Trastuzumab Rezetecan Shows Promise in HER2-Expressing GI Cancers

The novel HER2-targeted antibody-drug conjugate (ADC) trastuzumab rezetecan (SHR-A1811) showed meaningful antitumor activity with manageable toxicity in patients with HER2-expressing advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ) and colorectal cancer (CRC), according to phase 1 trial results published in the Journal of Clinical Oncology.¹

Gastric and colorectal cancers represent a substantial share of global cancer deaths, and HER2 has emerged as a clinically relevant target in both settings.² Although trastuzumab-based regimens have long anchored first-line treatment for HER2-overexpressing GC/GEJ, second- and later-line options have historically been limited.³ Accordingly, researchers decided to investigate trastuzumab rezetecan, which links a humanized HER2-targeting antibody to a DNA topoisomerase I inhibitor via a cleavable tetrapeptide linker. This design is intended to concentrate cytotoxic activity at the tumor while limiting off-target exposure.⁴

Between March 2021 and August 2023, 100 patients were enrolled in the open-label phase 1 trial (NCT04513223) across 16 centers in China. Of the study population, 57 had HER2-expressing GC/GEJ and 43 had HER2-expressing CRC. Participants received trastuzumab rezetecan intravenously every 21 days at doses ranging from 3.2 to 8.0 mg/kg, following an i3+3 dose-escalation design. The primary end points were dose-limiting toxicity (DLT) and overall safety.

Only 1 DLT occurred, a grade 4 platelet count decrease in the 8.0 mg/kg cohort, and 6.4 mg/kg every 3 weeks was ultimately selected as the recommended dose. Treatment-related adverse events (TRAEs) of grade 3 or higher were recorded in 66% of patients, most of which were hematologic: neutropenia, decreased white blood cell counts, and anemia. These events were generally reversible and managed through dose modifications or supportive care.

Five percent of patients stopped treatment due to TRAEs, a discontinuation rate comparable to that seen with trastuzumab deruxtecan in similar populations.⁵ Notably, the rate of treatment-related interstitial lung disease was only 2%, meaningfully lower than the 9.6% to 26.4% reported with trastuzumab deruxtecan across various tumor types.¹

Efficacy results were encouraging across all 3 subgroups analyzed. In 40 patients with HER2-positive GC/GEJ, the objective response rate (ORR) was 45.0%, with a median progression-free survival (PFS) of 9.0 months and a median overall survival (OS) of 16.3 months. Among 12 patients with HER2 IHC 2+ and ISH-negative disease—a group with very few approved treatment options—the ORR was 25.0%, with a durable median PFS of 12.2 months. In 37 patients with HER2-positive CRC, the ORR was 40.5%, with median PFS of 9.5 months and median OS of 22.7 months.

According to the study authors, these outcomes compare favorably with prior data from other HER2-targeted ADCs in similar settings. In previously treated HER2-positive GC/GEJ, trastuzumab deruxtecan and disitamab vedotin have reported ORRs of 24.8% to 42.8%, median PFS of 4.1 to 5.6 months, and median OS of 7.9 to 12.5 months.¹ In the CRC cohort, 2 phase 2 trials of trastuzumab deruxtecan demonstrated ORRs of 27.5% to 45.3% with a median OS of 13.4 to 15.5 months.¹ Also of note, trastuzumab rezetecan’s efficacy appeared largely preserved regardless of prior HER2-targeted therapy exposure.

The investigators acknowledged several limitations to their phase 1 study: the relatively small sample size inherent to a phase I design, restriction to Chinese clinical sites, and a GC/GEJ population predominantly with gastric (rather than gastroesophageal junction) primary tumors.

An editorial comment accompanying the article noted the findings represent an interesting signal warranting further development. Phase 2 and 3 investigations of trastuzumab rezetecan in these indications are anticipated, with ongoing exploration of an every-2-week dosing schedule to further reduce hematologic toxicity.¹

REFERENCES

1. Liu T, Luo S, Yuan X, et al. Trastuzumab rezetecan in human epidermal growth factor receptor 2–expressing advanced gastric cancer or gastroesophageal junction adenocarcinoma and colorectal cancer: a multicenter, open-label, phase I trial. J Clin Oncol. Published online March 4, 2026. doi:10.1200/JCO-25-00716

2. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi:10.3322/caac.21834

3. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X

4. Yao H, Yan M, Tong Z, et al. Safety, efficacy, and pharmacokinetics of SHR-A1811, a human epidermal growth factor receptor 2-directed antibody-drug conjugate, in human epidermal growth factor receptor 2-expressing or mutated advanced solid tumors: a global phase I trial. J Clin Oncol. 2024;42(31):3453-3465. doi:10.1200/JCO.23.02044

5. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02). Lancet Oncol. 2023;24(7):744-756. doi:10.1016/S1470-2045(23)00215-2