Table 1.

Off-target molecular alterations in the PI3K–mTOR pathway detected in patients suffering from FGFR3-driven urothelial cancers

Patient	Baseline tissue analysis	Baseline ctDNA (VAF)	FGFR inhibitor	BOR	PFS (months)	Postprogression tissue analysis	Postprogression ctDNA analysis (VAF)
MR15	FGFR3 S249C	NA	Erdafitinib	−30%	5.8	FGFR3 S249C	NA
	PIK3CA E545A					PIK3CA E545A
MR86	FGFR3 S249C	NA	Erdafitinib	−25%	2.7	FGFR3 S249C	NA
	PIK3CA E545K					FGFR3 N540K
						PIK3CA E545K
ST2267	FGFR3::TACC3	FGFR3::TACC3 8.03%	Futibatinib	+24%	1.7	NA	FGFR3::TACC3 4.16%
	PIK3CA H1047R
MR336	FGFR3 S249C	FGFR3 S249C 7.72%	Erdafitinib	−22%	5.6	FGFR3 S249C	FGFR3 S249C 10.38%
						PIK3CA E545K	PIK3CA E545K 7%
MR410	FGFR3 S249C	NA	Erdafitinib	−46%	19.6	FGFR3 S249C	FGFR3 S249C 45.94%
	TSC1 S561fs					FGFR3 ampl (>10 copies)	FGFR3 E589Q 31.12%
						TSC1 S561fs	TSC1 S561fs 69.96%
						PIK3CA E726K
M322	FGFR3::TACC3	FGFR3::TACC3 0.65%	Erdafitinib	−40%	3.7	TSC2 P28fs	FGFR3:TACC3 2.95%
							FGFR3 V555M 0.37%
							TSC2 P28fs 0.34%
M521	FGFR3::TACC3	NA	Erdafitinib	−39%	8.3	FGFR3::TACC3	NA
						TSC1 Q865*
MR1105	FGFR3::TACC3	NA	Futibatinib	−35%	7.7	NA	FGFR3::TACC3 9.8%
							TSC1 A186fs 1.8%
ST701	NA	FGFR3 S249C 0.2%	Erdafitinib	−39%	4.1	TSC1 Q830*	FGFR3 S249C 0.45%
							TSC1 Q830* 1.8%
MR246	FGFR3 S249C	NA	Erdafitinib	−21%	3.4	FGFR3 S249C	FGFR3 S249C 2.37%
							NF2 L163fs 0.21%
							FGFR2 V517M 0.12%
M2057	FGFR3 S249C	NA	Erdafitinib	+174%	1.4	PTEN C136fs	FGFR3 S249C 48.13%
						FGFR3 CNV (6 copies)

NOTE: Eleven out of 19 (58%) patients harbored alterations in genes belonging to the PI3K–mTOR pathway, with an enrichment in postprogression samples. Molecular alterations in bold were not present in baseline samples.

Abbreviations: ampl, amplification; BOR, best objective response; CNV, copy-number variation; NA, not assessed.