Abstract LB333: Synergistic antitumor efficacy and clinical translation of a novel dual-payload TROP2 ADC KH815 in combination with a PD-L1/VEGF bispecific antibody

Abstract Background: Although Anti PD- (L) 1-VEGF have shown substantial progress in cancer treatment, many patients still do not benefit from immune checkpoint inhibitor (ICI) monotherapy. To overcome resistance and enhance clinical efficacy, combination strategies with antibody-drug conjugates (ADCs) are being explored. Combining ADCs with immuno-oncology agents may enhance efficacy through complementary mechanisms. We hypothesize that the combination of a TROP2-targeted ADC, designed to induce immunogenic cell death, with a bispecific antibody targeting PD-L1 and VEGF can achieve synergistic antitumor activity by coupling direct tumor killing with enhanced immune activation and anti-angiogenesis. Preclinical Findings: We evaluated the combination of KH815, a first-in-class TROP2-targeted dual payloads ADC with dual topoisomerase I inhibitor (exatecan) and RNA polymerase inhibitor (triptolide), and a PD-L1/VEGF bispecific antibody in TROP2-high cell-derived xenograft (CDX) models. The combination of KH815 and PD-L1/VEGF bispecific antibody resulted in significantly enhanced tumor growth inhibition compared to either KH815 monotherapy or PD-L1/VEGF bispecific antibody monotherapy. The combination demonstrates potent synergistic efficacy, supporting the combination rationale of ADC-mediated killing with dual PD-L1/VEGF blockade. Early Clinical Data: In an ongoing, first-in-human Phase 1 study evaluating KH815 in participants with advanced solid tumors (NCT06885645), preliminary data indicated that KH815 had a favorable safety profile with a few low-grade toxicities and showed early signs of activity in squamous non-small cell lung cancer (sqNSCLC). The dose-escalation and back-fill cohorts remain ongoing. As of the data cutoff date (2025-12-22), within the dose range of 0. 5 to 5. 2mg/kg, no doselimiting toxicities (DLTs) were reported during the DLT-evaluable period, and no evidence of thrombocytopenia or interstitial lung disease were observed. Preliminary response were observed in the sqNSCLC subgroup, with a disease control rate (DCR) of 100% in medium dose group, particularly reaching an ORR of 50% at the dose level of 4 mg/kg. Antitumor activity was also observed in triple-negative breast cancer (TNBC). Conclusion: Preclinical studies have demonstrated enhanced antitumor effects with combination therapy involving KH815. Based on these early monotherapy clinical trial data, the findings suggest that a combination regimen based on the PD-L1/VEGF bispecific antibody may improve therapeutic efficacy, particularly in tumor types where KH815 monotherapy has shown initial activity. Following this, clinical studies evaluating the combination of KH815 with a PD-L1/VEGF bispecific antibody will also be initiated. Citation Format: Yonghao Zhao, Yiwei Li, Fusheng Wu, Lu Qi, Gang Lei, Yan Li, Yanhua Xu, Xiao Ke. Synergistic antitumor efficacy and clinical translation of a novel dual-payload TROP2 ADC KH815 in combination with a PD-L1/VEGF bispecific antibody abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB333.