MRG002-006: A multicenter phase II clinical trial of MRG002-ADC for unresectable locally advanced or metastatic urothelial cancer.

4570 Background: Overexpression of HER-2 is associated with poor prognosis of urothelial cancer, and anti-HER-2 antibody-drug conjugate (ADC) has shown a promising efficacy among the UC patients (pts) in recently studies. MRG002 is a novel HER2-targeted ADC being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2 positive UC pts. Methods: This is a single-arm, multicenter phase II study. Eligibility criteria included: histologically HER2-positive (IHC 2+ or 3+) UC pts confirmed by a central-laboratory, ECOG PS 0-1, prior received ≥1 standard treatment. Approximately 40 pts will be enrolled. In the initial dose finding stage, pts were assigned to receive MRG002 at a dose of 2.6 mg/kg or 2.2 mg/kg administered by intravenous infusion every 3 weeks. The dose expanding stage was subsequentially performed based on preliminary results. The primary endpoint was ORR per RECIST 1.1, secondary endpoints are safety, DOR, PFS and, OS. Results: As of December 31, 2021, a total of 39 pts were enrolled. Enrollment is estimated be completed in February 28, 2022, and results are expected to be updated before publication. Nine pts were dosed at 2.6 mg/kg and 26 pts were dosed at 2.2 mg/kg. Based on safety analysis, 2.2 mg/kg was adopted as the recommended dosage. At baseline, 80% pts (28/35) had visceral metastasis. Most pts (28/35) received ≥ 2 lines of treatment and 29 (83%) pts had prior immune checkpoint inhibitor (ICI) therapy. By the cut-off date, 23 pts were evaluable and the ORR was 65% (15/23, 95% CI: 44.9%–81.2%), with 9% CR, and the DCR was 91% (21/23, 95% CI: 73.2%–97.6%). The estimated median PFS for the 23 pts was 5.5 months (95% CI: 2.7–NR). Among the evaluable pts, 1 CR responder achieved a response duration of more than 9.5 months. Subgroup analysis indicated that the ORR was 65% among the 17 pts post ≥ 2 lines of treatment, and 78% among the 18 pts failed platinum-containing chemotherapy and ICI treatment. Most common treatment-related AEs determined by investigators were anemia (34%), alopecia (34%), AST increased (31%), neutrophil count decreased (26%), neuropathy peripheral (23%), constipation (17%), decreased appetite (17%); most were grade 1 or 2 per CTCAE 5.0. The incidence of SAE was 17% (6/35). At the dose of 2.6mg/kg, 1 pts discontinued the treatment due to hypotension and 1 pts experienced ileus, which was considered caused by neurotoxicity of MRG002. There were no similar events described above happened among the pts at the dose of 2.2mg/kg. Conclusions: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients, especially in those progressed after platinum-containing chemotherapy and ICI therapy. MRG002 at 2.2mg/kg showed a manageable safety profile in these pts. Further evaluation is ongoing. Clinical trial information: NCT04839510.