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

Author(s): Tianshu Liu, MD¹; Suxia Luo, MD²; Xianglin Yuan, MD³; Dong Liu, MD⁴; Zhaofei Zhou, BS⁵; Xin Wang, MD⁶; Yanhong Deng, MD⁷; Jun Chen, MD⁸; Mulin Liu, MD⁹; Huan Zhou, MD¹⁰; Xiubao Ren, MD¹¹; Wensheng Qiu, MD¹²; Yu Cao, MD¹³; Shirong Cai, MD¹⁴; Yugang Dong, MD¹⁵; Yanqiao Zhang, MD¹⁶; Wei Wang, MM¹⁷; Jun Liang, MD¹⁸; Pingsheng Xu, MD¹⁹; Heli Liu, MD²⁰; Kaijing Zhao, PhD²¹; Yang Fan, MM²¹; Ning Dou, PhD²¹; Chuanpei Huang, MD²¹; Jin Li, MD²²;

Source: DOI: 10.1200/JCO-25-00716

Dr. Anjan Patel's Thoughts

Encouraging phase I signal for this HER2-targeted Antibody-drug conjugate (ADC) in heavily pretreated GI cancers, 45% overall response rate (ORR) and 16.3mo median overall survival (OS) in HER2-positive gastric compares favorably with T-DXd benchmarks, and the 40.5% objective response rate (ORR) with 22.7mo OS in HER2-positive colorectal cancer (CRC) is notable. The 2% ILD rate looks meaningfully better than T-DXd’s reported range, which could be a real differentiator. Hematologic toxicity is substantial but manageable. Small China-only phase I, but worth watching closely as this advances.

PURPOSE

Antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) could be a promising strategy for HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ) and colorectal cancer (CRC). We conducted a phase I trial to assess trastuzumab rezetecan, a novel HER2-targeted ADC, in HER2-expressing advanced GC/GEJ and CRC.

METHODS

Patients with HER2-expressing advanced GC/GEJ and CRC whose disease progressed on and/or had no available/applicable standard treatment were enrolled. Patients were intravenously given trastuzumab rezetecan 3.2, 4.8, 6.4, and 8.0 mg/kg (once every 3 weeks) in an i3+3 dose-escalation scheme, followed by pharmacokinetics expansion selected doses and then clinical expansion. The primary end points were dose-limiting toxicity (DLT) and safety.

RESULTS

Between March 30, 2021, and August 1, 2023, 100 patients were enrolled (57 with GC/GEJ and 43 with CRC). One DLT occurred in the 8.0 mg/kg dose cohort. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 66 (66.0%) patients. Only 5 (5.0%) patients discontinued treatment because of TRAEs. In HER2-positive GC/GEJ (n = 40), trastuzumab rezetecan achieved an objective response rate (ORR) of 45.0%, a median progression-free survival (PFS) of 9.0 months (95% CI, 7.0 to 11.3), and a median overall survival (OS) of 16.3 months (95% CI, 12.4 to not reached [NR]). In GC/GEJ with HER2 immunohistochemical 2+ and in situ hybridization–negative (n = 12), trastuzumab rezetecan had an ORR of 25.0%, a median PFS of 12.2 months (95% CI, 2.8 to 14.0), and an immature median OS. In HER2-positive CRC (n = 37), trastuzumab rezetecan had an ORR of 40.5%, a median PFS of 9.5 months (95% CI, 7.3 to 11.2), and a median OS of 22.7 months (95% CI, 17.5 to NR).

CONCLUSION

Trastuzumab rezetecan showed tolerable safety and preliminary efficacy in HER2-expressing advanced GC/GEJ and CRC.

Author Affiliations

¹Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ²Phase I Clinical Research Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; ³Department of Digestive Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ⁴Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ⁵Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China; ⁶Department of GCP, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China; ⁷Oncology Internal Medicine First District, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; ⁸Oncology Department, The First Affiliated Hospital of Nanchang University, Nanchang, China; ⁹Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; ¹⁰Phase I Clinical Trial Lab, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; ¹¹Biotherapy Department, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China; ¹²Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China; ¹³Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China; ¹⁴Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; ¹⁵Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; ¹⁶Gastroenterology Ward 2, Harbin Medical University Cancer Hospital, Harbin, China; ¹⁷Gastroenterology and Urology Department II, Hunan Cancer Hospital, Changsha, China; ¹⁸Medical Oncology, Peking University International Hospital, Beijing, China; ¹⁹Phase I Clinical Research Laboratory, Xiangya Hospital Central South University, Changsha, China; ²⁰Gastroenterology, Xiangya Hospital Central South University, Changsha, China; ²¹Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co, Ltd, Shanghai, China; ²²Department of Oncology, Shanghai East Hospital, Shanghai, China

Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial

Open-label, phase 3 clinical trial, 382 patients were randomized to receive chemotherapy alone or chemotherapy plus tumor debulking. The overall survival rates were not statistically different, with a median overall survival in the chemotherapy alone group of 27.5 m vs 30.0 m in the chemotherapy plus tumor debulking group hence tumor debulking added to palliative systemic chemotherapy did not result in significantly improved survival compared with chemotherapy alone in patients with multiorgan metastatic colorectal cancer.

Atezolizumab plus FOLFOX for Stage III Mismatch Repair–Deficient Colon Cancer

This is a strong adjuvant signal in resected stage III dMMR colon cancer, adding atezolizumab to mFOLFOX6 cut the risk of recurrence or death in half and improved 3-year DFS from 76% to 86%. OS hasn’t separated yet, but that may be confounded by immunotherapy at relapse. Toxicity was higher, as expected, with more grade 3–4 events and immune-related adverse events (AE)s, but overall manageable. This feels practice changing for stage III dMMR disease.

Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer

The ALASCCA phase III trial randomized patients with resected stage I-III rectal or stage II-III colon cancer and PI3K pathway alterations to adjuvant aspirin (160 mg daily) or placebo for 3 years. In those with PIK3CA mutations, aspirin significantly reduced 3-year recurrence (~7.5% vs ~15%) and improved 3-year DFS (~90% vs 80%). Severe AEs were higher with aspirin (16.8% vs 11.6%), but the number needed to treat (NNT) to prevent one recurrence was as low as 6 in stage III rectal cancer. For our colorectal cancer (CRC) patients with PI3K pathway mutations, adjuvant aspirin looks like a practical, low-cost targeted option worth considering in routine care. This may make more sense than celecoxib as the long-term risk of aspirin use is more defined, and the cardiovascular benefits may also be applicable to some patients.

Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer

The MATTERHORN trial assessed patients with resectable gastric cancer/gastroesophageal junction cancer and assigned them 1:1 to perioperative durvalumab 1500 mg Q4W + FLOT (neoadjuvant and adjuvant) vs placebo + FLOT. Durvalumab + FLOT significantly improved 2-yr EFS (67.4% vs 58.5%) and increased pathological complete response (pCR) (19.2% vs 7.2%), with a numerically higher 2-year overall survival (OS) (75.7% vs 70.4%). Safety was comparable between arms (grade 3–4 AEs 71.6% vs 71.2%) with no excess surgical delays, unexpected toxicities or adjuvant initiation delays. Bottom line: Immunotherapy (IO) benefit appears linked to the FLOT backbone—as cis/FP + IO regimens have not consistently improved event-free survival (EFS)—and mature OS plus broader representation remain needed, but this looks like a meaningful advance.

Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer

The phase III DESTINY-Gastric04 trial randomized HER2+ metastatic gastric/GEJ adenocarcinoma progressing on trastuzumab to T-DXd versus RAM+PTX, showing a significant overall survival (OS) benefit with T-DXd (14.7 vs 11.4 months) and improved PFS (6.7 vs 5.6 months). Objective response rate (ORR) was higher with T-DXd (44.3% vs 29.1%), and duration of response was longer (7.4 vs 5.3 months). Grade ≥3 AE rates were comparable (50.0% vs 54.1%), though adjudicated ILD/pneumonitis was more frequent with T-DXd (13.9% vs 1.3%, mostly grade 1–2), underscoring the need for vigilant monitoring. Bottom line: T-DXd looks like the new second-line standard for HER2+ disease that stays HER2-positive post-trastuzumab—meaningful survival gains. Please make sure to plan for a repeat biopsy in this setting.