Carolina BioOncology Institute

Abstract Background Targeted therapies have transformed treatment for HR+/HER2- metastatic breast cancer (mBC), but optimal use depends on timely biomarker testing and matched therapy selection. This study evaluated national trends in PIK3CA, PTEN, AKT1 and ESR1 biomarker testing and treatment patterns among U.S. patients (pts) in community oncology clinics and examined factors associated with timely biomarker testing. Methods We conducted a retrospective cohort study of adult pts (≥18 years) with HR+/HER2- mBC treated between 01/01/2018 and 01/31/2025, using de-identified, electronic health record-derived data from the United States Flatiron Health Network. Eligible pts received at least one line of therapy at U.S. community oncology practices. Biomarker testing and treatment patterns across the first three lines of therapy (1L-3L) were analyzed descriptively. Logistic regression model evaluated associations between timely testing and baseline demographic, socioeconomic (SES), and clinical characteristics. Timely testing was defined as completing biomarker testing with results available before initiating a line of therapy for which an approved targeted treatment was available. Results Among 6,197 eligible pts who received 1L therapy, 3,550 progressed to 2L and 2,045 to 3L during the study period. Biomarker testing rates increased over time prior to 1L (from 4% in 2018 to 35% in 2024), 2L (from 9% to 69%), and 3L (from 13% to 83%). CDK4/6 inhibitors were the predominant 1L treatment regardless of biomarker status. In 2L and 3L, treatment patterns became more fragmented. Among pts with known PIK3CA mutations, the use of targeted approved therapies was 32% in 2L and 36% in 3L in 2019, compared to 27% and 29% in 2024. Among pts with ESR1+, elacestrant use rose from 22% in 2023 to 29% in 2024 in 2L and remained steady at 26-27% in 3L. In AKT1/PTEN+ pts, capivasertib use was 6% in 2L and 11% in 3L in 2024. Among pts with no test, or with negative or inconclusive biomarker results, 1% in 1L, 9% in 2L and 17% in 3L received Antibody Drug Conjugates in 2024. Treatment choices for dual-mutant (ESR1+ with either PIK3CA, AKT1 or PTEN) pts remained highly variable, with no dominant regimen: 27% received targeted therapies in 2L versus 34% in 3L. Pts were less likely to receive timely biomarker testing if they were older, lived in lower-SES areas, were treated at smaller practices, or had a worse ECOG score. However, timely testing became more common in more recent years. Conclusions Despite the availability of targeted therapies, major gaps persist in both biomarker testing and the uptake of these treatments. In 2024, nearly one-third of pts remained untested before 2L, and only 35% were tested prior to initiating 1L, limiting timely access to newly approved options. Even when actionable mutations were identified, over two-thirds of eligible pts did not receive matched therapies. Timely testing was less common in smaller practices and lower-SES settings, highlighting systemic barriers to precision oncology. To close these gaps, coordinated, equity-focused strategies are needed to improve timely testing and ensure appropriate use of targeted treatments across all pts populations. Study Number: SL46196 and PL-03044. Financial Statement: This study was sponsored by Genentech, Inc., a member of the Roche Group. Citation Format: I. M. Abbass, D. Lebovitch, N. Jain, T. Stricker, S. Nunnery, A. Pregenzer, E. Behan, R. Wang, L. Chen, P. Dhillon, Y. Liu, T. Szado, E. Yu, S. Ogale. Trends and Barriers in Biomarker Testing and Treatment Patterns in 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 PS1-12-27.

Abstract Background Claudin 18.2 (CLDN18.2) is a validated target in GEC, but novel approaches are needed. Givastomig/ABL111 (giva) is a first-in-class, bispecific antibody targeting tumoral CLDN18.2 and 4-1BB on adjacent T cells, preferentially activating T cells in the tumor microenvironment. Previously, the monotherapy phase 1 data showed that giva was safe and well tolerated in heavily pretreated GEC patients (pts). Here we report updated safety, efficacy, and biomarker data in GEC. Methods The study included dose escalation and dose expansion cohorts. During escalation, pts with solid tumors irrespective of CLDN18.2 expression received giva intravenously every 2 weeks (Q2W) across 8 dose levels (0.1-15 mg/kg), and every three weeks (Q3W) at 18 mg/kg. During expansion, CLDN18.2-positive (CLDN18.2+, ≥1% of tumor cells with ≥1+ intensity by immunohistochemistry) GEC pts were included. Differences in objective response rate (ORR) and disease control rate (DCR) between CLDN18.2-high pts (≥ 75% tumor cells of IHC 2+/3+) and CLDN18.2-low pts were evaluated by Chi-square test. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards. Outcomes for CLDN18.2+ GEC pts at doses ≥ 5 mg/kg are reported here. Results As of June 10, 2025, 45 pts with GEC received giva at 5 mg/kg (n=7), 8 mg/kg (n=5), 12 mg/kg (n=21), and 15 mg/kg (n=6) Q2W and 18 mg/kg Q3W (n=6). Pts had received a median of 3 prior therapies, including 74% with prior programmed death-(ligand) 1 inhibitor. No new safety signal was identified with longer follow up. No dose limiting toxicities were observed. Common treatment-related adverse events (≥15%, any grade/grade 3) included anemia (27%/9%), white blood cell count decrease (22%/7%), nausea (20%/2%), and ALT increase (16%/2%), AST increase (16%/4%). Partial responses (PR) were observed in 8 pts (1 PR each at 5 and 8 mg/kg, 4 PRs at 12 mg/kg, and 2 PRs at 18 mg/kg) with an ORR of 18%. CLDN18.2 expression in responders ranged from 11% (1+, 10%; 2+, 1%) to 100% (2+, 10%; 3+, 90%). Stable disease was observed in 14 pts (DCR 49%). 2 (4%) pts are ongoing, with 1 PR at 8 mg/kg at 33 months (mo) and 1 PR at 18 mg/kg at 10 mo. The median PFS (mPFS) and median OS (mOS) are 2.96 mo (95% CI 1.71-3.91) and 7.49 mo (95% CI 4.96-12.5), respectively. There is no statistical difference in ORR, DCR, PFS, or OS between CLDN18.2-high pts (n=21) and CLDN18.2-low pts (n=24): ORR 19% vs. 17% (p=1.00), DCR 57% vs. 42% (p=0.46), mPFS 3.68 mo vs. 1.84 mo, PFS hazard ratio (HR) 0.87 (p=0.67), and mOS 7.49 mo vs. 7.49 mo, OS HR 0.88 (p=0.74), respectively. Conclusions Giva was well tolerated up to 15 mg/kg Q2W and 18 mg/kg Q3W and continues to show encouraging monotherapy activity in heavily pre-treated GEC pts with a wide range of CLDN18.2 expression. Giva may have the ability to target pts with lower CLDN18.2 expression compared with other CLDN18.2 agents and is currently being tested in 1L GEC in combination with immunochemotherapy (NCT04900818). Citation Format: Samuel J. Klempner, Lin Shen, Farshid Dayyani, Jeremy Kratz, Xinjun Liang, Funan Liu, Zenning Wang, Laura Feller, Eugenia Girda, Hongming Pan, Sunnie Kim, Yanhong Deng, Ting Deng, Tianshu Liu, John Powderly, Kristen Spencer, Reva Schneider, Jordan Berlin, Claire (Cong) M. Xu, Christoph M. Ahlers, Xuejun M. Liu, Peter Sabbatini, Jinyoung Park, Yangmi Lim, Juyeun Jeon, Yuan Meng, Geoffrey Ku. Updated Safety, Efficacy and Biomarker Analysis from the Phase I Study of Givastomig, a Novel Claudin 18.2/4-1BB Bispecific Antibody, in Claudin 18.2 Positive Advanced Gastroesophageal Carcinoma (GEC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B016.

BackgroundT-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is an immune checkpoint receptor upregulated during anti-programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy for cancer. TIM-3 blockade may improve the antitumor activity of PD-1/PD-L1inhibition. This phase 1 study evaluated INCAGN02390, a novel, fully human Fc-engineered antibody against TIM-3.MethodsINCAGN02390 was evaluated by dose escalation at 10-1600 mg infused in 14-day cycles (every 2 weeks [Q2W]) in pretreated patients with select advanced/metastatic immunogenic solid tumors. Objectives included evaluation of safety/tolerability and maximum tolerated dose (MTD) (primary), pharmacokinetics, preliminary antitumor activity, pharmacodynamics, and immunogenicity (secondary).ResultsForty patients were enrolled and treated with INCAGN02390; 60% had previously received ≥3 lines of systemic therapy. Forty-eight percent had received a prior immune checkpoint inhibitor (anti−PD-1/PD-L1 therapy, 43%; anti-cytotoxic T-lymphocyte associated protein-4 therapy, 23%). No dose-limiting toxicities (DLTs) were observed and MTD was not reached. Twelve patients (30%) had treatment-related adverse events (TRAEs), most commonly fatigue and pruritus (n = 3 each); 3 (8%) had grade ≥3 TRAEs. Four patients (10%) experienced sponsor-assessed irAEs. One patient (3%) achieved partial response (duration, 5.7 months) and 6 had stable disease (≥56 days in all patients, >18 months in 2 patients).ConclusionsIn this heavily pretreated population, no DLTs were reported and modest efficacy was exhibited. A 400-mg Q2W dose was selected for phase II studies investigating INCAGN02390 as part of combination immunotherapies for advanced cancers.

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.

BackgroundALG.APV-527 is a bispecific antibody targeting costimulatory receptor 4-1BB (CD137) and the oncofetal tumor-associated antigen 5T4. 5T4 is expressed by multiple solid tumor types, such as non-small cell lung cancer, breast cancer, pancreatic, and gastrointestinal cancers with minimal expression in normal tissue. 4-1BB is an activation-induced costimulatory receptor that regulates immune responses of activated tumor-specific CD8 T cells and natural killer cells. ALG.APV-527 is designed to deliver a 5T4-conditional 4-1BB–mediated antitumor activity and minimize systemic immune activation and toxicity. Preclinically, ALG.APV-527 demonstrates robust antitumor activity by inhibiting the growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response,1 providing a rationale for evaluating ALG.APV-527 in patients with advanced solid tumors with the possibility of combining with immune checkpoint inhibitors (ICI).MethodsThe Phase 1 study is a first-in-human, open-label, multicenter trial consisting of up to six cohorts (0.1–15 mg/kg) in a 3+3 dose escalation of ALG.APV-527 monotherapy, administered intravenously Q2W, in adult patients with advanced solid tumors. Eligibility is limited to patients with tumor types identified as likely to express 5T4. Key endpoints include safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamic activity and clinical antitumor activity of ALG.APV-527.ResultsALG.APV-527 has been well tolerated in 18 enrolled patients, including 2 patients enrolled in dose level 5 (12 mg/kg). Enrollment and assessment of dose level 5 is ongoing. Most treatment-emergent adverse events (TEAEs) were mild to moderate and manageable in the clinic; Grade 1 (G1): 31 (41%), G2: 33 (43%), G3: 9 (12%), G4: 3 (4%), G5: 0. One patient experienced a G4 dose limiting toxicity of febrile neutropenia. MTD has not been determined. Pharmacokinetics was favorable: Serum concentrations were consistent with administered doses. Exposure is associated with changes in pharmacodynamic biomarkers reflecting ALG.APV-527 mode of action. Expression of 5T4 and 4-1BB was detected in tumor biopsies. Two heavily pretreated breast cancer patients experienced prolonged stable disease (SD) of over 7 months and 12 months (the second of which escalated to a higher dose level twice without any added adverse events and remains on study).ConclusionsAvailable data for ALG. APV-527 treatment demonstrates good tolerability, safety, biological activity, and prolonged SD in some patients suggesting clinical benefit of treatment. Upon determining the optimized dose, subsequent development will likely take place as a combination treatment.ReferenceNelson MH, Fritzell S, Miller R, Werchau D, Van Citters D, Nilsson A, Misher L, Ljung L, Bader R, Deronic A, Chunyk AG, Schultz L, Varas LA, Rose N, Håkansson M, Gross J, Furebring C, Pavlik P, Sundstedt A, Veitonmäki N, Ramos HJ, Säll A, Dahlman A, Bienvenue D, von Schantz L, McMahan CJ, Askmyr M, Hernandez-Hoyos G, Ellmark P. The bispecific tumor antigen-conditional 4-1BB x 5T4 agonist, ALG.APV-527, mediates strong T cell activation and potent anti-tumor activity in preclinical studies. Mol Cancer Ther. 2022;22(1).

3030 Background: ABBV-400 is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody conjugated to a potent inhibitor of topoisomerase 1 (Top1) payload. ABBV-400 has shown encouraging activity and demonstrated tolerability of dosages up to 3.0 mg/kg Q3W as monotherapy in patients with advanced solid tumors in an ongoing phase 1 study (1). Dosage optimization is a critical aspect of oncology drug development and FDA Project Optimus has focused on reformulating the dosage selection paradigm for oncology products. The phase 1 study included a dose optimization phase in mCRC patients in which 3 doses were evaluated (1.6, 2.4 and 3.0 mg/kg Q3W) to determine the optimal dose for further development. Herein, exposure-response analyses are reported to determine optimal monotherapy dose in mCRC patients. Methods: Data across a range of doses (1.6 – 6.0 mg/kg Q3W) from the phase 1 study (NCT05029882) were used. Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to characterize ABBV-400 conjugate and unconjugated payload PK and the relationship between exposures and efficacy (objective response rate [ORR]) and safety (Grade (Gr) ≥ 3 neutropenia, anemia and thrombocytopenia) endpoints. Relative dose intensity (RDI) analysis was performed. Results: ABBV-400 conjugate and payload PK were adequately described by a combined multi-analyte population PK model with first order kinetics (n=204). ABBV-400 conjugate average concentration was a better predictor of response and showed that higher exposure correlated with higher probability of response (n=122 CRC, ORR, p < 0.05) and safety events (n=204, Gr ≥ 3 neutropenia, anemia and thrombocytopenia, p < 0.001). Dose intensity analyses showed greater number of dose reductions for 3 mg/kg Q3W with effective (actual) dose received of 2.6 mg/kg Q3W in mCRC patients. E-R analyses for safety and efficacy and dose intensity analyses in mCRC 3L+ patients indicate that both 2.4 and 3.0 mg/kg doses provided meaningful efficacy (ORR); while the 3.0 mg/kg dose may provide higher response rates, the 2.4 mg/kg Q3W dosing regimen provides an optimal balance of safety and efficacy compared to 3.0 mg/kg Q3W. Conclusions: Population PK, E-R for efficacy and safety and RDI analyses and totality of clinical data supported the selection of 2.4 mg/kg Q3W as optimal ABBV-400 monotherapy dose for further study in mCRC patients. 1. Sharma M, et al. ASCO 2023. Abstract 3015. Clinical trial information: NCT05029882 .

2596 Background: Tifcemalimab, a humanized IgG4 antibody against BTLA, showed a tolerable safety profile and preliminary single-agent anti-tumor activity in pretreated pts with advanced malignancies. Here we report the dose escalation and cohort expansion study of tifcemalimab in combination with toripalimab (anti-PD-1) in pts with pretreated advanced malignancies. Methods: Eligible pts with advanced malignancies refractory to standard therapies were enrolled in the dose escalation and the cohort expansion phases of this study (NCT04137900). During dose escalation, tifcemalimab was administered at escalating doses of 20, 70, 200 and 500 mg in combination with 240 mg toripalimab given intravenously once every three weeks (Q3W) until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated. Study objectives included safety and efficacy. During cohort expansion, the combination of tifcemalimab (200mg Q3W) and toripalimab (240 mg Q3W) were further evaluated in five indication-specific cohorts (melanoma, non-small cell lung cancer [NSCLC], renal cell carcinoma [RCC], urothelial carcinoma [UC] and lymphoma) for safety and efficacy. Results: By December 16, 2023, a total of 16 pts received study treatment during dose escalation and 69 pts were treated during cohort expansion from 18 participating sites from the US. Pts were heavily pretreated with a median of 4 prior lines of therapy. The median age was 65 (range 32-85) years, 69% of pts were male. As of December 16, 2023, the median follow-up was 11.4 weeks. No DLT was observed during dose escalation. Treatment-emergent adverse event (TEAEs) occurred in 92% pts, 44% experienced grade 3 or higher TEAEs, including 2 (2%) treatment-related Grade 5 events. The most common TEAEs included: fatigue (27%), diarrhea (17%), nausea (17%), anemia (15%), arthralgia (15%), decreased appetite (15%), and dyspnea (15%). TEAE led to discontinuation of study drug in 6% of pts. Nineteen percent of pts experienced immune-related AEs. No new safety signal was identified outside the known risk profiles of tifcemalimab and toripalimab. Among 14 evaluable pts in the dose escalation phase, 8 had stable disease. Among 57 evaluable pts in the cohort expansion phase, 1 complete response (lymphoma), 6 partial responses (2 melanoma, 2 RCC, 1 NSCLC, 1 UC) and 17 stable disease were observed. The ORRs were 5%, 11%, 17%, 18% and 33% in the NSCLC, melanoma, UC, RCC and lymphoma cohorts respectively. All responders were refractory to prior immunotherapy and all responses were still ongoing by the cutoff date. Conclusions: Tifcemalimab in combination with toripalimab showed preliminary efficacy in immunotherapy-refractory pts with a manageable safety profile. Phase II combination studies in various advanced solid tumors are ongoing. Clinical trial information: NCT04137900 .