The Lynx Group
Cholangiocarcinoma News

Silmitasertib (CX-4945) plus Gemcitabine and Cisplatin as First-Line Treatment for Patients with Locally Advanced or Metastatic CCA

2021 Year in Review: Cholangiocarcinoma — December 17, 2021

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.

The multicenter, open-label, phase 1b/2 study S4-13-001 (ClinicalTrials.gov Identifier: NCT02128282) evaluated the safety and efficacy of the oral casein kinase 2 inhibitor silmitasertib (CX-4945) in combination with gemcitabine/cisplatin in patients with unresectable cholangiocarcinoma (CCA). Efficacy and safety results of the pooled analysis of the combined population (phases 1b and 2) were presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

This study included 2 phases. The phase 1b portion included dose-escalation, dose-expansion, and exploratory cohorts of silmitasertib with doses ranging from 200 to 1000 mg twice daily (6 days for the escalation/expansion cohorts; 10 and 21 days for the exploratory cohorts). Patients in the phase 2 portion of the study were treated with silmitasertib 1000 mg twice daily for 10 days in combination with gemcitabine/cisplatin (on days 1 and 8 of a 21-day cycle). The primary efficacy end point was progression-free survival (PFS).

The intent-to-treat (ITT) cohort included 88 patients; 87 participants received silmitasertib in the phase 1b (n = 50) and phase 2 (n = 37) portions of the study. The modified ITT (mITT) population included 55 evaluable patients who completed ≥1 full cycles of therapy without dosing interruption or dose reductions. In the combined population (n = 87), the median participant age was 60 years. The majority of patients were male (55%), had metastatic disease (82%), and had intrahepatic CCA (85%).

In the mITT population, the median PFS was 11.2 months, the median overall survival was 17.4 months, the overall response rate was 32.1%, and the disease control rate was 79.3%. At 10 months, PFS was 56.1%. In the safety population (n = 87), 91% of patients experienced ≥1 treatment-emergent adverse events (TEAEs) related to silmitasertib, with the most common (all grades) including diarrhea (66%), nausea (51%), vomiting (33%), fatigue (31%), and anemia (22%). The most common grade ≥3 TEAEs occurring in >10% of patients included anemia (8%), neutropenia (12%), diarrhea (14%), nausea (9%), and thrombocytopenia (8.0%). Treatment discontinuation due to TEAEs was reported in 11 patients (12.6%).

Preliminary evidence from the S4-13-001 study suggests that combination treatment with silmitasertib plus gemcitabine/cisplatin as first-line therapy showed promising efficacy and a favorable safety profile in patients with locally advanced or metastatic CCA. A randomized phase 3 trial is planned to further define the role played by silmitasertib in the treatment of locally advanced or metastatic CCA.

Source: Borad MJ, Bai LY, Chen MH, et al. Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: a phase Ib/II study. J Clin Oncol. 2021;39(suppl_3):312-312.

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.
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: