rogaratinib (BAY 1163877)

Efficacy for this combination at the RP2D was observed in tumors with low PD-L1 and was not dependent on FGFR3 gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and FGFR mRNA overexpression. ClinicalTrials.gov Identifier: NCT03473756.

P1, N=37, Completed, Bayer | Active, not recruiting --> Completed

P2, N=48, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=37, Active, not recruiting, Bayer | Phase classification: P1b/2 --> P1

Triple FGFR1/2, CDK4/6 and ER blockade appears safe at standard drug dosages and shows promising clinical activity in second-line HR+ FGFR1/2+ BC patients progressing on CDK4/6i plus AI.

Ongoing trials are evaluating the use of erdafitinib in non-muscle invasive urothelial carcinoma as well as in combination with enfortumab vedotin in the metastatic setting, while other FGFR targeted agents such as infigratinib, AZD4547, rogaratinib and pemigatinib continue to be in development. Future challenges will include strategies to overcome FGFR acquired resistance and efficacy and safety of combination therapies with erdafitinib and other FGFR targeted agents.

P2, N=48, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

Six pts (16.21%) received targeted therapy (Erdafitinib/Rogaratinib) with no improved mOS compared to standard therapy (p = 0.026). Activating FGFR fusions in NSCLC are rare events. The majority of patients are elder males with smoking history and predominantly squamous histology. The most frequent co-mutation is TP53 with prolonged OS comparing to TP53 WT patients.

P1; Active, not recruiting --> Completed | N=19 --> 9

P1; Recruiting --> Active, not recruiting

P2, N=48, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2023 --> Jan 2024 | Trial primary completion date: Jan 2023 --> Jan 2024

P2, N=15, Terminated, Swiss Group for Clinical Cancer Research | Active, not recruiting --> Terminated; Due to financial restructure of SAKK

To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/3 mRNA overexpression may be better predictors of rogaratinib response.

Despite preliminary signals of activity, rogaratinib failed to improve PFS in patients with advanced SQCLC overexpressing FGFR mRNA. FGFR inhibitors in SQCLC remain a challenging field, and more in-depth understanding of pathway crosstalks may lead to the development of drug combinations with FGFR inhibitors resulting in improved outcomes.

At current, erdafitinib, an inhibitor of FGFR1-4, is the only approved targeted therapy in metastatic UC following the BLC2001 study, which demonstrated a 49% overall response rate in patients with UC harboring an FGFR3 mutation. Additional FGFR-directed agents also continue to be investigated across multiple disease stages in FGFR-mutated UC including infigratinib, rogaratinib, and AZD4547, among others. Ongoing trials are combining these agents with immune checkpoint inhibitors and chemotherapy regimens. The precision medicine revolution has begun in UC, and FGFR3 inhibitors are leading the charge toward a more personalized, biomarker-driven treatment paradigm.

P2, N=15, Active, not recruiting, Swiss Group for Clinical Cancer Research | Trial primary completion date: Dec 2021 --> Dec 2023

The anticipated rate of positive screening is 40%; thus, we will screen approximately 70 patients. Present accrual/target accrual: 55/70 screened; 16 FGFR1/2-positive (of 28 planned); 2 accrued and treated.

Despite preliminary signal of activity, rogaratinib failed to improve PFS in patients overexpressing tumor FGFR mRNA . Further studies on a more reliable biomarker are needed, the development of rogaratinib in SQCLC has been put on hold by Bayer and the SAKK 19/18 study was terminated early due to lack of efficacy.

First-line treatment with the RP2D of R+A achieved favorable clinical efficacy and tolerability in pts with cisplatin-ineligible, metastatic UC characterized by high FGFR1/3 mRNA expression and generally low/negative PD-L1 expression . Encouraging efficacy was observed regardless of PD-L1 expression or FGFR3 mutation status, warranting future investigation.

P2, N=15, Active, not recruiting, Swiss Group for Clinical Cancer Research | Recruiting --> Active, not recruiting | N=24 --> 15

P2, N=48, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Jan 2022 --> Feb 2023 | Trial primary completion date: Jan 2022 --> Feb 2023

P1, N=16, Completed, Bayer | Active, not recruiting --> Completed

FGFR1 amplification and overexpression are associated to similar adverse prognosis in hormone-positive breast cancer. Capturing all the patients with adverse prognosis-linked FGFR1 aberrations requires assessing both features. Hormonal deprivation leads to FGFR1 overexpression, and FGFR1 overexpression and/or amplification are associated with resistance to hormonal monotherapy or in combination with palbociclib. Both resistances are reverted with triple ER, CDK4/6, and FGFR1 blockade.

Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I½ inhibitors...Ponatinib binds to FGFR4 in a DFG-D conformation and is classified as a type II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind covalently to their FGFR target and are classified as type VI inhibitors. Nintedanib, pazopanib, pemigatinib, rogaratinib, fisogatinib, and PRN1371 are FGFR inhibitors lacking drug-enzyme crystal structures...The development of FGFR inhibitors has lagged behind those of other receptor protein-tyrosine kinases. However, the FDA approval of erdafitinib for the treatment of urinary bladder cancers may stimulate additional work targeting the many other FGFR-driven neoplasms.

P1, N=19, Recruiting, Fundacion CRIS de Investigación para Vencer el Cáncer | Not yet recruiting --> Recruiting

P1, N=19, Not yet recruiting, Fundacion CRIS de Investigación para Vencer el Cáncer | Trial completion date: Oct 2022 --> Apr 2023 | Initiation date: Oct 2020 --> Jan 2021 | Trial primary completion date: Oct 2022 --> Apr 2023

P2, N=48, Not yet recruiting, National Cancer Institute (NCI)

P1; N=16; Active, not recruiting; Sponsor: Bayer; Trial completion date: Jun 2020 --> Sep 2020

P1; N=19; Not yet recruiting; Sponsor:Fundacion CRIS de Investigación para Vencer el Cáncer

Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment.

P1; N=16; Active, not recruiting; Sponsor: Bayer; Recruiting --> Active, not recruiting; N=65 --> 16; Trial completion date: Sep 2021 --> May 2020; Trial primary completion date: Sep 2021 --> Mar 2020

In this exploratory study, total FGFR1-4 mRNAh is a predictive biomarker for FGFRinh (e.g. rogaratinib) but not for MTKI such as lucitanib in BC PDXs. MTKI efficacy does not rely on mRNAh levels of its targets in BC.

P1, N=168, Completed, Bayer | Active, not recruiting --> Completed

Rogaratinib demonstrated a favorable safety and efficacy profile in pts with tumor FGFR1-3 mRNA-positive UC. TEAEs observed in >25% of pts. Clinical trial information: NCT01976741.

Pts were randomized 1:1 to 800 mg rogaratinib p.o. BID continuously or CT Q3W (i.v., docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2), and stratified by PIK3CA/RAS-activating mutations, prior immunotherapy, and modified 4-factor Bellmunt risk score. In pts with FGFR1/3 tumor mRNA-positive UC, rogaratinib had efficacy comparable with standard CT and an acceptable safety profile. Subgroup analysis suggests rogaratinib may be more active in pts with an FGFR3 DNA alteration. Sensitivity analysis of biomarker subgroups is ongoing.

Pts were randomized 1:1 to 800 mg rogaratinib p.o. BID continuously or CT Q3W (i.v., docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2), and stratified by PIK3CA/RAS-activating mutations, prior immunotherapy, and modified 4-factor Bellmunt risk score. In pts with FGFR1/3 tumor mRNA-positive UC, rogaratinib had efficacy comparable with standard CT and an acceptable safety profile. Subgroup analysis suggests rogaratinib may be more active in pts with an FGFR3 DNA alteration. Sensitivity analysis of biomarker subgroups is ongoing.

Rogaratinib demonstrated a favorable safety and efficacy profile in pts with tumor FGFR1-3 mRNA-positive UC. TEAEs observed in >25% of pts. Clinical trial information: NCT01976741.

P2; N=0; Withdrawn; Sponsor: Dana-Farber Cancer Institute; N=33 --> 0; Trial completion date: Jun 2021 --> Nov 2019; Not yet recruiting --> Withdrawn; Trial primary completion date: Dec 2020 --> Nov 2019

P2; N=33; Not yet recruiting; Sponsor: Dana-Farber Cancer Institute

P1, N=65, Recruiting, Bayer | Trial completion date: Mar 2021 --> Sep 2021 | Trial primary completion date: Mar 2021 --> Sep 2021

P1, N=65, Recruiting, Bayer | Not yet recruiting --> Recruiting