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New Precision Therapy for Bile Duct Cancer Extends Lives

An international multicentre trial involving UK researchers has demonstrated that a new personalised cancer treatment can radically improve the outlook for some patients with bile duct cancer.

In England, around 2800 people are diagnosed each year with bile duct cancer. Cancer Research UK said that over the last few years the number of people developing bile duct cancer has increased, however, the reason for this increase remains unclear. Some studies have suggested it might be "related to lifestyle choices" such as smoking and drinking alcohol, the charity said. 

The authors of the new study, published in the New England Journal of Medicine, pointed out that there are "very few treatment options" for bile duct cancer and survival is poor, with patients living on average for just 12 months after diagnosis. However, the researchers said that "alterations" in fibroblast growth factor receptor 2 (FGFR2) have emerged as "promising drug targets" for intrahepatic cholangiocarcinoma.

Genetic Target

For their multinational, open-label, single-group, phase 2 study researchers set out to investigate whether treatment with futibatinib – a next-generation, covalently binding FGFR1–4 inhibitor – could benefit those with the "rare cancer with a poor prognosis". Futibatinib targets a particular genetic alteration - FGFR2 fusion - which is found in around 14% of bile duct cancers. Of those people diagnosed annually in the UK with bile duct cancer, approximately 300 will have this genetic alteration, explained the authors.

The international trial, which was set across 13 countries (Australia, Canada, France, Germany, Hong Kong, Italy, Japan, South Korea, Netherlands, Spain, Taiwan, United Kingdom, and United States) and involved University College London (UCL) and University College London Hospitals NHS Trust (UCLH), Guy's and St Thomas' NHS Foundation Trust, The Christie NHS Foundation Trust and the Sarah Cannon Research Institute, recruited 103 patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy, excluding FGFR inhibitors, between April 16, 2018 and November 29, 2019.

The primary end point was objective response (partial or complete response) as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes.

For the trial patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen.

Treatment Turned on Its Head

When the patients were treated with futibatinib the results were "striking" said the authors. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months.

"Patients who were otherwise facing end-of-life care survived for up to 2 years when treated with the drug futibatinib, even though they had advanced cancer and had sometimes tried up to five other treatments beforehand," highlighted the authors.They also reported that no treatment-related deaths occurred, and that quality of life was maintained throughout treatment.

They added that the drug was "more effective" at reducing the size of the tumour than chemotherapy, with the cancer shrinking by over 40% compared with 25% on chemotherapy. The drug also produced modest side effects compared with chemotherapy, they reassured.

Common treatment-related grade 3 adverse events in patients were hyperphosphatemia (30%), increased aspartate aminotransferase level (7%), stomatitis (6%), and fatigue (6%).

Professor John Bridgewater, UCL Cancer Institute and UCLH, and European lead and senior author of the paper, said: "These results turn treatment for this group of patients on its head. Instead of treating them with the blunderbuss that is chemotherapy, which attacks healthy cells alongside the cancer, we can offer a personalised treatment that just targets a specific alteration within the cancer."

There are currently other FGFR inhibitors already in clinical use, including pemigatinib, which has been approved for use in the UK by the National Institute for Care and Health Excellence (NICE). However, existing FGFR inhibitors are known to be susceptible to resistance within the cancer, explained the authors. Laboratory tests have shown this is less likely to be a problem with futibatinib, they said, as it targets the FGFR abnormality in a "more specific way", and so is likely to be more effective than existing drugs.

Trials are already underway looking at the possibility of using FGFR2 inhibitors as a first line treatment in place of chemotherapy. 

"The question these trials now need to answer is not whether patients should be getting this treatment, but when," Professor Bridgewater stressed.

Remarkable Benefits Possible

Helen Morement, CEO of The Alan Morement Memorial Fund (AMMF), the cholangiocarcinoma charity, warmly welcomed the trial's success.

"For well over a decade there has been little in the treatment armoury for those with an inoperable cholangiocarcinoma. Chemotherapy, although it can be moderately effective for some, it is not effective for all, and the effectiveness is not known until the patient has received several cycles of chemotherapy and may have endured a number of difficult side effects, only to find there has been no advantage for them in reducing or stabilising their cancer," she explained.

"Now, for those whose cholangiocarcinoma is shown to have the FGFR2 fusion, futibatinib offers an important step forward. Not only is it a more personalised treatment which they know from the outset could have a positive impact on their cancer - bringing with it the hope of extending survival over the more standard chemotherapies and/or best supportive care that might be offered – but, as an oral therapy with tolerable side effects, it has quality of life advantages over conventional chemotherapy, including spending less time in hospital and away from loved ones.  

"Already an approved treatment in the USA, we now await NICE approval in due course …", she said.

"The benefits that patients saw in the trial were remarkable. It’s important that patients with bile duct cancer get their cancer tested to find out if they have this abnormality. We can't afford to mis one of these alterations," said Professor Bridgewater. "The difference they could make to treatment outcomes is dramatic."

Ms Morement emphasised that the "important milestone" underlined the necessity for all healthcare professionals to put their cholangiocarcinoma patients forward for molecular testing.

"Hopefully, this kind of genetically driven treatment will become the new normal for oncology. Personalised treatment has long been a buzz word in cancer, but this trial is the real thing – proving that it can be done and bring huge benefits to specific groups of patients," said Prof Bridgewater.

The study was supported by Taiho Oncology and Taiho Pharmaceutical. Dr Bridgewater was funded, in part, by the National Institute for Health and Care Research (NIHR) University College London Hospitals NHS Foundation Trust-University College London Biomedical Research Centre.