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
Mené sur 498 patients atteints d'un cancer du poumon non à petites cellules avec mutation EGFR, de stade localement avancé ou métastatique et ayant progressé après un traitement par inhibiteur de tyrosine kinase ciblant EGFR (âge médian : 60 ans ; durée médiane de suivi : 7,7 mois), cet essai de phase III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du ruzaltatug rézétécan (un conjugué anticorps-médicament ciblant HER3) par rapport à une chimiothérapie à base de sels de platine
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.
The Lancet , résumé, 2026