A novel inhibitor of casein kinase 2 (CK2) has shown preliminary evidence of efficacy in patients with locally advanced or metastatic cholangiocarcinoma, according to a phase I/IIb study presented at the 2021 Gastrointestinal Cancers Symposium.¹ 

Silmitasertib (CX-4945) is an oral small-molecule CK2 inhibitor that has exhibited preclinical antitumor activity and strong synergism with gemcitabine plus cisplatin. This triplet was evaluated in the open-label multicenter phase Ib/II S4-13-001 study of 88 patients with previously untreated locally advanced unresectable or metastatic cholangiocarcinoma. Most patients (85%) had intrahepatic tumors and metastatic disease (82%).

In the phase II portion, patients received silmitasertib at 1,000 mg twice daily for 10 days in combination with gemcitabine and cisplatin over a 21-day cycle. The interim analysis included the combined phase Ib and II cohorts.  

Mitesh J. Borad, MD

Lead investigator Mitesh J. Borad, MD, of the Mayo Clinic Cancer Center, described the rationale for this combination: “CK2 inhibition with silmitasertib is a first-in-class approach that is being extended to several malignancies. The target itself is a master regulator of many genes. In particular, it controls the phosphorylation of many downstream genes, including two that are involved in the DNA damage response, XRCC1 and MDC1. Inhibition of these proteins would synergize the treatment effect with both gemcitabine and cisplatin, which is a standard regimen in this disease. That was the rationale for this study.”

Promising Survival Observed

In 88 patients in the intent-to-treat analysis, median overall survival was 13.6 months. For the 55 evaluable patients in the modified intent-to-treat analysis—who had completed at least one cycle without dose modification—median overall survival rose to 17.4 months. 

The median progression-free survival was 11.1 months, overall response rate was 32.1% and 79.3% of patients achieved disease control, Dr. Borad reported.

Almost all patients (91%) experienced at least one treatment-related adverse event. The most associated with silmitasertib were diarrhea (65%), nausea (51%), vomiting (33%), fatigue (31%), and anemia (22%). The most common grade ≥ 3 adverse events were diarrhea (14%), neutropenia (11%), nausea (9%), anemia (8%), and thrombocytopenia (8%). Eleven patients (13%) discontinued treatment due to side effects. 

“The modified intent-to-treat survival of 17.4 months seems promising,” Dr. Borad commented, “but we need to take into consideration some caveats.”  He noted that patient selection in single-arm phase II studies varies, results from older trials may not be particularly relevant in the era of advances in treatments.  The data are considered promising enough, however, to launch a phase III trial of the regimen, with overall survival as the primary endpoint, he said. 

DISCLOSURE: Dr. Borad has stock or other ownership interests in AVEO, Gilead Sciences, Intercept Pharmaceuticals, and Spectrum Pharmaceuticals; has served in a consulting or advisory role for Agios, ArQule, Celgene, De Novo Pharmaceuticals, Exelixis, Fujifilm, G1 Therapeutics, Genentech, Halozyme, Immunovative Therapies, Imvax, Inspyr Therapeutics, Insys Therapeutics, Klus Pharma, Lynx Group, Merck, Novartis, Pieris Pharmaceuticals, Taiho Pharmaceutical, and Western Oncolytics; has received institutional research funding from Adaptimmune, Agios, ARIAD, Basilea, BiolineRx, Boston Biomedical, Celgene, Dicerna, Eisai, EMD Serono, Halozyme, ImClone Systems, Incyte, Isis Pharmaceuticals, MedImmune, Merck Serono, miRNA Therapeutics, Puma Biotechnology, QED Therapeutics, RedHill Biopharma, Senhwa Biosciences, Sillajen, Sun Biopharma, Taiho Pharmaceutical, Threshold Pharmaceuticals, and Toray Industries; and has received travel funding from ArQule, AstraZeneca, and Celgene.

REFERENCE

1. Borad MJ, Bai L-Y, Chen M-H, 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. 2021 Gastrointestinal Cancers Symposium. Abstract 312. Presented January 15, 2021.