Efficacy and safety of first-line oral vinorelbine plus firmonertinib in refractory EGFR -mutated non-small cell lung cancer: study protocol of a multicenter, non-randomized, two-cohort study

Background: Although combinations of third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with chemotherapy or amivantamab have significantly improved progression-free survival (PFS) and overall survival (OS) compared with EGFR-TKI monotherapy in EGFR -mutated advanced non-small cell lung cancer (NSCLC), the increased toxicities and requirement for intravenous administration of chemotherapy limit their practicality. Patients with EGFR -mutated advanced NSCLC who develop M1c2 disease or exhibit elevated programmed death-ligand 1 (PD-L1) expression represent a clinically refractory subgroup with a high unmet need for effective and convenient combination strategies. Objectives: This study is designed to evaluate the efficacy and safety of an all-oral regimen combining vinorelbine and firmonertinib (a third-generation EGFR-TKI) as first-line treatment in this refractory population. Design: This open-label, non-randomized, two-cohort study is conducted at two centers in China. Systematic treatment-naïve patients with histopathology confirmed EGFR -mutated (exon 19 deletion or exon 21 L858R mutation) NSCLC, who are not amenable to curative surgery or radiotherapy, will be recruited. Cohort 1 will comprise 54 metastatic NSCLC patients with M1c2 disease, and Cohort 2 will consist of 77 locally advanced or metastatic NSCLC patients with a PD-L1 tumor proportion score of ⩾25%. Recruitment began on December 11, 2025, and is currently in progress. Methods and analysis: During the one-cycle safety run-in period, six patients received oral vinorelbine (60 mg/m 2 on days 1 and 8) plus firmonertinib (80 mg once daily) as the starting dose. Dosing regimen for the subsequent expansion cohort will be determined based on the safety data from the safety run-in period. The treatment cycle is repeated every 3 weeks and will continue until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed PFS. Secondary endpoints are objective response rate, disease control rate, OS, and safety. Ethics: This study has received ethics approval from the ethical committee of the Shanghai Chest Hospital (approval number: IS25204). Discussion: To the best of our knowledge, this study represents the first evaluation of vinorelbine plus firmonertinib in EGFR -mutated locally advanced or metastatic NSCLC with M1c2 disease or elevated PD-L1 expression, aiming to provide an effective, tolerable, and convenient all-oral treatment option for this refractory population. Trial registration: The study protocol (version 1.2; July 18, 2025) was registered on October 24, 2025, at the Chinese Clinical Trial Registry (ChiCTR2500111096).