RC48G001: A phase 2 study of disitamab vedotin in HER2-expressing previously treated advanced UC.

LBA631 Background: An estimated 60%-80% of patients (pts) with UC have HER2-expressing tumors. DV is an ADC comprising a novel anti-HER2 antibody, disitamab, and an MMAE payload. DV demonstrated promising antitumor activity and a manageable safety profile as monotherapy in Chinese pts with HER2-expressing (IHC 1+ or greater) la/mUC refractory to prior therapies. We report the primary analysis from Cohorts A and B of the global RC48G001 study assessing DV monotherapy in pts with HER2-expressing la/mUC (HER2-positive: IHC 3+, or IHC 2+/ISH-positive [Cohort A]; HER2-low: IHC 2+/ISH-negative, or IHC 1+ [Cohort B]) who progressed following systemic therapy. Methods: RC48G001 (or C5731002) is a global, multicohort, single-arm, open-label, phase 2 study that enrolled pts with la/mUC who received 1-2 prior systemic therapies (incl. a platinum-containing regimen). HER2 expression was determined by central laboratory using the VENTANA HER2 IHC and HER2 Dual ISH DNA Probe Cocktail assays. Pts received 1.5 mg/kg DV monotherapy IV once per 2-week cycle. The primary endpoint (EP) was cORR per RECIST 1.1 by BICR. Secondary EPs included DOR, DCR, PFS (all per RECIST 1.1 by BICR), OS, and safety. A genAI tool (09/05/25; Pfizer; GPT-4o) assisted with the 1st draft; authors assume content responsibility. Results: At data cutoff (Sep 12, 2025), 73 pts were enrolled in Cohort A and 78 pts in Cohort B. 54.8% and 39.7% of pts had ECOG PS 0, and 68.5% and 82.1% had visceral disease in each cohort, respectively. Cohort A included 69.9% pts with IHC 3+ and 30.1% pts with IHC 2+/ISH-positive la/mUC. Cohort B included 28.2% pts with IHC 1+ and 69.2% pts with IHC 2+/ISH-negative la/mUC. Median follow-up was 11.3 months for Cohort A and 17.1 months for Cohort B. Pts received a median of 9 DV cycles in both cohorts. cORR per BICR was 54.9%, with a CR rate of 16.9%, in Cohort A, and 52.6%, with a CR rate of 18.4%, in Cohort B (Table). mPFS by BICR was 5.7 months in both cohorts. mOS was 20.0 months and 17.0 months in Cohort A and B, respectively. Grade ≥3 TRAEs occurred in 62 (41.1%) pts, with fatigue (13.9%) being the most common. 16.6% of pts discontinued treatment (tx) due to AEs, most commonly peripheral sensory neuropathy (6.0%). Conclusions: This is the first presentation of DV monotherapy outcomes in a global population with HER2-expressing la/mUC. DV demonstrated promising antitumor activity and a manageable safety profile, consistent with results from China, supporting further evaluation. Clinical trial information: NCT04879329 . Cohort A Cohort B n=71 n=76 cORR, a n % (95% CI) - CR - PR 39 (54.9)(42.7, 66.8)12 (16.9) 27 (38.0) 40 (52.6) (40.8, 64.2) 14 (18.4) 26 (34.2) mDOR, a mo (95% CI) 5.8 (4.6, 9.4) 6.9 (4.7, 9.4) DCR, a,b n % (95% CI) 62 (87.3) (77.3, 94.0) 64 (84.2) (74.0, 91.6) n=73 n=78 mPFS, a mo (95% CI) 5.7 (4.1, 7.1) 5.7 (4.6, 6.9) mOS, mo (95% CI) 20.0 (12.8, NE) 17.0 (9.6, 23.9) a By BICR. b Defined as the proportion of pts with confirmed CR/PR, or who met SD criteria at least once after tx initiation at an interval of ≥5 wk.