The Lynx Group
Cholangiocarcinoma News

Phase 1 Results of Gunagratinib in Patients with Advanced Solid Tumors Harboring FGFR Pathway Alterations

2021 Year in Review: Cholangiocarcinoma — December 17, 2021

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.

Gunagratinib (ICP-192) is a novel, irreversible pan-FGFR inhibitor that showed activity against the acquired resistance to first-generation reversible FGFR inhibitors. The phase 1/2a, first-in-human clinical study ICP-CL-00301 (ClinicalTrials.gov Identifier: NCT03758664) evaluated the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of gunagratinib in patients with advanced solid tumors.

The study design includes a dose escalation (modified 3+3 design) followed by dose expansion. Eligible patients with advanced solid tumors with or without FGF/FGFR alterations were enrolled in the study. In the dose-escalation phase, patients were treated with escalating doses (2 mg, 4 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, and so forth) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. In the dose-expansion phase, patients with cholangiocarcinoma (CCA) who harbor FGFR2 gene fusions/translocations and who had received ≥1 first-line chemotherapy treatments were administered gunagratinib daily at 12 mg continuously. The data cutoff was February 2021.

At data cutoff, a total of 30 patients were enrolled in the study, with 23 participants in the dose-escalation phase and 7 patients in the dose-expansion phase. The median age of the study population was 55.0 years (range, 28.0-75.0 years), 56.7% were male, and the Eastern Cooperative Oncology Group performance status was between 0 and 1.

The maximum tolerated dose had not been reached, and no dose-limiting toxicities were reported. In both cohorts, the most common treatment-related adverse events, occurring in >20% of the patients, included hyperphosphatemia (73.33%), hypercalcemia (33.33%), hypertriglyceridemia (23.33%), increased alanine aminotransferase (23.33%), increased aspartate aminotransferase (26.67%), and diarrhea (26.67%). Hyperphosphatemia was observed at all dose levels and at doses of ≥8 mg once daily; it was managed with oral phosphate binders, as needed.

Pharmacokinetic/pharmacodynamic analysis found dose-dependent increases in plasma exposure (maximum concentration [Cmax], area under the concentration time-curve to the last measured concentration [AUClast]) with oral dosage levels of gunagratinib. Increases in serum phosphorus were reported with gunagratinib doses of ≥8 mg once daily.

Among patients with FGF/FGFR gene aberrations (n = 12), the overall response rate was 33.3%, including 1 (8.3%) patient with CCA who experienced a complete response and 3 (25%) patients with partial responses. The disease control rate was 91.7% (11 of 12 patients).

Based on these results, the researchers concluded that gunagratinib is safe and well-tolerated in patients with advanced solid tumors, including CCA.

Source: Guo Y, Yuan C, Ying J, et al. Phase I result of ICP-192 (gunagratinib), a highly selective irreversible FGFR inhibitor, in patients with advanced solid tumors harboring FGFR pathway alterations. J Clin Oncol. 2021;39(suppl_15):4092-4092.

Related Items

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.
2021 Cholangiocarcinoma Year in Review
By Rachna T. Shroff, MD, MS
2021 Year in Review: Cholangiocarcinoma
This edition of Year in Review is focused on cholangiocarcinoma (CCA), which is a diverse group of malignancies characterized by genomic heterogeneity that potentially drives its pathogenesis. Below is a quick review of some of the topics discussed in this issue, with a focus on recent advances, potentially practice-changing developments, and ongoing challenges in CCA.

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: