Abstract PS4-06-28: Initial clinical and pharmacology results from START-002: 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 mTNBC or

Abstract Background: Invikafusp alfa (“invika”) 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 TILs. Clinically, invika monotherapy generates a potent and selective expansion of mainly CD8+ Vβ6/ Vβ10 T cells. 0.08mg/kg was selected as RP2D and has demonstrated clinically meaningful single-agent anti-tumor activity in anti-PD(L)-1 resistant tumors, including objective responses in patients with TMB-H TNBC, CRC, NSCLC, and other tumor types resistant to anti-PD(L)-1. Based on these initial results, US FDA granted Fast Track Designation for invika in TMB-H CRC. Sacituzumab govitecan (SG), an antibody drug conjugate (ADC), is FDA approved for patients with metastatic TNBC and HR+/HER2- mBC. Preclinical studies indicate ADCs enhance tumor immunogenicity by promoting immunogenic cell death, increased antigen presentation, and tumor immune infiltration. Combination of ADCs with immunotherapy has the synergistic potential to enhance tumor eradication, help overcome resistance mechanisms, and improve overall treatment outcomes in breast cancer patients. Methods: START-002 is a Ph 1b/2 study to evaluate invika in combination with SG in patients with mTNBC or HR+/HER2- MBC. In Ph1b, patients were enrolled to 2 safety run-in cohorts at 0.04 mg/kg or 0.08mg/kg of invika with standard dose of SG (10mg/kg). Ph2 includes expansion cohorts for patients with mTNBC or HR+/HER2- mBC. Primary objective is to characterize the safety of invika + SG and to evaluate preliminary anti-tumor activity of the combination. Results: As of 15 Sep 2025, 11 patients with mTNBC or HR+/HER2- mBC were enrolled in 2 safety run-in cohorts. No DLTs were observed. Most common AEs (occurring in ≥2 patients) included neutrophil count decreased, diarrhea, alopecia, and stomatitis considered related to SG; cytokine release syndrome related to invika; fatigue and platelet count decreased considered related to either or both drugs. No ICANS or irAEs were reported. Treatment-related AEs were predominantly low grade 1 or 2, with exception of neutrophil count decreases, which were mainly grade 3. In the 0.04 mg/kg safety run-in cohort, 5 patients had at least 1 tumor assessment. Four experienced disease control (1 confirmed partial response (cPR) +3 SD) and 1 disease progression. The cPR was observed in a patient with HR+/HER2- mBC with liver and bone metastases, who progressed after 4 lines of endocrine and chemo-based regimens. The 3 patients with SD all experienced some degree of tumor reduction at the first scan but did not meet criteria for PR. Enrollment to the 0.08 mg/kg safety cohort has been completed with the first 3 patients reporting SD after completing at least one tumor assessment. Nanostring gene expression analyses in Ph1b demonstrated unequivocal expansion of Vβ6/10 T cells after the 1st dose of invika in mBC patients treated with this combination, similar to the selective expansion of Vβ6/10 T cells observed with invika monotherapy. Conclusions: Invika in combination with SG is feasible and safe at the doses tested. Combination safety profile is consistent with the known safety profile of each individual agent. Consistent with its mechanism of action, invika demonstrated unequivocal expansion of Vβ6/10 T cells when given with SG in mBC patients. Initial clinical anti-tumor activity including a cPR has been observed in patients with previously treated mBC. A RP2D has been selected and enrollment to Ph2 expansion cohorts is ongoing to further investigate the clinical activity of this promising novel combination therapy. Citation Format: S. J. Isakoff, A. Martynova, P. L. Bedard, A. Bardia, M. E. Gatti-Mays, N. LeVasseur, A. Varkaris, A. Bayliffe, W. Randolph, K. Srinivasan, S. McCue, K. Liu, Z. Su, K. Chin, V. Kaklamani, K. McCann, E. Hamilton. Initial clinical and pharmacology results from START-002: 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 mTNBC or HR+/HER2- mBC [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 PS4-06-28.