In the latest 2025V1 edition of the NCCN guidelines for non-small cell lung cancer, FGFR is identified as an emerging biomarker for the use of Erdafitinib in patients with metastatic NSCLC, targeting pathogenic or possibly pathogenic variants of the FGFR gene ^[1]. While the level of evidence proposed cannot be equated with star targets such as EGFR/ALK, it is evident that FGFR is advancing towards becoming a drug target for pan-cancer.

Figure 1. The Diagnosis and Treatment of Non-Small Cell Lung Cancer NCCN Guideline 2025V1

The fibroblast growth factor (FGF) signaling pathway plays a crucial role in numerous physiological processes, including embryo formation, wound repair, and angiogenesis. The fibroblast growth factor receptor (FGFR) is a receptor that binds to members of the FGF protein family. However, when FGFR is abnormally activated, it is closely associated with the development of tumors. Notably, variations in FGFR are significant.

Figure 2. Classical FGF/FGFR signaling pathway ^[2]

FGFR mainly includes several types of FGFR1-4, and their variation types include gene amplification, fusion, and mutation. In his research, foreign scholar Helsten T elaborated the variation frequency and main variation types of FGFR in common cancers^[3]. By testing NGS of 4853 cancer patients, we found that the overall variation frequency of FGFR was about 7%, and the variation of FGFR1 was more common than that of FGFR2-4 (Fig. 3).

Figure 3. Frequency of variation and proportion of variation by subtype in the overall population of FGFR

The majority of FGFR variations are gene amplifications, with gene point mutations and gene rearrangements being the least common. FGFR mutations are predominantly found in bladder cancer, cholangiocarcinoma, breast cancer, and central nervous system tumors, with each type of tumor exhibiting distinct mutation patterns. For instance, FGFR3 activation and mutation are prevalent in urothelial carcinoma, whereas FGFR2 gene fusion is more frequently observed in cholangiocarcinoma (Figure 4).

Fig. 4. Distribution of cancer and mutation types in population with FGFR mutation

In the study of 675 NSCLC patients, a significant difference was observed in the frequency of FGFR alterations between squamous cell carcinoma (N = 93) and adenocarcinoma (N = 408) (Figure 5), with the FGFR1 gene being amplified.

Figure 5. distribution of FGFR variation in non-small cell lung cancer

The following FGFR inhibitors have been approved for the treatment of solid tumors:

These drugs are primarily categorized into two groups: multi-kinase FGFR inhibitors and selective FGFR inhibitors. Erdafitinib and Futibatinib, for instance, are classified as pan-FGFR inhibitors, whereas Pemigatinib and Infigratinib fall under the FGFR1/2/3 inhibitors. They function by interacting with the ATP-binding site in the tyrosine kinase domain of FGFR, thereby obstructing aberrant signal transduction and fulfilling the goal of treating tumors. The objective response rate for patients with solid tumors who receive an approved FGFR inhibitor is roughly 20-40%, while the complete response rate for patients with FGFR1 rearrangement myeloma or lymphoma treated with Pemigatinib is 77%.

Outreach studies on marketed drugs

· Indication expansion: marketed FGFR inhibitors such as Pemigatinib and Erdafitinib are exploring for the treatment of more types of tumors. For example, Pemigatinib was used in addition to cholangiocarcinoma to study its efficacy in other solid tumors with FGFR2 variation.

· Coadministration studies: The use of FGFR inhibitors in combination with other anticancer agents to improve therapeutic efficacy. Such as the treatment of urothelial carcinoma with the combination of Erdafitinib and immune checkpoint inhibitor.

However, the application of FGFR inhibitors also faces a number of challenges. Among them, hyperphosphatemia is one of the common side effects, which will also limit the clinical benefits of these drugs due to resistance mutations in the FGFR gene, activation of bypass signaling pathways, changes in the TP53 gene, and subtype transformation related to epithelial-mesenchymal transformation.

Prospective data indicate that the activity of selective FGFR2 or FGFR3 inhibitors is not affected by tumor suppressor gene mutations and that these agents are unlikely to induce hyperphosphatemia; These more selective drugs are expected to form the third generation of FGFR inhibitors for cancer patients with FGFR2 /3 changes ^[4].

To overcome the limitations of existing FGFR inhibitors, researchers are actively developing new drugs:

l New small molecule inhibitor: Tinengotinib of TransThera published the latest research results on advanced pansolid tumors carrying FGFR1-3 mutation on the American Association for Cancer Research (AACR) in 2024. It has shown efficacy on a variety of cancers. The global multi-center registered Phase 3 clinical trial for cholangiocarcinoma was conducted in China, United States, Korea, Europe and other places.

l Antibody-coupled drug: BG-C137 for Injection of Baekje Shenzhou is an FGFR2b ADC drug, which was approved for clinical use in China in December 2024. Prior to that, a Phase 1a/b clinical study has been started in the United States, and it is intended to be developed for patients with advanced solid tumors.

l Other drugs under development, such as next-generation inhibitors such as Lirafugratinib and LOXO-435, and the FGFR2-specific antibody Bemarituzumab, are expected to reduce the risk of side effects and overcome the resistance mutations.

In conclusion, the mutation of FGFR gene is closely related to the occurrence and development of tumor. Although some achievements have been made against the mutant drugs, they still face many challenges. It is believed that with the deepening of research, more and more effective drugs will appear, bringing better treatment effect and quality of life for patients.

References:

1. NCCN Guidelines for Diagnosis and Treatment of Non-small Cell Lung Cancer 2025 v1

2. Signal Transduct Target Ther. 2020 Sep 2:5(1):181.

3. Clin Cancer Res. 2016 Jan 1; 22(1):259-67.

4. Nat Rev Clin Oncol. 2024 Apr; 21(4):312-329.