Ruzaltatug rezetecan, a HER3-directed ADC, vs platinum-based chemotherapy (PBC) in EGFR-mutated advanced NSCLC progressing after EGFR-TKI: Interim analyses (IA) from the phase 3 HERON-Lung01 trial

doi:10.1016/s0140-6736(26)01899-4

HERON-Lung01

Paziente / Popolazione Intervento / Esposizione Confronto Esito

In patients with EGFR-mutated advanced nonsquamous NSCLC progressing after EGFR-TKI, ruzaltatug rezetecan improved progression-free survival compared with platinum-based chemotherapy.

N

498pazienti

Disegno

Phase 3 trial that randomised 1:1 patients with EGFR-mutated (Ex19del/L858R) advanced nonsquamous NSCLC progressing after EGFR-TKI to ruzaltatug rezetecan (SHR-A2009), a HER3-directed ADC, or platinum-based chemotherapy (pemetrexed plus carboplatin or cisplatin, then maintenance pemetrexed), with crossover to ruzaltatug rezetecan allowed after progression (NCT06671379).

Esito

Progression-free survival per blinded independent central review (BICR).

RisultatoAt the prespecified PFS interim analysis (median follow-up 7.7 mo), median BICR-assessed PFS was 8.3 with ruzaltatug rezetecan vs 5.4 mo with platinum-based chemotherapy (HR 0.47, 95% CI 0.36-0.60; 1-sided P <0.0001), with benefit across all prespecified subgroups including brain metastases and EGFR mutation type. Overall survival was immature (HR 0.70, 95% CI 0.43-1.14), with 19.4% post-progression crossover from the chemotherapy arm. Objective response rate 60.0% vs 34.3%, disease control rate 92.8% vs 83.1% and median duration of response 8.5 vs 4.4 mo per BICR. Grade ≥3 treatment-related adverse events occurred in 40.7% vs 38.9%, most commonly decreased neutrophil count (25.8% vs 19.2%). Interstitial lung disease occurred in 6 patients (2.4%; grade 1-2, n=5; grade 3, n=1) with ruzaltatug rezetecan. Treatment-related adverse events led to discontinuation in 1.2% vs 1.3%.

Xu C, Zhang Y, Lin G, et al. The Lancet. 2026. 10.1016/s0140-6736(26)01899-4

Discussione e critica

This randomised phase 3 trial shows a large and statistically significant PFS benefit over platinum-based chemotherapy, assessed by blinded independent central review and consistent across prespecified subgroups. It is an interim analysis with a median follow-up of only 7.7 months, and overall survival is immature, with a confidence interval that crosses 1. Later OS readouts will also be confounded by the crossover from the chemotherapy arm. The abstract does not say whether patients and investigators were blinded, gives no quality-of-life data and no subgroup figures, and the study was funded by Jiangsu Hengrui Pharmaceuticals.