved as only one dose limiting toxicity (DLT) has been observed to date. A DLT of Grade 3 Infusion Reaction was seen in 1 of 21 patients treated at the 120 mg/m 2 dose level. Encouraging anti-tumor activity was seen across all dose levels and in various tumor indications such as breast, esophageal, ovarian and gallbladder cancer and in patients with HER2+ and HER2 low tumors. Of interest, 10 patients with HER2+ esophageal cancer, who had received prior therapy (median 3, range 1-6), have been enrolled in the study. All patients had received prior HER2-targeting therapies such as trastuzumab or trastuzumab emtansine. Among these 10 patients, 5 have achieved a response and 3 demonstrated stable disease > 6 months resulting in a clinical benefit rate (CBR) of 80% with IKS014. Conclusions: These early signs of activity and the high CBR in this small subset of pretreated patients with esophageal cancer warrant further exploration. Clinical trial information: NCT05872295 .

The investigational agent osivelotor, a small molecule hemoglobin (Hb) modifier in development for the treatment of sickle cell disease (SCD), acts by increasing Hb‐oxygen affinity and inhibiting the polymerization of sickle Hb. We report safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the first two phase 1 clinical trials of osivelotor in healthy participants and participants with SCD. Healthy participants (N = 129) were randomized to receive either osivelotor or placebo in single‐ascending doses (50–3,000 mg) or multiple‐ascending doses (loading doses, then 15–100 mg once‐daily maintenance doses through 14 days). A population PK‐based adaptive design was used to inform loading‐ and maintenance‐dose regimens from emerging data. Osivelotor was generally well tolerated, demonstrated dose‐dependent PK exposure increase, and had a terminal elimination half‐life of 19.9 to 30.7 days, with high partitioning into the red blood cell (RBC) compartment in healthy participants. In participants with SCD (N = 6), osivelotor treatment for up to 6 weeks was generally well tolerated; no participants discontinued due to treatment‐emergent adverse events. Disease‐dependent PK was observed in participants with SCD; notably, the terminal elimination half‐life was shorter (~10 days) than in healthy participants. The percentage of Hb bound by osivelotor (%Hb occupancy) increased in a dose‐dependent fashion, and improvements in Hb concentration and markers of hemolysis appeared related to osivelotor concentration. Furthermore, Hb‐oxygen affinity and RBC deformability improved, whereas dense RBCs and circulating sickled cells decreased. In conclusion, once‐daily osivelotor was generally well tolerated at exposures associated with meaningful PD activity, supporting the ongoing clinical investigation.

Background: New therapies are needed for patients with relapsed or refractory (r/r) CLL/SLL following covalent and/or non-covalent BTK inhibitors. While early clinical data showed encouraging anti-tumor activities from BTK degraders in these patients, resistance to both BTK inhibitors and degraders have already been reported. In addition, concerns with emerging clinical safety signals from these degraders may limit their longer-term use. DZD8586 is a rationally designed LYN/BTK dual inhibitor with high selectivity against other TEC family members. Here we report results from ongoing phase 1/2 clinical studies of DZD8586 in r/r CLL/SLL patients with prior treatment of covalent and/or non-covalent BTK inhibitors as well as BTK degraders. Methods: The data from two clinical studies, TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120), were pooled for efficacy and safety analysis in patients with CLL/SLL. In addition to PK, modulation of pharmacodynamic biomarkers was also evaluated. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria as appropriate. Results: As of January 3, 2025, a total of 40 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). The median age was 64.5 years, 62.5% were male, and 60% had ECOG score of 1 or 2. A total of 30 patients were evaluable for efficacy analysis. The median number of prior therapies was 2 (range 1–8). Most common prior CLL/SLL therapies included BTK inhibitor (76.7%), and Bcl-2 inhibitor (43.3%). Patients previously treated by non-covalent BTK inhibitor (13.3%) and BTK degrader (13.3%) were also included in the subgroup efficacy analysis. At the doses ≥ 50 mg QD, tumor response was observed. At the recommended phase 2 dose (RP2D) of 50 mg QD, 10 out of 14 patients achieved tumor response, with overall response rate (ORR, including PR and PR-L) was 71.4%. Efficacy was observed in patients with prior BTK inhibitor treatment (ORR 56.5%), and Bcl-2 inhibitor treatment (ORR 46.2%). Three out of 4 patients who received prior BTK degrader treatment achieved tumor response (ORR 75%). Deepening response was observed with longer treatment time. The longest responder was on therapy for 12.1 months. DZD8586 was well tolerated across the doses investigated. At the RP2D, the most common TEAEs of grade ≥ 3 were neutropenia (15%) and pneumonia (10%). No bleeding or atrial fibrillation was reported. No grade 4/5 AEs reported. PK/PD results confirmed dose/exposure-dependent pathway inhibition by DZD8586. Conclusion: DZD8586 showed encouraging anti-tumor activity with well-tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader and Bcl-2 inhibitor treatment. The updated data will be presented at the meeting. Keywords: molecular targeted therapies; chronic lymphocytic leukemia (CLL); molecular targeted therapies Potential sources of conflict of interest: G. Chong Consultant or advisory role: Bristol Myers Squibb, Regeneron Pharmaceuticals, Inc, Takeda M. B. Geyer Consultant or advisory role: Takeda, Sanofi K. Fang Employment or leadership position: Dizal C. Y. Cheah Consultant or advisory role: Roche, Janssen, Gilead, AstraZenecca, Lilly, Beigene, Menarini, Dizal, Abbvie, Genmab, Sobi, CRISPR Therapeutics. BMS, Regeneron. Honoraria: Roche, Janssen, Gilead, AstraZenecca, Lilly, Beigene, Menarini, Dizal, Abbvie, Genmab, Sobi, CRISPR Therapeutics. BMS, Regeneron.

Abstract Background: Both B7H3 and PD-(L)1 are highly expressed in various solid tumors, including lung cancer, hepatocellular cancer, breast cancer, melanoma, and many others. Dual blockade of B7H3 and PD-(L)1 improved antitumor activity compared to either agent alone. However, no bispecific antibodies targeting both PD-(L)1 and B7H3 are in clinical development. DB-1419 is a bispecific antibody-drug conjugate (ADC) comprised of a humanized anti-B7H3/PD-L1 IgG1 antibody covalently linked to a proprietary DNA topoisomerase I inhibitor (P1003) via a cleavable linker containing maleimide tetrapeptide, with a drug-to-antibody ratio of approximately 8. Preclinical studies demonstrated that DB-1419 exhibited both direct cancer cell killing and immune-modulating functions. These studies warrant further clinical development of DB-1419. Methods: This is a multicenter, open-label, multiple-dose, first-in-human Phase 1/2a study (NCT06554795) to assess the safety, tolerability, and anti-tumor activities of the study drug DB-1419 in participants with pretreated advanced/metastatic solid tumors unselected for B7H3/PD-L1 expression. The trial is planned to enroll 360 participants from the United States, Australia, and China (90 in Phase 1a and 270 in Phase 1b/2a). In phase 1a (the dose escalation part), participants who have previously treated, histologically confirmed, unresectable advanced/metastatic solid tumors will be enrolled to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D). Approximately six ascending dose levels of DB-1419 (accelerated titration design for the first dose level and “3+3” design for other dose levels) will be administrated by intravenous infusion. When a dose level is confirmed to be safe by the Safety Monitoring Committee (SMC), backfill participants may be enrolled to further evaluate the safety, tolerability, preliminary efficacy, and PK characteristics. Phase 1b/2a (the dose expansion part) will initiate with selected indications (e.g., small cell lung cancer [SCLC], hepatocellular cancer, and non-small cell lung cancer) randomized to one of two different dose levels for dose optimization. Five other cohorts will enroll participants with melanoma, esophageal squamous cell carcinoma, triple-negative breast cancer, extensive-stage SCLC who have received 4 cycles of first-line induction therapy without disease progression, and other solid tumors to further assess the safety and tolerability, antitumor activity, and other exploratory endpoints of DB-1419. The study is currently open in multiple centers and is on recruiting. As of Dec 05, 2024, four participants have been enrolled in Australia and the United States. Enrollment in China is scheduled to commence in March 2025. Citation Format: Shun Lu, Charlotte Lemech, Afaf Abed, John Powderly, Stephen V. Liu, Ziming Li, Li Jiang, Wei Gu, Qiqi Liu, Lianghua Fang, Yang Qiu, Rong Shi, Yujie Liu. A phase 1/2a, multicenter, open-label, first in human study of a bispecific ADC targeting B7H3 and PDL1 (DB-1419) in advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT121.