Abstract Background: Invikafusp alfa (STAR0602) is a novel, first-in-class dual T cell agonist that selectively targets subsets of T cells expressing the germline-encoded variable Vβ6 and Vβ10 variant TCRs that are enriched in tumor-infiltrating lymphocytes. The completed Ph1 dose escalation of monotherapy invikafusp alfa identified a recommended Ph 2 dose (0.08mg/kg IV Q2W) and demonstrated clinically meaningful single-agent anti-tumor activity in anti-PD(L)-1 resistant tumors, including objective responses in patients with tumor mutation burden-high (TMB-H) colorectal cancer (CRC), non small cell lung cancer, and gastroesophageal junction cancer. Invikafusp alfa promoted potent and selective expansion of mainly CD8+ Vβ6/ Vβ10 T-cells. Based on these initial clinical results, US FDA granted Fast Track Designation for invikafusp alfa in TMB-H CRC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC), is FDA approved for patients with pre-treated unresectable locally advanced (LA) or metastatic triple-negative breast cancer (mTNBC) and HR-positive/HER2-negative breast cancer (HR+/HER2- mBC). Preclinical studies indicate that treatment with ADCs enhances tumor immunogenicity by promoting immunogenic cell death, increased antigen presentation and tumor immune infiltration. These effects are likely mediated by cytotoxic tumor cell death and subsequent release of tumor-associated antigens. Recent clinical results from the ASCENT-04 trial demonstrated improved progression-free survival in previously untreated PD-L1+ mTNBC patients who received the combination of SG and pembrolizumab, thus confirming the clinical potential of combining an ADC with an IO agent in metastatic breast cancer. START-002 explores the hypothesis that combining SG’s immunomodulatory potential with invikafusp alfa’s selective activation and expansion of tumor-reactive Vβ6/Vβ10 T-cells, will enhance anti-tumor responses and result in improved clinical outcomes in breast cancer patients. Methods: Study design: START-002 is a phase 1b/2 open label, multi-center study to determine the safety, feasibility, and anti-tumor activity of invikafusp alfa in combination with SG in patients with mTNBC or HR+/HER2- mBC. Patients will receive SG on Days 1 and 8 of a 21-day cycle and STAR0602 only on Day 8. Ph1 enrollment will start with an initial 5 patient Safety Run-in cohort at the 0.04 mg/kg dose level of STAR0602 + SG and may proceed to include 1 of 2 dose groups of STAR0602 (0.08 mg/kg or 0.02 mg/kg) + SG in order to determine the recommended dose of STAR0602 that will be used in the Ph2 cohort expansion phase. Using a Simon’s 2-stage design, Ph2 will enroll 20 participants into 2 separate expansion cohorts of patients who have either mTNBC or HR+/HER2- mBC. Major eligibility criteria: TNBC cohort: LA or mTNBC, ≥2 prior systemic therapies, at least 1 for metastatic disease. HR+/HER2- mBC cohort: LA or metastatic HR+/HER2- BC, prior endocrine based therapy and ≥1 additional systemic therapy in the metastatic setting. Prior topoisomerase 1 inhibitor therapy is excluded. Primary objective and endpoint: The primary objective of this Ph1b/2 study is to characterize the safety and tolerability of invikafusp alfa when given together with sacituzumab govitecan, and to evaluate preliminary anti-tumor activity of the combination treatment. The primary endpoints are safety and overall response rate per RECIST and iRECIST. Enrollment to the Ph1 safety run-in cohorts is ongoing. Clinical Trial Information: NCT06827613 Citation Format: S. Isakoff, P. Bedard, A. Martynova, A. Bardia, M. Gatti-Mays, N. LeVasseur, A. Varkaris, W. Randolph, K. Srinivasan, S. McCue, A. Bayliffe, K. Liu, Z. Su, K. Chin, V. Kaklamani, K. McCann, E. Hamilton. A phase 1b/2 clinical investigation of invikafusp alfa (STAR0602), a first-in-class dual T-cell agonist, in combination with sacituzumab govitecan in patients with metastatic TNBC or HR+/HER2- MBC (START-002 trial) 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 PS5-09-16.
Isakoff et al. (Tue,) studied this question.