derazantinib (ARQ 087)

Derazantinib as monotherapy or in combination with atezolizumab was well-tolerated but did not show sufficient efficacy to warrant further development in mUC.

P1/2, N=47, Terminated, Basilea Pharmaceutica | Phase classification: P1b/2 --> P1/2

A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment.

The combination showed synergy (5) or additivity (2), and no antagonism, with synergy significantly associated (P < 0.05) with higher levels of M2-type macrophages. The association of strong efficacy of the combination in vivo with M2 macrophages, which are known to express CSF1R, and the absence of synergy in vitro is consistent with the tumor microenvironment also being a factor in DZB efficacy and suggests additional means by which DZB could be stratified for cancer treatment in the clinic.

P1b/2, N=47, Terminated, Basilea Pharmaceutica | Completed --> Terminated; Terminated prematurely for administrative reasons not related to patient safety.

DZB inhibited growth of three tumor xenograft models with reported expression or amplification of CSF1R, whereas the specific FGFRi, pemigatinib, had no efficacy. Similar modulation of the tumor microenvironment was observed in an FGFR-insensitive syngeneic bladder model, MBT-2. These data confirm CSF1R as an important oncology target for DZB and provide mechanistic insight for the ongoing clinical trials, in which DZB is combined with the PD-L1 antibody, atezolizumab.

P1b/2, N=47, Completed, Basilea Pharmaceutica | Active, not recruiting --> Completed | Trial completion date: Jul 2023 --> Dec 2022 | Trial primary completion date: Jul 2023 --> Dec 2022

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.

No abstract available

P2, N=148, Completed, Basilea Pharmaceutica | Active, not recruiting --> Completed

P1b/2, N=95, Completed, Basilea Pharmaceutica | Active, not recruiting --> Completed | Trial completion date: Oct 2023 --> Sep 2022 | Trial primary completion date: Jul 2023 --> Sep 2022

DZB is also in a phase-2 trial for gastric cancer (GC), where it is combined with the current standard-of-care (SoC) paclitaxel and the VEGFR2-antibody (Ab), ramucirumab...When the mean tumor size was at least 80 mm3, mice were treated with vehicles (po, ip and iv), DZB alone (35 or 75 mg/kg, po, qd), paclitaxel (15 mg/kg, iv, qw) or the VEGFR2-Ab, DC101 (10 mg/kg, ip, 2qw)... DZB is well-tolerated when combined with paclitaxel and a VEGFR2-Ab in murine syngeneic models, and shows an additive effect in the orthotopic breast models. These data support the ongoing clinical trial with DZB in GC (FIDES-03, NCT04604132). No

P1b/2, N=95, Active, not recruiting, Basilea Pharmaceutica | Recruiting --> Active, not recruiting | N=272 --> 95

P1b/2, N=47, Active, not recruiting, Basilea Pharmaceutica | Recruiting --> Active, not recruiting | N=254 --> 47

Pemigatinib and Infigratinib have received accelerated FDA approval for chemorefractory CCA with FGFR2 F . Conclusions Derazantinib results in meaningful clinical benefit for pts with FGFR2 genetic aberrations including FGFR2 F and FGFR2 MA . Derazantinib-related toxicities were limited: PPE, stomatitis, retinal or nail toxicity were infrequent in the study population.

P2, N=148, Active, not recruiting, Basilea Pharmaceutica | Recruiting --> Active, not recruiting

P2, N=37, Recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Not yet recruiting --> Recruiting | Initiation date: Jan 2022 --> Apr 2022

DZB (65-75 mg/kg) and another FGFR-inhibitor, pemigatinib (1 mg/kg) were dosed daily, orally, and the murine PDL1-Antibody (PDL1-Ab) was dosed at 5-10 mg/kg, i.p., 2qw. DZB is a potent inhibitor of CSF1R in vitro. In combination with a murine PDL1-Ab, DZB showed a positive interaction in the orthotopic syngeneic breast tumor model, 4T1, against both the primary tumor and metastases. These data support clinical trials in which DZB is combined with the PDL1-Ab, atezolizumab (NCT04604132, NCT04045613).

Forty two (42) patients with FGFR2 fusions and 9 patients with FGFR2 rearrangements received FGFR inhibitors: these include infigratinib (13), pemigatinib (17), futibatinib (14), derazantinib (5), and zoligratinib (2). The genomic evolution post-progression on FGFR inhibition involves acquired resistance in multiple pathways. Targeting co-alterations acquired post-progression with drug combination may overcome these resistance mechanisms and potentiate the efficacy of FGFR inhibition.

The clinical safety profile of derazantinib was well manageable and compared favorably to the FGFR inhibitor class, particularly with a low incidence of drug-related hand-foot syndrome, stomatitis, retinal and nail toxicity. These findings support the need for increased molecular profiling of cholangiocarcinoma patients.

P2, N=37, Not yet recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

This interim data in study FIDES-01 suggest that derazantinib treatment provides clinical benefit to pts with advanced iCCA harboring FGFR2M/A who progressed after at least one line of standard chemotherapy. To our knowledge, this is the first report of clinically meaningful anti-tumor efficacy in a prospectively planned cohort of iCCA pts harboring FGFR2M/A. The study is ongoing to accrue 43 patients, assessing derazantinib as a therapeutic option for FGFR2M/A+ iCCA pts after disease progression on first-line treatment.

No abstract available

P2, N=143, Recruiting, Basilea Pharmaceutica | Trial completion date: Dec 2021 --> Jun 2022 | Trial primary completion date: Oct 2021 --> Jun 2022

Derazantinib showed clinically meaningful efficacy with durable objective responses, and a manageable safety profile with a particularly low incidence of drug-related hand-foot syndrome, stomatitis, retinal or nail toxicity in pts with iCCA harboring FGFR2fus.

P1b/2, N=272, Recruiting, Basilea Pharmaceutica | Trial completion date: May 2022 --> Oct 2023 | Trial primary completion date: Apr 2022 --> Jul 2023

The promising results of pemigatinib and infigratinib in advanced unresectable cholangiocarcinoma harboring FGFR2 fusions or rearrangement, and erdafitinib in metastatic urothelial carcinoma with FGFR2 and FGFR3 genetic aberrations, lead to their accelerated approval by the United States (USA) FDA. Along with these agents, many phase II/III clinical trials are currently evaluating the use of derazantinib, infigratinib, and futibatinib either alone or in combination with immunotherapy...In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. This work would invariably help practicing oncologists to effectively manage the unique toxicities of FGFR inhibitors.

Infigratinib, futibatinib, pemigatinib and derazantinib have all demonstrated promising activity in patients with cholangiocarcinoma harboring FGFR2 fusion. Eventually, head-to-head trials will be needed to fully understand the benefits of each agent and the role of reversible versus irreversible FGFR2 inhibitors.

We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma.

In addition, cross-resistance to other FGFR inhibitors infigratinib, pemigatinib, derazantinib and AZD4547 was observed. In conclusion, we show that multiple factors contribute to the development of resistance against erdafitinib in an FGFR2-mutant endometrial carcinoma cell line. BET-bromodomain inhibitors are of potential interest as therapeutic agents to overcome resistance against FGFR inhibitors.

The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib. We reviewed skin AEs reported with FGFR inhibitors and provide management and supportive care guidelines for physicians, aiming to increase awareness of skin events in clinical practice and provide practical guidance on the most effective treatment strategies. Early intervention and effective management may improve treatment adherence, optimize outcomes, and improve patient quality of life.

We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB; formally, ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA...These correlated in vitro studies suggest that FGFR may play an important role in the pathogenesis and biology of CCA. Our findings support the notion that FGFR inhibitors, like DZB, should be further evaluated at the clinical stage as targeted therapy for CCA treatment.

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...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)...Clinical trial information: NCT04045613. Research Funding: Basilea Pharmaceutica International Ltd.

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...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)...Clinical trial information: NCT04045613. Research Funding: Basilea Pharmaceutica International Ltd.

Research Funding: Basilea Pharmaceutica International Ltd. Pharmaceutical/Biotech Company