Therapeutic Targeting of FGFR Signaling in Head and Neck Cancer

Abstract

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent cancer worldwide, with an annual incidence of 600,000 new cases. Despite of advances in surgery, chemotherapy, and radiotherapy, the overall survival for HNSCC patients hasn’t been significantly improved over the past several decades. FGF/FGFR genomic alterations are frequently detected in HNSCC, including amplification, activating mutation, and chromosomal rearrangement. Among them, FGFR1 amplification, FGF amplifications, and FGFR3 mutations are the most prevalent. In addition, FGF/FGFR expression has also been observed in the majority of HNSCC. However, the prognostic value of FGF/FGFR aberrations remains unclear, especially for gene amplification and overexpression. Nonetheless, FGF/FGFR has been a promising target for HNSCC treatment, and recent preclinical studies demonstrate the potential of the combination treatment regimens involving FGFR inhibitors on HNSCC. Therefore, there are a number of FGFR inhibitors currently in clinical trials for the treatment of head and neck cancers.

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent cancer worldwide, with a global incidence of over 600,000 new cases every year¹. HNSCC commonly arises from the squamous cells of the mucosal lining of oral cavity, oropharynx, larynx, and hypopharynx, accounting for 90% of the head and neck cancers (HNC)². HNC can also originate from the salivary glands, sinuses, and muscles or nerves in the head and neck region, but they are much less common than HNSCC³. The two classical risk factors for HNSCC are alcohol consumption and tobacco use, and in recent years, human papillomavirus (HPV) has also been recognized as a high-risk factor, especially for oropharyngeal SCCs (OPSCC)². In spite of the progress and advances in surgery, radiotherapy, and chemotherapy over the past several decades for the treatment of HNSCC, the overall survival rate for HNSCC hasn’t been significantly improved, with the five-year survival rate around 50% and over 300,000 deaths annually^1,4. Therefore, there is still a significant unmet need for the development of new therapies, including targeted therapies, immunotherapies, and combination therapies, for the treatment of HNSCC patients.

Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase (RTK) superfamily⁵ and consist of four family members (FGFR1–4)⁶. All FGFRs share a common construct composed of one extracellular domain, one single-pass transmembrane helix, and one intracellular tyrosine kinase domain⁷. The extracellular region of FGFRs contains three immunoglobulin-like domains responsible for the ligand binding⁷. FGFs, the corresponding growth factor ligands, can mediate a variety of cellular responses by binding to FGFRs with the cofactors, heparin sulfate or Klotho. FGF binding can cause the dimerization and autophosphorylation of FGFRs, which can lead to the activation of FGFR kinase, followed by the recruitment and activation of downstream cellular signaling pathways⁷. The four major signaling pathways controlled by FGFRs are RAS/RAF/ERK, PI3K/Akt, STATs, and PLCγ1 (Fig. 1). Therefore, FGFR signaling plays a critical role in various biological processes, including embryogenesis, organogenesis, tissue repair and wound healing, and tumor angiogenesis, etc⁷.

Figure 1. FGF/FGFR intracellular signaling transduction network.

FGF ligands and the cofactors, heparin sulfate (HS) or Klotho, will first bind to the immunoglobulin-like domains in the extracellular region of FGFRs, which will lead to FGFR dimerization and autophosphorylation. Tyrosine autophosphorylation sites of FGFR are indicated in red dots. FGFR autophosphorylation can activate FGFR kinase activity and recruit downstream signaling molecules. The four major signaling pathways that will be recruited and activated by FGFR are RAS/RAF/ERK (red), PI3K/AKT (light green), STAT1/3/5 (gray), and PLCγ1 (blue). The activation of PLCγ1 can cleave phospholipid phosphatidylinositol 4,5-biphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphote (IP₃), which can further activate PKC and intracellular Ca²⁺ signaling, respectively. I/II/III, immunoglobulin-like domain I/II/III.

FGFR genomic alterations have been implicated in ~7% of all human malignancies, including urothelial, breast, endometrial, lung, and ovarian cancer⁸. In particular, FGFR aberrations are one of the most frequent RTK genomic alterations in HNSCC⁹, making FGF/FGFR axis a promising target for the development of new treatment options for HNSCC patients. FGF/FGFR genomic alterations can be divided into ligand-dependent aberrations, which involves FGF genomic alterations, and ligand-independent aberrations that consist of FGFR aberrations¹⁰ (Fig. 2). FGFR gene amplifications, gain-of-function activating mutations, and chromosomal rearrangements/gene fusions are the three major classes of FGFR genomic alterations¹¹. In this review, we will summarize the recent studies of FGFR genomic alterations in HNSCC and the current progress in terms of the development of FGFR-oriented therapeutic strategies for HNSCC patients, including FGFR targeted therapies as monotherapies and in combination with other chemo-, radio-, target-, and immuno-therapies.

Figure 2. FGF/FGFR genomic alterations in HNSCC.

Ligand-dependent aberrations include FGF amplifications and mutations. Wild-type FGF ligands are indicated in blue spheres and FGFs with mutations are in dark red spheres. Ligand-independent aberrations consist of FGFR amplifications, mutations, and chromosomal rearrangements/gene fusions. Wild-type FGFRs are in red, FGFR mutations are indicated by orange stars, and gene fusion partners are in green and blue. The figure was created with BioRender.com.

FGFR genomic alterations in HNSCC

FGF/FGFR gene deregulation, including gene amplification, mutation, and chromosomal rearrangement, has been detected in ~30–50% HNSCC patients based on the genomic analysis of a The Cancer Genome Atlas (TCGA) HNSCC cohort^12,13. Among them, FGFR1 gene amplification, FGF3/4/19 gene amplifications, and FGFR3 mutations are the most frequent FGF/FGFR genomic alterations^9,12,13 (Table 1 and Fig. 2).

Table 1.

FGF/FGFR genomic alterations in HNSCC

Genes	Genomic alterations	Description	Frequency in HNSCC
FGF	Amplifications	FGF3, FGF4, FGF6, FGF19, FGF23	~20–25%
FGFR1	Amplification	Predominantly detected in HPV-negative HNSCC	~5–30%
	Mutations		~1.4%
FGFR2	Mutations	FGFR2 N549D, N549K; Predominantly detected in HPV-positive HNSCC	~4.3%-17.6%
FGFR3	Mutations	FGFR3 V50I, S131L, E157K, R248C, S249C, A393E, K413N, E629K, K650Q, R671G, G697C, D764H, D788N; Predominantly detected in HPV-positive HNSCC	~5.8–62%
	Fusions	FGFR3-TACC3; Predominantly detected in HPV-positive HNSCC	~2.5–3.7%
FGFR4	Mutations		~8%
	SNP	Can give rise to FGFR4 G388R	~33.8%

SNP, single nucleotide polymorphism.

FGF ligand amplification and overexpression

FGF2 is the most well-studied FGF ligand in HNSCC. FGF2 has been reported to be highly expressed in up to 60% of HNSCC tumor¹⁴. Multiple studies observed that FGF2 is over-expressed in HNSCC tumor and cell lines^15,16, and FGF2 overexpression is related to tumor aggressiveness and unfavorable prognosis^17,18, while other reports suggest that the a statistically significant enhancement of FGF2 expression in their studies is less clear¹⁹. Marshall and colleagues demonstrated that FGF2 are frequently co-expressed with FGFRs in the majority of HNSCC cell lines they tested, which can form an autocrine loop to drive oncogenesis²⁰. FGF2 and FGFRs are more highly expressed in early stages of HNSCC and well differentiated tumors^15–17, which indicates that FGFR signaling may play a role in early-stage tumor initiation and development. This is in consistent with the observation that most of the potentially malignant oral lesions that transformed into oral squamous cell carcinoma express FGF2 and FGFR2¹⁶. In addition to FGF2 overexpression, FGF2 single nucleotide polymorphism is also reported to be associated with overall survival of the HNSCC patients treated by chemoradiotherapy¹⁸. Other than FGF2, gene amplifications of FGF3, FGF4, and FGF19 have also been detected in more than 20% of HNSCC patients in one TCGA cohort¹². FGF19 mainly signals through FGFR4 and FGF19 amplification and overexpression is related to poor prognosis for HNSCC patients²¹.

FGFR1 amplification and overexpression

FGFR1 gene amplification is one of the most frequent FGF/FGFR genomic alterations in HNSCC, which has been reported in ~5–30% HNSCC patients^13,22,23. FGFR1 gene amplification is predominantly detected in HPV-negative HNSCC patients^22,24,25 and is more prevalent in laryngeal (LPSCC) and hypopharyngeal squamous cell carcinoma (HPSCC)^26,27, which is consistent with the fact that HPV mainly affect oropharyngeal squamous cell carcinoma (OPSCC), rather than LPSCC and HPSCC⁴. In addition, FGFR1 and FGFR3 amplifications have also been observed in some rare HNSCC, such as external auditory canal SCC²⁸. The prognostic value of FGFR1 amplification in HNSCC is debatable, and recently, more studies reported that FGFR1 amplification is not related to patient overall survival^29,30. One of the plausible explanations is that FGFR1 amplification is not associated with FGFR1 expression level^25,30. On the other hand, FGFR1 overexpression has been observed in ~10–82% of HNSCC patients^26,31,32 and there is no difference in FGFR1 expression between HPV-positive and HPV-negative HNSCC patients²⁵. However, at present, conflicting results in terms of FGFR1 expression as a prognosis biomarker have been reported. Multiple studies demonstrated that FGFR1 overexpression is related to poor prognosis in HPV-negative HNSCC patients^31,33,34, whereas others suggest the contrary^26,29,35. The perceived discrepancy may be attributed to a number of factors including: the difference in the cutoff value for FGFR1 expression, various anatomic positions of HNSCC, different sample size, and distinct patient ethnicities from different studies. In line with this suggestion, Fisher and colleagues reported that the sensitivity of AZD4547, a selective FGFR inhibitor, is not associated with FGFR expression level in a panel of ten HNSCC cell lines they examined, including both HPV-positive and HPV-negative cells³². Therefore, the prognostic value of FGFR1 amplification and overexpression should be further examined in a larger patient cohort and stratified based on HPV status and anatomic positions, etc. Additionally, other than gene amplification, FGFR1 mutations are also detected in ~1.4% HNSCC patients³⁶.

FGFR2 mutations and overexpression

Genomic alterations in FGFR2 are less prevalent than FGFR1 and FGFR3 in HNSCC. FGFR2 mutations, such as FGFR2 N549D and N549K, have been detected in ~4.3%-17.6% HNSCC patients^13,36,37 (Table 1 and Fig. 2). Unlike FGFR1 gene amplification, FGFR2 mutations are mainly enriched in HPV-positive HNSCC patients³⁷. In addition, FGFR2 is more expressed in HNSCC tumor tissue than normal epithelium^16,19 and the majority of HNSCC expresses FGFR2³².

FGFR3 mutations and fusions

FGFR3 mutations have been implicated in ~5.8–24% of HNSCC patients^36,38,39 (Table 1 and Fig. 2), and FGFR3 S249C is the most prevalent gain-of-function mutation^37,40. Of note, FGFR3 G649C, which is a constitutively activating mutation in FGFR3 kinase domain, was also reported in 62% (44/71) of one Japanese HNSCC cohort⁴¹. In addition, FGFR3-TACC3 fusion is also reported in ~2.5–3.7% of HNSCC patients^24,42. Intriguingly, different HNSCC patients may have distinct breakpoints for FGFR3-TACC3 fusion⁴², which may affect the tumorigenic abilities of the FGFR3-TACC3 fusions⁴³. FGFR3-TACC3 is considered as a constitutively activated oncogene and has also been detected in other cancers, including bladder cancer⁴⁴ and glioblastoma⁴⁵. Similar to FGFR2 mutations, FGFR3 mutations and fusions are also primarily detected in HPV-positive HNSCC²⁵ and FGFR3 mutations are usually associated with worse 3-year disease-free survival³⁹. Furthermore, a number of studies reported that FGFR3 is over-expressed in HNSCC tumor tissue as compared with the non-cancerous control tissue^16,19. However, contrary to these results, other studies by Mässenhausen and colleagues suggest that FGFR3 is more highly expressed in normal mucosa, compared to the HNSCC primary tumor, and FGFR3 expression further decreased as tumor progressed⁴⁶. And in accordance with FGFR1 overexpression, the prognostic value of FGFR3 overexpression is also contradictive and there has been accumulating evidence showing that FGFR3 expression is not related to patient overall survival^32,33,47.

FGFR4 genomic alterations and overexpression

FGFR4 is much less studied than other FGFRs in HNSCC. FGFR4 is highly expressed in 16–39% of HNSCC patients³⁵, and FGFR4 overexpression has been reported to be associated with poorer overall survival of HNSCC patients in several studies^48,49. In addition, one of the FGFR4 single nucleotide polymorphisms that gives rise to the FGFR4 G388R mutation is demonstrated to be associated with advanced HNSCC tumor stages and reduced disease-free survival⁴⁸. Furthermore, FGFR4 mutations are also observed in ~8% of HNSCC patients based on the analysis from one of the TCGA HNSCC cohorts¹³.

Current progress in the development of FGF/FGFR-oriented therapies for HNSCC

Due to the prevalence of FGF/FGFR genomic alterations and overexpression in HNSCC, FGF/FGFR axis has been a promising target for the treatment of HNSCC patients. Constitutively activated aberrations, such as gain-of-function mutations and chromosomal rearrangements, are usually regarded as driver mutations for oncogenesis, and the effects of FGFR inhibitors on the tumors with those constitutively activated FGFR genomic aberrations have been extensively demonstrated both preclinically and clinically^50–52. However, the sensitivity of FGFR inhibitors varies dramatically among the HNSCC with wild-type FGF/FGFR overexpression and/or FGFR amplifications^32,53. Therefore, recent studies have been primarily focusing on the development of new combination treatments that concatenate FGFR inhibitors with chemo-, radio-, immuno-, and/or other targeted therapies.

FGFR inhibitors and chemotherapies

Surgery, chemotherapy, and radiation are the three typical standard-of-care strategies for treatment of HNSCC patients. Aytatli and colleagues indicated that the activation of FGFR/Akt/SOX2 signaling pathway is upregulated in taxol-resistant HNSCC cell lines and AZD4547 can potentiate the anti-tumor effects of taxol and cisplatin in those cell lines⁵⁴. SOX2 is SRY-Box transcription factor 2, which is essential for the maintenance of the stem cell features in tumors⁵⁵. Consistent with this finding, McDermott and colleagues found FGF2 expression is increased in head and neck cancer stem cells after cisplatin treatment⁵⁶, suggesting that FGF/FGFR signaling may play a role in the resistance of HNSCC to cisplatin. Likewise, Holzhauser and colleagues revealed that Erdafitinib (JNJ-42756493), another selective FGFR inhibitor, can be synergistic or additive with cisplatin and docetaxel in most of the tonsillar (TSCC) and base of tongue (BOTSCC) squamous cell carcinoma cell lines they tested, regardless of FGFR mutation status⁵⁷.

FGFR inhibitors and radiotherapies

Ishigami and colleagues performed microarray analysis and found that FGFR3 is overexpressed in oral squamous cell carcinoma (OSCC) cell lines that are resistant to radiation therapy, compared to radiosensitive OSCC cell lines⁵⁸. When FGFR3 is knocked down by siRNA or inhibited by selective FGFR inhibitors, radiosensitivity can be induced in the radioresistant cell lines⁵⁹. And consistent with that observation, multiple studies have reported that AZD4547 can also augment the response to radiotherapy of HNSCC both in vitro and in vivo, by inducing apoptosis and potentially inhibiting mTOR signaling pathway^32,53. However, this AZD4547-mediated radio-sensitization is limited to only the HNSCC cell lines that are sensitive to AZD4547 monotherapy, and the cell lines that are not responsive to AZD4547 cannot exhibit radio-sensitization³².

FGFR inhibitors and other targeted therapies

There has been accumulating evidence indicating that FGFR expression level is not related to FGFR inhibitor sensitivity in HNSCC with wild-type FGFR overexpression and/or FGFR amplifications^32,53. One of the possible explanations is that wild-type FGFR overexpression is not the only driver factor for HNSCC oncogenesis and the activation of other alternative signaling pathways can lead to the resistance to FGFR inhibition, which is a common mechanism for the resistance of targeted therapies in cancer⁶⁰. This idea is verified by the study showing that some HNSCC cell lines can rely on multiple RTKs for full growth and survival, including FGFRs, ERBB family, and MET⁶¹. And inhibiting all of those RTKs simultaneously can achieve synergistic effects in those cell lines⁶¹. Likewise, FGF/FGFR genomic alterations and overexpression may also cause the resistance to other targeted therapies. Gyanchandani and colleagues revealed that FGF2 and FGFR3 expression can be upregulated after long-term treatment of bevacizumab, a VEGF-A monoclonal antibody, which can mediate the resistance to bevacizumab⁶². Combination treatment of bevacizumab with a selective FGFR inhibitor, PD-173074, can sensitize the HNSCC tumor to bevacizumab in vivo. Similarly, it has also been reported that upregulation of FGF2 expression and FGFR3 phosphorylation after selumetinib treatment, a MEK inhibitor, can mediate the resistance to selumetinib⁶³. In addition, high throughput screening identified that FGFR inhibitors and EGFR inhibitors can achieve synergistic effects both in HNSCC cell lines and xenografts⁶⁴. This is further validated by Koole and colleagues who demonstrated that EGFR signaling can mediate the AZD4547 resistance in some HNSCC cell lines and AZD4547 and gefitinib can synergistically inhibit the proliferation of those cell lines³¹. Furthermore, Kumar and colleagues confirmed that the secretion of HGF and FGF2 by cancer-associated fibroblast (CAF) and HNSCC tumor, respectively, can mediate the interaction between HNSCC tumor and CAF⁶⁵. In line with this finding, FGFR inhibitors and MET inhibitors can achieve additive inhibitory effects on HNSCC growth both in vitro and in vivo.

In addition to co-targeting FGFR with other RTKs, the combination between FGFR inhibitors and inhibitors for other kinases has also been explored. Singleton and colleagues performed a kinome RNAi screen and identified that FGFR inhibitors and mTOR inhibitors can achieve synergism in HNSCC cell lines regardless of FGFR mutations⁶⁶. Similar to this, PI3K inhibitors have also been reported to be synergistic or additive with FGFR inhibitors in TSCC/BOTSCC cell lines disregarding FGFR and PI3K mutation status⁵⁷.

FGFR inhibitors and immunotherapies

Immunotherapy has opened a new era for cancer treatment over the past decades. FDA approved two PD-1 monoclonal antibodies, pembrolizumab and nivolumab, for the treatment of HNSCC⁶⁷. However, only a small portion of HNSCC patients (~10–20%) can benefit from immune checkpoint inhibitors⁶⁸. The combinatorial effects between FGFR inhibitors and immunotherapies have been more extensively investigated in other cancers, including breast⁶⁹, lung⁷⁰, and bladder cancers⁷¹, whereas studies of such combination are still very limited in HNSCC. Kono and colleagues demonstrated that PD-173074 and anti-PD-1 antibodies showed synergistic anti-tumor effects in HNSCC xenografts, and FGFR inhibitors can recruit CD4+ and CD8+ T cells to the tumor environment⁷². Furthermore, they also revealed that FGFR inhibitors can upregulate the expression of MHC class I and MHC class II both in vitro and in vivo by inhibiting MAPK signaling pathway⁷².

FGFR inhibitors and tumor microenvironment

Tumor microenvironment is essential for the regulation of tumor initiation, progression, metastasis, and drug sensitivity⁷³. It has been reported that FGF2 and FGFR1 expression in the fibroblasts of OSCC is related to tumor metastasis and poor prognosis⁷⁴. And consistent with that observation, in vitro studies showed that co-culturing with fibroblasts can enhance the proliferation of HNSCC cell lines⁷⁵. Furthermore, this fibroblast-enhanced tumor growth can also be suppressed by PD-174074 in vivo through FGFR inhibition, which can lead to stromal component shrinkage, decreased proliferation, and increased apoptosis⁷⁵.

Current FGFR inhibitors in clinical trials

Based on the progress and results from preclinical studies, FGFR inhibitors show substantial potential for treatment of HNSCC patients. In fact, one HNSCC patient with gene amplifications of multiple FGFs, including FGF3, FGF4, FGF6, FGF19, and FGF23, achieved a complete response to a FGFR inhibitor⁷⁶. In addition, another head and neck cancer patient with FGF3 and FGF19 amplifications achieved stable disease for 4 months after ponatinib treatment, a multi-target FGFR inhibitor⁷⁷. In two phase I clinical trials of rogaratinib, out of 10 HNSCC patients who received rogaratinib, two patients achieved partial response and four patients showed stable disease^51,52, indicating the efficacy of FGFR inhibitors in HNSCC patients. Furthermore, 1 out of 9 head and neck cancer patients achieved partial response in a phase I clinical trial of pemigatinib⁷⁸. However, the patient with the partial response did not possess any known FGF/FGFR aberrations⁷⁸ and the underlying mechanism(s) of the response still needs to be further explored. In addition, anlotinib is another multi-target FGFR inhibitor that targets at FGFR, VEGFR, PDGFR, and c-Kit. One phase II clinical trial of anlotinib on recurrent or metastatic nasopharyngeal carcinoma patients revealed that out of 39 enrolled patients, 8 patients achieved partial response and 20 patients reached stable disease⁷⁹.

Therefore, there are several FGFR inhibitors currently in clinical trials for treatment of head and neck cancers (Table 2), including [225Ac]-FPI-1966, nintedanib, dovitinib, anlotinib, ICP-192, and AZD4547. [225Ac]-FPI-1966 is a FGFR targeted alpha therapeutic that conjugate vofatamab, a FGFR3 monoclonal antibody, with actinium-225, an alpha particle emitting radionuclide. Nintedanib and dovitinib are both multi-target FGFR inhibitors. Nintedanib can target at FGFR, VEGFR, and PDGFR, and dovitinib can inhibit FGFR, VEGFR, c-Kit, and Flt3. ICP-192 is an irreversible selective FGFR inhibitor that can covalently bind to FGFR. Anlotinib is now currently examined in phase II clinical trials as a part of combination therapies. Anlotinib and chemoradiation are currently tested on locally advanced nasopharyngeal carcinoma patients, and the combination of anlotinib and PD-1 monoclonal antibody are investigated on advanced head and neck cancer. In addition, lenvatinib, a multi-target FGFR inhibitor that targets at FGFR, VEGFR, PDGFR, c-Kit, and RET, is currently in clinical trials for the treatment of adenoid cystic carcinomas of the salivary glands⁸⁰ (Table 2).

Table 2.

Representative clinical trials of FGFR inhibitors for head and neck cancers

Inhibitors	Inhibitor types	ClinicalTrials.gov ID	Phase	Conditions or diseases	Status
Lenvatinib	Multi-kinase FGFR inhibitor (FGFR, VEGFR, PDGFR, c-Kit, RET)	NCT02860936	2	Adenoid Cystic Carcinomas of the Salivary Glands	Completed
Nintedanib	Multi-kinase FGFR inhibitor (FGFR, VEGFR, PDGFR)	NCT03292250	2	HNSCC	Completed
Dovitinib	Multi-kinase FGFR inhibitor (FGFR, VEGFR, c-Kit, Flt3)	NCT01831726	2	Hematologic malignancies and/or solid tumors, including head and neck cancers	Completed
ICP-192	Selective FGFR inhibitor	NCT03758664	1/2	Solid tumors, including head and neck cancers	Recruiting
AZD4547	Selective FGFR inhibitor	NCT02465060	2	Lymphomas, multiple myeloma, and advanced malignant solid neoplasm, including head and neck carcinoma	Recruiting
Rogaratinib	Selective FGFR inhibitor	NCT01976741	1	Refractory, locally advanced or metastatic solid tumors, including head and neck cancer	Completed
[225Ac]-FPI-1966	FGFR targeted alpha therapeutics	NCT05363605	1/2	Advanced solid tumors, including head and neck squamous cell carcinoma	Recruiting
Anlotinib + Chemoradiation	Anlotinib (FGFR, VEGFR, PDGFR, c-Kit inhibitor)	NCT05232552	2	Locally advanced nasopharyngeal carcinoma	Recruiting
Anlotinib + Penpulimab	Anlotinib (FGFR, VEGFR, PDGFR, c-Kit inhibitor), Penpulimab (PD-1 monoclonal antibody)	NCT04203719	2	Advanced head, neck and chest cancers	Unknown

Besides the clinical trials that include HNC patients, there are a number of clinical trials of FGFR inhibitors on solid tumors (Table 3), which do not necessarily include HNC patients but can be applied for the treatment of HNC in future studies. These clinical trials include multi-target FGFR inhibitors (lucitanib, 3D185, sulfatinib, MAX-40279–01, TT-00420, and regorafenib), selective FGFR inhibitors (erdafitinib, HMPL-453, futibatinib, KIN-3248, infigratinib, ASP-5878, LY2874455, CPL304110, pemigatinib, and E7090), monoclonal antibodies (Bemarituzumab and BAY1179470), antibody-drug conjugates (LY3076226), FGF ligand traps (GSK3052230), and combination treatments (FGFR inhibitors with PI3K inhibitors, mTOR inhibitors, chemotherapy, or immunotherapy).

Table 3.

Representative clinical trials of FGFR inhibitors for solid tumors

Inhibitors	Inhibitor types	ClinicalTrials.gov ID	Phase	Conditions or diseases	Status
Lucitanib	Multi-kinase FGFR inhibitor (FGFR, VEGFR, PDGFR)	NCT01283945	1/2	Solid Tumors	Completed
3D185	Multi-kinase FGFR inhibitor (FGFR, CSF1R)	NCT04221204	1	Solid tumors	Recruiting
Sulfatinib	Multi-kinase FGFR inhibitor (FGFR, VEGFR, CSF1R)	NCT02133157	1	Tumors	Completed
MAX-40279–01	Multi-kinase FGFR inhibitor (FGFR, Flt3)	NCT05369286	1	Solid tumors	Recruiting
TT-00420	Multi-kinase FGFR inhibitor (FGFR, VEGFR, Aurora Kinases, JAK)	NCT04742959	1/2	Advanced solid tumors	Recruiting
Regorafenib	Multi-kinase FGFR inhibitor (RET, VEGFR, c-KIT, PDGFR, FGFR, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, SAPK2, PTK5, Abl)	NCT04116541	2	Malignant solid tumors	Recruiting
Erdafitinib	Selective FGFR inhibitor	NCT04083976	2	Advanced solid tumors	Recruiting
HMPL-453	Selective FGFR inhibitor	NCT05173142	1/2	Solid tumors	Recruiting
Pemigatinib	Selective FGFR inhibitor	NCT04591431	2	Progressive diseases of breast cancer, metastatic gastrointestinal tumors, non-small cell lung cancer or others	Recruiting
Futibatinib	Selective FGFR inhibitor	NCT04189445	2	Advanced or metastatic solid tumors	Recruiting
KIN-3248	Selective FGFR inhibitor	NCT05242822	1	Solid tumors	Recruiting
Infigratinib	Selective FGFR inhibitor	NCT04233567	2	Advanced or metastatic solid tumors	Recruiting
ASP-5878	Selective FGFR inhibitor	NCT02038673	1	Solid tumors	Completed
LY2874455	Selective FGFR inhibitor	NCT01212107	1	Advanced cancer	Completed
CPL304110	Selective FGFR inhibitor	NCT04149691	1	Advanced solid malignancies	Recruiting
E7090	Selective FGFR inhibitor	NCT04962867	2	Advanced or recurrent solid tumors	Recruiting
Bemarituzumab	Monoclonal antibody	NCT05325866	1	Solid tumors	Not yet recruiting
BAY1179470	Monoclonal antibody	NCT01881217	1	Advanced, refractory solid tumors	Completed
LY3076226	Antibody-drug conjugate	NCT02529553	1	Advanced or metastatic cancer	Completed
GSK3052230	FGF ligand trap	NCT01868022	1	Neoplasms	Completed
EVER4010001 + Pembrolizuman	EVER4010001 (FGFR4 inhibitor), Pembrolizuman (PD-1 inhibitor)	NCT04699643	1/2	Advanced solid tumors	Recruiting
Infigratinib + BYL719	Infigratinib (selective FGFR inhibitor), BYL719 (PIK3K inhibitor)	NCT01928459	1	Advanced or metastatic solid tumors	Completed
Nintedanib + Pembrolizumab	Nintedanib (FGFR, VEGFR, PDGFR inhibitor), Pembrolizumab (PD-1 inhibitor)	NCT02856425	1	Advanced solid tumors	Recruiting
Surufatinib + Gemcitabine	Surufatinib (FGFR, VEGFR, CSF1R inhibitor), Gemcitabine (Chemotherapy)	NCT05093322	1/2	Recurrent or refractory solid tumors or lymphoma	Recruiting
Nintedanib + Everolimus	Nintedanib (FGFR, VEGFR, PDGFR inhibitor), Everolimus (mTOR inhibitor)	NCT01349296	1	Solid tumors	Completed

Future perspective

Due to the prevalence of FGF/FGFR genomic alterations and overexpression in HNSCC, FGF/FGFR has been a potential target for the treatment of HNSCC. However, the prognostic value of FGF/FGFR aberrations, especially gene amplification and overexpression, are still unclear. The prognosis of HNSCC patients with FGF/FGFR alterations should be examined in a larger sample size, and patients might need to be stratified based on HPV status, patient ethnicity, genomic alterations, and HNSCC anatomic positions. In addition, even though FGF/FGFR overexpression has been detected in the majority of the HNSCC patients, the sensitivity to FGFR inhibitor varies dramatically in the HNSCC with wild-type FGF/FGFR overexpression. Therefore, the underlying molecular mechanism(s) of this variation needs further study. This mechanistic information will provide a better understanding of the molecular features of HNSCC expressing FGF/FGFR and can also contribute to the future development of better FGFR targeted therapies. Other than developing more potent FGFR inhibitors with less side effects, combination treatment is another promising strategy for the future development of FGFR-oriented therapies. In particular, combining FGFR inhibitors with chemo-, radio-, immuno-, and/or other targeted therapies has already demonstrated considerable potential in preclinical studies, which can be further explored and tested in clinical trials.

Summary

FGF/FGFR genomic alterations, including gene amplification, gain-of-function mutation, and chromosomal rearrangement, are one of the most prevalent RTK aberrations in HNSCC. FGFR1 gene amplification, FGF gene amplifications, and FGFR3 mutations are among the most frequent aberrations in HNSCC patients. In addition, FGF/FGFR expression has also been observed in the majority of HNSCC. However, the prognostic value of FGF/FGFR aberrations remains obscure, especially for gene amplification and overexpression. Thus, proper biomarkers which can distinguish HNSCC patients that may benefit from FGFR inhibitors are still urgently needed. Nevertheless, FGF/FGFR demonstrates substantial potential as a target for the treatment of HNSCC. Recent studies in terms of the development of FGFR-oriented therapies for HNSCC have been focusing on combination strategies. Particularly, FGFR inhibitors combined with chemo-, radio-, immuno-, and/or other targeted therapies have already shown considerable efficacy and potency for the treatment of HNSCC in preclinical studies. Therefore, a number of FGFR inhibitors are currently in clinical trials, including multi-target FGFR inhibitors, selective FGFR inhibitors, FGFR targeted alpha therapeutics, monoclonal antibodies, antibody-drug conjugates, FGF ligand traps, and several combination treatments involving FGFR inhibitors.