The role of FGFR signaling in SCLC and NSCLC: Current insights and therapeutic perspectives

Summary

Lung cancer remains a leading cause of cancer related mortality worldwide and is characterized by marked biological heterogeneity and frequent therapeutic failure. Although lung cancer is broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) based on distinct cellular origins and clinical behaviors, both entities rely on aberrant signaling networks to sustain tumor growth and disease progression. Despite advances in biomarker guided therapeutic strategies, approaches centered on individual genetic alterations have shown limited durability, in part due to tumor evolution and cellular plasticity. Among signaling pathways shared across lung cancer subtypes, fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) signaling has been implicated in regulating tumor proliferation, angiogenesis, and adaptive responses to therapy. Here, we argue that the limited clinical success of FGFR-targeted therapies in lung cancer reflects constraints of alteration-centered targeting rather than an absence of biological relevance. We propose that FGFR signaling functions as a context-dependent adaptive node, whose therapeutic significance emerges under selective pressure and acquired resistance.

Graphical abstract

Biological sciences; Cell biology; Molecular biology

Introduction

Lung cancer remains one of the leading causes of cancer-related mortality worldwide and is broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is an aggressive neuroendocrine malignancy characterized by rapid progression, early dissemination, and frequent relapse after initial treatment response. In contrast, NSCLC comprises a heterogeneous group of tumors with diverse histological and molecular features, and biomarker-guided therapeutic strategies have improved treatment outcomes in selected patient populations.^1,2,3

Fibroblast growth factor receptor (FGFR) signaling has been studied as one of the signaling pathways associated with lung cancer biology. Through interactions with fibroblast growth factor (FGF) ligands, FGFRs regulate cellular processes such as proliferation, survival, differentiation, angiogenesis, and tissue repair. In cancer, dysregulation of this pathway can contribute to tumor growth and disease progression.^4,5

In lung cancer, FGFR-related alterations and pathway activation have been reported in both NSCLC and SCLC, suggesting that FGFR signaling may have biological and clinical relevance across histological subtypes. However, the clinical significance of FGFR signaling in lung cancer remains less clearly defined than that of several established oncogenic drivers. FGFR alterations are diverse, their functional consequences can vary by tumor context, and therapeutic responses to FGFR-targeted approaches have been inconsistent.^6,7,8

FGF/FGFR signaling, alterations, and therapeutic targeting in lung cancer

The FGF/FGFR axis consists of a diverse ligand-receptor network that regulates multiple developmental, homeostatic, and pathological processes. The FGF family comprises 22 ligands that can be broadly categorized into canonical paracrine FGFs, endocrine FGFs, and intracellular FGFs, whereas the FGFR family includes four canonical receptor tyrosine kinases, FGFR1–4, and the atypical receptor fibroblast growth factor receptor-like 1 (FGFRL1, also known as FGFR5). Canonical FGFRs share a conserved structure composed of extracellular immunoglobulin-like domains, a transmembrane region, and an intracellular tyrosine kinase domain. Alternative splicing of the IgIII domain, ligand-specific receptor affinity, and cofactor-dependent binding through heparan sulfate proteoglycans (HSPGs) or Klotho family proteins collectively shape receptor-ligand specificity. This ligand-receptor diversity provides the biological basis for the context-dependent nature of FGFR signaling and therapeutic targeting in cancer.^9,10

FGFR signaling and alterations in lung cancer

Upon FGF ligand binding, FGFRs undergo receptor dimerization and autophosphorylation, leading to activation of downstream signaling cascades such as MAPK/ERK, PI3K/AKT, and PLCγ/PKC. These pathways regulate cellular proliferation, survival, differentiation, motility, angiogenesis, and adaptive responses to cellular stress. In cancer, aberrant FGFR signaling can therefore support tumor growth and progression through both genetically driven and non-genetic mechanisms.^5,10,11

Aberrant FGFR signaling in cancer can arise through several types of alterations, including amplification, overexpression, mutation, and fusion or rearrangement (Figure 1A). Gene amplification increases FGFR copy number and may enhance receptor expression or downstream signaling, as reported in several tumor types, including squamous lung cancer and breast cancer. FGFR overexpression can occur with or without detectable copy-number alteration and may reflect transcriptional, epigenetic, or microenvironment-dependent regulation of the pathway. Activating mutations, particularly those affecting extracellular, transmembrane, or kinase domains, can promote ligand-independent receptor activation, alter receptor conformation, or modify ligand-binding properties, with well-characterized examples in urothelial cancer, endometrial cancer, and selected lung cancer subsets. FGFR fusions or rearrangements can generate constitutively active receptor products, often through partner-mediated dimerization or loss of regulatory regions, and are clinically relevant in cancers such as cholangiocarcinoma, urothelial cancer, glioma, and rare NSCLC subsets. These alteration types are not functionally equivalent. For example, fusions and activating mutations are more likely to induce ligand-independent signaling, whereas amplification and overexpression may increase receptor abundance and signaling capacity while remaining influenced by ligand availability, receptor isoform usage, and cellular context. Therefore, each alteration type may differ in oncogenic strength, pathway dependency, and therapeutic predictability.^5,12,13

Figure 1.

Schematic overview of FGFR alterations and their clinical relevance in lung cancer

Left: FGFR alterations can occur through gene amplification, mutation, fusion, or receptor overexpression, leading to changes in receptor abundance, structure, ligand responsiveness, or downstream signaling activity. Middle: in lung cancer, FGFR alterations show distinct patterns between NSCLC and SCLC. In NSCLC, FGFR1 amplification, FGFR2 fusion, FGFR3 mutation, receptor overexpression, and squamous NSCLC-associated enrichment have been reported. In SCLC, FGFR alterations are generally less frequent, although FGFR1 amplification and lineage plasticity may contribute to context-dependent FGFR signaling. Right: reported clinical associations of FGFR alterations include poorer overall survival, aggressive progression, metastatic potential, and reduced treatment response in selected contexts. These features should be interpreted according to alteration type, tumor lineage, and molecular context rather than as uniform consequences of all FGFR alterations.

Created with BioRender.com.

In NSCLC, FGFR alterations have been most extensively investigated in squamous cell carcinoma, where FGFR1 amplification has been reported as a recurrent event. Additional FGFR alterations, including FGFR2 or FGFR3 mutations and FGFR fusion events such as FGFR3-TACC3, occur less frequently but may define molecularly selected subsets. Beyond structural genomic alterations, altered expression of FGF ligands or FGFRs may also contribute to pathway activation in specific tumor contexts. These findings support the biological relevance of FGFR signaling in NSCLC, although the clinical implications vary according to histology, alteration type, and coexisting molecular features (Figure 1B).^6,7,14,15

In contrast to the more genomically stratified FGFR landscape of NSCLC, the role of FGFR signaling in SCLC remains less clearly defined. Recurrent and therapeutically actionable FGFR alterations appear less frequent in SCLC, yet several lines of evidence suggest that FGFR-related signaling may still be biologically relevant. FGFR1 amplification has been reported in a subset of SCLC, and experimental studies have implicated FGF/FGFR signaling in tumor cell survival, proliferation, and adaptive behavior. In addition, atypical FGFR family members such as FGFR5 have been linked to SCLC biology through overexpression-based mechanisms rather than classical kinase-domain alterations. These findings suggest that, in SCLC, FGFR may be less established as a conventional alteration-defined target but may contribute to tumor biology through context-dependent signaling mechanisms that remain incompletely understood (Figure 1B).^7,16,17

Collectively, these observations indicate that FGFR alterations and pathway activation in lung cancer should be interpreted according to tumor subtype and alteration context. As summarized in Figure 1C, FGFR-related events have been associated with tumor progression, poor prognosis, therapeutic resistance, or other clinical features in selected settings, rather than as uniform consequences of all FGFR-altered tumors. Therefore, the presence of an FGFR alteration should not be interpreted as a binary predictor of clinical behavior or therapeutic response, but as a molecular feature whose significance depends on lineage-specific background, alteration type, and pathway activation state. This complexity provides the rationale for FGFR-directed therapeutic strategies that intervene at different levels of the FGF/FGFR axis.^7,13,18

FGF/FGFR-targeted therapy and current limitations

FGF/FGFR-targeted therapy has been developed to suppress the pathway at multiple regulatory levels, including ligand availability, receptor engagement, and intracellular kinase activity. These strategies can be broadly classified into extracellular approaches, which interfere with FGF ligand binding or receptor activation at the cell surface, and intracellular approaches, which inhibit the catalytic activity of the FGFR kinase domain.^5,7,10

Extracellular targeting strategies include FGF ligand traps, receptor-targeting antibodies, and allosteric receptor-level inhibition. FGF ligand traps act as soluble decoy receptors that sequester FGF ligands and limit their interaction with endogenous FGFRs. FP1039/GSK3052230 represents this ligand-trap approach by using the extracellular domain of FGFR1 fused to an IgG Fc region to neutralize selected FGF ligands. Receptor-targeting antibodies provide another extracellular strategy by interfering with ligand binding, receptor activation, or receptor-mediated downstream signaling. Bemarituzumab, an FGFR2b-directed antibody, and vofatamab, an FGFR3-directed antibody, illustrate receptor-level targeting, although their clinical development has largely focused on non-lung tumor contexts. In addition, alofanib represents an allosteric extracellular FGFR2 inhibitor that binds an allosteric site within the FGFR2 extracellular domain, providing a non-ATP-competitive approach to receptor-level inhibition. Extracellular strategies therefore provide a mechanistically distinct way to suppress upstream FGFR signaling by limiting ligand availability or receptor activation at the cell surface, although their application requires consideration of ligand redundancy, receptor isoform specificity, and the difficulty of defining ligand-dependent tumor contexts.^{19,20,21,22,23,24,25}

By contrast, most FGF/FGFR-targeted drug development has focused on small-molecule inhibition of the intracellular receptor tyrosine kinase domain. FGFR tyrosine kinase inhibitors (TKIs) directly suppress catalytic activity by targeting the ATP-binding pocket or adjacent regulatory regions within the kinase domain. Suppression of kinase-domain activity reduces FGFR autophosphorylation and limits downstream MAPK/ERK, PI3K/AKT, and PLCγ/PKC signaling. Reversible ATP-competitive inhibitors, including erdafitinib, pemigatinib, infigratinib, AZD4547, rogaratinib, and derazantinib, inhibit FGFR phosphorylation by competing with ATP binding. These inhibitors differ in selectivity across FGFR paralogs and in their preferred kinase conformation, including DFG-in or DFG-out binding states near the activation loop. Ponatinib illustrates DFG-out FGFR kinase inhibition, although it should be interpreted as a multikinase inhibitor with FGFR activity rather than an FGFR-selective agent. Covalent inhibitors provide another strategy for kinase-domain suppression. Futibatinib/TAS120 irreversibly inhibits FGFR1–4 through covalent binding near the ATP-binding pocket, thereby enabling sustained pathway inhibition and activity against selected resistance-associated FGFR kinase-domain alterations. Thus, although intracellular FGFR inhibitors differ in reversibility, binding mode, and selectivity, most converge on pharmacologic suppression of the FGFR kinase domain.^{5,26,27,28,29,30,31,32,33,34,35,36,37,38}

The extensive development of kinase-domain inhibitors highlights both the druggability and the therapeutic challenge of FGFR signaling. Despite multiple approaches to inhibit FGFR kinase activity, clinical benefit in lung cancer has remained limited and context-dependent. One major constraint is on-target toxicity, reflecting the physiological roles of FGFR signaling in normal tissues. Hyperphosphatemia is a characteristic toxicity of systemic FGFR inhibition, and additional adverse events involving the skin, nails, mucosa, gastrointestinal tract, and eyes can limit dose intensity or treatment duration. Selectivity constraints are also important, because inhibition of multiple FGFR paralogs may increase toxicity, whereas selective inhibition of a single receptor may be insufficient when ligand or receptor redundancy maintains pathway activity.^{5,7,18,26,31,39,40}

In addition to pharmacologic limitations, biological features of lung cancer can restrict the efficacy of FGF/FGFR-targeted therapy. The presence of an FGFR alteration or elevated FGFR expression does not necessarily indicate FGFR pathway dependency, and coexisting oncogenic drivers or adaptive signaling networks may reduce the effectiveness of FGFR inhibition. Furthermore, bypass pathway activation can maintain downstream survival signaling in treatment-resistant contexts, thereby limiting the activity of FGFR-directed monotherapy. As summarized in Figure 2, current FGF/FGFR-targeted approaches face shared limitations related to on-target toxicity, selectivity constraints, ligand/receptor redundancy, variable FGFR dependency, and bypass pathway activation. These limitations indicate that the activity of FGF/FGFR-targeted therapy in lung cancer depends not only on pharmacologic inhibition of the pathway, but also on the biological context in which FGFR signaling operates.^{7,18,26,31,41}

Figure 2.

Overview of FGFR targeting modalities and therapeutic limitations

FGF-mediated FGFR activation induces receptor dimerization and phosphorylation, leading to canonical downstream signaling through MAPK/ERK, PI3K/AKT, and PLCγ/PKC pathways. FGFR-directed therapeutic strategies can be broadly divided into extracellular and intracellular approaches. Extracellular targeting includes FGF ligand traps, receptor-targeting antibodies, and allosteric receptor-level inhibition, which interfere with ligand availability, ligand-receptor interaction, or receptor activation at the cell surface. Intracellular targeting is mainly achieved by FGFR TKIs, including DFG-in, DFG-out, and covalent inhibitors that suppress kinase-domain activity through distinct binding modes. Although these agents differ in reversibility, binding mode, and selectivity, most intracellular FGFR inhibitors converge on suppression of the FGFR kinase domain. Despite these diverse modalities, FGFR-directed therapies remain limited by on-target toxicity, selectivity constraints, ligand/receptor redundancy, variable FGFR dependency, and bypass pathway activation. Created with BioRender.com.

Current limitations and next-generation strategies for FGFR-targeted approaches in lung cancer

As described above, FGF/FGFR-targeted therapies have been developed to inhibit ligand availability, receptor engagement, and intracellular kinase activity. However, the remaining limitations of FGFR-directed therapy in lung cancer extend beyond the mechanisms or potency of available inhibitors. Even when FGFR signaling can be pharmacologically suppressed, its therapeutic application is affected by the low frequency and heterogeneity of FGFR alterations, uncertain prediction of pathway dependency, on-target toxicity, and resistance-associated signaling changes. Therefore, these limitations need to be considered not only as biological or pharmacological issues, but also as factors that shape the clinical use of FGFR-targeted approaches. In the following sections, these unresolved issues are first discussed as clinical hurdles and then linked to next-generation strategies that may better define when, where, and how FGFR signaling should be therapeutically targeted in lung cancer.^{5,7,15,42,43,44}

Clinical hurdles arising from current FGFR-targeted approaches

In lung cancer, the clinical hurdles associated with FGFR-targeted approaches arise in part from the difficulty of translating diverse FGFR-related events into predictable therapeutic dependencies (Figure 3, left). FGFR alterations have been reported across lung cancer subtypes, but they occur in a relatively limited proportion of patients compared with several established oncogenic drivers. This low prevalence limits the accumulation of sufficiently large clinical datasets, making it difficult to define reproducible biomarker patterns or therapeutic response profiles. This issue is further complicated by the heterogeneity of FGFR-related alterations, including amplification, overexpression, mutation, and fusion. These events are often grouped under the broad category of FGFR alteration, but they do not necessarily produce equivalent biological outputs or therapeutic implications. As a result, the clinical interpretation of FGFR in lung cancer is affected by two overlapping problems: the limited number of FGFR-defined cases and the high molecular variability within those cases. Together, these features make it difficult to establish FGFR as a uniform therapeutic target and may contribute to the inconsistent activity reported with FGFR-directed approaches.^{6,14,17,18,31}

Figure 3.

Current limitations and next-generation strategies for FGFR-targeted approaches in lung cancer

Current limitations: FGFR-targeted approaches in lung cancer are constrained by clinical, pharmacological, and biological limitations. Clinically, FGFR-altered lung cancers represent a limited patient population, and their molecular heterogeneity, small clinical cohorts, and limited single-agent efficacy have made it difficult to establish a broadly effective FGFR-directed strategy. Pharmacologically, direct FGFR inhibition may affect both tumor cells and normal cells that depend on physiological FGF/FGFR signaling, contributing to on-target toxicity. Biologically, FGFR-driven tumors may show partial response to FGFR inhibition but subsequently undergo resistant regrowth through drug tolerance, tumor state shift, or signaling rewiring.

Next-generation strategies: future FGFR-directed approaches should move beyond simple alteration-based selection and direct single-target inhibition. Instead, FGFR-altered tumors may need to be stratified according to tumor phenotype and interpreted through functional pathway state, intervention point, and therapeutic relevance. Integrating phenotype, therapy, and target information may provide a framework for new therapeutic approaches that better reflect the context-dependent biology of FGFR signaling in lung cancer. Extracellular FGF inhibition and resistance-guided strategies are shown as representative examples of approaches that extend beyond conventional direct FGFR inhibition.

Created with BioRender.com.

Therapeutic window constraints represent another major clinical hurdle. FGFR signaling is involved in normal physiological processes, including phosphate homeostasis, tissue maintenance, and repair, and systemic inhibition of this pathway can therefore produce mechanism-based toxicities. Hyperphosphatemia is a characteristic adverse event of FGFR blockade, while mucosal, dermatologic, nail, gastrointestinal, and ocular toxicities can also affect tolerability. These adverse events are clinically important because FGFR-targeted therapy may require sustained pathway suppression to achieve sufficient antitumor activity. In lung cancer, this issue becomes more complex when FGFR inhibition is considered as part of combination therapy, particularly in resistance-associated settings where parallel or downstream survival pathways may also need to be suppressed. Therefore, the toxicity associated with FGFR inhibition should not be viewed only as a treatment-limiting adverse effect, but also as a reflection of the broad involvement of FGFR signaling in normal tissue regulation. This reinforces the importance of identifying lung cancer contexts in which FGFR dependency is strong enough to support therapeutic intervention despite the narrow therapeutic window.^39,40,45,46

Limited and variable efficacy of FGFR-targeted therapy represents another clinical hurdle in lung cancer. Although FGFR inhibitors can suppress FGFR signaling, their antitumor activity in lung cancer has often been partial, context-dependent, or insufficiently durable rather than uniformly effective. This limitation is further complicated by the narrow therapeutic window of FGFR inhibition. Because sustained pathway suppression may be required to achieve meaningful antitumor activity, dose reduction, treatment interruption, or early discontinuation caused by on-target toxicities may reduce the depth or duration of pathway suppression and allow residual tumor cells to persist under therapeutic pressure. Because lung cancer-specific studies of acquired resistance to FGFR inhibitors remain limited, resistance mechanisms defined in other FGFR-driven tumors should be used as a mechanistic framework rather than directly generalized to lung cancer. Within this framework, residual tumor cells may become less responsive to sustained FGFR inhibition through secondary FGFR alterations, downstream signaling reactivation, or compensatory bypass pathways. Consequently, the clinical problem is not limited to whether FGFR can be inhibited initially, but extends to whether FGFR inhibition can be maintained long enough and matched to the signaling state that sustains residual tumor survival. This concern is particularly relevant in lung cancer, where FGFR signaling may act either as a therapeutic target in selected FGFR-altered tumors or as an adaptive bypass pathway during resistance to other targeted therapies.^{29,41,47,48,49,50,51}

Taken together, these clinical hurdles suggest that the limitations of FGFR-targeted therapy in lung cancer are not caused by a single barrier, but by the combined effects of molecular heterogeneity, narrow therapeutic window, and treatment-associated adaptation or bypass signaling. The low frequency and functional diversity of FGFR-related alterations make it difficult to define a consistent FGFR-dependent tumor group, while on-target toxicity can restrict the intensity and duration of pathway suppression. In addition, partial or insufficiently durable inhibition may allow residual tumor cells to persist under therapeutic pressure and engage resistance-associated signaling programs. These issues do not argue against the biological relevance of FGFR signaling in lung cancer; rather, they indicate that FGFR-directed therapy requires a more precise understanding of when FGFR signaling is functionally important, how strongly tumors depend on this pathway, and which level of the FGF/FGFR axis should be therapeutically intercepted. Therefore, overcoming these hurdles will likely require approaches that move beyond alteration status or inhibitor potency alone and instead integrate FGFR signaling with the biological and treatment state of the tumor.

Context-specific strategies for next-generation FGFR targeting

The clinical hurdles described above support a shift toward next-generation FGFR-targeted strategies that move beyond alteration-driven selection and single-node inhibition alone (Figure 3, right). Rather than treating FGFR alterations as uniform therapeutic indicators, future approaches should define the phenotypic and signaling states in which FGFR activity contributes to tumor maintenance, therapeutic adaptation, or resistance. This requires identifying not only whether FGFR should be targeted, but also which level of the FGF/FGFR axis or connected signaling network should be intercepted, and whether FGFR inhibition should be applied as a single-agent strategy or as part of a resistance-guided combination approach.^5,7,26,31,41

Phenotype-based stratification is not simply a classification of tumors by FGFR alteration type, but an attempt to define tumor states in which FGFR signaling is biologically active and therapeutically relevant. Such states may be shaped by histological subtype, lineage programs, epithelial or mesenchymal features, ligand and receptor expression, downstream pathway activation, or treatment-induced resistance. This approach is particularly important in lung cancer, where FGFR-defined cases are limited and molecularly heterogeneous, and where NSCLC and SCLC differ substantially in their cellular origin, molecular landscape, and therapeutic context. By incorporating these phenotypic and signaling features, FGFR-targeted therapy may be directed toward tumors in which FGFR activity is more likely to contribute to tumor behavior, adaptive signaling, or resistance, rather than toward all FGFR-altered tumors as a uniform group.^{17,41,52,53,54}

FGF/FGFR signaling should also be viewed as a multi-level signaling axis rather than a single receptor-centered target. Depending on the tumor state, FGFR pathway activity may be maintained by ligand-dependent or paracrine activation, receptor overexpression, activating receptor alterations, kinase-domain dependency, downstream pathway activation, or compensatory bypass signaling. In ligand-driven contexts, extracellular FGF inhibition or receptor-level targeting may be more relevant, whereas activating receptor alterations may favor kinase-domain inhibition. In resistance-associated states, the therapeutically relevant point may extend beyond FGFR itself to downstream MAPK/ERK or PI3K/AKT signaling, parallel receptor tyrosine kinases, or the original oncogenic driver. Therefore, intervention point identification requires a broader view of the FGF/FGFR signaling network, in which direct FGFR inhibition and targeting of FGFR-associated ligand, receptor-level, downstream, or bypass signaling nodes are considered as potential therapeutic strategies.^19,47,48,55

From a therapeutic perspective, phenotype-based stratification and intervention point identification should ultimately be integrated into treatment design. In this approach, FGFR-targeted therapy is not selected solely on the basis of FGFR alteration status, but is matched to the tumor phenotype, the signaling state that maintains FGFR pathway activity, and the level of the FGF/FGFR axis that is most appropriate for therapeutic intervention. Such an approach may help distinguish tumors in which direct FGFR kinase inhibition is sufficient from those in which ligand availability, receptor-level activation, downstream signaling, or resistance-associated bypass pathways should also be considered. Therefore, the future direction of FGFR-targeted therapy in lung cancer may depend less on expanding single-agent FGFR inhibition alone and more on designing state-matched strategies that integrate phenotype, target, and therapeutic context.^{10,31,41,48,52,56,57}

Extracellular FGF inhibition and resistance-guided strategies provide representative examples of this broader approach. Extracellular targeting strategies, including ligand blockade or receptor-level inhibition, may be useful when ligand-dependent or paracrine FGFR activation contributes to pathway activity, and they may offer an alternative therapeutic window compared with intracellular kinase-domain inhibition. However, their clinical relevance in lung cancer will require careful definition of ligand-dependent tumor contexts. In contrast, resistance-guided strategies may be particularly relevant in FGFR-driven tumors that acquire resistance to FGFR inhibitors or in lung cancers where FGFR signaling emerges as a compensatory bypass pathway after selective therapeutic pressure. In these settings, understanding the resistant tumor state and the associated signaling phenotype may guide the use of alternative FGFR-directed agents, downstream pathway inhibitors, or rational combination strategies. These examples should not be interpreted as universal solutions for all FGFR-altered lung cancers, but as representative directions for moving beyond conventional alteration-based FGFR targeting. Together, these concepts are summarized in Figure 3, which illustrates the transition from current limitations to a more refined approach for next-generation FGFR targeting.^{26,47,50,53,54,57}

Clinical landscape of FGFR targeting in lung cancer

FGFR signaling has biological relevance in lung cancer through tumor-intrinsic signaling and adaptive pathway regulation that can influence tumor growth, survival, and therapeutic response. However, as discussed above, the clinical translation of FGFR-directed therapy has remained limited by the low frequency and heterogeneity of FGFR-related alterations, uncertain prediction of pathway dependency, on-target toxicity, and resistance-associated signaling. This gap is particularly evident when FGFR targeting is considered within the broader clinical landscape of lung cancer, where biomarker-guided therapies have been extensively integrated into NSCLC treatment, whereas targeted treatment options for SCLC remain comparatively limited. Accordingly, the clinical status of FGFR targeting in lung cancer is best viewed not as a single alteration-defined treatment category, but as an evolving therapeutic concept that may become relevant in selected molecular, phenotypic, and resistance-associated contexts.

FDA-approved therapeutic landscape in SCLC and NSCLC

The FDA-approved therapeutic landscape of lung cancer has expanded substantially, but the number of agents that have successfully reached routine clinical use remains limited relative to the broad range of molecular targets and therapeutic strategies investigated in lung cancer (Table 1). This imbalance is particularly evident in SCLC, where approved systemic treatment options remain comparatively restricted. Platinum plus etoposide chemotherapy has long served as the therapeutic backbone of SCLC treatment, and immune checkpoint inhibitors, including atezolizumab and durvalumab, have been incorporated into first-line extensive-stage SCLC therapy. Additional approved agents, such as lurbinectedin and the DLL3-targeted T cell engager tarlatamab, have expanded treatment options in the relapsed setting. Lurbinectedin provides a transcription-directed therapeutic approach, whereas tarlatamab represents an immune-redirection strategy targeting DLL3-expressing SCLC cells. However, unlike NSCLC, SCLC still lacks FDA-approved small-molecule therapies directed against its recurrent genomic alterations, and no FGFR-targeted therapy has been approved in this setting.^58,59,60

Table 1.

FDA-approved systemic therapies and molecular targets in NSCLC and SCLC

Disease	Drug/class	Target/alteration	Approval and setting	Key trials (NCT)
NSCLC	Osimertinib	EGFR act.; T790M	2018; IV/1L 2020; IB–IIIA adj	FLAURA — NCT02296125 AURA3 — NCT02511106 AURA — NCT02151981
NSCLC	Osimertinib + chemo	EGFR Ex19del/L858R	2023; IV/1L	FLAURA2 — NCT04035486
NSCLC	Amivantamab + lazertinib	EGFR Ex19del/L858R	2024; IV/1L	MARIPOSA — NCT04487080
NSCLC	Amivantamab	EGFR Ex20ins	2021; IV/1L 2024; IV/1L	CHRYSALIS — NCT02609776 NCT04538664
NSCLC	Alectinib	ALK fusion	2017; I–III adj 2023; I–III adj	ALEX — NCT02075840 ALINA — NCT03456076
NSCLC	Lorlatinib	ALK fusion; G1202R	2020; IV/1L	CROWN — NCT03052608
NSCLC	Brigatinib	ALK fusion	2017; IV/1L 2020; IV/1L	ALTA-1L — NCT02737501
NSCLC	Repotrectinib	ROS1 fusion; G2032R	2023; IV/1L	TRIDENT-1 — NCT03093116
NSCLC	Entrectinib	ROS1/NTRK fusion	2019; IV/1L	STARTRK-2 — NCT02568267 STARTRK-1 — NCT02097810
NSCLC	Crizotinib	ROS1 fusion	2016; IV/1L	PROFILE1001 — NCT00585195
NSCLC	Capmatinib	MET Ex14skip	2020; IV/1L 2022; IV/1L	GEOMETRY — NCT02414139
NSCLC	Tepotinib	MET Ex14skip	2021; IV/≥1L	VISION — NCT02864992
NSCLC	Selpercatinib	RET fusion	2020; IV/1L 2022; IV/1L	LIBRETTO-001 — NCT03157128
NSCLC	Pralsetinib	RET fusion	2020; IV/1L	ARROW — NCT03037385
NSCLC	Dabrafenib + trametinib	BRAF V600E	2017; IV/1L	COMBI-v — NCT01336634 COMBI-d — NCT02034110
NSCLC	T-DXd	HER2 mut./overexp.	2022; IV/≥2L	DESTINY-Lung02 — NCT04644237
NSCLC	Sotorasib	KRAS G12C	2021; IV/≥2L	CodeBreak100 — NCT03600883
NSCLC	Adagrasib	KRAS G12C	2022; IV/≥2L	KRYSTAL-1 — NCT03785249
NSCLC	Pembrolizumab	PD-1; PD-L1 ≥1%	2022; IB–IIIA adj	KEYNOTE-091 — NCT02504372
NSCLC	Pembrolizumab + Pem/Plat	PD-1	2018; IV/1L (non-sq)	KEYNOTE-189 — NCT02578680
NSCLC	Pembrolizumab + Tax/Plat	PD-1	2018; IV/1L (sq)	KEYNOTE-407 — NCT02775435
NSCLC	Atezolizumab	PD-L1	2019; I–III adj	IMpower010 —NCT02486718 IMpower110 —NCT02409342
NSCLC	Nivolumab + ipilimumab + chemo	PD-1 + CTLA-4	2020; IV/1L	CheckMate9LA — NCT03215706
NSCLC	Durvalumab	PD-L1	2018; III unres.	PACIFIC — NCT02125461
NSCLC	Bevacizumab + chemo	VEGF	2006; IV/1L	ECOG4599 — NCT00021060
NSCLC	Ramucirumab + docetaxel	VEGFR2	2014; IV/≥2L	REVEL — NCT01168973
NSCLC	Dato-DXd	TROP2	2025; IV/≥2L	TROPION-Lung05 — NCT04484142
NSCLC	Ensartinib	ALK fusion	2024; IV/1L	eXalt3 — NCT02767804
SCLC	Atezolizumab + EP	PD-L1	2019; ES-SCLC 1L	IMpower133 — NCT02763579
SCLC	Durvalumab + EP	PD-L1	2020; ES-SCLC 1L	CASPIAN — NCT03043872
SCLC	Lurbinectedin	RNA Pol II	2020; ES-SCLC ≥2L	ATLANTIS — NCT02566993
SCLC	Tarlatamab	DLL3 TCE	2024; ES-SCLC ≥2L	DeLLphi-301 — NCT05060016 DeLLphi-304 — NCT05740566

1L, first-line; ≥2L, second-line or later; adj, adjuvant; unres., unresectable; LA/met, locally advanced or metastatic; ES-SCLC, extensive-stage small cell lung cancer; sq, squamous; non-sq, non-squamous; EP, etoposide + platinum; Pem/Plat, pemetrexed + platinum; Tax/Plat, taxane + platinum; TCE, T cell engager; act., activating; Mut, mutation; ins, insertion; del, deletion; Ex, Exon.

In contrast, NSCLC has been the major setting for biomarker-guided drug development in lung cancer. EGFR-mutant NSCLC represents one of the most established examples, with EGFR TKIs such as osimertinib used to inhibit oncogenic EGFR kinase activity and improve outcomes in molecularly selected patients. ALK-rearranged NSCLC is treated with ALK inhibitors such as alectinib and lorlatinib, which target fusion-driven kinase signaling and have improved disease control, including in settings where central nervous system activity is clinically important. ROS1 fusion-positive disease is similarly treated with ROS1-directed inhibitors such as entrectinib and repotrectinib, while MET exon 14 skipping alterations are targeted by MET inhibitors such as capmatinib and tepotinib. RET fusion-positive NSCLC has also become therapeutically actionable through selective RET inhibitors such as selpercatinib and pralsetinib. Downstream or non-receptor oncogenic drivers are also represented in the approved treatment landscape, including BRAF V600E with dabrafenib plus trametinib and KRAS G12C with sotorasib or adagrasib. In addition, HER2-altered NSCLC can be treated with antibody-drug conjugates such as trastuzumab deruxtecan, reflecting the expansion of targeted therapy beyond conventional kinase inhibitors. Immune checkpoint inhibitors targeting PD-1 or PD-L1, anti-angiogenic agents such as bevacizumab and ramucirumab, and antibody-drug conjugates such as datopotamab deruxtecan further broaden the therapeutic options available across different NSCLC settings. The full list of representative FDA-approved agents and their molecular targets is summarized in Table 1.^{61,62,63,64,65,66,67,68,69,70,71,72,73}

This contrast between SCLC and NSCLC illustrates both the success and the incompleteness of precision oncology in lung cancer. Despite the rapid expansion of biomarker-guided therapies, clinically established therapeutic targets still represent only a subset of the molecular alterations reported in this disease. This gap is particularly evident in SCLC, where approved targeted treatment options remain scarce, but it is also relevant to selected molecular subsets of NSCLC that lack established targeted therapies. Among these unresolved areas, FGFR represents a notable example. Although FGFR alterations occur at relatively low frequency in lung cancer, patients with FGFR-altered tumors currently lack an FDA-approved FGFR-targeted treatment option, underscoring the gap between molecular detection and clinically established therapeutic intervention.^7,27,74

Ongoing clinical development and the position of FGFR-directed strategies

Following the approved therapeutic landscape summarized above, ongoing clinical trial activity provides an additional perspective on how lung cancer therapy is evolving beyond currently established treatment options. To examine recent clinical development trends, data were retrieved from the ClinicalTrials.gov database using predefined search criteria. As of October 1, 2025, a total of 1,735 active interventional lung cancer trials were identified. The search included interventional studies registered under the term “lung cancer” with study status classified as not yet recruiting, recruiting, or active but not recruiting. This search was used to capture active clinical development activity relevant to lung cancer during the 2023–2025 review period. These trials were manually grouped into four major strategic categories: optimization of existing therapeutic strategies, discovery of novel targets and mechanisms, early-stage and perioperative therapeutic interventions, and dedicated research in SCLC. Representative clinical studies, therapeutic objectives, and major target classes for each category are summarized in Table 2.

Table 2.

Representative clinical studies and therapeutic development trends in lung cancer (2023–2025)

Category	Estimated proportion	Representative study	Clinical objective	Major Target
1. Optimization of existing therapeutic strategies	42.40%	FLAURA2 (NCT04035486, 2023)	Optimize first-line EGFR-targeted therapy through combination with platinum-based chemotherapy	EGFR TKI + Chemo
		MARIPOSA (NCT04487080, 2024)	Improve first-line treatment of EGFR-mutated NSCLC through dual EGFR-directed strategy	EGFR TKI + EGFR/MET antibody
		PAPILLON (NCT04538664, 2023/2024)	Optimize first-line treatment for EGFR Ex20ins NSCLC by combining amivantamab with chemotherapy	EGFR/MET antibody + Chemo
2. Discovery of novel targets and mechanisms	23.70%	CodeBreaK 200 (NCT04303780, 2023)	Validate next-generation KRAS G12C inhibition in previously treated KRAS G12C-mutant NSCLC	KRAS G12C Inhibitor
		TROPION-Lung05 (NCT04484142, 2025)	Evaluate TROP2-directed ADC in advanced/metastatic NSCLC with actionable genomic alterations after targeted therapy and platinum chemotherapy	ADC (TROP2)
		DESTINY-Lung02 (NCT04644237, 2023)	Evaluate HER2-directed ADC therapy in HER2-mutant unresectable or metastatic NSCLC	HER2 ADC
3. Early-stage and perioperative therapy	24.70%	KEYNOTE-671 (NCT03425643, 2023)	Improve event-free and overall survival through perioperative pembrolizumab plus chemotherapy in resectable NSCLC	Perioperative IO + Chemo
		CheckMate 77T (NCT04025879, 2024)	Evaluate perioperative nivolumab plus chemotherapy followed by adjuvant nivolumab in resectable NSCLC	Perioperative IO + Chemo
		AEGEAN (NCT03800134, 2023)	Evaluate perioperative immunotherapy or targeted therapy strategies in resectable NSCLC	Perioperative IO + Chemo
4. Dedicated research in small-cell lung cancer	9.00%	IMforte (NCT05091567, 2025)	Evaluate lurbinectedin plus atezolizumab as maintenance therapy in extensive-stage SCLC	Transcription inhibitor + PD-L1
		ADRIATIC (NCT03703297, 2024)	Extension of long-term survival and establishment of new standards of care for limited-stage SCLC	Adjuvant IO
		DeLLphi-304 (NCT05740566, 2025)	Compare tarlatamab with standard chemotherapy in previously treated SCLC	DLL3 T cell engager

Estimated proportions were calculated from active interventional lung cancer trials retrieved from ClinicalTrials.gov using predefined search criteria: “lung cancer;” not yet recruiting, recruiting, or active but not recruiting studies; and interventional studies. The search was performed to capture clinical trial activity relevant to lung cancer drug development during the 2023–2025 review period. Trials were manually grouped by therapeutic objective and major target class; values should be interpreted as approximate estimates of clinical development trends rather than exact epidemiologic proportions.

ADC, antibody-drug conjugate; Chemo, chemotherapy; DLL3, delta-like ligand 3; EGFR, epidermal growth factor receptor; Ex, exon; Ex19del, exon 19 deletion; Ex20ins, exon 20 insertion; HER2, human epidermal growth factor receptor 2; IO, immunotherapy; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal-epithelial transition factor; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; SCLC, small cell lung cancer; TCE, T cell engager; TKI, tyrosine kinase inhibitor; TROP2, trophoblast cell-surface antigen 2.

This overview indicates that recent lung cancer clinical development is expanding across multiple directions rather than being limited to the discovery of single new molecular targets. A substantial proportion of studies focuses on optimizing established therapeutic backbones, including targeted therapy, immunotherapy, chemotherapy, and their combinations. Other studies aim to develop novel targets or therapeutic platforms, such as KRAS G12C inhibitors, TROP2-directed antibody-drug conjugates, and DLL3-directed T cell engagers, while additional efforts are directed toward early-stage or perioperative treatment settings. Dedicated SCLC research remains a smaller but clinically important category, reflecting the persistent need for more effective therapeutic strategies in this aggressive disease. This classification was designed to capture current development trends in lung cancer therapy and was informed by major oncology guidelines and policy reports, including IQVIA Global Oncology Trends, CSCO/NCCN guidelines, the US National Cancer Plan, and the NCI Annual Plan and Professional Judgment Budget.^{61,70,71,75,76,77,78,79,80,81,82,83,84,85,86,87}

Within this broader trial landscape, FGFR-directed strategies remain less prominent than several approved or actively expanding therapeutic classes. However, the continued evaluation of FGFR-directed approaches suggests that FGFR signaling remains a biologically and therapeutically relevant axis that has not been fully resolved by current lung cancer treatment strategies. The limited scale of FGFR-related clinical development should therefore be interpreted in the context of the challenges discussed above, including low alteration frequency, molecular heterogeneity, uncertain prediction of FGFR dependency, and toxicity constraints. These barriers have slowed the clinical expansion of FGFR targeting and suggest that conventional alteration-driven or inhibitor-centered approaches may be insufficient to define the most appropriate therapeutic settings. Accordingly, ongoing FGFR-related development should be viewed as a selected but important therapeutic direction, with potential value in molecularly defined subgroups and ligand- or receptor-dependent signaling states that are not fully addressed by currently approved therapies.^5,7,88

FGFR-mediated bypass signaling as a resistance-associated therapeutic context

Although FGFR-directed strategies remain less established than other biomarker-guided approaches in lung cancer, ongoing clinical and translational efforts suggest that FGFR signaling may retain therapeutic relevance in selected contexts. In this regard, resistance-associated FGFR targeting represents one of the most clinically interpretable settings. Rather than functioning only as a primary alteration-defined driver, FGFR signaling can act as a compensatory bypass pathway that sustains tumor survival when another oncogenic pathway is pharmacologically inhibited.^41,52,89

In EGFR TKI-treated lung cancer, activation of alternative receptor tyrosine kinase pathways can maintain downstream signaling despite inhibition of the primary EGFR-driven axis. FGFR-mediated bypass signaling represents one such mechanism, in which FGFR activation can support PI3K-AKT and RAS-RAF-MEK-ERK signaling, thereby preserving tumor cell proliferation, migration, and survival. In this context, FGFR inhibition is not intended to treat all FGFR-altered lung cancers, but rather to intercept a resistance-associated signaling route that becomes functionally important under selective therapeutic pressure.^41,52,89

Figure 4 summarizes this concept. EGFR TKI treatment suppresses EGFR on-target signaling, but FGFR bypass signaling can maintain downstream PI3K-AKT and RAS-ERK pathway activity. Dual EGFR and FGFR blockade may therefore suppress both the primary driver pathway and the compensatory bypass route, reducing survival signaling and restoring therapeutic sensitivity in selected resistance contexts. This model illustrates how FGFR targeting may be most informative when applied according to treatment history, pathway dependency, and resistance state rather than FGFR alteration status alone.^41,52,90

Figure 4.

FGFR-mediated bypass signaling as a resistance-associated therapeutic context in EGFR TKI-treated lung cancer

EGFR inhibition can be bypassed by compensatory activation of FGFR signaling, allowing downstream PI3K/AKT and RAS/ERK pathway activity to persist despite EGFR blockade. This FGFR-mediated bypass signaling may support tumor cell proliferation, migration, and survival under EGFR TKI treatment. Combined inhibition of EGFR and FGFR may suppress both the primary EGFR pathway and the compensatory FGFR bypass axis, providing a rationale for resistance-guided therapeutic strategies. Created with BioRender.com.

In addition to resistance-informed bypass targeting, several clinical attempts suggest that FGFR-directed strategies are beginning to move beyond conventional single-agent kinase-domain inhibition. One example is combination-based targeting, such as sintilimab plus pemigatinib in PD-L1-positive, FGFR-mutated advanced NSCLC (NCT05004974). Another example is extracellular-level intervention using the FGF ligand trap GSK3052230/FP-1039, which was evaluated in combination with chemotherapy in FGFR1-amplified NSCLC (NCT01868022). Although these approaches remain investigational and have not established an approved FGFR-directed strategy in lung cancer, they indicate that FGFR is being clinically explored through alternative intervention points and combination-based designs rather than only through direct FGFR TKI monotherapy.^19,91

Taken together, these examples suggest that the limited clinical progress of FGFR-directed therapy in lung cancer should not be interpreted simply as evidence that FGFR lacks therapeutic value. Rather, it reflects the constraints of conventional alteration-centered and inhibitor-centered approaches. Given the biological importance of FGFR signaling and its continued investigation in selected lung cancer contexts, future clinical development may require more refined strategies that incorporate pathway dependency, intervention point, treatment history, and resistance-associated tumor state.

Discussion/future perspectives and challenges

The limited clinical progress of FGFR-directed therapy in lung cancer should not be interpreted as evidence that FGFR lacks therapeutic value. Rather, it reflects the limitations of conventional approaches that have primarily relied on alteration status, kinase-domain inhibition, and context-independent patient selection. FGFR alterations are relatively infrequent and biologically heterogeneous in lung cancer, and their presence alone does not necessarily define FGFR pathway dependency or therapeutic response. Therefore, the future value of FGFR targeting will depend on whether FGFR signaling can be interpreted within the specific tumor state in which it becomes functionally important.

FGFR should therefore be understood not as a uniformly actionable oncogenic alteration, but as a context-dependent signaling axis. This perspective is particularly important because FGFR may function differently across biological and treatment settings, including primary alteration-defined tumors, ligand- or receptor-dependent states, and acquired resistance contexts. The example of FGFR-mediated bypass signaling in EGFR TKI-treated lung cancer illustrates this broader principle: FGFR may acquire therapeutic relevance not only as an initiating driver, but also as an adaptive survival pathway under selective therapeutic pressure. Thus, the key issue is not simply whether FGFR can be inhibited, but whether FGFR dependency can be defined in the appropriate molecular, phenotypic, and treatment context.

Future FGFR-targeted strategies should therefore move beyond the simple expansion of additional FGFR inhibitors. Instead, future studies should refine how FGFR dependency is identified, how intervention points are selected, and how FGFR-directed therapy is integrated with resistance-informed or combination-based treatment strategies. This shift is especially important in lung cancer, where FGFR-directed clinical development remains limited and uneven across disease subtypes. Compared with NSCLC, where FGFR alterations and emerging therapeutic approaches have been more actively investigated, SCLC remains underexplored, with fewer clinical data and limited mechanistic evidence linking FGFR biology to therapeutic intervention. Therefore, future studies should avoid treating lung cancer as a single uniform disease context and should instead define FGFR relevance separately within NSCLC and SCLC according to their distinct molecular landscapes, lineage states, and therapeutic vulnerabilities.

Importantly, recent mechanistic and platform-based studies suggest that the way FGFR signaling is studied and therapeutically approached is beginning to change. FGFR activity is increasingly being examined beyond a simple ligand-receptor activation model, with growing attention to receptor clustering, intracellular trafficking, compartment-specific signaling, and post-translational regulation. In parallel, emerging therapeutic platforms, including degradation-based approaches such as PROTACs and glycan-targeting degraders, suggest that FGFR suppression may eventually extend beyond conventional ATP-competitive kinase blockade. Although these approaches remain largely preclinical or have not yet been fully translated into lung cancer clinical practice, they provide a conceptual basis for rethinking how FGFR activity can be measured, interpreted, and therapeutically controlled.^{92,93,94,95,96,97}

Conclusion

Taken together, FGFR should not be viewed as a failed or low-priority therapeutic target in lung cancer solely because of its low alteration frequency or limited success in prior trials. Instead, FGFR is better understood as a conditional therapeutic axis whose clinical relevance depends on tumor phenotype, pathway dependency, intervention point, and treatment-induced adaptive state. Reframing FGFR in this way may help bridge the gap between molecular detection, biological dependency, and clinically meaningful intervention, while also encouraging more focused investigation of FGFR biology in both NSCLC and the still underexplored SCLC setting.

Acknowledgments

This research was supported by the National Research Foundation of Korea (NRF) funded by the Korea Government (MSIT) (no. RS-2024-00335760), by the Global Learning and Academic Research Institution for Master’s, PhD Students, and Postdocs (LAMP) Program of the NRF funded by the Ministry of Education (no. RS-2023-00301914), and by the Post-Doc. Growth-type Research Support Program (S048789) of the NRF funded by the Korean Government (no. RS-2025-25437447).

Author contributions

B.C.K.: conceptualization, resources, data curation, formal analysis, validation, investigation, visualization, methodology, writing – original draft, and writing – review and editing; G.T.L.: methodology and writing – review and editing; M.J.: methodology, writing – review and editing; H.J.C.: methodology and writing – review and editing; K.-B.K.: conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, investigation, visualization, and methodology. All authors have read and agreed to the published version of the manuscript.

Declaration of interests

The authors declare no competing interests.

Declaration of generative AI and AI-assisted technologies in the writing process

The authors declare that no generative AI tools were used to generate scientific content or interpret data in this manuscript.