Interim results from the phase 3 HERON-Lung01 trial, presented at the ESMO 2026 Congress and published concurrently in The Lancet, show that ruzaltatug rezetecan—a HER3-directed antibody–drug conjugate (ADC)—significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy in patients with EGFR-mutated advanced non-squamous non-small-cell lung cancer (NSCLC) that progressed after EGFR tyrosine kinase inhibitor (TKI) therapy.
At a prespecified interim analysis with a median follow-up of 7.7 months, blinded independent central review (BICR)-assessed median PFS was 8.3 months with ruzaltatug rezetecan versus 5.4 months with chemotherapy (hazard ratio 0.47 [95% CI 0.36–0.60]; one-sided p<0.0001). Overall survival (OS) data were immature at this analysis and a definitive OS benefit has not yet been established.
Key finding
In this interim analysis of a phase 3 trial conducted entirely in China, ruzaltatug rezetecan reduced the risk of progression or death by 53% versus platinum-based chemotherapy in EGFR-TKI-resistant NSCLC, though OS results remain immature and generalisability to broader populations is not yet established.
Study Design
| Trial | HERON-Lung01 (NCT06671379); randomised, open-label, phase 3; 62 sites in China |
|---|---|
| Population | Adults aged 18–75 with locally advanced or metastatic non-squamous NSCLC harboring an EGFR activating mutation (exon 19 deletion or L858R), progressing during or after EGFR-TKI therapy (n=498) |
| Treatment | Ruzaltatug rezetecan 8.0 mg/kg IV Q3W vs pemetrexed 500 mg/m² plus carboplatin (AUC 5) or cisplatin 75 mg/m² Q3W for 4 cycles, followed by maintenance pemetrexed; crossover from chemotherapy permitted after progression |
| Primary endpoint | PFS per BICR in the intention-to-treat population |
| Key secondary endpoints | OS, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), safety |
Randomisation was stratified by presence of brain metastases, EGFR mutation subtype, and use of a first-line third-generation EGFR-TKI. The trial enrolled 498 patients between November 2024 and January 2026; recruitment is complete and the trial is ongoing. The median patient age was 60.0 years (IQR 54.0–68.0), with 55% female and 45% male participants.
Results and Safety
The primary endpoint was met at the prespecified interim analysis (data cutoff April 15, 2026). BICR-assessed PFS favoured ruzaltatug rezetecan across all prespecified subgroups, including patients with brain metastases and those stratified by EGFR mutation subtype. The ORR was 60.0% with ruzaltatug rezetecan versus 34.3% with chemotherapy, the DCR was 92.8% versus 83.1%, and the median DoR was 8.5 months versus 4.4 months per BICR. Overall survival trended in favour of ruzaltatug rezetecan (HR 0.70; 95% CI 0.43–1.14), but the data were described as immature; 19.4% of patients in the chemotherapy arm crossed over to ruzaltatug rezetecan following disease progression, which may confound future OS analyses.
Grade ≥3 treatment-related adverse events (TRAEs) occurred in 41% of patients receiving ruzaltatug rezetecan and 39% of those receiving chemotherapy. The most common grade ≥3 TRAEs in the ruzaltatug rezetecan arm were decreased neutrophil count (26%), decreased white blood cell count (12%), and anaemia (6%), compared with 19%, 12%, and 11%, respectively, in the chemotherapy arm. Interstitial lung disease (ILD) was reported in 6 patients (2.4%) receiving ruzaltatug rezetecan; five cases were grade 1–2 and one was grade 3. TRAEs led to treatment discontinuation in 1% of patients in each arm. One death in the ruzaltatug rezetecan group was considered by the investigator to be possibly treatment-related, though the cause was listed as unknown.
Clinical Context
Patients with EGFR-mutated NSCLC who progress after EGFR-TKI therapy, including third-generation agents such as osimertinib, represent a population with limited and largely chemotherapy-based second-line options. HER3 is broadly expressed in NSCLC and has emerged as a target of interest following activity signals from other HER3-directed ADCs in this setting. The HERON-Lung01 results add ruzaltatug rezetecan to a growing class of ADCs demonstrating activity in EGFR-TKI-resistant disease, with investigators concluding that the data support its consideration as a potential standard-of-care option in this setting.
Several questions remain. The trial was conducted exclusively at sites in China, and whether the efficacy and safety profile will translate to broader international populations is not yet known. Overall survival data are immature, and the impact of post-progression crossover on long-term outcomes is uncertain. Ruzaltatug rezetecan does not currently hold regulatory approval in any market, and no submission timelines were disclosed in the source material.
Sources
- Xu C, et al. “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.” Conference abstract (LBA72). ESMO 2026 Congress. Abstract LBA72.
- Xu C, Zhang Y, Lin G, et al. “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.” The Lancet, 2026. View Source.