Azvudine combined with Doxitinib, a potential therapy for EGFRm + NSCLC

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), is the current standard first-line therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC). Although Osimertinib significantly improves progression-free survival (PFS), some patients exhibit intrinsic resistance, and nearly all eventually develop acquired resistance. Doxitinib, a deuterated analog of Osimertinib, retains potent EGFR inhibitory activity while significantly reducing the formation of toxic metabolites by up to 80% in preclinical models, suggesting an improved safety profile and the potential for enhanced therapeutic efficacy through higher tolerated dosing. In a phase 1/2 clinical study (ChiCTR2000039281), Doxitinib demonstrated a favorable safety profile without dose-limiting toxicities (DLTs) across doses ranging from 20 to 240 mg daily in patients previously treated with EGFR TKIs. Encouraging clinical activity was observed, including antitumor responses in brain metastases. The ongoing expansion phase is further evaluating Doxitinib in EGFRm⁺ NSCLC patients naïve to EGFR-TKI therapy. To overcome resistance and enhance antitumor efficacy, we combined Doxitinib with Azvudine (FNC), a fluorinated nucleoside analog with dual antitumor mechanisms. FNC inhibits tumor cell proliferation via its active triphosphate metabolite, which incorporates into DNA or RNA to disrupt nucleic acid synthesis, induce replication stress, and arrest tumor growth. Moreover, FNC modulates the tumor immune microenvironment (TIME) by suppressing myeloid-derived suppressor cell (MDSC) differentiation and infiltration while enhancing CD8⁺ T cell and NK cell activation, thus shifting the TIME from immunosuppressive to immunoreactive-an essential factor in overcoming EGFR-TKI resistance. In vitro, the combination of FNC and Doxitinib additively inhibited the proliferation of NCI-H1975 (EGFR L858R/T790M/C797S) triple-mutant NSCLC cells. In vivo, the combination achieved superior tumor growth inhibition compared to either monotherapy in the NCI-H1975 (EGFR L858R/T790M) xenograft model. Collectively, these findings suggest that the combination of FNC and Doxitinib represents a promising therapeutic strategy to enhance efficacy and overcome acquired resistance in EGFRm⁺ NSCLC. Based on these preclinical and clinical findings, a phase 1/2 clinical trial will be initiated to evaluate the safety and efficacy of this combination therapy in EGFR-mutant NSCLC patients.