Nectin-4 targeted ADC, SHR-A2102, in patients with advanced or metastatic urothelial carcinoma: A phase 1 study.

657 Background: SHR-A2102 is a novel ADC that consists of a fully humanized IgG1 monoclonal antibody targeting nectin-4, a cleavable linker, and a topoisomerase I inhibitor payload with high membrane permeability and potent cell-killing efficacy. We have initiated a first-in-human phase 1 study to assess the safety, tolerability, and efficacy of SHR-A2102 in advanced solid tumors. Here, we present preliminary findings, focusing on urothelial carcinoma. Methods: Patients (pts) with locally advanced unresectable or metastatic urothelial carcinoma, who had failed or were intolerant to standard therapies, were eligible. SHR-A2102 was given intravenously at 1, 2, 4, 6, 8 mg/kg on D1 Q3W and 4 mg/kg on D1 and D8 Q3W during dose escalation. 6 and 8 mg/kg were selected for dose and efficacy expansions. Results: As of Aug 2, 2024, 73 UC pts were enrolled (median age: 65 yrs; ≥2 lines of prior systemic therapies: 57.5%; prior ADC: 42.5%). Efficacy outcomes were summarized in Table. Confirmed ORR was 38.4% (28/73; 95% CI, 27.2–50.5) in all pts, and was 32.3% (10/31; 95% CI, 16.7–51.4) in the 6 mg/kg dose group and 50.0% (16/32; 95% CI, 31.9–68.1) in the 8 mg/kg dose group. 6-mo DoR rate was 59.3% (95% CI, 23.1–83.0) in all pts, and was 66.7% (95% CI, 5.4–94.5) and 54.0% (95% CI, 12.7–83.2) in the 6 and 8 mg/kg groups, respectively. Of note, 31 pts had received ADC prior to study treatment; among them, 12 (38.7%; 95% CI, 21.9–57.8) pts achieved confirmed PR. Overall, TRAEs of grade 3 or worse occurred in 32 (43.8%) pts, with the most common (≥10%) being anemia (23.3%), decreased WBC count (19.2%), and decreased neutrophil count (17.8%). Conclusions: SHR-A2102 showed promising anti-tumor activity in pts with advanced or metastatic urothelial carcinoma, even after ADC therapy, along with manageable safety profile. Clinical trial information: NCT05735275 . Efficacy summary. All UC pts(N=73) 6 mg/kg(N=31) 8 mg/kg (N=32) ADC pretreated pts (N=31) Best overall response, n (%) Confirmed PR 28 (38.4) 10 (32.3) 16 (50.0) 12 (38.7) SD 30 (41.1) 18 (58.1) 10 (31.3) 11 (35.5) PD 12 (16.4) 3 (9.7) 3 (9.4) 7 (22.6) NE 3 (4.1) 0 3 (9.4) 1 (3.2) Confirmed ORR, % (95% CI) 38.4 (27.2–50.5) 32.3 (16.7–51.4) 50.0 (31.9–68.1) 38.7 (21.9–57.8) DCR, % (95% CI) 79.5 (68.4–88.0) 90.3 (74.3–98.0) 81.3 (63.6–92.8) 74.2 (55.4–88.1) 6-mo DoR rate, % (95% CI) 59.3 (23.1–83.0) 66.7 (5.4–94.5) 54.0 (12.7–83.2) 60.0 (12. 6–88.2) 6-mo PFS rate, % (95% CI) 41.4 (23.6–58.4) 54.7 (24.0–77.4) 38.0 (13.4–62.7) 39.1 (16.6–61.3)