Abstract CT045: Initial clinical and translational results and selection of recommended phase 2 dose (RP2D) from START-002: A Phase 1b/2 study of invikafusp alfa, a first-in-class dual T-cell agonist, in combination with sacituzumab govitecan in meta

Abstract Background: Invikafusp alfa (invika), a first-in-class (FIC) dual T-cell agonist, as monotherapy, showed 1) selective activation and expansion of mainly CD8⁺ Vβ6 T cells with a central memory phenotype in peripheral blood and tumor; 2) confirmed objective responses in patients with anti-PD(L)1-resistance across 7 different solid tumors including TNBC. Preclinical tumor models including breast cancer showed combining invika with cytotoxic agents enhanced antitumor activity. Sacituzumab govitecan (SG), a TROP-2-directed antibody-drug conjugate (ADC), is approved for metastatic TNBC and HR+/HER2- mBC. Published data suggest that ADCs enhance tumor immunogenicity, providing further rationale for combination with invika. Methods: START-002 is an ongoing Phase 1b/2 study evaluating invika in combination with SG in mTNBC or HR+/HER2- mBC. Phase 1b had two cohorts (invika at 0.04 or 0.08 mg/kg) in combination with SG (10 mg/kg). After recommended Phase 2 dose (RP2D) selection, Phase 2 expansion cohorts in mTNBC and HR+/HER2- mBC was initiated. Results: Translational and Clinical Pharmacology (Phase 1b; n = 8): Nanostring showed selective TRBV6 expansion (∼10% to ∼40% of total T cells) in all patients at both 0.04 and 0.08 mg/kg of invika peaking ∼ 7 days post the 1st dose, similar to what was seen with invika monotherapy. Dose-dependent increases in Cmax and AUC similar to monotherapy were observed, indicating SG did not impact invika exposure. Initial Clinical Results (Phase 1b/2): In 22 patients (9 TNBC and 13 HR+/HER2- mBC) treated, the most common adverse events were neutropenia, diarrhea, alopecia, and stomatitis (SG-related); Grade 1& 2 cytokine release syndrome (invika-related); and fatigue and thrombocytopenia (attributed to either or both). Among 10 patients (4 TNBC and 6 HR+/HER2- mBC) who had at least 1 post treatment tumor evaluation, two HR+/HER2- patients had confirmed partial responses, one TNBC patient had an unconfirmed complete response, and six patients had stable disease (90% disease control rate). Five of 10 patients remained on treatment for ≥5 months. Invika 0.08 mg/kg in combination with SG 10 mg/kg was selected as RP2D. Conclusions: This first-in-human study demonstrates 1) the feasibility and safety of invika, a FIC dual T-cell agonist, in combination with SG, a standard-of-care ADC; 2) dose-dependent expansion of Vβ6 T cells; 3) antitumor activity, including confirmed responses, in heavily pre-treated mBC patients. Phase 2 expansion is ongoing to further study the efficacy and safety of this novel combination in patients with mBC. Citation Format: Steven J Isakoff, Anastasia Martynova, Philippe L Bedard, Margaret E Gatti-Mays, Nathalie LeVasseur, Andreas Varkaris, William Randolph, Karunya Srinivasan, Shannon McCue, Zhenming Shun, Ke Liu, Zhen Su, Kevin Chin, Virginia Kaklamani, Kelly McCann, Erika Hamilton. Initial clinical and translational results and selection of recommended phase 2 dose (RP2D) from START-002: A Phase 1b/2 study of invikafusp alfa, a first-in-class dual T-cell agonist, in combination with sacituzumab govitecan in metastatic triple-negative or HR+/HER2- breast cancer [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(8_Suppl):Abstract nr CT045.