Updated Results for Infigratinib in Metastatic Urothelial Cancer

Updated results, published in Cancer, demonstrated that infigratinib retains significant activity in patients with metastatic urothelial cancer (mUC).

Moreover, the study found that the nature of mutations noted in upper tract urothelial carcinoma (UTUC) appears to differ from that of the mutations found in urothelial carcinoma of the bladder (UCB), with the caveat of a small sample size, a higher rate of FGFR3 S249C mutations, and a smaller repertoire of mutations observed. 

Given the findings presented in this study regarding infigratinib in patients with UTUC, the researchers suggest the planning of a phase III, adjuvant study performed predominantly in this population. 

“To our knowledge, these are the highest response rates achieved in a UTUC cohort to date and this is the only targeted therapy found to have differentiated efficacy in patients with UTUC compared with those with UCB,” the authors wrote.

A total of 67 eligible patients with metastatic urothelial carcinoma activating FGFR3 mutations and/or fusions were enrolled in the study, and the majority (70.1%) had received ≥2 prior antineoplastic therapies. Researchers performed genomic profiling on formalin-fixed, paraffin-embedded tissues and blood was collected for cell-free DNA analysis using a 600-gene panel. 

Participants were given 125 mg of infigratinib orally daily (3 weeks on, 1 week off) until disease progression or intolerable toxicity occurred. In the UTC cohort of 8 patients, researchers observed 1 complete response (CR) and 3 partial responses (PRs), for an overall response rate (ORR) of 50%, while the remaining patients achieved a best response of stable disease (SD). Ddisease control rate (DCR) was 100%. Of the 59 patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%).

Additionally, differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), as well as a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%).

“Similar to the tissue-based genomic profiling in the current study, pretreatment cfDNA analysis demonstrated an increase in mutations and gain and/or loss of gene copy that are known to alter protein function among patients with UCB versus those with UTUC,” the authors wrote. “Together, these data suggest a less heterogenous mutation profile in patients with UTUC com- pared with those with UCB, which may lead to a greater likelihood that FGFR3 is the primary alteration driving the cancer in UTUC and therefore a greater likelihood of response to infigratinib.”

Given the small sample size, the researchers were limited in their ability to correct for potentially confounding clinical and demographic variables that could have affected the outcome. The conclusions surrounding the genomic findings in cfDNA were also potentially altered by the lack of available blood specimens in several patients. However, it should be also be noted that the findings in the cfDNA and tissue specimens were somewhat consistent (i.e., a lesser degree of genomic diversity in UTUC vs UCB). 

Reference:

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. doi:10.1002/cncr.32806.