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Early Dose-Escalation Data Confirm Potential of FGFR2 Inhibitor in Liver Cancer

By: Celeste L. Dixon
Posted: Friday, July 7, 2023

Dose-escalation data from the ongoing ReFocus study not only point to 70 mg daily as the best dose of RLY-4008 for patients with cholangiocarcinoma and other solid tumors, but also to evidence that this FGFR2 inhibitor’s selective targeting has wide therapeutic potential. In this first-in-human study, the compound showed efficacy across FGFR2-altered solid tumors and genomic alterations, according to Mitesh J. Borad, MD, of Mayo Clinic Arizona, Scottsdale, and colleagues, who presented their work at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 4009). According to the team, the differentiated safety profile of RLY-4008 seems to allow it to circumvent FGFR1- and FGFR4-related toxicity.

This phase I/II open-label study involved 116 adults with advanced, FGFR2-altered solid tumors, most of them (n = 91) cholangiocarcinomas. Half of the participants had prior FGFR inhibition treatment; the median number of prior therapy lines was three. No grade 4 or 5 treatment-related adverse effects were reported, but 105 patients discontinued treatment after a median of 24 weeks, mostly (n = 81) because of disease progression.

“Oncogenic FGFR2 alterations represent a broad therapeutic opportunity, [because] they drive multiple solid tumors, particularly cholangiocarcinoma,” pointed out Dr. Borad and co-investigators. In the past, however, “off-isoform toxicity and on-target resistance [have limited] the benefit of approved pan-FGFR inhibitors.” In contrast, RLY-4008 is an oral FGFR2 inhibitor that is “designed to overcome these limitations by targeting FGFR2 driver alterations and resistance mutations.”

Some patients with FGFR2-altered cholangiocarcinoma with fusions or rearrangements achieved clinically meaningful disease control and durable responses with RLY-4008. In the entire study cohort, across doses and FGFR2 alterations, 64% (n = 74) had radiographic tumor reductions, and 72% (n = 83) had stable disease or a partial response; this included four of four patients with cholangiocarcinoma, all FGFR inhibitor–naive, who achieved a confirmed partial response with the recommended phase II dose.

For more from Dr. Borad, see this video on treatment guidelines for diagnosing and managing hepatocellular cancers.

Disclosure: The study authors’ disclosure information can be found at

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