Rogaratinib (BAY-1163877): A Comprehensive Monograph on a Pan-FGFR Inhibitor in Oncology

Executive Summary

Rogaratinib, also known by its development code BAY-1163877, is an orally bioavailable, potent, and selective small molecule inhibitor of fibroblast growth factor receptors 1 through 4 (FGFR1-4). Developed by Bayer, this investigational agent has been evaluated for the treatment of various advanced solid tumors.[1] As a therapeutic agent, Rogaratinib functions as an adenosine triphosphate (ATP)-competitive inhibitor, designed to reversibly occupy the kinase domain of the FGFRs. This action effectively blocks receptor autophosphorylation and subsequent activation of downstream signaling cascades, most notably the FGFR/ERK pathway, which are critical for the proliferation, survival, and angiogenesis of many cancer types.[1]

The clinical development of Rogaratinib has been extensive and has yielded a complex set of outcomes that provide significant learnings for the field of targeted oncology. The drug has been investigated across a spectrum of malignancies, including urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), breast cancer, and various sarcomas.[3] The results have been mixed, underscoring the challenges of targeting the FGFR pathway. A key Phase II study in squamous NSCLC (SAKK 19/18) was terminated early for lack of efficacy, leading to the discontinuation of development in that indication.[5] Similarly, the pivotal Phase II/III FORT-1 trial, which evaluated Rogaratinib as a monotherapy in previously treated, FGFR mRNA-positive UC, was halted before progressing to Phase III after an interim analysis showed non-superiority over standard chemotherapy.[6] In stark contrast, the Phase Ib/II FORT-2 trial demonstrated highly promising results, where Rogaratinib in combination with the PD-L1 inhibitor atezolizumab yielded a high response rate in first-line, cisplatin-ineligible UC patients, suggesting a powerful synergistic effect.[7]

Central to the narrative of Rogaratinib's development is the evolution of its biomarker strategy. The program was initially predicated on the hypothesis that FGFR mRNA overexpression could serve as a broad patient selection biomarker. However, the outcomes of the monotherapy trials challenged this premise. Subsequent exploratory analyses, particularly from the FORT-1 trial, revealed that underlying FGFR DNA alterations (mutations or fusions) were a much stronger predictor of response to single-agent therapy.[6] The success of the FORT-2 combination trial further complicated this picture, as robust efficacy was observed in the mRNA-positive population, even in the absence of DNA alterations or high PD-L1 expression, pointing toward an immunomodulatory mechanism of action.[7]

Throughout its clinical evaluation, Rogaratinib has demonstrated a manageable and predictable safety profile. The most frequently observed adverse events are consistent with the known on-target class effects of FGFR inhibitors, primarily hyperphosphatemia, diarrhea, and stomatitis, which are generally mild to moderate in severity and can be managed with supportive care and dose modifications.[1]

In conclusion, Rogaratinib stands as a significant investigational agent whose clinical journey has provided critical insights into the complexities of targeting the FGFR signaling axis. While its path as a monotherapy has faced considerable hurdles, its potential as a combination agent with immunotherapy has opened a promising new avenue for development. The story of Rogaratinib underscores the importance of a nuanced, context-dependent biomarker strategy and highlights the potential for kinase inhibitors to modulate the tumor microenvironment and enhance the efficacy of immuno-oncology agents.

Chemical Identity and Physicochemical Properties

The precise identification and characterization of a small molecule's chemical and physical properties are foundational to its development as a pharmaceutical agent. These properties dictate its formulation, stability, and pharmacokinetic behavior. Rogaratinib has been thoroughly characterized across multiple chemical and pharmaceutical databases.

Systematic Identification

Rogaratinib is known by several identifiers across different nomenclature systems and databases, ensuring its unambiguous reference in scientific literature and regulatory documents. Its universally recognized name is Rogaratinib, which is its International Nonproprietary Name (INN).[11] During its development by Bayer, it was designated with the code BAY-1163877.[11]

For cataloging purposes, Rogaratinib is assigned unique identifiers in major drug and chemical registries. Its DrugBank Accession Number is DB15078 [11], and its Chemical Abstracts Service (CAS) Registry Number is 1443530-05-9.[11] The systematic chemical name, according to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature, is 4-[[4-amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f]triazin-7-yl]methyl]piperazin-2-one.[11]

Additional identifiers provide comprehensive cross-referencing capabilities, including its Unique Ingredient Identifier (UNII) of 98BSN6N516, its ChEMBL ID of CHEMBL3963485, and its European Community (EC) Number of 948-594-9.[11]

Chemical Structure and Formula

The molecular composition and structure of Rogaratinib define its interaction with its biological targets. Its molecular formula is $C_{23}H_{26}N_{6}O_{3}S$, corresponding to a molecular weight of 466.56 g/mol.[11] This structure consists of a fused pyrrolo[2,1-f]triazine core, which is substituted with a benzothiophene moiety on one side and a piperazin-2-one group on the other, as depicted in its 2D chemical structure.[4] The structure can be unambiguously represented by the Simplified Molecular Input Line Entry System (SMILES) string: CC1=CC2=C(C(=C1)OC)SC(=C2)C3=C4C(=NC=NN4C(=C3COC)CN5CCNC(=O)C5)N.[11]

Physicochemical Properties

The physical and chemical properties of Rogaratinib influence its behavior in biological systems and its suitability for oral administration. It is described as an off-white to white solid powder.[14] In early clinical trials, it has been formulated as both an oral solution and as tablets to facilitate administration.[20]

Its solubility profile is a key determinant of its formulation and absorption characteristics. Rogaratinib is reported to be insoluble in aqueous media like water and also in ethanol, but it demonstrates solubility in organic solvents such as dimethyl sulfoxide (DMSO).[13] Various sources report its solubility in DMSO to be in the range of 6 mg/mL to 16 mg/mL, with some variability potentially attributable to batch differences or experimental conditions.[13]

Computational models provide additional insights into its drug-like properties. The partition coefficient (logP), a measure of lipophilicity, is estimated to be between 1.78 and 1.9, suggesting moderate lipophilicity that is favorable for membrane permeability.[15] Its strongest basic pKa is calculated to be 4.68, indicating it is a weak base.[15] Other computed properties, such as a Polar Surface Area of 107.01 Ų, 2 hydrogen bond donors, and 7 hydrogen bond acceptors, are consistent with established parameters for orally bioavailable drugs. Indeed, Rogaratinib is predicted to comply with Lipinski's Rule of Five, a set of guidelines used to evaluate the druglikeness of a chemical compound.[15] A summary of these properties is provided in Table 1.

Table 1: Chemical and Physical Properties of Rogaratinib

Property	Value
Common Name	Rogaratinib
Development Code	BAY-1163877
IUPAC Name	4-[[4-amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f]triazin-7-yl]methyl]piperazin-2-one
Molecular Formula	$C_{23}H_{26}N_{6}O_{3}S$
Molecular Weight	466.56 g/mol
CAS Number	1443530-05-9
DrugBank ID	DB15078
Appearance	Off-white to white solid
Solubility	Insoluble in Water/Ethanol; Soluble in DMSO
logP	1.78 - 1.9
pKa (Strongest Basic)	4.68
Polar Surface Area	107.01 Ų
Rule of Five Compliance	Yes

Preclinical Pharmacology

The preclinical characterization of an investigational drug is essential to establish its mechanism of action, potency, selectivity, and anti-tumor activity. The preclinical data for Rogaratinib provided a strong rationale for its advancement into clinical trials, defining it as a potent and selective pan-FGFR inhibitor with significant efficacy in appropriately selected cancer models.

Mechanism of Action and Pharmacodynamics

Rogaratinib's primary mechanism of action is the potent and selective inhibition of all four members of the fibroblast growth factor receptor family: FGFR1, FGFR2, FGFR3, and FGFR4.[1] It is a small molecule designed for oral administration that functions as an ATP-competitive inhibitor. By reversibly binding to the ATP-binding pocket within the intracellular kinase domain of the FGFRs, Rogaratinib prevents the transfer of a phosphate group from ATP to tyrosine residues on the receptor. This action blocks the receptor's autophosphorylation and subsequent activation, thereby inhibiting the initiation of downstream signaling cascades.[1]

The quantitative inhibitory activity of Rogaratinib has been extensively documented through various biochemical and cellular assays, as summarized in Table 2. Radiometric kinase assays and binding studies demonstrate high-potency inhibition across the FGFR family. For example, IC₅₀ values, which represent the concentration of the drug required to inhibit 50% of the enzyme's activity, are in the low nanomolar range for FGFR1, FGFR2, and FGFR3.[13] While there is some variability in the reported potency against FGFR4 across different sources—with IC₅₀ values ranging from 1.2 nM to 201 nM—its binding affinity ($K_d$) to FGFR4 remains high at 7.6 nM.[13] This variability in FGFR4 inhibition could be attributable to differences in experimental conditions, such as ATP concentration in the assays, suggesting that its activity against this specific isoform may be more context-dependent.

A key attribute of a targeted therapy is its selectivity, which minimizes the potential for off-target toxicities. Rogaratinib has demonstrated a high degree of selectivity for the FGFR family. A comprehensive KINOMEscan™ profiling against a panel of 468 kinases showed that at a concentration of 100 nM, only four other non-mutant kinases exhibited significant binding competition (>65%).[1] Even at a higher concentration of 1 µM, only 18 additional kinases were affected, underscoring its focused activity.[1] This selectivity is particularly notable when compared to related receptor tyrosine kinases, such as the vascular endothelial growth factor receptors (VEGFRs). Rogaratinib's binding affinity for VEGFR1 and VEGFR3 is approximately 100-fold lower than its affinity for FGFR1, a finding that translates to cellular activity where inhibition of VEGF-stimulated growth is significantly less potent than inhibition of FGF-stimulated growth.[23] This high degree of selectivity is a desirable characteristic that distinguishes Rogaratinib from broader multi-kinase inhibitors.

By inhibiting FGFR activation, Rogaratinib effectively blocks the downstream signaling pathways that drive tumor growth. The primary pathway affected is the mitogen-activated protein kinase (MAPK) cascade, also known as the FGFR/ERK pathway. Inhibition of this pathway leads to a reduction in cell proliferation.[4] The drug also impacts other critical signaling networks, including the PI3K/AKT and STAT pathways, which are involved in cell survival and gene expression.[1]

Table 2: In Vitro Inhibitory Activity of Rogaratinib Against FGFR Isoforms and Other Kinases

Target Kinase	Assay Type	Value (nM)	Source(s)
FGFR1	IC₅₀	1.8	13
	IC₅₀	11.2	18
	Ki	12.2	25
	$K_d$	1.6	23
FGFR2	IC₅₀	<1	13
	$K_d$	5.0	23
FGFR3	IC₅₀	9.2	13
	IC₅₀	18.5	18
	IC₅₀	24.8	25
	$K_d$	7.8	23
FGFR4	IC₅₀	1.2	13
	IC₅₀	201	18
	$K_d$	7.6	23
VEGFR3/FLT4	IC₅₀	127	18
	IC₅₀	130	23
CSF1R	IC₅₀	166	23
Tie2	IC₅₀	1,300	23

Preclinical Efficacy

The anti-tumor potential of Rogaratinib was validated in a series of preclinical efficacy studies, both in vitro and in vivo. These studies not only confirmed its activity but also established the foundational biomarker hypothesis for its clinical development.

In vitro studies demonstrated potent anti-proliferative effects across a wide panel of human cancer cell lines. This activity was particularly pronounced in cell lines known to be "addicted" to FGFR signaling, derived from various cancer types including lung (e.g., H1581 and DMS114 cell lines), breast, colon, and bladder cancer.[18] In highly sensitive FGFR1-amplified lung cancer cell lines, the concentration required to inhibit growth by 50% (GI₅₀) was in the range of 36 to 244 nM.[18]

A crucial finding from these preclinical investigations was the strong correlation between the sensitivity of cancer cell lines to Rogaratinib and the overall expression level of FGFR mRNA.[1] This observation suggested that measuring FGFR mRNA could be a viable strategy to identify tumors dependent on FGFR signaling and, therefore, likely to respond to treatment. This hypothesis became a cornerstone of the initial clinical development program.

The promising in vitro results were subsequently confirmed in in vivo animal models. Rogaratinib exhibited robust anti-tumor efficacy in multiple cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, particularly those characterized by high FGFR mRNA expression.[1] The correlation between FGFR mRNA levels and treatment response was also observed in these in vivo studies, further strengthening the rationale for using mRNA expression as a patient selection biomarker.[4]

Preclinical studies also provided early insights into potential mechanisms of resistance. It was shown that the ectopic overexpression of another receptor tyrosine kinase, MET, could confer resistance to Rogaratinib. MET overexpression was found to activate downstream signaling through the ERK1/2 and AKT pathways, bypassing the FGFR blockade and sustaining tumor cell proliferation and survival.[18] This finding is significant as it anticipates a potential clinical challenge of acquired resistance and suggests a rational therapeutic strategy—such as combining an FGFR inhibitor with a MET inhibitor—to overcome it in patients who relapse.

Clinical Pharmacokinetics and Metabolism

The study of a drug's pharmacokinetics (PK)—its absorption, distribution, metabolism, and excretion (ADME)—is critical for determining an appropriate dosing regimen and understanding its behavior in humans. The clinical PK profile of Rogaratinib has been characterized through dedicated studies in healthy volunteers and as part of broader clinical trials in cancer patients.

Human ADME Studies

To formally elucidate the ADME properties of Rogaratinib in humans, Bayer initiated a dedicated Phase 1 mass balance study (NCT03484585). This open-label, single-center study was designed to investigate the metabolism, excretion routes, and overall recovery of the drug following a single 200 mg oral dose of radiolabeled [¹⁴C]Rogaratinib administered as a solution to healthy male volunteers.[26] The study protocol involved an extensive sampling schedule over 168 hours post-dose, with measurements of the parent drug and total radioactivity in plasma, whole blood, urine, and feces. This design allows for a comprehensive characterization of the drug's absorption, metabolic fate, and primary routes of elimination from the body.[26] While the specific results of this study are not detailed in the available documentation, its execution is a key step in the formal clinical development required for regulatory assessment.

Absorption and Bioavailability

Data from the first-in-human Phase 1 trial (NCT01976741) in patients with advanced solid tumors indicated that Rogaratinib is rapidly absorbed following oral administration.[28] This is consistent with preclinical PK studies in rats and dogs, which demonstrated oral bioavailability of 46% and 35%, respectively, providing an initial estimate of its absorption efficiency.[28] The drug has been administered in clinical trials as both an oral solution and a tablet formulation.[20]

Distribution

Preclinical data provide an initial understanding of the drug's distribution. In rats and dogs, the steady-state volumes of distribution were 0.54 L/kg and 1.2 L/kg, respectively, suggesting moderate distribution into tissues.[28] The comprehensive human ADME study (NCT03484585) was designed to provide definitive data on the distribution of Rogaratinib in humans.

Metabolism

The metabolic pathway of Rogaratinib is a critical aspect of its clinical pharmacology, as it determines the potential for drug-drug interactions (DDIs). In vitro studies have identified the cytochrome P450 (CYP) enzyme system as the primary route of metabolism. Specifically, Rogaratinib is preferentially metabolized by CYP3A4, with a smaller contribution from CYP2C9.[1]

This heavy reliance on CYP3A4 for clearance has significant clinical implications. CYP3A4 is a major drug-metabolizing enzyme involved in the breakdown of a large number of medications. Consequently, there is a high potential for DDIs when Rogaratinib is co-administered with drugs that are strong inhibitors or inducers of this enzyme. Strong CYP3A4 inhibitors (e.g., certain antifungals, antibiotics) could increase Rogaratinib plasma concentrations, potentially leading to increased toxicity. Conversely, strong CYP3A4 inducers (e.g., certain anticonvulsants, herbal supplements like St. John's Wort) could decrease its concentration, potentially compromising efficacy. Recognizing this risk, clinical trial protocols for Rogaratinib have consistently included exclusion criteria prohibiting the concomitant use of strong CYP3A4 modulators, a crucial consideration for patient safety and trial integrity.[29]

Elimination and Pharmacokinetic Parameters

Data from the first-in-human study (NCT01976741) established key pharmacokinetic parameters in cancer patients. The average plasma terminal half-life ($t_{1/2}$) was determined to be 12.7 hours.[28] This half-life is sufficiently long to support a twice-daily (BID) dosing schedule, which helps to maintain drug concentrations at a steady state above the target inhibitory levels required for sustained FGFR pathway blockade.

Pharmacokinetic assessments have been integrated into multiple clinical trials. A Phase 1 study in Japanese patients with solid tumors (NCT02592785) found that the PK exposure in this population was comparable to that observed in Western subjects, suggesting that major dose adjustments based on this specific ethnicity are not necessary.[31] Key PK parameters, including the maximum plasma concentration ($C_{max}$) and the area under the concentration-time curve (AUC), were designated as primary or secondary endpoints in several Phase 1 studies, including NCT01976741 and the FORT-2 combination trial (NCT03473756), to fully characterize the drug's behavior alone and in combination with other agents.[32]

Clinical Development and Efficacy Analysis

The clinical development program for Rogaratinib has been extensive, spanning multiple phases, tumor types, and therapeutic strategies. The journey has been marked by both significant setbacks and promising new directions, providing a rich case study in the complexities of targeted drug development, particularly concerning biomarker selection. A summary of the key clinical trials is presented in Table 3.

Table 3: Summary of Key Clinical Trials for Rogaratinib

NCT Identifier	Trial Acronym/Name	Phase	Status	Condition(s)	Intervention(s)	Key Objective
NCT01976741	Dose Escalation Study	1	Completed	Advanced Solid Tumors	Rogaratinib Monotherapy	Determine MTD, RP2D, safety, and preliminary efficacy 1
NCT03410693	FORT-1	2/3	Completed	Urothelial Carcinoma	Rogaratinib vs. Chemotherapy	Compare efficacy and safety in FGFR mRNA+ patients 35
NCT03473756	FORT-2	1b/2	Completed	Urothelial Carcinoma	Rogaratinib + Atezolizumab	Evaluate safety and efficacy of the combination 7
NCT03762122	SAKK 19/18	2	Terminated	Squamous NSCLC	Rogaratinib Monotherapy	Determine clinical activity in FGFR mRNA+ patients 5
NCT04483505	ROGABREAST	1	Completed	Breast Cancer	Rogaratinib + Palbociclib + Fulvestrant	Determine RP2D and safety of the triplet combination 38
NCT04595747	Sarcoma/GIST Study	2	Active, not recruiting	Sarcoma (FGFR altered), SDH-deficient GIST	Rogaratinib Monotherapy	Evaluate efficacy in genetically defined populations 29
NCT03484585	Human Mass Balance	1	Completed	Healthy Volunteers	[¹⁴C]Rogaratinib	Characterize human ADME 18

Foundational Phase 1 Studies (NCT01976741)

The clinical journey of Rogaratinib began with the first-in-human study, NCT01976741, a multicenter Phase 1 trial with dose-escalation and dose-expansion cohorts.[1] The study enrolled patients with various advanced solid tumors who were ineligible for standard therapy. The dose-escalation phase investigated total daily doses ranging from 100 mg (50 mg BID) to 1600 mg (800 mg BID).[21]

The primary objectives were to assess safety, tolerability, and to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). The study found that Rogaratinib was well-tolerated across the dose range investigated. No dose-limiting toxicities (DLTs) were reported, and the MTD was not reached.[10] Based on the overall safety and pharmacokinetic profile, a dose of 800 mg twice daily was established as the RP2D for monotherapy and was selected for the dose-expansion phase.[10]

The dose-expansion phase focused on patients whose tumors were pre-screened for and found to have FGFR mRNA overexpression. In 100 evaluable patients across these expansion cohorts, a preliminary signal of efficacy was observed, with an overall objective response rate (ORR) of 15% (15 responses).[1] Notably, the clinical activity was most pronounced in the cohort of patients with urothelial carcinoma, which accounted for 12 of the 15 observed responses.[1] This strong signal in UC provided the direct impetus for the subsequent, more focused investigation of Rogaratinib in this disease.

Investigation in Urothelial Carcinoma: The FORT Program

Based on the promising results from the Phase 1 expansion cohort, Bayer launched the FORT program to rigorously evaluate Rogaratinib in urothelial carcinoma. This program consisted of two key trials, FORT-1 and FORT-2, which ultimately led to a major strategic shift in the drug's development.

FORT-1 (NCT03410693): A Pivotal Setback and a Key Insight

The FORT-1 study was a large, randomized, open-label Phase II/III trial designed to confirm the efficacy of Rogaratinib monotherapy.[6] The trial enrolled patients with locally advanced or metastatic UC who had progressed after at least one prior platinum-containing chemotherapy regimen. A key eligibility criterion was the presence of FGFR1 or FGFR3 mRNA overexpression in tumor tissue. Patients were randomized 1:1 to receive either Rogaratinib at the RP2D of 800 mg BID or the investigator's choice of standard-of-care chemotherapy (docetaxel, paclitaxel, or vinflunine).[6]

The primary efficacy results from the planned interim analysis of the Phase II portion were definitive and led to a halt in the program. As shown in Table 4, Rogaratinib failed to demonstrate superiority over chemotherapy. The ORR was 20.7% in the Rogaratinib arm compared to 19.3% in the chemotherapy arm. Furthermore, there was no benefit in median overall survival (OS), which was 8.3 months with Rogaratinib versus 9.8 months with chemotherapy (Hazard Ratio, 1.11).[6] Because the trial did not meet its prespecified efficacy criteria for continuation, enrollment was stopped, and the study did not proceed to the Phase III stage.[6]

While the primary outcome was disappointing, a retrospective, exploratory biomarker analysis from FORT-1 provided a critical insight that reshaped the understanding of the drug. In the subset of patients whose tumors had both FGFR3 mRNA overexpression and a co-occurring FGFR3 DNA alteration (such as a mutation or fusion), the ORR with Rogaratinib was 52.4%. This was substantially higher than the 26.7% ORR observed with chemotherapy in the same genetically defined subgroup.[6] This finding strongly suggested that for single-agent activity, true oncogenic addiction driven by a genetic alteration is a more powerful predictor of response than mRNA overexpression alone.

Table 4: Comparative Efficacy Outcomes from the FORT-1 Trial (Rogaratinib vs. Chemotherapy)

Efficacy Endpoint	Rogaratinib Arm (n=87)	Chemotherapy Arm (n=88)	Hazard Ratio (95% CI) / p-value
Overall Population (FGFR mRNA+)
Objective Response Rate (ORR)	20.7% (95% CI, 12.7-30.7)	19.3% (95% CI, 11.7-29.1)	N/A
Median Overall Survival (OS)	8.3 months (95% CI, 6.5-NE)	9.8 months (95% CI, 6.8-NE)	1.11 (0.71-1.72); p=0.67
Exploratory Subgroup (FGFR3 mRNA+ & DNA Altered)
Objective Response Rate (ORR)	52.4% (11/21)	26.7% (4/15)	N/A

FORT-2 (NCT03473756): A New Direction with Combination Therapy

Following the results of FORT-1, the FORT-2 trial explored a different therapeutic strategy: combining Rogaratinib with immunotherapy. This Phase Ib/II study evaluated Rogaratinib plus the PD-L1 inhibitor atezolizumab as a first-line treatment for cisplatin-ineligible patients with locally advanced or metastatic UC whose tumors overexpressed FGFR1/3 mRNA.[7]

The Phase Ib portion of the study first established the safety and RP2D for the combination. It was determined that a dose of Rogaratinib 600 mg BID (lower than the monotherapy RP2D) combined with standard-dose atezolizumab (1200 mg every 21 days) was the optimal regimen. The higher 800 mg dose of Rogaratinib was associated with a significantly higher rate of treatment discontinuations due to adverse events (55% vs. 27% with the 600 mg dose).[7]

The efficacy results at the RP2D were striking and stood in sharp contrast to the monotherapy data. The combination of Rogaratinib and atezolizumab achieved an ORR of 53.8%, which included a 15% rate of complete responses (CR).[7] This response rate is substantially higher than what has been historically observed with either agent alone in similar patient populations (typically in the 21-24% range).

The most profound finding from FORT-2 came from its biomarker analysis. The high efficacy of the combination was observed irrespective of established biomarkers for either drug class. Among the patients who responded to the combination therapy, 11 of 14 (79%) had low PD-L1 protein expression, and 12 of 14 (86%) did not have an underlying FGFR3 gene alteration.[7] This suggests a synergistic mechanism of action. One hypothesis is that FGFR inhibition by Rogaratinib may modulate the tumor microenvironment, potentially by reducing immunosuppressive signals or increasing T-cell infiltration, thereby sensitizing tumors to the effects of PD-L1 blockade. This finding opens up the possibility of benefiting a much broader population of patients with FGFR mRNA-positive tumors, not just the small subset with specific genetic drivers.

Evaluation in Squamous NSCLC (SAKK 19/18, NCT03762122)

The development of Rogaratinib was also pursued in advanced squamous non-small cell lung cancer (SQCLC), another tumor type with a notable prevalence of FGFR pathway alterations. The SAKK 19/18 trial was a Phase II study designed to assess the efficacy of Rogaratinib monotherapy (600 mg BID) in pretreated SQCLC patients selected based on FGFR1-3 mRNA overexpression.[5]

The trial's outcome was unambiguous. It was terminated early due to a lack of efficacy based on a prespecified futility analysis. The primary endpoint of 6-month progression-free survival (PFS) was not met; only one of the first ten evaluable patients achieved this endpoint, whereas the protocol required at least two for the trial to continue.[5] The investigators concluded that FGFR mRNA overexpression was not a reliable predictive biomarker for Rogaratinib monotherapy in this setting. Following these results, Bayer announced that the development of Rogaratinib in SQCLC would be put on hold.[5] This outcome, along with the FORT-1 results, provided strong evidence that the mRNA-only biomarker strategy was insufficient for single-agent Rogaratinib.

Studies in Other Malignancies

The investigation of Rogaratinib has extended to several other cancer types, reflecting a strategy to follow the FGFR alteration signal across different histologies.

• Breast Cancer (ROGABREAST, NCT04483505): This completed Phase I trial explored a rational triplet combination in advanced hormone receptor-positive (HR+), HER2-negative breast cancer. The study evaluated Rogaratinib plus the CDK4/6 inhibitor palbociclib and the selective estrogen receptor degrader (SERD) fulvestrant.[38] Patients were selected for FGFR1 or FGFR2 positivity and had previously progressed on a CDK4/6 inhibitor-based regimen. This trial design addresses the known role of FGFR signaling as a potential mechanism of resistance to endocrine and CDK4/6 therapies.
• Sarcoma and GIST (NCT04595747 / NCI-2020-08011): This ongoing Phase II trial, sponsored by the National Cancer Institute (NCI), reflects the refined biomarker strategy. It is enrolling two distinct cohorts: patients with various types of advanced sarcoma that harbor a documented FGFR1-4 alteration (mutation, fusion, or amplification), and patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST), who are enrolled regardless of their FGFR status.[29] The sarcoma cohort represents a move toward a purely genetically defined patient population for monotherapy, while the GIST cohort explores the drug's activity in a rare tumor subtype with limited treatment options.

Integrated Safety and Tolerability Profile

A comprehensive assessment of a drug's safety and tolerability is paramount to understanding its clinical utility. Across its extensive clinical development program, Rogaratinib has demonstrated a generally manageable and consistent safety profile. The majority of treatment-emergent adverse events (TEAEs) are mild to moderate (Grade 1 or 2) in severity and are largely predictable based on its mechanism of action as an FGFR inhibitor.[28]

Common Treatment-Emergent Adverse Events

The most frequently reported TEAEs are on-target effects related to the inhibition of FGFR signaling in normal tissues. A summary of common TEAEs from key trials is presented in Table 5.

• Hyperphosphatemia: This is the most common TEAE associated with Rogaratinib, reported in approximately 60% to 77% of patients across studies.[5] This effect is a direct consequence of FGFR1 inhibition in the renal tubules, which play a role in phosphate homeostasis.[1] Importantly, nearly all cases of hyperphosphatemia are asymptomatic, Grade 1 or 2 in severity, and can be effectively managed with dietary modifications, phosphate-lowering agents, or temporary dose interruptions, rarely leading to treatment discontinuation.[1]
• Gastrointestinal Toxicities: Diarrhea is another very common adverse event, affecting 52% to 65% of patients. Other frequent GI side effects include decreased appetite (38%), nausea, and stomatitis (inflammation of the mouth).[7] These events are typically low-grade and can be managed with standard supportive care.
• Constitutional Symptoms: Fatigue is a commonly reported symptom, consistent with many systemic cancer therapies.[7]

Table 5: Summary of Common Treatment-Emergent Adverse Events (All Grades, ≥20% Incidence) Across Major Trials

Adverse Event	FORT-1 (Rogaratinib Arm)	FORT-2 (600mg Combo Arm)	SAKK 19/18 (Monotherapy)
Hyperphosphatemia	45.3%	58%	60%
Diarrhea	55.8%	65%	20%
Fatigue	Not specified ≥20%	41%	Not specified ≥20%
Decreased Appetite	Not specified ≥20%	Not specified ≥20%	Not specified ≥20%
Nausea	32.6%	42%	Not specified ≥20%
Dry Mouth	Not specified ≥20%	Not specified ≥20%	20%
Stomatitis	Not specified ≥20%	Not specified ≥20%	Not specified ≥20%
Rash	Not specified ≥20%	Not specified ≥20%	Not specified ≥20%
Alopecia	Not specified ≥20%	Not specified ≥20%	Not specified ≥20%

High-Grade and Serious Adverse Events

While most TEAEs are low-grade, Grade 3 or 4 events do occur. The most common high-grade events reported in clinical trials include fatigue, asymptomatic elevations in lipase, and rash.[8] In the randomized FORT-1 trial, the incidence of Grade 4 TEAEs was notably lower in the Rogaratinib arm (4.7%) compared to the chemotherapy arm (18.3%). This difference was driven primarily by the high rate of Grade 4 neutropenia associated with chemotherapy, an effect not commonly seen with Rogaratinib.[6]

Serious adverse events (SAEs) considered related to Rogaratinib treatment have been reported but are relatively infrequent. These have included isolated cases of acute kidney injury, severe diarrhea requiring hospitalization, and retinal disorders.[10]

Adverse Events of Special Interest

Certain adverse events warrant special attention due to their known association with the FGFR inhibitor class.

• Retinal Disorders: Ocular toxicity is a recognized class effect of FGFR inhibitors. In the FORT-1 trial, retinal disorders of any grade were reported in 30.2% of patients treated with Rogaratinib, compared to only 3.7% of those receiving chemotherapy.[6] These events can include central serous retinopathy or retinal pigment epithelial detachment (RPED). Most cases are low-grade, but they necessitate baseline and on-treatment ophthalmologic monitoring for patients receiving Rogaratinib.

Dose Modifications and Discontinuations

The management of TEAEs often requires adjustments to the treatment regimen. Dose interruptions and reductions are common for patients on Rogaratinib. For instance, in the FORT-2 combination study, 69% of patients required a dose interruption and 46% required a dose reduction to manage side effects.[8] This high rate of modification suggests that maintaining the optimal therapeutic dose while ensuring tolerability can be a clinical challenge. The therapeutic window may be relatively narrow, a conclusion supported by the observation in FORT-2 that the 800 mg dose led to a much higher rate of permanent discontinuation (55%) compared to the 600 mg dose (27%), justifying the selection of the lower dose as the RP2D for the combination therapy.[8] This finding highlights a critical principle in the development of combination therapies: the optimal dose of a drug as a single agent may not be the optimal or most tolerable dose when combined with another therapeutic agent.

The Evolving Biomarker Strategy

The clinical development of Rogaratinib offers a compelling narrative on the evolution of a biomarker strategy, moving from a broad, expression-based hypothesis to a more nuanced, context-dependent approach. This journey provides valuable lessons for the entire field of targeted oncology.

Initial Hypothesis: FGFR mRNA Overexpression

The preclinical foundation for Rogaratinib was built on the strong and consistent observation that anti-tumor activity, both in vitro and in vivo, correlated with high levels of FGFR mRNA expression.[1] This led to the formulation of a clinical development strategy based on the hypothesis that FGFR mRNA overexpression could serve as a predictive biomarker to identify a broad patient population likely to benefit from treatment. This approach was attractive because it promised to expand eligibility beyond the relatively small subset of patients with rare, specific FGFR gene fusions or activating mutations, which were the focus for many other FGFR inhibitors.[1] The initial Phase 1 expansion cohorts were enrolled based on this mRNA-positive selection criterion.

Challenge to the Hypothesis (Monotherapy)

The viability of the mRNA-only hypothesis for Rogaratinib monotherapy was rigorously tested in two key Phase II trials, both of which delivered results that challenged its utility.

1. FORT-1 in Urothelial Carcinoma: This randomized trial directly compared Rogaratinib to chemotherapy in an FGFR mRNA-positive population. The finding that Rogaratinib was not superior to chemotherapy demonstrated that, for the broad group of patients selected solely on mRNA expression, the targeted agent offered no significant clinical advantage.[6] This was a major setback for the simple expression-based biomarker strategy.
2. SAKK 19/18 in Squamous NSCLC: This trial, which also used FGFR mRNA overexpression for patient selection, was terminated early for futility.[5] The lack of a meaningful efficacy signal in this population further solidified the conclusion that mRNA overexpression, by itself, was an insufficiently predictive biomarker for single-agent Rogaratinib activity.

Emergence of a Refined Hypothesis: The Role of DNA Alterations

The turning point in understanding the appropriate biomarker for monotherapy came from the exploratory sub-analysis of the FORT-1 trial. This analysis revealed a potent efficacy signal that was hidden within the larger, non-responsive population. In the small subset of patients who had both high FGFR3 mRNA levels and a co-existing FGFR3 DNA alteration (a mutation or fusion), the objective response rate to Rogaratinib was 52.4%.[6] This was substantially higher than the response rate seen with chemotherapy in the same subgroup (26.7%) and far exceeded the ~20% response rate in the overall trial population.

This finding fundamentally reframed the biomarker question for monotherapy. It suggested that while mRNA overexpression may indicate some level of pathway activity, true "oncogene addiction"—the state in which a tumor is critically dependent on a single signaling pathway for its survival—is more reliably identified by the presence of a potent genetic driver event. For single-agent efficacy, mRNA level appears to be an imperfect surrogate for this underlying genetic dependency.

A New Paradigm for Combination Therapy

Just as the monotherapy story was being clarified, the results from the FORT-2 trial introduced an entirely new and distinct biomarker paradigm. This study tested Rogaratinib in combination with the immunotherapy agent atezolizumab, still using FGFR mRNA overexpression for patient selection. The combination yielded a high ORR of 53.8%.[7]

The most significant aspect of this result was that the efficacy was largely independent of the biomarkers that predict response to either agent alone. The majority of responders had low PD-L1 expression (a marker for immunotherapy response) and, crucially, did not have the FGFR DNA alterations that the FORT-1 analysis had identified as key for monotherapy response.[7]

This outcome suggests a mechanism of synergy where FGFR inhibition by Rogaratinib may be altering the tumor microenvironment to make it more permissive to an anti-tumor immune response. In this context, general FGFR pathway activation (as indicated by high mRNA levels) may be a sufficient condition for the combination to be effective, even without a hardwired genetic driver.

The clinical development of Rogaratinib thus reveals not a single, failed biomarker strategy, but a more sophisticated, multi-faceted picture. The data collectively point toward a tailored, dual-biomarker approach for the future development and application of this drug. For use as a monotherapy, patient selection should likely be restricted to those with confirmed potent FGFR genetic alterations. In contrast, for use in combination with immuno-oncology agents, a broader selection criterion based on evidence of general pathway activation, such as high FGFR mRNA expression, may be the optimal strategy to identify patients who can benefit from the synergistic immunomodulatory effects of the combination.

Regulatory Status and Concluding Synthesis

The culmination of preclinical and clinical data shapes a drug's regulatory trajectory and its ultimate place in the therapeutic landscape. Rogaratinib remains an investigational agent, and its journey provides a clear example of how clinical trial outcomes can pivot a drug's development strategy and define its future potential.

Current Development Status

As of the latest available information, Rogaratinib has not received marketing approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any indication.[52] Its development status varies by indication, reflecting the mixed results from its clinical program.

• Discontinued Indications: Following the negative results of the SAKK 19/18 trial, development of Rogaratinib as a monotherapy for squamous non-small cell lung cancer has been discontinued.[3] Similarly, the Phase II/III FORT-1 trial in urothelial carcinoma did not proceed to its Phase III stage after failing to show superiority over chemotherapy, effectively halting the monotherapy development path in that specific patient population.[6]
• Active Investigation: Development remains active in several areas. The most promising path is in combination with immunotherapy for urothelial carcinoma, based on the strong positive results from the FORT-2 study. Active trials are also ongoing to evaluate Rogaratinib in breast cancer (the ROGABREAST trial) and in specific, genetically defined populations of sarcoma and GIST.[3]
• Regulatory Filings: There have been no major marketing authorization applications submitted to the FDA or EMA. One procedural regulatory action of note is the EMA's decision on April 17, 2019, to grant a product-specific waiver for Rogaratinib's Paediatric Investigation Plan (PIP) for the treatment of urothelial carcinoma. This decision waives the requirement for the sponsor to conduct pediatric studies for this specific indication but is not related to an assessment of the drug's efficacy or safety for marketing approval.[54]

Competitive Landscape

The therapeutic space for FGFR inhibitors is evolving, with several agents in development and one major approval setting a clinical and regulatory benchmark. Erdafitinib (Balversa) is an oral pan-FGFR inhibitor that received FDA approval for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma harboring susceptible FGFR3 or FGFR2 genetic alterations who have progressed on prior platinum-containing chemotherapy.[9]

The approval of erdafitinib validates the FGFR pathway as a druggable target in urothelial cancer and defines the current standard of care for this genetically selected patient population. For Rogaratinib, this creates both a challenge and an opportunity. To compete as a monotherapy, Rogaratinib would need to demonstrate a superior or differentiated profile in a similar, genetically defined population. However, its most significant potential for differentiation now lies in the combination setting. The robust efficacy demonstrated in the FORT-2 trial in a broader, mRNA-positive population—including patients without the genetic alterations required for erdafitinib eligibility—suggests that Rogaratinib could fill a distinct and larger medical need as a partner for immunotherapy.

Concluding Synthesis and Future Perspective

Rogaratinib is a well-characterized, potent, and highly selective pan-FGFR inhibitor. Its preclinical profile provided a strong rationale for its development, and its clinical safety profile has been shown to be manageable and consistent with its mechanism of action.

The drug's development as a monotherapy has been challenging, primarily due to an initial reliance on an overly broad biomarker strategy based on FGFR mRNA overexpression. The definitive outcomes of the FORT-1 and SAKK 19/18 trials, which showed a lack of superior efficacy compared to standard of care, were significant setbacks for this approach and led to a necessary re-evaluation of the development strategy.

Despite these challenges, the clinical program has generated invaluable scientific and clinical insights. The potent efficacy signal observed in the exploratory analysis of the FGFR DNA-altered subset of the FORT-1 trial provides clear validation of the target in genetically defined patient populations. This finding aligns the potential monotherapy application of Rogaratinib with that of other successful targeted therapies, where efficacy is greatest in tumors driven by a specific oncogenic alteration.

The most promising path forward for Rogaratinib, however, has been illuminated by the success of the FORT-2 trial. The study's demonstration of a high response rate for the Rogaratinib-atezolizumab combination in first-line urothelial cancer has opened an exciting new avenue for development. The finding that this efficacy extends to patients with low PD-L1 expression and those without FGFR genetic alterations is particularly significant. It suggests a potential synergistic mechanism capable of overcoming primary resistance to immunotherapy and expanding the population of patients who could benefit from checkpoint inhibition.

Based on the totality of the evidence, the future of Rogaratinib likely lies not as a broadly applied monotherapy but as a precision medicine tool deployed in two distinct, biomarker-guided contexts:

1. As a targeted monotherapy for patients whose tumors are driven by specific, potent FGFR genetic alterations, such as fusions or activating mutations.
2. As a novel immuno-oncology combination agent for a wider group of patients whose tumors exhibit evidence of general FGFR pathway activation, such as high mRNA expression, where its primary role may be to modulate the tumor microenvironment and sensitize the cancer to checkpoint inhibitors.

The critical next step for the Rogaratinib program will be to validate the compelling findings from the single-arm FORT-2 study in a large, randomized controlled trial. Further investigation into the precise immunomodulatory mechanisms underlying the observed synergy will also be essential. If confirmed, this strategy could position Rogaratinib as a key component of a new standard of care in urothelial carcinoma and potentially other cancers where both the FGFR pathway and immune evasion play a role.

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