ASP2998, a trophoblast cell-surface antigen 2 (TROP2)–targeted immunostimulatory antibody-drug conjugate with dual payloads, in patients with locally advanced unresectable or metastatic solid tumors: A phase 1b/2 study.

TPS2665 Background: TROP2 is a type I transmembrane glycoprotein involved in cell proliferation, migration, and survival, that is upregulated in and is associated with poor prognosis in patients (pts) with several malignancies including urothelial carcinoma, non-small cell lung cancer, gastric cancer and breast cancer. TROP2 antibody drug conjugates (ADCs) have demonstrated clinical efficacy and are approved for metastatic breast cancer and epidermal growth factor receptor-mutated non-small cell lung cancer. ASP2998 is a dual-payload (topoisomerase I inhibitor plus stimulator of interferon genes STING agonist) immunostimulatory ADC targeting TROP2. ASP2998 monotherapy has shown preclinical antitumor activity in a syngeneic mouse model bearing human TROP2-expressing tumors that was superior to single-payload topoisomerase I inhibitor TROP2 ADCs. Methods: This first-in-human, multicenter, open-label, phase 1b/2 dose escalation (DESC) and expansion (DEXP) study, is evaluating the safety, tolerability, recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD), preliminary antitumor activity, and pharmacokinetic profile of ASP2998 in pts with locally advanced unresectable or metastatic solid tumors. Initial DESC of ASP2998 includes 6 dose levels (n≥3 per dose level) to determine the RP2D and/or MTD. Eligible pts (aged ≥18 years) include those with urothelial carcinoma, non-small cell lung cancer, gastric/gastroesophageal junction cancer, or locally confirmed human epidermal growth factor receptor 2-negative breast cancer, who have progressed on, are ineligible for, or have refused all available standard therapies per investigator’s decision. At DEXP, multiple dose levels of ASP2998 may be evaluated based on the totality of data to optimize dosage in at least one tumor type (n≤40 per dose level per tumor type). Eligible DEXP pts with non-small cell lung include those who have received ≤3 prior lines of therapy and known programmed death-ligand 1 status, without actionable oncogenic alterations, who have progressed on or after platinum-based chemotherapy and/or checkpoint inhibitors. Eligible DEXP pts with urothelial carcinoma include those who have received ≤3 prior lines of therapy and progressed on or after enfortumab vedotin plus pembrolizumab. Prior exposure to TROP2, STING agonists or topoisomerase I inhibitor-directed therapy is permitted at DESC but not DEXP. Tumor-specific backfill pts can be enrolled in the DESC cohorts at dose levels that are deemed safe and tolerable, and will be counted towards the corresponding tumor-specific DEXP cohorts. Recruitment is ongoing with 196 planned pts (36 in DESC; 160 in DEXP). ClinicalTrials.Gov Identifier: NCT07287995. Clinical trial information: NCT07287995 .