A pooled analysis of JSKN003, a biparatopic anti-HER2 antibody conjugate (ADC), in patients with advanced HER2-overexpressing (IHC 3+) gastrointestinal tumors.

3022 Background: JSKN003 is a biparatopic HER2-targeting ADC conjugated with a topoisomerase I inhibitor (TOP1i) payload via a dibenzocylooctyne tetrapeptide linker. The efficacy and safety of JSKN003 in several solid tumors have been highlighted in previous reports. Methods: JSKN003-101 and JSKN003-102 are dose escalation and expansion studies involving Australian and Chinese patients (pts) with metastatic solid tumors. This pooled analysis of two studies was performed to assess the efficacy and safety in advanced HER2-overexpressing (IHC 3+) gastric or gastroesophageal cancer (GC/GEJC) and colorectal cancer (CRC) pts. Results: As of data cutoff (18 Dec 2024), 40 patients with HER2-overexpressing (IHC 3+ by local lab) gastrointestinal tumor (23 in GC/GEJC and 17 in CRC) were enrolled across 7 dose levels: 2.1 mg/kg (n = 1), 4.2 mg/kg (n = 1), 5.2 mg/kg (n = 1), 6.3 mg/kg (n = 33), 7.3 mg/kg (n = 1), 8.4 mg/kg (n = 2), 10.5 mg/kg (n = 1). The median follow-up time of two studies was 7.16 months. Most pts were heavily pretreated (37.5% had ≥3 lines of prior treatment; 45.0% received irinotecan; 67.5% received anti-HER2 therapy; 42.5% received IO therapy). Four of the 17 CRC pts were RAF/RAS mutations (n = 2 RAS-mut, n = 2 RAF-mut). Thirty-nine patients had at least one tumor assessment after baseline. The overall response rate (ORR) per RECIST v1.1 in HER2-overexpressing gastrointestinal tumor was 66.7% and the disease control rate (DCR) was 94.7%. Among 22 GC/GEJC pts, the ORR was 68.2% and DCR was 95.5%. The median progression-free survival (PFS) was 9.59 months (95% CI: 2.96, NE) with 66.3% (95% CI: 29.4, 87.1) PFS rate at 6 months. Among 17 CRC pts, the ORR was 64.7% (66.7% in RAF-wild pts, n = 15) and DCR was 94.1%. The mPFS was 13.77m (95% CI: 7.1, NE) with 94.1% (95% CI: 65, 99.2) PFS rate at 6 months. The median overall survival (OS) was not yet mature. Notably, one BRAF-mut patient achieved PR at first tumor assessment after baseline, two RAS-mut pts achieved PR and duration was over 48 weeks. The most common treatment-related adverse events (TRAEs) included nausea, diarrhea, neutropenia, decreased appetite, vomiting, rash, anemia and fatigue. Grade 3/4 neutropenia was observed in 2 (5.0%) pts, Grade 3/4 anemia was observed in 1 (3.0%) pts. No TEAEs led to death or treatment discontinuation. Interstitial lung disease (ILD) occurred in 3 (7.5%; n = 2 G1; n = 1 G2) pts. Conclusions: JSKN003 demonstrated promising efficacy in heavily pretreated pts with advanced HER2-overexpressing gastrointestinal tumors, with a manageable and predictable safety profile. Clinical trial information: NCT05494918 , NCT05744427 .