684P - Phase I trial of SHR-A1811 in HER2-expressing advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) and colorectal cancer (CRC)

Background

SHR-A1811 is a novel ADC consisting of a humanized, anti-HER2 IgG1 mAb bound to a DNA topoisomerase I inhibitor payload via a cleavable, tetrapeptide-based linker. We conducted a phase 1 trial to assess SHR-A1811 in HER2-expressing locally advanced or metastatic GC/GEJ and CRC.

Methods

Patient (pts) who had failed or had no available/applicable standard treatment were enrolled. Pts were given SHR-A1811 at 3.2, 4.8, 6.4 and 8.0 mg/kg (Q3W, iv) in an i3+3 dose-escalation (DE) scheme, followed by PK expansion at selected tolerable doses and then clinical expansion at RP2D. The primary endpoints were DLT, safety and RP2D.

Results

As of data cutoff (Apr. 21, 2023), 98 pts were enrolled, including 55 GC/GEJ and 43 CRC pts (HER2-positive, 72.7%/86.0%; ≥2 lines of prior therapy, 29.1%/67.4%). During DE, 1 DLT (grade 4 decreased platelet count) occurred at 8.0 mg/kg. Combined with dose-proportional systemic exposure of SHR-A1811, total antibody, and payload at 3.2-8.0 mg/kg, and general treatment tolerability and an ORR of 50.0% (6/12) at 6.4 mg/kg during DE and PK expansion, 6.4 mg/kg was established as RP2D. Overall, the respective ORR in GC/GEJ and in HER2-positve GC/GEJ at RP2D were 38.2% (21/55; 95% CI 25.4-52.3) and 43.8% (14/32; 95% CI 26.4-62.3); the corresponding ORR in CRC were 44.2% (19/43; 95% CI 29.1-60.1) and 46.9% (15/32; 95% CI 29.1-65.3). Additional tumor response data are shown in the table. The respective 6-mo PFS rates in GC/GEJ and in HER2-positve GC/GEJ at RP2D were 71.0% (95% CI 54.0-82.7) and 73.9% (95% CI 52.1-86.9); the corresponding rates in CRC were 75.6% (95% CI 57.9-86.6) and 85.5% (95% CI 65.6-94.3). Grade ≥3 TRAEs occurred in 67 of 98 pts (68.4%), with all events occurring in ≥10% being hematotoxicities. No interstitial lung disease was reported. Table: 684P

Efficacy outcomes

^∗HER2-expressing, IHC1+, 2+, or 3+ or ISH+. ^†HER2-positive, IHC3+ or IHC2+/ISH+. ^‡Unconfirmed response.

Conclusions

SHR-A1811 showed an acceptable safety profile and promising clinical activity in pts with HER2-expressing GC/GEJ and CRC. Further investigation was warranted.

Clinical trial identification

NCT04513223.

Editorial acknowledgement

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals, Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals, Co., Ltd.

Disclosure

Y. Shen, N. Dou, C. Huang: Financial Interests, Personal, Full or part-time Employment: Hengrui. All other authors have declared no conflicts of interest.