One of the hot targets in the pan-cancer therapy - FGFR

The following article is transferred from?Xiamen Spacegen.Co.,Ltd?（SpaceGen cancer research newsletter）

Background:

The FGFR (Fibroblast Growth Factor Receptor) family mainly comprises four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. Each subtype possesses a structural pattern consisting of an extracellular domain for ligand binding, a transmembrane domain, and an intracellular domain for receptor phosphorylation. These receptors are part of the tyrosine kinase signaling pathway responsible for cell proliferation and differentiation. Molecular alterations in FGFR can lead to aberrant FGF/FGFR signaling, promoting cell proliferation, angiogenesis, invasion, metastasis, and anti-apoptosis, which are associated with a wide range of human malignancies. The fusion and dysregulation of FGFR are closely related to the occurrence and development of various cancers. Currently, FGFR gene variations have been reported in more than ten malignant tumors, including cholangiocarcinoma, urothelial carcinoma (20%), breast cancer, lung cancer, hepatocellular carcinoma, and various solid tumors.

In January 2016, an article published in Clinical Cancer Research used next-generation sequencing technology to detect FGFR mutations in 4,853 patient samples from various cancers, including amplifications, mutations, and rearrangements. Among the sequenced samples, the study observed an overall incidence rate of FGFR mutations at 7.1%, with gene rearrangements being the least prevalent at 8% [1].

Up to this point, FGFR inhibitors can be categorized into three main types: tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and FGF ligand traps [2].

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1. Tyrosine Kinase Inhibitors (TKIs):

TKIs can be further classified into multi-target FGFR inhibitors and selective FGFR inhibitors. Selective FGFR TKIs are divided into three classes:

???a. Pan-FGFR inhibitors: These inhibitors effectively target FGFR1 to FGFR4 simultaneously.

???b. FGFR1-3 inhibitors: These inhibitors effectively target FGFR1 to FGFR3 but have weak inhibitory effects on FGFR4.

???c. FGFR4 inhibitors: These inhibitors have weaker selectivity against FGFR1 to FGFR3.

Erdafitinib?was the first FGFR inhibitor approved globally and was granted approval by the U.S. FDA in 2019 for the treatment of urothelial carcinoma. The results of the BLC2001 (NCT02365597) Phase II clinical trial showed promising outcomes in 99 patients with urothelial carcinoma harboring FGFR2/FGFR3 alterations. The overall response rate (ORR) was 40% (complete response [CR] 3%, partial response [PR] 37%), with a median progression-free survival (PFS) of 5.5 months and a median overall survival (OS) of 13.8 months. These positive results led to Erdafitinib becoming the first FDA-approved oral selective FGFR inhibitor.

?Following Erdafitinib, pemigatinib and infigratinib were subsequently approved for the treatment of cholangiocarcinoma, further fueling the research interest in FGFR TKIs. As FGFR is expressed in various cancer types, ongoing exploration of FGFR TKIs in different cancer types is continuously taking place.

The development of FGFR inhibitors represents a significant advancement in targeted cancer therapies, offering potential treatment options for patients with FGFR-altered cancers. As research in this area continues, the hope is that FGFR inhibitors will further improve outcomes and expand their applications across multiple cancer types.

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Exploration in Gastric Cancer

In the context of precision oncology, various new potential molecular pathways serve as novel targets for drug development in gastric cancer. One of these targets is the Fibroblast Growth Factor Receptor (FGFR). The figure below shows the anatomical distribution and relative incidence of subtypes from The Cancer Genome Atlas (TCGA) throughout the entire stomach. The table provides different molecular and clinical characteristics for each of the four subtypes.

?A multicenter, open-label, single-arm phase IIa study (NCT05019704) investigated the efficacy and safety of infigratinib in patients with advanced solid tumors who had previously received at least two lines of systemic therapy and harbored FGFR2 gene amplification. The study included patients with locally advanced or metastatic gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma with FGFR2 gene amplification, as well as other advanced solid tumors with other FGFR gene alterations.

The study results demonstrated that among the previously treated patients with locally advanced or metastatic gastric cancer or GEJ adenocarcinoma, and who carried FGFR2 gene amplification, the objective response rate (ORR) was 25.0% (n = 20), and the median duration of response (DOR) was 3.8 months [4].

These findings indicate that infigratinib showed a certain level of effectiveness in this specific group of patients with advanced gastric and gastroesophageal junction cancers who had FGFR2 gene amplification. However, it is important to note that this was a single-arm study, and further investigations, including randomized controlled trials, are needed to confirm the drug's efficacy and safety in a larger population of patients with similar genetic alterations.

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Exploration in Hematologic Tumors:

On August 26, 2022, the U.S. Food and Drug Administration (FDA) approved Pemazyre (pemigatinib) for the treatment of adult patients with relapsed or refractory myeloid and lymphoid neoplasms (MLNs) harboring FGFR1 gene rearrangements, based on data from the FIGHT-203 trial. The study included 28 patients with relapsed or refractory MLNs with FGFR1 rearrangements. Among the 18 patients with chronic myeloid phase with or without extramedullary disease (EMD), 14 achieved complete remission (CR) (78%), with a median time to CR of 104 days. Among the four patients with or without EMD in the bone marrow, two achieved CR, and among the three patients with EMD, one achieved CR. The overall complete cytogenetic response rate was 79%, including three patients without morphological evidence?[5].

Exploration in Pan-Cancer:

At the 2023 AACR (American Association for Cancer Research) Annual Meeting, data from the FIGHT-207 Phase II trial were presented, indicating that Pemazyre demonstrated efficacy and good tolerability in heavily treated patients with advanced/metastatic or unresectable solid tumors harboring FGFR mutations or fusions/rearrangements, including cholangiocarcinoma, central nervous system (CNS) tumors, gynecologic tumors, and pancreatic cancer. The study results showed that the objective response rate (ORR) for patients with FGFR fusions or rearrangements (n=49; Cohort A) was 26.5% (95% CI, 15.0%-41.1%), and the disease control rate (DCR) was 65.3% (95% CI, 50.4%-78.3%). For patients carrying actionable FGFR single nucleotide variants (SNVs) (n=32; Cohort B), the ORR was 9.4% (95% CI, 2.0%-25.0%), and the DCR was 56.3% (95% CI, 37.7%-73.6%). For patients with FGFR kinase domain mutations or mutations of uncertain significance (n=26; Cohort C), the ORR was 3.8% (95% CI, 0.1%-19.6%), and the DCR was 34.6% (95% CI, 17.2%-55.7%)?[6]. Thus, Pemazyre demonstrated broad anti-tumor activity across various cancer types.

Summary:

FGFR has been found to be involved in various processes of cancer development, making it a promising target for the "pan-cancer" treatment approach. Currently, multi-target FGFR inhibitors and three selective FGFR inhibitors (Erdafitinib, Pemigatinib, and Infigratinib) have received FDA approval, which is likely to drive the use of other selective FGFR inhibitors in clinical settings.

The clinical application of FGFR inhibitors faces three main challenges: the emergence of acquired resistance, patient selection, and systemic adverse reactions. To address acquired resistance, covalent inhibitors, anti-FGFR monoclonal antibodies, and FGF ligand traps are being developed, which may also reduce systemic adverse reactions. Combination therapy and the development of single compounds with dual targets are also potential solutions for acquired resistance?[2].

Precision medicine is currently a major focus in cancer treatment, and patient selection plays a critical role in cancer therapy. Next-generation sequencing (NGS) may help detect specific molecular defects in diagnosis and disease progression and aid in preselecting patient populations for clinical trials. Therefore, identifying appropriate biomarkers in patients to select the most suitable FGFR inhibitor for optimal efficacy is crucial.

References:

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

2. Advances in Targeted Therapy for FGFR in Cancer

3. Nat Rev Clin Oncol 2021 Aug;18(8):473-487

4. ClinicalTrials.gov Identifier: NCT05019794

5. FDA Official Website

6. 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT016

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