Gopa Iyer, MD, highlights findings from FORAGER-1 in metastatic urothelial carcinoma

In this video, Gopa Iyer, MD, shares the background and findings from the study, “A first-in-human phase 1 study of LY3866288 (LOXO-435), a potent, highly isoform-selective FGFR3 inhibitor (FGFR3i) in advanced solid tumors with FGFR3 alterations: Initial results from FORAGER-1,” which was presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.

Iyer is a genitourinary medical oncologist, an early drug development specialist, and the section head of bladder cancer at Memorial Sloan Kettering Cancer Center in New York, New York.

Video Transcript:

FGFR3 genetic alterations are found in up to 20% of patients with metastatic urothelial cancer. There is a targeted therapy, erdafitinib, which is FDA approved for the management of these patients, but it's an inhibitor of FGFR 1, 2, 3, and 4. So, it's associated with off-target toxicities because it inhibits FGFR 1, 2 and 4, in addition to FGFR3, and that can limit its use clinically.

FORAGER-1 is a phase 1 trial of LY3866288, or LOXO-435. This is an FGFR3 isoform-specific inhibitor. It's very potent. It's very selective for FGFR3 instead of FGFR 1 and 2. The goal of the study was to see if this drug had a much better safety profile than erdafitinib and was also effective in treating patients with metastatic urothelial cancer with FGFR3 alterations.

So, the study was a dose escalation study. There are also additional dose optimization and dose expansion cohorts that are ongoing right now. In the dose escalation, they looked at between 6 mg daily and 400 mg twice daily of the drug. Throughout that entire dose expansion, they did not see any dose-limiting toxicity, so the drug was well tolerated. The most common treatment emergent adverse event was diarrhea, but that was actually fairly low-grade in most patients and quite manageable. Otherwise, we did see some asymptomatic liver enzyme elevations and some fatigue. Again, these really were not significant clinical toxicities. What was most important was that many of the side effects that we see that are the high-grade toxicities with erdafitinib, because it inhibits FGFR 1, 2, and 4, specifically, skin toxicities and ocular toxicities, were notably quite low or even absent with LOXO-435.

In terms of efficacy, in 39 patients with metastatic urothelial cancer, the objective response rate was 41%. Of note, in 10 of those patients who had already received erdafitinib or other FGFR inhibitors and whose disease had progressed in most of those cases, the response rate was 50%, so 6 out of 12 patients had responses to LOXO-435. Based on all of these data, it seems like this is a much better tolerated drug, at least right now, than erdafitinib. It seems to show similar efficacy to erdafitinib.

There are plans now to continue the dose optimization to identify the exact dose for a further expansion. There's also a plan to open some of those additional dose expansion cohorts, including a triplet regimen of LOXO-435 in combination with enfortumab vedotin and pembrolizumab, which are the first-line combination treatment right now in metastatic urothelial cancer.

This transcript was AI generated and edited by human editors for clarity.