Comprehensive genomic profiling of tumor tissue and cfDNA of patients enrolled in the phase 2 study of infigratinib underscored the heterogeneity of CCA and the potential clinical utility of cfDNA to identify FGFR2 fusions.
Fibroblast growth factor receptor 2 (FGFR2) alterations, predominantly FGFR2 fusions, occur in 11% of CCAs. Infigratinib (BGJ398) is a selective adenosine triphosphate (ATP)-competitive FGFR1-3 TKI that has demonstrated promising antitumor activity in early-phase clinical trials in patients with solid tumors, including advanced CCA harboring FGFR2 alterations.1-3 A multicenter, open-label, phase 2 study (NCT02150967) evaluated the efficacy and safety of infigratinib in patients with previously treated advanced CCA harboring FGFR2 fusions.3 Biomarker analyses of patients enrolled in this phase 2 study were conducted to determine genomic alterations; these results were presented at the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium and summarized here.
In this study, patients aged ≥18 years with histologically or cytologically confirmed advanced or metastatic intrahepatic CCA containing FGFR2 fusions or other FGFR alterations whose disease had progressed on or who were intolerant to previous cisplatin- or gemcitabine-based therapy were enrolled. Eligible patients received oral infigratinib 125 mg once daily on days 1 to 21 every 28 days until unacceptable toxicity, disease progression, and/or investigator discretion or consent withdrawal.
At the time of analysis, a total of 71 patients with FGFR2 fusions were enrolled, the majority of whom were women (62%) with median age of 53 years. More than half (55%) of patients had received ≥2 previous lines of therapy. Following a median duration of treatment of 5.4 months, overall response rate (ORR; confirmed and unconfirmed) was 31.0% (95% confidence interval [CI], 20.5%-43.1%) and confirmed ORR was 26.9% (95% CI, 16.8%-39.1%). Disease control rate (DCR) was 83.6% (95% CI, 16.8%-39.1%), and median progression-free survival was 6.8 months. Grade 3/4 adverse events occurring in ≥5% of patients included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia syndrome.
Comprehensive genomic profiling was performed using a 324-gene panel on tumor tissue (N = 71) collected at screening (prior to therapy). Biomarker analysis in all 71 patients identified 32 unique FGFR2 fusion genes, with FGFR-BICC1 being the most common (37%) fusion partner. Tumor genomic profiles of each subject revealed that the most frequently altered genes were BAP1 (36%), ARID1B (25%), MLL3 (20%), and PIK3CA (20%). Actionable mutations were identified in IDH1 and PIK3CA as well as copy number changes in CDK4 and MET. In 5 subjects with FGFR2 fusions, amplification of FGFR2 (N = 1) occurred coincident with mutations in FGFR2 (N = 3) and FGFR3 (N = 1). Tumor mutational burden was assessed in 15 patients; all 15 had low tumor mutation burden.
Circulating-free DNA (cfDNA) was collected at screening and analyzed by NGS using a 600-gene panel. Most commonly occurring alterations in cfDNA were TP53 (50%), BAP1 (33%), and HLA-A (33%). Among patients with tumor tissue and cfDNA (N = 14), FGFR2 fusions were concordant in 67% of patients.
These results illustrate the genomic heterogeneity underlying the pathobiology of CCA. The higher proportion of FGFR alterations attest to the validity of targeting this pathway in these tumors. Preliminary results from cfDNA analysis suggest that cfDNA may be a noninvasive means of identifying FGFR2 fusions with potential clinical utility in CCA and warranting further development.
Source: Makawita S, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 579.
References
- Guagnano V, Kauffmann A, Wohrle S, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 2012;2:1118-1133.
- Nogova L, Sequist LV, Perez Garcia JM, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol. 2017;35:157-165.
- Javle MM, Lowery M, Shroff RT, et al. Phase II Study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276-282.
