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 While 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 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 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 in nature—namely 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 reached 40.5%, with a median PFS of 9.5 months and a 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 II 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.

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.

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.

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.