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

Background: Invikafusp alfa (invika), a first-in-class (FIC) dual T-cell agonist, as monotherapy, showed 1) selective activation and expansion of mainly CD8⁺ Vbeta6 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 Vbeta6 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.