A new drug based on precision medicine has been shown to be effective in treating patients with advanced intrahepatic cholangiocarcinoma, an aggressive cancer that affects the intrahepatic bile duct. There is currently no standard treatment for advanced disease after first-line chemotherapy. Between 10 and 20% of patients have a genetic profile with a fusion in the FGFR2 gene.
The results of the Phase II PHOENIX-CCA2 clinical trial show that the use of futibatinib, a new generation oral drug, in cholangiocarcinoma patients with intrahepatic FGFR2 gene fusion already received clinical benefit with chemotherapy treatment. Research has also shown the sensitivity of liquid biopsy for genetic profiling of patients through analysis of circulating tumor DNA even before surgery can select patients for their genetic profiling even before a tumor tissue biopsy is obtained.
The results of this trial, in which researchers from the Vall d’Hebron Institute of Oncology (VHIO) and the Vall d’Hebron Hospital participated, were published in the New England Journal of Medicine. The incidence of intrahepatic cholangiocarcinoma is increasing worldwide. Surgery is the best curative option, but up to two-thirds of patients have disease recurrence.
Patients with intrahepatic cholangiocarcinoma have an overall 5-year survival rate of less than 8%, and the median overall survival is approximately 1 year after diagnosis. And there is currently no standard treatment for advanced disease after first-line chemotherapy.
“In this sense, intrahepatic cholangiocarcinoma is an orphan disease, since we do not have many active treatments. For this reason, we are researching the alternatives of different refined drugs in which a percentage of patients with a certain genetic profile may benefit from other drugs more than others”, explains Dr. Josep Tabernero, director of the Institute of Vall d’Hebron, Oncology (VHIO); head of the Medical Oncology Service of the University of Vall d’Hebron, co-author of the study.
“Between 10 and 20% of patients with cholangiocarcinoma have a fusion or translocation (a type of genetic alteration) in the fibroblast growth factor receptor 2 (FGFR2) gene, which offers a promising therapeutic approach to this disease,” adds Dr. Tabernero. .
New generation or breakthrough therapy drugs are new pharmaceutical drugs based on gene therapy, cell therapy or tissue technology. Futibatinib is a new generation drug capable of inhibiting the FGFR gene and has demonstrated antitumor activity in patients with FGFR tumors, as well as less susceptibility to tumors acquiring resistance mutations. In other words, it took longer for tumor cells to acquire drug resistance than other FGFR inhibitors.
The PHOENIX-CCA2 study, a phase II clinical trial, the results of which were recently published in the New England Journal of Medicine, treated patients with unresectable or metastatic intrahepatic cholangiocarcinoma with FGFR2 translocation and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitor drugs).
Tumor biopsies were used for patients with FGFR2 translocations, but liquid biopsies were also performed to analyze the genetic profile of ctDNA (circulating tumor DNA) in patient plasma. “This technique is not as invasive as a biopsy of the tumor tissue and can be performed even before surgery to select patients who benefit from the genetic profile of the treatment,” said Dr. Shop
Patients received oral futibatinib once daily as a continuous regimen. The main endpoint was objective response, the percentage of patients in whom the tumor shrank or disappeared. Secondary objectives included duration of response, progression-free and overall survival, safety, and patient-reported outcomes.
“The trial included a total of 103 patients with unresectable or metastatic intrahepatic cholangiocarcinoma with mutations in the FGRF2 gene. 43 of them (42%) responded favorably and the mean duration of response was 9.7 months,” describes Dr. Teresa Macarulla, medical oncologist at the Universitari Vall d’Hebron, and head of the Gastrointestinal Tumors Group, and endocrinologists from the VHIO who participated in the study.
The median progression-free survival (the time between the start of treatment and tumor regrowth) was 9 months and the overall survival was 21.7 months. The patient’s quality of life remained stable for an average of 9 months after treatment. “Responses were consistent across all patient groups, including patients with severe pre-treated disease, older adults, and patients with TP53 mutations,” said Dr. Macarulla
“These results indicate that we have a new precision medicine for patients facing intrahepatic cholangiocarcinoma with this specific genetic profile,” said Dr. Josep Tabernero. “There are other investigations in which different treatments are being tested for patients with intrahepatic cholangiocarcinoma with different genetic profiles so that we can provide different types of patients with the treatment that will provide the most clinical benefit. This is another step in this ongoing fight to find new treatments that can make the disease more manageable over time .