基于循环肿瘤DNA（ctDNA）对晚期实体瘤患者中成纤维细胞生长因子受体（FGFR）2/3抑制剂lavengratinib（ABSK061）获得性耐药的谱分析

Background: Aberrant activation of FGFR signaling is implicated in tumorigenesis across multiple cancer types. Lavengratinib, the first-in-class selective FGFR2/3 inhibitor, showed encouraging efficacy and a favorable safety profile as monotherapy in pts with FGFR2/3 alterations in a phase 1 study (NCT05244551). We used next-generation sequencing (NGS) of ctDNA to define the molecular mechanism of acquired resistance to lavengratinib. Method: Pts with FGFR2/3 activating alterations who had progressed on or declined standard therapy, and who had no prior FGFR inhibitor treatment, were treated with lavengratinib. Pts with both baseline and post-progression ctDNA samples were included in the study. Sequential ctDNA profiling (Onco Sonar, Genetron) was performed to compare genomic alterations at baseline and at disease progression. Result: Seventeen pts with paired baseline and post-progression ctDNA samples were analyzed in this study, containing individuals with cholangiocarcinoma (CCA), gastric cancer (GC), non-small-cell lung cancer (NSCLC), cervical cancer and urothelial carcinoma. All the pts initially achieved an objective response or stable disease before developing progression. Seven pts acquired one or more secondary mutations in the kinase domain of FGFR2 or FGFR3. In FGFR2 -altered pts, 15 residues in FGFR2 kinase domain were found mutated at the time of resistance to lavengratinib. The molecular brake residue N549 was the most frequently affected site. Additional recurrent mutations involved L617, the molecular brake residue E565 and the gatekeeper residue V564, particularly in FGFR2 -amplified GC and CCA with FGFR2 fusion. These putative cases of FGFR2 acquired resistance in GC were consistently polyclonal, a pattern also commonly observed in CCA. In one cervical cancer pt with FGFR3 S249C, an emergent FGFR3 M528I was detected at progression. In contrast, FGFR2 -altered NSCLC was prone to develop acquired alterations in genes involved in RTK/RAS pathways other than FGFR2 , suggesting the resistance mainly driven by bypass mechanisms in this indication. Moreover, ATM , a key gene in the DNA damage response (DDR) network, exhibited the highest incidence of off-target emergent mutations across tumor types. Conclusion: This study revealed diverse genomic mechanisms imparting acquired resistance to the selective FGFR2/3 Inhibitor lavengratinib, including secondary FGFR2/3 kinase domain mutations as well as off-target alterations in RTK/RAS and DDR pathways. In GC and CCA, polyclonal FGFR2 acquired mutations represent a convergent, on-target resistance mechanism to FGFR inhibition. These findings provide molecular insights into resistance mechanisms and guide the combination and sequential therapy strategies to overcome resistance in FGFR2/3 driven advanced solid tumors.