Izalontamab brengitecan versus platinum-based chemotherapy in EGFR-mutated advanced non-squamous non-small-cell lung cancer after progression on third-generation EGFR tyrosine kinase inhibitors (PANKU-Lung01): a multicentre, randomised, open-label, phase 3 trial in China.

Systemic therapy for EGFR-mutant advanced non-small cell lung cancer has improved markedly over the past decade ^[1]. First-line treatment with the third-generation TKI osimertinib has achieved a median progression-free survival of 18.9 months, superior to first-generation agents ^[2], and it is also superior to platinum-pemetrexed regimens when used in T790M-positive patients after progression on first-line TKI ^[3]. However, the real clinical challenge lies after resistance to third-generation TKIs: as early as the first-generation TKI era, the optimal strategy after resistance was unclear, and the IMPRESS study explored the route of continuing gefitinib combined with chemotherapy ^[5]; in recent years, phase III trials have successively confirmed that amivantamab plus chemotherapy ^[6] and ivonescimab plus chemotherapy ^[7] can significantly prolong PFS after osimertinib progression, while antibody-drug conjugates (ADCs) as a class of strategy have also accumulated phase III evidence in previously treated NSCLC ^[8]. Given that lung adenocarcinoma in East Asian populations has unique genomic characteristics ^[4], testing new drugs in Chinese populations has a practical rationale.

PANKU-Lung01 is a multicenter, randomized, open-label phase III trial conducted precisely in this context. It enrolled 432 of 654 screened patients across 73 centers in China with EGFR-mutant, non-squamous NSCLC that had progressed after third-generation TKI therapy and with no prior chemotherapy in the advanced setting. Patients were randomized 1:1 to iza-bren (2.5 mg/kg, administered intravenously on days 1 and 8 of each 3-week cycle) or pemetrexed combined with carboplatin/cisplatin for 4–6 cycles (pemetrexed maintenance therapy was allowed). The primary endpoint was PFS assessed by blinded independent central review. At a median follow-up of approximately 15 months, median PFS was 11.1 months in the iza-bren group versus 5.7 months in the chemotherapy group (HR 0.40, 95% CI 0.31–0.51; one-sided p<0.0001). Regarding safety, the incidence of grade ≥3 treatment-related adverse events was 79% versus 62%, predominantly hematologic toxicity; permanent discontinuation due to toxicity occurred in only 2% in each group, there was 1 treatment-related death in each group, and interstitial lung disease occurred in 2 patients (1%) in the iza-bren group.

The advance of this study lies in the following: iza-bren is an EGFR×HER3 bispecific ADC carrying a cleavable linker and the Ed-04 payload ^[9]; after binding to EGFR or HER3 on the tumor cell surface, it enters cells via endocytosis ^[10], and it has been described as first-in-class ^[11]. Unlike the bispecific antibody plus chemotherapy approach in MARIPOSA-2 ^[6], PANKU-Lung01 defeated chemotherapy head-to-head as a single agent; the authors stated that, to their knowledge, this is the first phase III evidence for a bispecific ADC, supporting iza-bren as a potential treatment option for this population. The drug is also currently being further validated under the designation BMS-986507 in another randomized, open-label phase II/III study, IZABRIGHT-Lung01, versus platinum chemotherapy ^[12].

In terms of limitations, the study used an open-label design (although the primary endpoint was assessed by blinded independent central review); grade ≥3 toxicity was clearly higher than with chemotherapy and was mainly myelosuppression, so hematologic management will deserve attention in clinical use; overall survival is currently based only on an interim analysis, with no specific data given in the abstract, and whether a survival benefit can be established awaits final results; moreover, the evidence comes from a Chinese non-squamous population, and broader populations and long-term safety remain to be answered by subsequent data.