medwireNews: People with upper tract urothelial carcinoma (UTUC) may derive a greater benefit from treatment with infigratinib, an FGFR1–3 tyrosine kinase inhibitor, than those with urothelial carcinoma of the bladder (UCB), suggests an analysis of a phase 1 trial.
The trial previously demonstrated promising response rates in the overall cohort comprising previously treated patients with metastatic UC harboring activating FGFR3 mutations.
But noting that UTUC and UCB “may have distinct biologic underpinnings,” Sumanta Pal (City of Hope Comprehensive Cancer Center, Duarte, California, USA) and colleagues “sought to determine whether patients with UTUC and UCB had a distinct pattern of response.”
The study, reported in Cancer, included 67 individuals – eight with UTUC and 59 with UCB – who received infigratinib 125 mg/day for 21 days of each 28-day cycle, with dose reductions to 100 mg/day and 75 mg/day permitted.
Among the UTUC patients, one achieved a complete response and three had partial responses, translating to an overall response rate (ORR) of 50%, with a disease control rate (DCR) of 100% as the best response of the remaining four patients was stable disease.
By contrast, the ORR and DCR among UCB patients were 22% and 59%, respectively, with 13 partial responses contributing to the ORR, and 22 patients with a best response of stable disease.
Pal et al note that these responses are some of “the most robust signals of activity in UTUC presented to date.”
They add that median overall survival and progression free survival were also better in the UTUC cohort than the UCB cohort, at 21.82 versus 7.00 months and 8.54 versus 3.65 months, respectively, and the toxicity was comparable.
Analysis of tumor tissue and cell-free DNA genomic profiles revealed “notable differences” in FGFR3 alterations between patients with UTUC versus UCB, “underscoring the distinct biology of these diseases,” according to the researchers.
Indeed, tumor tissue analysis revealed that FGFR3 R248C mutations were more common in UTUC than UCB tumors (50 vs 12%), as were FGFR3–TACC3 fusions (13 vs 7%), but FGFR3 S249C mutations were less common (38 vs 59%) with concordant results in nearly 80% of the patients for whom cell-free DNA was available for analysis.
In both analyses, UTUC tumors had a less complex and less heterogeneous genomic profile compared with UCB tumors, “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,” say the study authors.
The authors of an accompanying comment agree, noting that “[t]his suggests that targeted inhibition of FGFR3 may be most beneficial against UTUC and that the high response rate of infigratinib, in particular, may be due to its high specificity for FGFR3.”
Chelsea Osterman and Matthew Milowsky, from the University of North Carolina in Chapel Hill, USA, also postulate: “Alternatively, it may be that the specific FGFR alteration is important and that the increased frequency of R248C mutations among patients with UTUC may have contributed to the higher response rate.”
Pal and team note “the caveat of the small sample size” but conclude that “[t]he results of the current study regarding infigratinib in patients with UTUC offer support to a planned phase 3, adjuvant study performed predominantly in this population.”
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Cancer 2020; doi:10.1002/cncr.32806
Cancer 2020; doi:10.1002/cncr.32804