HER3-directed ruzaltatug rezetecan extends PFS versus chemotherapy in EGFR-mutated NSCLC

Human idea, AI creation9 Nov 2026Oncology Respiratory medicine

In a phase 3 trial in China, the HER3-directed antibody-drug conjugate ruzaltatug rezetecan prolonged progression-free survival over platinum-pemetrexed chemotherapy in EGFR-mutated advanced NSCLC after EGFR-TKI failure.

Illustration of two researchers with a lung model, antibody on a phone screen, DNA helixes, lab glassware and data charts — Image: human idea, AI creation

Summarised study

Xu CR, Zhang Y, Lin G, Wang H, Wang Q, Huang D, 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. Lancet. 2026;408(10567):1969-1978. doi:10.1016/S0140-6736(26)01899-4. PMID: 42933457. PubMed

Key findings

HERON-Lung01 randomised 498 patients whose advanced NSCLC harboured an EGFR mutation progressing after EGFR-TKI therapy to ruzaltatug rezetecan (n=250) or chemotherapy (n=248).
Median BICR-assessed 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).
Grade 3 or worse TRAEs occurred in 101 (41%) of 248 patients on ruzaltatug rezetecan and 93 (39%) of 239 on chemotherapy.
TRAEs resulted in stopping treatment in three (1%) patients in each group.
One death of undetermined cause among patients given ruzaltatug rezetecan group was considered by the investigator to be possibly treatment related.

Background

Ruzaltatug rezetecan is an antibody-drug conjugate that targets HER3¹. In a phase 1 trial in previously treated EGFR-mutated non-small-cell lung cancer (NSCLC), it demonstrated antitumour activity and a manageable safety profile¹. HERON-Lung01 compared it with chemotherapy in patients whose EGFR-mutated advanced NSCLC had progressed on treatment with an EGFR-directed tyrosine kinase inhibitor (TKI)¹.

Trial design

This randomised, open-label, phase 3 study was run at 62 centres in China (NCT06671379²)¹. Participants were aged 18-75 years and had non-squamous NSCLC that was locally advanced or metastatic, with an activating EGFR mutation (exon 19 deletion or L858R) and disease progression during or after EGFR-TKI treatment¹.

Patients were allocated 1:1 to one of two regimens¹:

ruzaltatug rezetecan 8.0 mg/kg
pemetrexed 500 mg/m2 with carboplatin (AUC 5) or cisplatin 75 mg/m2 for four cycles, then pemetrexed maintenance

All drugs were given intravenously on day 1 every 3 weeks¹. Stratification factors for randomisation were brain metastases (present or absent), the subtype of EGFR mutation, and whether a third-generation EGFR-TKI had been given first line¹. The main endpoint of the trial was progression-free survival (PFS) according to BICR (blinded, independent central review), within the intention-to-treat population¹.

Efficacy

Between Nov 29, 2024, and Jan 29, 2026, 498 patients were randomised, 250 to ruzaltatug rezetecan and 248 to chemotherapy¹. Median age was 60.0 years (IQR 54.0-68.0), and 276 (55%) were female¹.

At the prespecified interim analysis, median follow-up was 7.7 months (95% CI 7.1-8.3)¹. Median BICR-assessed PFS was 8.3 months versus 5.4 months (hazard ratio 0.47 [95% CI 0.36-0.60]; one-sided p<0.0001)¹.

Safety

Grade 3 or higher treatment-related adverse events (TRAEs) affected 101 (41%) of 248 patients on ruzaltatug rezetecan and 93 (39%) of 239 on chemotherapy¹. The most frequent were decreased neutrophil count (26% vs 19%), reduced white blood cell count (12% in each arm) and anaemia (6% vs 11%)¹. Three (1%) patients in each arm stopped treatment because of TRAEs¹. The investigator judged one death of undetermined cause in the ruzaltatug rezetecan arm as possibly treatment-related¹.

Interpretation

The authors concluded that ruzaltatug rezetecan significantly extended PFS relative to chemotherapy, along with manageable safety, and that the data support it as a possible therapeutic option for these patients¹. Recruitment is complete and the trial continues¹. Jiangsu Hengrui Pharmaceuticals funded the study¹.

References

Xu CR, Zhang Y, Lin G, Wang H, Wang Q, Huang D, 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. Lancet. 2026;408(10567):1969-1978. doi:10.1016/S0140-6736(26)01899-4. PMID: 42933457. PubMed
ClinicalTrials.gov. Accessed November 9, 2026. https://clinicaltrials.gov/study/NCT06671379.

This article is not medical advice. Always check the source and local prescribing information before making treatment decisions. Patients should seek a personal assessment by a licensed physician.