Efficacy and safety of RC48-ADC in triple-negative breast cancer subtypes: FUSCC-TNBC-umbrella trial results.

1109 Background: RC48-ADC is a novel HER2-targeting antibody-drug conjugate. This study evaluated RC48-ADC in pretreated triple-negative breast cancer (TNBC) patients with low HER2 expression, stratified by AR status. Methods: In this phase Ib/II trial, pretreated metastatic TNBC patients with low HER2 expression were enrolled: RL group (LAR subtype, n=20) and RO group (non-LAR subtype, n=20). All received RC48-ADC 2.0 mg/kg intravenously every 2 weeks. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: 40 heavily pretreated patients were enrolled (median 2 previous lines, range 1-7). In the overall population, best ORR was 35.0% (confirmed ORR: 32.5%), DCR 47.5%, median PFS 4.0 months. RL group showed better outcomes: best ORR 45.0% vs 25.0%, confirmed ORR 40.0% vs 25.0%, DCR 50.0% vs 45.0%, median PFS 4.9 vs 3.1 months. Median OS was not reached in RL group vs 16.6 months in RO group. Most common treatment-related adverse events (TRAEs) were AST increased (70% vs 40%) and ALT increased (65% vs 20%), mostly grade 1-2. Peripheral neuropathy occurred in 15% (RL) and 10% (RO) patients. Hematologic toxicities were mild. No treatment-related deaths occurred. Conclusions: RC48-ADC showed promising antitumor activity with manageable safety in pretreated TNBC patients with low HER2 expression, particularly in LAR subtype. The 35.0% ORR in heavily pretreated TNBC warrants further investigation in biomarker-selected populations. Clinical trial information: NCT03805399 . Efficacy and key safety outcomes of RC48-ADC in overall population and by subgroups. Outcomes Overall (n=40) RL Group (n=20) RO Group (n=20) Efficacy Confirmed ORR, n (%) 13 (32.5) 8 (40.0) 5 (25.0) Best ORR, n (%) 14 (35.0) 9 (45.0) 5 (25.0) DCR, n (%) 19 (47.5) 10 (50.0) 9 (45.0) Median PFS, months 4 4.9 3.1 Median OS, months NR NR 16.6 Best Response, n (%) CR 1 (2.5) 1 (5.0) 0 (0.0) PR 13 (32.5) 8 (40.0) 5 (25.0) SD 5 (12.5) 1 (5.0) 4 (20.0) PD 21 (52.5) 10 (50.0) 11 (55.0) Selected TRAEs, n (%) AST increased - Grade 1-2 22 (55.0) 14 (70.0) 8 (40.0) - Grade ≥3 0 (0.0) 0 (0.0) 0 (0.0) ALT increased - Grade 1-2 17 (42.5) 13 (65.0) 4 (20.0) - Grade ≥3 0 (0.0) 0 (0.0) 0 (0.0) Peripheral neuropathy <jats:td colspan="1