The first potent, highly selective, oral FGFR2 inhibitor RLY-4008 demonstrated encouraging efficacy across patients with FGFR2-altered solid tumors, according to phase 1/2 data.

These results were presented at the 2023 ASCO Annual Meeting by Mitesh Borad, MD, Mayo Clinic Arizona, Scottsdale, Arizona, on Sunday, June 4, 2023, in Chicago, Illinois.

The open label ReFocus trial enrolled 116 patients with FGFR2-altered solid tumors, including 91 patients with cholangiocarcinoma. Of all the patients enrolled there were 82 with FGFR2 fusions/rearrangements, 27 with mutations, and 6 with amplification. Patients received RLY-4008 twice a day on a 4-week cycle. The outcomes were treatment-related adverse events, pharmacokinetics, circulating tumor DNA (ctDNA), and anti-tumor activity.

Anti-tumor activity was detected across all doses and FGFR2 alterations, among patients with cholangiocarcinoma and other solid tumors. The recommended phase 2 dose was determined to be 70 mg daily based on pharmacokinetics, safety, and anti-tumor activity. Radiographic tumor reductions were seen in 64%, stable disease or partial response in 72%. All 4 patients with cholangiocarcinoma and FGFR2 fusions/rearrangements who had not yet been exposed to any FGFR inhibition and who received the recommended phase 2 dose achieved a confirmed partial response. Among patients with cholangiocarcinoma and FGFR2 fusions/rearrangements, there was clinically meaningful disease control and durable responses.

A total of 105 patients discontinued treatment, 81% because of progressive disease and 3% because of adverse events. The most common treatment-related adverse events, across all doses, were low-grade palmar-plantar erythodysesthesia, stomatitis, dry mouth, alopecia, and dry eye. There were no grade 4/5 treatment-related adverse events observed.

Dr Borad and coauthors concluded these data “confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity.” They added that phase 2 of this trial is ongoing across all solid tumors, with the intent to register patients with cholangiocarcinoma and FGFR2 fusions/rearrangements who have not yet received FGFR2 inhibition.

Source:

Borad M, Schram AM, Kim RD. Updated dose escalation results for ReFocus, a first-in-human study of highly selective FGFR2 inhibitor RLY-4008 in cholangiocarcinoma and other solid tumors. Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 4009