Novel ADC Elicits Meaningful Activity in Pretreated HER2-Mutant NSCLC

"The substantial and durable activity observed in this study supports further investigation of trastuzumab rezetecan in earlier disease stages," according to the study authors.

Treatment with trastuzumab rezetecan (SHR-A1811) demonstrated clinically meaningful activity and a manageable safety profile among patients with previously treated HER2-mutated non–small cell lung cancer (NSCLC), according to phase 2 findings from the phase 1/2 HORIZON-Lung trial (NCT04818333) published in Lancet Oncology.1

Based on independent review committee (IRC) assessment, the confirmed objective response rate (ORR) was 73% (95% CI, 63.3%-82.0%). Additionally, the disease control rate (DCR) was 98.9% (95% CI, 94.2%-100.0%), and the median duration of response (DOR) was not reached (NR; 95% CI, 8.3 months to NR). Responses with trastuzumab rezetecan occurred across prespecified and post hoc subgroups based on characteristics such as prior lines of therapy, previous anti-HER2 tyrosine kinase inhibitor treatment, and brain metastases.

Data showed a median progression-free survival (PFS) of 11.5 months (95% CI, 9.9-NR) per IRC evaluation and a 6-month PFS rate of 86.8% (95% CI, 77.4%-92.5%) per post hoc analysis. Additionally, post hoc analysis highlighted a median PFS of 9.9 months (95% CI, 8.4-NR) in patients with brain metastases and 11.5 months (95% CI, 10.5-NR) in those without; the median PFS was 12.3 months (95% CI, 9.9-NR) in patients with the Ala775_Gly776insTyrValMetAla mutation vs 11.5 months (95% CI, 7.6-NR) in those with other mutations.

Overall survival (OS) data were not yet mature at the time of analysis, with deaths observed in 3% (n = 3/94) of patients.

“[T]rastuzumab rezetecan showed clinically meaningful activity and a manageable safety profile in patients with previously treated HER2-mutant NSCLC, providing a potential new treatment option for this population,” lead study author Ziming Li, MD, from the Shanghai Lung Cancer Center at Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine in Shanghai, China, wrote with coauthors.1 “The substantial and durable activity observed in this study supports further investigation of trastuzumab rezetecan in earlier disease stages.”

Developers designed trastuzumab rezetecan as a novel antibody drug conjugate formed from a humanized HER2-directed monoclonal antibody linked to a DNA topoisomerase I inhibitor drug through a tetrapeptide-based linker. Investigators hypothesize that the agent’s payload may demonstrate high membrane permeability and potent cytotoxicity, which can facilitate on-target and bystander killing effects.

In the single-arm phase 2 HORIZON-Lung study, 94 patients received trastuzumab rezetecan at a recommended phase 2 dose of 4.8 mg/kg intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, new anti-cancer therapy, or investigator decision.

The trial’s primary end point was IRC-assessed ORR per RECIST v1.1 criteria. Secondary end points included DCR, DOR, PFS, OS, and safety.

Patients 18 years and older with advanced NSCLC harboring HER2 expression, amplification, or mutation and receipt of prior platinum-based chemotherapy for advanced or metastatic disease were eligible for enrollment on the trial.2 Additional requirements for study entry included having an ECOG performance status of 0 or 1 and at least 1 measurable lesion per RECIST v1.1 guidelines. Those who previously received HER2 antibody drug conjugates or had central nervous system metastasis or meningeal metastasis with clinical symptoms were ineligible for enrollment.

The median patient age was 57.5 years (IQR, 50-64), and most were female (55%) and Han Chinese (98%). Additionally, most of the study population had an ECOG performance status of 1 (81%), no smoking history (64%), adenocarcinoma (97%), stage IV disease (98%), and HER2 mutations located in the kinase domain (97%). The median number of prior lines of treatment was 2 (IQR, 1-2), and all patients had received prior platinum-based chemotherapy (100%) or anti–PD-1 or anti–PD-L1 agents (100%).

All patients experienced any type of treatment-related adverse effect (TRAE), with grade 3 or higher TRAEs occurring in 62%. The most common grade 3/4 TRAEs included decreased neutrophil counts (40%), decreased white blood cell counts (27%), anemia (23%), decreased platelet counts (11%), and decreased lymphocyte counts (7%). TRAEs resulted in dose interruptions, reductions, and discontinuations in 30%, 17%, and 1% of patients, respectively.

Serious TRAEs affected 23% of the study population, which included decreased platelet counts (6%), decreased neutrophil counts (6%), interstitial lung disease (5%), decreased white blood cell counts (4%), and anemia (4%). Data showed 2 deaths associated with AEs, which were instances of progression of malignant neoplasm that investigators assessed as unrelated to study treatment.

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. Lancet Oncol. Published online February 25, 2025. doi:10.1016/ S1470-2045(25)00012-9
2. A study of SHR-A1811 in subjects with advanced non-small cell lung cancer. ClinicalTrials.gov. Updated June 13, 2024. Accessed March 4, 2025. https://tinyurl.com/4unycw93