ESMO 2022 - First highly-targeted therapy against the FGFR2 gene in biliary tract cancer

11th September

ESMO 2022

First highly-targeted therapy against the FGFR2 gene in biliary tract cancer

Biliary tract cancers are rare but aggressive and carry a poor prognosis. They offer little in terms of therapeutic options. The ReFocus trial led by Gustave Roussy demonstrates the efficacy of a new highly-targeted therapy inhibiting expression of the FGFR 2 gene, which is present in 15–20% of biliary tract cancers. The preliminary findings of the trial were presented at the ESMO 2022 Congress. RLY-4008 effected disease control in 88% of the patients treated in this study. This treatment is more effective, active in cases with mutations contributing to resistance to therapy and associated with less toxicity in patients with these cancers. 

Study presented Sunday 11th September at 3.45 pm in an oral session (proffered paper) at the ESMO (European Society for Medical Oncology) Congress by Dr Antoine Hollebecque, oncologist in the Gustave Roussy Drug Development Department (DITEP).

Biliary tract cancers (cholangiocarcinomas) are rare, 3,000 new cases per year, but they are aggressive and carry a poor prognosis. Often diagnosed when already at an advanced stage (metastatic), they are not suitable for surgery. Treatment options remain limited to two lines of chemotherapy. About 10 to 15% of these patients have an FGFR2 fusion gene detected in tumour biopsy or fluid. Medication, pemigatinib, is already available in France. This agent falls within the class of FGFR pan-inhibitors and targets mutations of FGFR 1 to 4 genes with an efficacy or mean response rate of 20-40% over 5 to 10 months.

Promising novel therapy targeted solely on the FGFR2 gene

RLY-4008 is a new agent which is capable of blocking the FGFR2 receptor highly selectively. The   ReFocus trial seeks to use this agent to target mutations of the FGFR2 gene more effectively, escape the mechanisms of drug-resistance that develop, and limit the toxicity of pemigatinib and its therapeutic class.

This phase I-II trial is sponsored by Relay Therapeutics and conducted in a number of international centres. The results were reported for a cohort of 38 patients with biliary tract cancer carrying a fusion or rearrangement of the FGFR2 gene, who had never received treatment with another FGFR inhibitor. The main ReFocus objectives were to determine a recommended dose for the use of RLY-4008 and to demonstrate tumour efficacy (degree and duration of response) and safety in use.

To establish the optimal dose, patients received various doses of the new agent. At the time of analysis of the results, 63% of the patients, all doses taken together, were responding to the treatment. When the treatment was given at the optimal dose of 70 mg (17 patients), the response rate was 88%. The level of disease control measured by CT examination at two months was 100%. “There was no immediate escape from treatment efficacy,” explained Dr Hollebecque, oncologist in the Gustave Roussy Drug Development Department (DITEP).

The main side effects reported were those recognised for FGFR2 inhibitors: nail separation, hand-foot syndrome and mucositis (inflammation of buccal mucosa).       

At the time of presentation of the findings, 15 patients were still receiving treatment. Additional results relating to response duration are awaited. “RLY-4008 reduces disease burden markedly but it is still too early to know whether this will be long-term. These initial results show greater specificity of this agent compared with that of the FGFR pan-inhibitors, suggesting that access to this medication should be speeded up,” concluded Dr Hollebecque. Recruitment to the study is ongoing.

Abstract n°LBA12

Efficacy of RLY-4008, a highly selective FGFR2 inhibitor, in patients (pts) with a FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial
Proffered paper session
Sunday 11^th September | 3.45 – 3.55 pm