The Lynx Group
Cholangiocarcinoma News

Biomarker Analysis in a Phase 2 Study of Infigratinib (BGJ398) for CCA with FGFR2 Fusions

2020 Year in Review: Cholangiocarcinoma — December 17, 2020

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

  1. 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.
  2. 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.
  3. 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.

Related Items

Phase 1 Results of Gunagratinib in Patients with Advanced Solid Tumors Harboring FGFR Pathway Alterations
2021 Year in Review: Cholangiocarcinoma
A phase 1/2a, first-in-human clinical study demonstrated that the highly selective, irreversible pan-FGFR inhibitor gunagratinib was safe and well-tolerated in patients with advanced solid tumors, including CCA.
Prognostic Value of FGFR2 Alterations in Patients Receiving Systemic Chemotherapy for Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
A retrospective analysis indicated the prognostic value of FGFR2 fusions/rearrangements in patients with intrahepatic CCA receiving systemic chemotherapy, which warrants additional study.
FGFR2 Fusion and/or Rearrangement Profiling in Chinese Patients with Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
Epidemiologic data assessed the incidence rate of FGFR2 gene fusion or rearrangement in Chinese patients with intrahepatic CCA, including those with heterogeneous FGFR2 partner genes.
A Comprehensive Genomic and Immune Profiling Study of IDH1- and IDH2-Driven Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
A comprehensive genomic and immune characterization of IDH-mutated and wild-type intrahepatic CCA revealed significant differences in genetic alterations.
Characteristics of IDH Mutations in Bile Duct Carcinoma in a Chinese Population
2021 Year in Review: Cholangiocarcinoma
A retrospective analysis in a large Chinese patient cohort with bile duct carcinoma indicated that activating IDH1/2 mutations occurred at a lower rate compared with that previously reported in the global population.
Silmitasertib (CX-4945) plus Gemcitabine and Cisplatin as First-Line Treatment for Patients with Locally Advanced or Metastatic CCA
2021 Year in Review: Cholangiocarcinoma
Preliminary evidence suggests that combination treatment with silmitasertib plus gemcitabine/cisplatin as first-line therapy has promising efficacy and a favorable safety profile in patients with locally advanced or metastatic CCA.
Targeted Therapies in CCA: Assessment of US Oncologist Practice Patterns
2021 Year in Review: Cholangiocarcinoma
Findings from a clinical practice assessment identified gaps in knowledge, competence, and confidence regarding testing and the use of targeted therapies in patients with unresectable CCA, underscoring the important role of education in overcoming these gaps.
First-Line Toripalimab plus Lenvatinib in Combination with GemOx Chemotherapy for Advanced Intrahepatic CCA
2021 Year in Review: Cholangiocarcinoma
Results of a phase 2 study indicate that toripalimab and lenvatinib in combination with GemOx chemotherapy provide antitumor activity and reasonable tolerability in patients with advanced intrahepatic CCA.
Comparative Landscape of Actionable Somatic Alterations in Advanced CCA from Circulating Tumor and Tissue-Based DNA Profiling
2021 Year in Review: Cholangiocarcinoma
Findings from a retrospective analysis support the use of both tissue and liquid biopsy biomarker testing to guide therapy selection in patients with advanced CCA, particularly when tissue may not be readily available.
Tibsovo (Ivosidenib) FDA Approved for Advanced or Metastatic Cholangiocarcinoma and IDH1 Mutation
By Loretta Fala
2021 Year in Review: Cholangiocarcinoma
Cholangiocarcinoma (CCA) is an aggressive cancer of the bile duct that forms inside the liver (ie, intrahepatic) or outside the liver (ie, extrahepatic, including perihilar and distal tumors). Individuals with colitis or certain liver diseases may have an increased risk for CCA. Although the precise incidence of CCA is unknown, an estimated 8000 new cases of CCA are diagnosed annually in the United States. It is likely, however, that this number is higher, because CCA is difficult to diagnose and may be misclassified at times.

Subscribe to CCA News

Stay up to date with personalized medicine by subscribing to receive the free CCA News print publication or weekly e‑Newsletter.

I'd like to receive: