Ruzaltatug rezetecan versus chemotherapy for EGFR-mutated advanced non-small-cell lung cancer progressing after EGFR tyrosine kinase inhibitor therapy (HERON-Lung01): interim analysis of a randomised, open-label, phase 3 trial in China

Abstract

BACKGROUND Ruzaltatug rezetecan is a novel HER3-directed antibody-drug conjugate that has shown promising antitumour activity and manageable safety in pretreated EGFR-.mutated non-small-cell lung cancer (NSCLC) in a phase 1 trial. We aimed to compare the efficacy and safety of ruzaltatug rezetecan with chemotherapy in patients with EGFR-mutated advanced NSCLC that had progressed after EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS HERON-Lung01 is a randomised, open-label, phase 3 trial conducted at 62 sites in China. Eligible patients were aged 18-75 years, with locally advanced or metastatic non-squamous NSCLC harbouring an EGFR activating mutation (exon 19 deletion or L858R mutation), and had progressed during or after EGFR-TKI therapy. Patients were randomly assigned (1:1) to receive ruzaltatug rezetecan 8·0 mg/kg or chemotherapy comprising pemetrexed 500 mg/m2 plus carboplatin (area under the curve 5) or cisplatin 75 mg/m2 for four cycles, followed by maintenance pemetrexed. All treatments were administered intravenously on day 1 of each 3-week cycle. Block randomisation was stratified by presence of brain metastases, EGFR mutation subtype, and use of a first-line third-generation EGFR-TKI. The primary endpoint was progression-free survival (PFS), as assessed by blinded independent central review (BICR), in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT06671379). Recruitment is complete, with the trial ongoing. FINDINGS Between Nov 29, 2024, and Jan 29, 2026, 498 patients were randomly assigned to receive ruzaltatug rezetecan (n=250) or chemotherapy (n=248). The median age was 60·0 years (IQR 54·0-68·0); 276 (55%) patients were female and 222 (45%) male. At the prespecified interim PFS analysis, median follow-up was 7·7 months (95% CI 7·1-8·3). BICR-assessed PFS was significantly longer with ruzaltatug rezetecan than with chemotherapy (median 8·3 months vs 5·4 months; hazard ratio 0·47 [95% CI 0·36-0·60]; one-sided p<0·0001). Grade 3 or worse treatment-related adverse events (TRAEs) occurred in 101 (41%) of 248 patients receiving ruzaltatug rezetecan and 93 (39%) of 239 patients receiving chemotherapy, most commonly decreased neutrophil count (64 [26%] of 248 patients vs 46 [19%] of 239 patients), decreased white blood cell count (29 [12%] vs 29 [12%]), and anaemia (15 [6%] vs 26 [11%]). TRAEs led to treatment discontinuation in three (1%) patients in the ruzaltatug rezetecan group and three (1%) in the chemotherapy group. One death (unknown cause) in the ruzaltatug rezetecan group was considered by the investigator to be possibly treatment related. INTERPRETATION Ruzaltatug rezetecan significantly prolonged PFS compared with chemotherapy, with a manageable safety profile, in EGFR-TKI-resistant, EGFR-mutated advanced NSCLC. These data support ruzaltatug rezetecan as a potential treatment option in this setting.