In the phase III HERON-Lung01 trial, ruzaltatug rezetecan significantly prolonged progression-free survival compared with chemotherapy and showed a manageable safety profile in patients with EGFR tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to Xu et al. The findings, which were presented during the European Society for Medical Oncology (ESMO) Congress 2026 (Abstract LBA72) and simultaneously published in The Lancet, were interpreted by the investigators as supporting the novel HER3-directed antibody-drug conjugate as a potential standard-of-care option in this setting.
The investigators noted that ruzaltatug rezetecan had demonstrated antitumor activity and a manageable safety profile in previously treated patients with EGFR-mutated NSCLC in a phase I trial. Regarding the present study, they wrote, “Our findings validate HER3 as a relevant therapeutic target….”
Study Details
The investigators focused on patients with locally advanced or metastatic nonsquamous NSCLC harboring an EGFR exon 19 deletion or L858R mutation who experienced disease progression during or after EGFR TKI therapy at 62 sites in China. A total of 498 patients (median age = 60 years; 55% female) were randomly assigned 1:1 to either receive ruzaltatug rezetecan (8 mg/kg) or chemotherapy with pemetrexed plus the investigator’s choice of carboplatin or cisplatin for four cycles, followed by maintenance pemetrexed. All treatments were administered intravenously every 3 weeks.
The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival in the intention-to-treat population. At this prespecified interim analysis, median follow-up was 7.7 months.
Key Findings
Median BICR-assessed progression-free survival was 8.3 months with ruzaltatug rezetecan and 5.4 months with chemotherapy (hazard ratio = 0.47; one-sided P < .0001).
The rates of grade 3 or higher treatment-related adverse events were 41% with ruzaltatug rezetecan and 39% with chemotherapy, with the most common being decreased neutrophil count (26% vs 19%), decreased white blood cell count (both 12%), and anemia (6% vs 11%). Treatment discontinuation because of treatment-related adverse events was reported in 1% of both groups. One death of unknown cause in the ruzaltatug rezetecan group was considered possibly treatment-related by the investigators.
“Its efficacy, together with a differentiated safety and administration profile, could position ruzaltatug rezetecan distinctly among available post–EGFR TKI regimens and HER3-directed agents in development,” the investigators concluded.
They continued, “The satisfactory tolerability also supports development in combination regimens, with encouraging activity observed in NSCLC with or without actionable genomic alterations in an ongoing phase Ib/II study; a phase III trial of ruzaltatug rezetecan plus the third-generation EGFR TKI aumolertinib as first-line therapy for EGFR-mutated advanced NSCLC is underway.”
Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China, is the corresponding author of the article in The Lancet.
Disclosure: The study was funded by Jiangsu Hengrui Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.
