rogaratinib (BAY 1163877) / Bayer - LARVOL DELTA

Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study. (PubMed, Lancet Oncol) - P1 | "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."

Biomarker • Clinical • Journal • P1 data • Acute Kidney Injury • Bladder Cancer • Fatigue • Genito-urinary Cancer • Head and Neck Cancer • Hypoglycemia • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Ophthalmology • Renal Disease • Retinal Disorders • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Thoracic Cancer • Urothelial Cancer

FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression. (PubMed, J Clin Oncol) - P2/3 | "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."

Journal • P2/3 data • Oncology • Solid Tumor • Urothelial Cancer • FGFR1 • FGFR3

Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer: The FORT-2 Phase 1b Nonrandomized Clinical Trial. (PubMed, JAMA Oncol) - P1 | "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."

Clinical • IO biomarker • Journal • P1 data • Fatigue • Genito-urinary Cancer • Metabolic Disorders • Nephrology • Oncology • Renal Disease • Solid Tumor • Urothelial Cancer • FGFR • FGFR1 • FGFR3

Testing the Anti-cancer Drug, Rogaratinib (BAY 1163877), for Treatment of Advanced Sarcoma With Alteration in Fibroblast Growth Factor Receptor (FGFR 1-4), and in Patients With SDH-deficient Gastrointestinal Stromal Tumor (GIST) (clinicaltrials.gov) - P2 | N=48 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jul 2026 ➔ Jul 2027 | Trial primary completion date: Jul 2026 ➔ Jul 2027

Trial completion date • Trial primary completion date • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • FGFR

Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial. (PubMed, Nat Med) - P2 | "We conducted a phase 2 trial of pan-fibroblast growth factor receptor inhibitor rogaratinib in patients with sarcoma and report here on the cohort of patients with advanced SDH-deficient GIST...This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier: NCT04595747 ."

Journal • P2 data • Fatigue • Gastrointestinal Stromal Tumor • Metabolic Disorders • Nephrology • Oncology • Renal Disease • Sarcoma • Solid Tumor • FGF3 • FGF4 • FGFR • FGFR1 • KIT • PDGFRA

Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial (Nature) - "Twenty-four patients received rogaratinib and ten experienced partial responses for an objective response rate of 41.7%. Median PFS was 31.0 months (95% confidence interval 20.2–not reached), and 1-year PFS was 77.4% (95% confidence interval 61.7–97.1). Toxicities were manageable and included hyperphosphatemia, fatigue and diarrhea. Elevations in phosphorous were seen across the cohort, consistent with target engagement of FGFR1. Whole-exome and next-generation sequencing revealed alterations in the SDH subunit coding genes (SDHx) as expected. This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation."

P2 data • Gastrointestinal Stromal Tumor

Incidence and outcomes of FGFR inhibitor-associated retinopathy of patients treated with oral erdafitinib across the clinical trial program. (PubMed, Oncologist) - "FGFRi-associated retinopathy can be managed with dose reductions, interruptions, or discontinuations. Proactive collaboration between ophthalmologists and oncologists is required to ensure that erdafitinib delivers clinical benefit to patients while managing their potential adverse symptoms of FGFRi-associated retinopathy."

Journal • Genito-urinary Cancer • Oncology • Ophthalmology • Retinal Disorders • Solid Tumor • Urothelial Cancer

Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms (AACR 2024) - "At 20 mg/kg, olverembatinib showed superior efficacy vs ponatinib (10 mg/kg) and rogaratinib (50 mg/kg). Olverembatinib exerts promising antitumor effects in SDH-deficient neoplasms and can modulate multiple signal pathways involved in angiogenesis, apoptosis, proliferation, and survival. The results provide a preclinical rationale for future development of olverembatinib in SDH-deficient cancers."

Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • CASP3 • EPAS1 • FGFR1 • HIF1A • SDHA • SDHB

Fibroblast growth factor receptor (FGFR) inhibition demonstrates anti-tumor activity in succinate dehydrogenase deficient gastrointestinal stromal tumor (SDHd GIST) (AACR 2025) - P2 | " FGFRi rogaratinib (R) and pemigatinib (P) were evaluated separately in SDHd GIST PDX (PG-20) and compared to vehicle, sunitinib, and regorafenib. FGFR inhibition demonstrates notable activity in SDHd GIST. Preclinical data suggest this is a class effect of drugs which inhibit FGFRs. This work supports targeting aberrant FGFR signaling arising from epigenetic alterations in pts with SDHd GIST."

Stroma • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • FGF3 • FGF4 • FGFR • FGFR1 • SDHA • SDHC • SDHD

Co-clinical trial targeting ER, FGFR and CDK4/6 in resistant hormone-positive breast cancer with FGFR alterations. (PubMed, NPJ Precis Oncol) - "Using patient-derived organoids (PDOs), we demonstrated that FGFR-amplified PDOs respond to fulvestrant, palbociclib, and rogaratinib only when PIK3CA and ESR1 are wild-type. Toxicity was manageable and consistent with prior data. Our findings highlight biomarker-driven approaches as essential for refining FGFR-targeted strategies in this resistant population."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • FGFR • FGFR1 • HER-2 • PIK3CA

Recent update of treatment using targeted agents in GIST (KINGCA Week 2025) - "Even in the second-line, activities of sunitinib and ripretinib appear to be dependent on secondary mutations, either in ATP-binding or activation loop domain. PDGFRA exon 18 D842V-mutated GIST is highly resistant to imatinib, however, avapritinib demonstrated an excellent ORR (91%) with median PFS of 34.0 months...Dabrafenib plus trametinib is recommended for GIST with BRAF mutations (V600E), and entrectinib and larotrectinib are recommended for GIST with NTRK-fusions. For SDH-GIST, several investigational drugs, including temozolomide, are being evaluated. Among them, rogaratinib, a pan-FGFR inhibitor, appears to be most promising with ORR of 42% and median PFS of 31 months. Right now, there is no recommendation for NF1-associated GIST, but case report and clinical trials for NF1- plexiform neurofibromas may indicate potential activities of selective MEK1/MEK2 inhibitors, such as trametinib and selumetinib, which require future clinical trials. In summary, activities..."

Neurofibromatosis • BRAF • MAP2K2 • NF1 • NTRK • PDGFRA

Recent Advances in Succinate Dehydrogenase Deficient Gastrointestinal Stromal Tumor Systemic Therapies. (PubMed, Curr Treat Options Oncol) - "In our current practice we typically treat advanced symptomatic SDH-Def GIST with the anti-angiogenic TKIs, sequentially treating with sunitinib, regorafenib and pazopanib...Olverembatinib and rogaratinib have shown promising activity in pre-clinical models and small SDH-Def GIST cohorts. Other agents whose benefits are explored here include the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab and temozolomide, whether as monotherapy or in combination with INBRX-109 (a pro-apoptotic antibody) or olaparib. Additional research into TKI agents with anti-vascular endothelial growth factor receptor (VEGFR) and anti-fibroblast growth factor receptor (FGFR) activity in this clinical setting is needed. Patients with SDH-Def will benefit more broadly from ongoing explorations of treatments with alternative mechanisms of action, especially those that exploit cellular pathways involved in SDH-Def GIST tumorigenesis."

Journal • Review • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Metabolic Disorders • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • FGFR

Testing the Anti-cancer Drug, Rogaratinib (BAY 1163877), for Treatment of Advanced Sarcoma With Alteration in Fibroblast Growth Factor Receptor (FGFR 1-4), and in Patients With SDH-deficient Gastrointestinal Stromal Tumor (GIST) (clinicaltrials.gov) - P2 | N=48 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2025 ➔ Jul 2026 | Trial primary completion date: Jan 2025 ➔ Jul 2026

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • FGFR

Selective activity of rogaratinib in PIK3CA- and ESR1-wild-type, FGFR1/2-amplified hormone receptor-positive breast cancer (HR+/HER2- BC): a co-clinical trial (SABCS 2024) - "PDTOs viability was explored in response to rogaratinib, fulvestrant, palbociclib, camizestrant, and alpelisib in monotherapy or in combinations. A high percentage (43%) of second-line HR+/HER2- BC displays FGFR1/2 overexpression or amplification, of which approximately half are wild-type for ESR1 and PIK3CA. FGFR1/2 inhibition with rogaratinib in combination with palbociclib and fulvestrant is active in second-line, FGFR1/2-amplified/overexpressed HR+/HER2- BC, but the activity is restricted to wild-type PIK3CA/ESR1 patients. These results frame the population in which the development of this combination should be focused."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • FGFR1 • HER-2 • PIK3CA

The FGFR inhibitor Rogaratinib reduces microglia reactivity and synaptic loss in TBI. (PubMed, Front Immunol) - "FGFR inhibition selectively prevented FGFR phosphorylation in the microglia, dampened the overall neuroimmunological response and enhanced the preservation of neuronal and synaptic integrity. Thus, FGFR inhibitors may be relevant targets for drug repurposing aimed at modulating microglial reactivity in TBI."

IO biomarker • Journal • CNS Disorders • Inflammation • Vascular Neurology • CCL4 • CCR4 • CD40LG • CXCR3 • ERBB4 • FGFR3 • FGFR4 • MMP3 • SLC2A1

CHARACTERIZATION OF INTRAHEPATIC RECURRENCE FOLLOWING LIVER-DIRECTED SURGERY IN PATIENTS WITH METASTATIC SDH-DEFICIENT GASTROINTESTINAL STROMAL TUMOR GIST): RISE AND STABILIZATION OF THE GISTLETS (CTOS 2024) - P2 | "Three patients were enrolled onto NCT04595747 and received rogaratinib with stability of disease... In this cohort of metastatic SDH-deficient GIST, patients uniformly developed early hepatic recurrence following hepatectomy; however, in most patients, these hepatic recurrences were characterized by small size and relative stability or even spontaneous regression after initial growth. Treatment teams must be aware of this phenomenon to optimally counsel patients pre-operatively. That said, patients with SDH-deficient GIST liver metastases should still be considered for hepatic resection when appropriate, since durable debulking is achievable for most patients."

Clinical • Metastases • Stroma • Surgery • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hepatocellular Cancer • Oncology • Sarcoma • SDHA • SDHB • SDHC • SDHD

FORT-2: Phase 1b/2 Study of Rogaratinib (BAY1163877) in Combination With Atezolizumab in Urothelial Carcinoma (clinicaltrials.gov) - P1 | N=37 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Oncology • Solid Tumor • Urothelial Cancer

Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer (JAMA Oncol) - P1/2 | N=66 | FORT-2 (NCT03473756) | Sponsor: Bayer | "Among 153 patients screened, 73 (48%) had tumors with FGFR1/3 mRNA overexpression, and 37 patients were enrolled and treated (median [range] age, 75.0 [47.0-85.0] years; 32 [87%] male). The most common treatment-emergent adverse events (TEAEs) included diarrhea in 23 patients (62%), hyperphosphatemia in 19 (51%), and fatigue in 15 (41%). Grade 3 or higher TEAEs were reported in 27 patients (73%), and 4 grade 5 TEAEs were reported, though unrelated to treatment. The RP2D was rogaratinib 600 mg in combination with atezolizumab 1200 mg."

P1/2 data • Urothelial Cancer

Testing the Anti-cancer Drug, Rogaratinib (BAY 1163877), for Treatment of Advanced Sarcoma With Alteration in Fibroblast Growth Factor Receptor (FGFR 1-4), and in Patients With SDH-deficient Gastrointestinal Stromal Tumor (GIST) (clinicaltrials.gov) - P2 | N=48 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2024 ➔ Jan 2025 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Metastases • Stroma • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • FGFR

Phase I study of the FGFR inhibitor rogaratinib, fulvestrant and palbociclib in advanced hormone receptor-positive (HR+) breast cancer (BC) with FGFR1/2 amplification and/or overexpression (FGFR1/2+) (SABCS 2023) - 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."

Metastases • P1 data • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • FGF23 • FGFR1 • FGFR2

FORT-2: Phase 1b/2 Study of Rogaratinib (BAY1163877) in Combination With Atezolizumab in Urothelial Carcinoma (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Bayer | Phase classification: P1b/2 ➔ P1

Combination therapy • Metastases • Phase classification • Oncology • Solid Tumor • Urothelial Cancer

A PHASE 2 STUDY OF ROGARATINIB (BAY 1163877) IN SOFT TISSUE SARCOMAS: INITIAL RESULTS IN COHORT OF PATIENTS WITH SUCCINATE DEHYDROGENASE (SDH)-DEFICIENT GASTROINTESTINAL STROMAL TUMOR (GIST) (CTOS 2023) - No abstract available

Clinical • P2 data • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Testing the Anti-cancer Drug, Rogaratinib (BAY 1163877), for Treatment of Advanced Sarcoma With Alteration in Fibroblast Growth Factor Receptor (FGFR 1-4), and in Patients With SDH-deficient Gastrointestinal Stromal Tumor (GIST) (clinicaltrials.gov) - P2 | N=48 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Stroma • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • FGFR

Treatment approaches for FGFR-altered urothelial carcinoma: targeted therapies and immunotherapy. (PubMed, Front Immunol) - "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."

IO biomarker • Journal • Review • Oncology • Solid Tumor • Urothelial Cancer • FGFR • FGFR2 • FGFR3

Current developments in FGFR inhibitors for urothelial cancer (YouTube) - "Daniel Petrylak, MD...gives an overview of FGFR inhibition in urothelial cancer. With the exception of erdafitinib, relatively few FGFR inhibitors including infigratinib and rogaratinib have shown success in clinical trials. This interview took place at the American Society of Clinical Oncology (ASCO) 2023 Annual Congress in Chicago, IL."

Interview • Video