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501 Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which showed meaningful clinical benefit in cholangiocarcinoma patients (pts) with FGFR2-driven (fusions, mutations or amplifications) tumors (NCT03230318). The current study explored the activity of DZB in patients with mUC and FGFR1-3 GA (NCT04045613). Methods: Eligible pts with advanced mUC and ≥1 prior lines of standard treatment and FGFR1/2/3 mutations/short variants and rearrangements/fusions confirmed by central/local NGS testing received DZB 300 mg QD (N = 32) or 200 mg BID (N = 17). Primary efficacy endpoint was objective response rate (ORR) by central radiology review per RECIST v1.1. Key secondary efficacy endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Adverse events were assessed according to NCI CTCAE v5.0. Results: From 01/2020 to 01/2022, 282 pts were screened and 49 pts were included in the study and received DZB. The median age was 67 years, 30.6% of pts were female, 94% had an ECOG 0/1, 75.5% had ≥2 prior treatment lines, 77.6% had received prior immune-checkpoint inhibitors. At data cutoff (30-Aug-2022), all pts had discontinued treatment. Confirmed ORR was 8.2% (95% CI 2.2, 19.6) based on 4 PRs (all with FGFR3 S249C mutation/ FGFR3 TACC3 fusion) and the DCR was 28.6% (95%CI: 16.6, 43.3). PFS ranged 0.3-8.8 months, and OS ranged 0.3-21.4 months. Median duration of response was 6.9 months, and longest time on treatment was 18 months. Most common all-grade treatment-emergent adverse events were transaminase increased (40.8%), nausea (38.8%), fatigue (32.7%) and decreased appetite (30.6%). Drug-related retinal events (12.2%), nail toxicities (6.1%), stomatitis (4.1%) and palmar-plantar erythrodysesthesia (PPE) (0%) were infrequent. Safety and efficacy results were similar in patients receiving 300 mg QD or 200 mg BID. Conclusions: Derazantinib showed signals of clinical activity in some patients with mUC and FGFR1-3 GA but the observed ORR and PFS did not meet contemporary benchmarks that would support further clinical development of derazantinib as monotherapy in this indication. Derazantinib showed a well-manageable safety profile with low rates of hand-foot syndrome, stomatitis, nail toxicity and retinal side effects. Clinical trial information: NCT04045613 .

437 Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which demonstrated antitumor activity in preclinical and clinical studies (in cholangiocarcinoma patients [pts] with FGFR2-driven tumors and in FGFR1-3-driven urothelial cancer [UC] PDX models). In CSF1-stimulated mouse bone-marrow derived macrophages, DZB reduced CSF1R phosphorylation with a maximal effect similar to the selective CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+AZB is a rationale combination to be investigated in immunogenic and FGFR-driven tumors like UC. Methods: FIDES-02 is a multi-cohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+AZB in combination. To determine the RP2D of DZB+AZB, a total of 26 pts with UC (N = 4) and other solid tumors (N = 22), of whom 7 pts carried various FGFR genetic aberrations (GA), were enrolled at 2 dose levels (DL) (1200 mg AZB Q3W + 200 mg [DL1] / 300 mg [DL2] DZB QD) and treated until disease progression or unacceptable toxicity. Both DLs were divided into MTD (endpoint: dose-limiting toxicity [DLT] at D21) and expansion cohorts to investigate both acute and delayed adverse events (AEs) per CTCAE v5. Results: In the MTD cohorts of both DL1 (N = 7) and DL2 (N = 6) no DLTs were observed, and the DL1 and DL2 expansion cohorts subsequently enrolled 7 and 6 pts, respectively. The most frequent treatment-emergent AEs across both DLs were fatigue (31%), nausea (27%), diarrhea (23%), the most frequent laboratory abnormalities were increased ALT (58%), and AST (50%). Non-DLT grade (G) ≥ 3 treatment-related AEs (TRAE) across both DLs were G3 diarrhea (4%), G3 nausea (4%), G3 asthenia (4%), oral fungal infection (4%) and one case of immune-related G4 nephritis (4%). Dose interruptions / reductions and discontinuations due to TRAEs occurred in 19% and 8%, respectively. Pharmacokinetic analyses demonstrated that DZB exposure parameters and AZB serum concentrations in pts treated with DZB+AZB were similar to those assessed in pts under DZB / AZB monotherapy. At data cut-off, 2 of 14 (DL1) and 7 of 12 pts (DL2) were still on treatment. Median duration of treatment in DL1 was 9.7 weeks (range, 9-25), and best overall response per investigator assessment was SD in 4 of 10 efficacy-evaluable DL1 pts. DL2 efficacy analysis was uninformative at cutoff. The combination of 1200 mg AZB Q3W with both 200 mg and 300 mg QD DZB was found to be safe and tolerable. Conclusions: The combination of DZB+AZB is safe at both investigated DLs, the RP2D has been determined as 300 mg DZB QD+1200 mg AZB Q3W. DZB can be safely dosed at its monotherapy RP2D in this novel combination with AZB. The anti-tumor efficacy of DZB+AZB is currently being investigated in adequately designed cohorts of FIDES-02 with enrichment for UC pts with FGFR GA. Clinical trial information: NCT04045613.

TPS590 Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In UC, FGFR genetic aberrations include FGFR1/2/3 mutations (M) and, less commonly, fusions (F), while the role of amplifications warrants further research. Prognosis of UC patients is overall poor and treatment options are limited. DZB is an oral small-molecule FGFR1/2/3 and CSF1R kinase inhibitor, which demonstrated promising antitumor activity in preclinical studies, including FGFR-driven patient-derived xenograft models. Preclinical data show that DZB reduced CSF1-stimulated CSF1R phosphorylation in macrophages, with a maximal effect similar to the CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+A (PD-L1 immune-checkpoint blockade [ICB]) is a rationale combination for immunogenic tumors like UC. FIDES-02 is a multicenter, multicohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+A combination. Methods: The study evaluates 300 mg DZB p.o. daily or DZB+A (1200 mg i.v.) in UC patients with FGFR1-3 M/F per liquid or tissue biopsy-based NGS. Cohort 1 (C1) enrolls pts after one or more standard chemotherapy ± ICB regimens (Phase 2; treatment: DZB); C2 enrolls patients with any advanced solid tumor, any FGFR status, any prior treatment (Phase 1b; for RP2D of DZB+A); C3 enrolls first-line patients with cisplatin-ineligible, PD-L1-low UC (Phase 2; DZB v DZB+A); C4 enrolls UC patients resistant to FGFR inhibitor treatment (Phase 2; DZB v DZB+A). Treatment will continue until disease progression, intolerance, withdrawal of informed consent, or death. Using Simon’s two-stage designs, objective response rate (per RECIST 1.1 central review) is the primary endpoint to assess the antitumor activity of DZB or DZB+A in Ph2. Main secondary objectives include evaluation of median PFS, duration of response, safety profile, HR-QoL (incl., QLQ C30, FACT-Bl, EQ-5D), and symptom response from baseline. The study was initiated in July 2019 and C1 (N=71) and C2 (N=24) are currently open for enrollment. Clinical trial information: NCT04045613.