Infigratinib Demonstrates Clinical Activity Across Settings in Urothelial Cancer


Infigratinib was found to demonstrate clinical activity in patients with metastatic urothelial carcinoma, regardless of what line of therapy it was administered.

Yung Lyou, MD, PhD

Yung Lyou, MD, PhD, assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope

Yung Lyou, MD, PhD

Infigratinib was found to demonstrate clinical activity in patients with metastatic urothelial carcinoma, regardless of what line of therapy it was administered, according to results of a retrospective analysis presented at the 2020 ASCO Virtual Scientific Program.1

Results showed that the overall confirmed objective response (complete response [CR] or partial response [PR]) was 30.8% (95% CI, 9.1%-61.4%) in patients who received infigratinib as a first-line therapy and was 24.1% (95% CI, 13.5%-37.6%) in those who received it as a second- or later-line treatment, leading to a total confirmed objective response of 25.4% (95% CI, 15.5-37.5).

Notably, the activity was most significant in a subset of patients with upper tract urothelial cancer, which is enriched for FGFR3-driven disease. In this subset, the confirmed objective response rate (ORR) was 50% (95% CI, 15.7%-84.3%) and the disease control rate (DCR) was 100% for those who received infigratinib as second- or later-line treatment.

"Our data suggests similar activity of infigratinib in patients receiving it in the first-line setting versus subsequent lines for advanced urothelial carcinoma," lead study author Yung Lyou, MD, PhD, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, said in a poster presentation during the virtual meeting. "These results suggest that infigratinib has activity in patients with advanced urothelial carcinoma, regardless of the line of treatment."

Advanced urothelial carcinoma continues to be an incurable disease for many patients. Platinum-based chemotherapy continues to serve as the foundation for treatment; only approximately 15% to 40% of patients respond to checkpoint inhibitors. Moreover, an estimated 20% of patients with lower tract disease, and 40% to 75% of those with upper tract disease have FGFR3 activating mutations, suggesting it to be a potential new target for novel therapies.

Infigratinib is a potent, oral, selective ATP-competitive FGFR1/2/3 inhibitor that has previously reported to have significant clinical activity in patients with advanced urothelial cancer whose tumors harbor FGFR3 alterations.2,3 In the retrospective analysis of this phase 1b trial, investigators sought to determine whether differences existed with regard to infigratinib activity based on the number of prior lines of therapy that patients could have received.

In the trial, 67 patients with advanced or metastatic urothelial cancer that harbored FGFR3 alterations were treated with oral infigratinib at 125 mg once daily on days 1 to 21 every 28 days until disease progression or unacceptable toxicity. Dose reductions to 100 mg daily, followed by 75 mg daily, were permitted and further reductions were permitted on an individualized basis.

To be eligible for enrollment, patients must have progressed on, or were intolerant to, platinum-based chemotherapy, unless contraindicated. Patients also had to undergo baseline imaging, including CT of the chest, abdomen, and pelvis, as well as brain MRI or CT and technetium bone scan. Follow-up serial imaging comprised the same baseline CT imaging, along with bone scan if indicated, at 8-week intervals thereafter.

The primary end point of the trial was to compare the ORR via RECIST v1.0 criteria in patients receiving infigratinib up front (n = 13) versus those receiving the agent in a later-line setting (n = 54). Secondary outcome measures included a comparison of DCR and PFS in both arms, as well as best overall response, overall survival (OS), safety, and pharmacokinetics.

For responses, investigators used the chi-square test and utilized; additionally, they used the Kaplan-Meier method with log-rank test to compare PFS outcomes. Moreover, comparisons were also made across individual lines of therapy with the use of descriptive statistics to optimally fit the number of patients in each subgroup. Tissue and blood specimens were also genomically assessed.

Slightly more than half (56.7%) of patients were younger than 65 years, and 68.7% of patients were male. Additionally, 31.3% of patients had a World Health Organization performance status of 0, 53.7% had a status of 1, and 14.9% of patients had a performance status of 2. Furthermore, 17.9%, 40.3%, 37.3%, and 4.5% of patients had Bellmunt Criteria risk scores of 0, 1, 2, and 3, respectively. Most patients had urothelial bladder cancer (88.1%) versus upper tract urothelial cancer (11.9%), and nearly two-thirds of patients overall (61.2%) had visceral lung disease, while 37.3% had visceral liver metastases. Additionally, 41.8% of patients had lymph node metastases and 61.2% had bony metastases. Notably, 19.4% of patients received prior immunotherapy.

In the response assessment, data in the overall population showed that there was 1 CR, which occurred in the later-line arm and translated to a 1.5% CR rate. Four PRs (30.8%) and 12 PRs (22.2%) were reported in the frontline and later-line arms, respectively, which translated to a 23.9% total PR rate. The stable disease (SD) rate was 15.4% and 44.4%, respectively, leading to an overall 38.8% SD rate. Progressive disease (PD) was reported in 46.2% of patients on frontline infigratinib and 22.2% of those on later-line treatment for a 26.9% overall PD rate; 1 patient on frontline treatment had an unknown response versus 5 patients who received infigratinib later on.

The best overall response (BOR) was 38.5% (95% CI, 13.9%-68.4%) with up-front infigratinib and 42.6% (95% CI, 29.2%-56.8%) with later-line infigratinib, leading to a total BOR of 41.8% (95% CI, 29.8%-54.5%); the DCR was 46.2% (95% CI, 19.2%-74.9%) and 68.5% (95% CI, 54.4%-80.5%), respectively, which led to a total 64.2% DCR (95% CI, 51.5%-75.5%).

When stratified by patients with urothelial bladder cancer, no CRs were reported in either group; however, 4 PRs (30.8%) were observed in those who received up-front infigratinib and 9 PRs (19.6%) were reported in those who received later-line therapy, leading to a total PR rate of 22%. SD was reported in 15.4% and 43.5% of patients with frontline and later-line infigratinib, respectively, leading to an overall SD rate of 37.3%. The PD rates were 46.2% and 26.1% in the first- and later-line settings, respectively, with a total PD rate of 30.5%. The confirmed objective response was 30.8% with frontline infigratinib and 19.6% with later-line treatment, leading to an overall confirmed objective response of 22.0%.

The BOR in this population was 38.5% (95% CI, 13.9%-68.4%) and 39.1% (95% CI, 25.1%-54.6%) for up-front and later-line infigratinib, respectively, leading to an overall BOR of 39.0% (95% CI, 26.5%-52.6%). Finally, the DCR was 46.2% (95% CI, 19.2%-74.9%) with frontline infigratinib and 63.0% (95% CI, 47.5%-76.8%) with second- or later-line therapy, which translated to a 59.3% BOR (95% CI, 45.7%-71.9%).

In the overall population, the median PFS was similar between arms, with a median 3.65 months (95% CI, 0.95-7.43) in the first-line infigratinib arm compared with 3.75 months in the second- or later-line group (95% CI, 3.09-5.42). The findings were similar with regard to OS; the median OS was 7.93 months (95% CI, 2.40—not evaluable) and 7.75 months (95% CI, 5.72-13.67), respectively, and were not found to be statistically significantly different from one another.

Regarding safety, all-grade and grade 3/4 adverse events (AEs) occurred in 98.5% and 68.7% of patients, respectively. Grade 3/4 AEs comprised of hyperphosphatemia (1.5%), fatigue (7.5%), anemia (7.5%), decreased appetite (4.5%), dry mouth (1.5%), nausea (4.5%), stomatitis (3.0%), vomiting (4.5%), diarrhea (3.0%), abdominal pain (1.5%), dyspepsia (1.5%), and arthralgia (3.0%).

All-grade hyperphosphatemia, which was reported in 46.3% of patients, is known to be a commonly associated AE with FGFR inhibition, Lyou explained. Fatigue and constipation (37.3% each) were also commonly reported AEs.

The investigators did note in the presentation that the study had limitations, such as that a relatively small proportion of patients received infigratinib in the first-line setting, and that the current data also reflect an unplanned subset analysis.

The results support the ongoing PROOF 302 study (NCT04197986), which is comparing adjuvant infigratinib with placebo in patients with resected disease, and in an upper tract urothelial carcinoma—enriched population, according to the investigators. In this research, disease-free survival (DFS) via central review will serve as the primary end point and secondary end points will include investigator-reviewed DFS, metastasis-free survival, OS, and safety/tolerability.


  1. Lyou Y, Grivas P, Rosenberg JE, et al. Infigratinib and treatment response in advanced/unresectable or metastatic urothelial carcinoma in first-line and later-line treatment settings. J Clin Oncol. 2020;38(suppl 15; abstr 5038). doi:10.1200/JCO.2020.38.15_suppl.5038
  2. Pal SK, Rosenberg JE, Hoffman-Censits JH, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1—3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov. 2018;8(7):812-821. doi:10.1158/2159-8290.CD-18-0229
  3. Pal SK, Bajorin D, Dizman N, et al. Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell-free DNA results. Cancer. 2020;126(11):2597-2606. doi:10.1002/cncr.32806

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