Abstract CT198: A first-in-human study evaluating safety, tolerability and efficacy of TEV-56278, as monotherapy and in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors

Abstract Background: Direct immune stimulation using cytokines, including interleukin-2 (IL-2), drives immune-mediated cytotoxic cancer responses. Toxicity of high-dose IL-2 limits its activity and clinical utility. Preclinical studies show that targeting IL-2 to specific cell subsets substantially increases its therapeutic index. In multiple cancers, tumor-infiltrating T-cells display higher levels of programmed cell death protein (PD-1) relative to circulating and tissue-resident T-cells, making PD-1 a target for selective delivery of IL-2. TEV-56278 is a human antibody-cytokine fusion protein comprised of an antibody targeting PD-1 and attenuated IL-2. TEV-56278 is designed to deliver IL-2 selectively to PD-1+ T cells, thus amplifying anti-tumor T-cell activity while minimizing off-target systemic toxicities. Furthermore, its binding to PD-1 receptors does not block ligand binding and does not compete for binding with known PD1-blocking antibodies, allowing for combination use. Here, we describe a phase 1a/1b trial design evaluating TEV-56278 as monotherapy and in combination with pembrolizumab. Methods: This multicenter, open-label, Phase 1, first-in-human, dose-escalation, dose-expansion study is being conducted in 3 parts. Patients >18 years of age with various locally advanced or metastatic solid tumors who have progressed on or were intolerant to standard of care therapies and resistant to anti-PD-(L)1 treatment will be included. The primary objective of dose escalation is to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of TEV-56278 alone and in combination with pembrolizumab. Secondary objectives include assessment of pharmacokinetics (PK) and anti-tumor activity. Determination of the maximum tolerated dose will be based on a Bayesian optimal interval (BOIN) design. Additional pharmacodynamic and biomarker data, including biomarkers of IL-2 signaling and activation of PD-1+ T cells, will be collected during backfill of monotherapy dose cohort(s). After determination of the monotherapy RP2D, 2 cohorts of patients with locally advanced or metastatic primary and secondary resistant melanoma (A&B) and 2 cohorts of primary and secondary resistant non-small cell lung cancer (NSCLC; [C&D]) will be accrued to evaluate the primary objective of anti-tumor activity. The Simon two-stage admissible design will be used for Cohort B (RP2D and a dose <rp2d); a="" bayesian="" approach="" will="" be="" used="" for="" a,="" c,="" and="" d="" with="" rp2d.="" the="" objective="" response="" rate="" (orr)="" duration="" of="" (dor)="" assessed="" based="" on="" evaluation="" criteria="" in="" solid="" tumors="" (recistv1.1).="" secondary="" objectives="" include="" safety,="" tolerability,="" pk="" other="" efficacy="" measures.="" this="" study="" is="" open="" participant="" enrollment,="" targeting="" up="" to="" 240="" patients="" (nct06480552). Citation Format: Jason John Luke, Lillian L. Siu, Mario Sznol, Yael Shalit, Jerry Weaver, Samhita Chakraborty. A first-in-human study evaluating safety, tolerability and efficacy of TEV-56278, as monotherapy and in combination with pembrolizumab in participants with locally 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 CT198.