Trastuzumab Rezetecan Is Safe, Efficacious for Patients With HER2-Mutated Non-Small Cell Lung Cancer

Trastuzumab rezetecan (SHR-A1811; Jiangsu Hengrui Medicine Co) demonstrated substantial improvements in tumor and lesion reduction in patients with human epidermal growth factor receptor 2 (HER2)-mutated non-small cell lung cancer (NSCLC). The authors reported that the antibody-drug conjugate (ADC) yielded a confirmed objective response rate (ORR) in 73% of patients.¹

3D rendering of antibody drug conjugate molecules | Image Credit: © Love Employee - stock.adobe.com

Lung cancer is the third most common type of cancer in the United States and the leading cause of cancer-related deaths. Nearly 87% of all lung cancer diagnoses are NSCLC; however, only 25% to 30% of patients will benefit from treatment. According to the American Lung Association, approximately 2% of patients with NSCLC harbor HER2 mutations, which greatly impact treatment responses and overall outcomes.^2,3

Trastuzumab rezetecan is a novel ADC consisting of a humanized HER2-directed monoclonal antibody conjugated to a cleavable tetrapeptide-based using a DNA topoisomerase I inhibitor. In the multicenter, single-arm, phase 2 trial HORIZON-Lung trial (NCT04818333), researchers assessed the safety, tolerability, pharmacokinetics, and efficacy of trastuzumab rezetecan for injection in subjects with advanced NSCLC with HER2 expression, amplification, or mutation. The study was conducted across 35 hospitals in China and included a total of 94 patients (45% male, 55% female; median age 57.5 years).^1,4,5

The trial participants received trastuzumab rezetecan at a dosage of 4.8 mg/kg intravenously every 3 weeks. Of the 94 patients, 23% had previously had anti-HER2 tyrosine kinase inhibitor treatment, and all had received platinum-based chemotherapy and anti-PD-1/L1 therapy. The primary end point, ORR, was assessed by an independent review committee in patients who received at least 1 cycle of treatment.¹

At the median follow-up of 8.7 months, 73% of patients had a confirmed ORR (95% CI 63.3–82.0).¹

"In this regard, it could be concluded that trastuzumab rezetecan performed slightly better, showing both a better [ORR] and disease control rate than trastuzumab deruxtecan, with similar toxicity and less severe interstitial lung disease," Wolfgang Brueckl, MD, Paracelsus Medical University and General Hospital Nuremberg in Germany, said in an article by MedPage Today. "This improvement could be due to the different design of trastuzumab rezetecan, which has a drug-antibody ratio of 6:1 and some modifications between the linker and the payload to improve stability and prevent early release of the toxin."⁵

In the study, the most common grade 3 to 4 treatment-related adverse events (TEAEs) included decreased neutrophil count (40%), followed by decreased white blood cell count (27%), and anemia (23%). Additionally, 11% of patients experienced decreased platelet counts, while 7% had decreased lymphocyte counts.¹

Serious TEAEs were reported in 23% of patients and included decreased platelet count and neutrophil count, each occurring in 6% of patients. Interstitial lung disease was observed in 5% of patients, whereas decreased white blood cell count and anemia were each reported in 4% of cases. Other serious adverse events included vomiting and pneumonia, each affecting 3% of patients. Less common events included hyponatremia (2%), as well as pyrexia, small intestinal obstruction, nausea, and chronic obstructive pulmonary disease, each occurring in 1% of patients. Notably, there were no treatment-related deaths in the study.¹

REFERENCES

1. Li Z, Wang Y, Sun Y, et al. Trastuzumab rezetecan, a HER2-directed antibody–drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study. The Lancet Oncology. February 25, 2025. doi: 10.1016/S1470-2045(25)00012-9

2. Glecirasib improved response rates, survival in patients with non-small cell lung cancer. Pharmacy Times. February 27, 2025. Accessed February 28, 2025. https://www.pharmacytimes.com/view/glecirasib-improved-response-rates-survival-in-patients-with-non-small-cell-lung-cancer

3. HER2 and lung cancer. American Lung Association. January 22, 2025. Accessed February 28, 2025. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/her2#:~:text=HER2%20mutations%20tend%20to%20be,cancer%20patients%20have%20HER2%20mutations

4. A study of SHR-A1811 in subjects with advanced non-small cell lung cancer. Updated June 13, 2024. Accessed February 28, 2025. https://clinicaltrials.gov/study/NCT04818333

5. Novel drug shrinks 73% of HER2-mutant lung cancers. MedPage Today. February 26, 2025. Accessed February 28, 2025. https://www.medpagetoday.com/hematologyoncology/lungcancer/114398