FGFR2 amplification

In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription-replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer.

P1/2, N=490, Active, not recruiting, Relay Therapeutics, Inc. | Trial completion date: Oct 2024 --> Aug 2025 | Trial primary completion date: Jun 2024 --> Sep 2024

P2, N=168, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jul 2024 --> Oct 2024

Further research and awareness is necessary to highlight the different types of ampullary cancer given the significant clinical implications. Figure: Image 1: (A) Endoscopic imaging of ampullary mass (B) EUS depicting ampullary mass

Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%...CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials...Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

P2, N=115, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

This study demonstrated that a subset of RHOA-mutant diffuse-type gastric cancers develops through the transformation of very well-differentiated adenocarcinoma of intestinal type. Our observations suggest a mixed mucin phenotype as a risk factor and alterations in p53 and E-cadherin as drivers of diffuse-type transformation.

Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active.

P1/2, N=540, Active, not recruiting, Relay Therapeutics, Inc. | Recruiting --> Active, not recruiting

Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations.

Moreover, compound (S)-23 exhibited favorable pharmacokinetic properties, low potential for drug-drug interactions, and very potent antitumor activity in MFE-296 xenograft mouse models with a TGI of 99.1% at the dose of 10 mg/kg. These findings demonstrate that compound (S)-23 is a potential therapeutic agent for FGFR mutant tumors.

our findings suggest that concurrent amplification of FGFR2 and MET in GC patients is associated with clinical aggressiveness and may contribute to non-responsiveness to chemotherapy or targeted therapy.

Among unresectable/recurrent GC population, EOCG has displayed distinct genetic profiles of GAs compared to LOGC. CGP tests may be useful in expanding treatment opportunities for patients with unresectable/recurrent EOGC.

Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

In heavily pretreated patients with metastatic TNBC harboring FGFR2 gene amplification, futibatinib monotherapy demonstrated modest anticancer activity. Futibatinib was tolerable and had an acceptable safety profile, consistent with previous data. Further biomarker work to identify patients who might benefit most from futibatinib is ongoing.

Triple FGFR1/2, CDK4/6 and ER blockade appears safe at standard drug dosages and shows promising clinical activity in second-line HR+ FGFR1/2+ BC patients progressing on CDK4/6i plus AI.

Evidence suggests that cfDNA analysis can provide accurate and reliable information on somatic genomic alterations in patients with GC, potentially replacing tissue biopsy as a diagnostic and prognostic tool. Through cfDNA analysis for molecular profiling, it may be possible to translate the molecular classification into therapeutic targets and predictive biomarkers, leading to personalized treatment options for patients with GC in the future.

We conclude the well-established MMTV-Myc mouse model presents further opportunities for investigation of human breast cancer heterogeneity.

Of the 12 patients with PIK3CA mutation detected in liquid and/or tissue, 8 were detected in both tissue and liquid, 2 detected in tissue alone and 2 detected in liquid alone. Conclusions Liquid-based NGS can be applied in clinical practice to identified clinically important mutations in Asian patients with recurrent breast cancer (BC) and de novo stage IV metastatic BC.

Conclusions In general, SHP099 can not only boost the tumor-cytotoxicity effect and overcome the drug resistance of AZD4547, but also activate cytotoxic T lymphocytes to kill tumor cells in FGFR2-alterated gastric cancers. Our results demonstrate the utility and feasibility of combining SHP2 to FGFR2 inhibitors for GC patients with FGFR2 alteration.

Given the rarity of status detection dMMR, a study in a larger number of patients is required, however, our data also confirm the presence of heterogeneity in dMMR status, and probably the possibility of metastasis of a more aggressive pMMR clone. Heterogeneity in PD-L1 is not rare and has practical significance.

No drug-induced death was reported. Conclusions Infigratinib in GC/GEJ patients with FGFR2 gene amplification has shown an inspiring clinical improvement, with acceptable tolerance, which is a potential first TKI regimen that precisely targeting in this population.

Conclusions The first ecDNA directed therapy, BBI-355, demonstrated significant anti-tumor activity as a single agent and in combination with targeted therapies in multiple ecDNA+ oncogene amplified tumor models. Clinical testing in patients with oncogene amplification is ongoing.

P2, N=168, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jun 2023 --> Jul 2024

P1, N=169, Recruiting, Abbisko Therapeutics Co, Ltd | Not yet recruiting --> Recruiting | Initiation date: Dec 2022 --> Jun 2023

Clone EPR24075-418 showed the best result in assessing the expression of FGFR2: the correlation with FISH results in reaction 3+ was 100%. Due to the high heterogeneity of FGFR2 expression, it is recommended to either examine the material of the primary tumor and metastasis, or evaluate a large volume of the primary tumor.

P2, N=115, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Oct 2023 --> Jun 2024 | Trial primary completion date: Apr 2023 --> Mar 2024

In MKN-45 subcutaneous xenografts, nintedanib, epirubicin, docetaxel and irinotecan reduced tumor growth (range: 68-87%), while 5-FU and oxaliplatin had a smaller effect (40%)...Nintedanib showed notable antitumor efficacy and significantly improved taxane or irinotecan chemotherapy responses. These findings indicate that nintedanib, alone and in combination with a taxane or irinotecan, has the potential for improving clinical GAC therapy.

P2; N=23; Recruiting; Sponsor:Kidney Cancer Research Bureau

Futibatinib demonstrated modest antitumor activity in heavily pretreated patients with advanced or metastatic gastric or GEJ cancer harboring FGFR2 amplification, with a predictable and manageable safety profile. No new safety signals were observed.

After 24 months of follow-up, patients with FGFR2b overexpression treated with bemarituzumab + mFOLFOX6 continued to show clinically meaningful outcomes over patients treated with placebo + mFOLFOX6; more pronounced efficacy was observed in patients with ≥10% of tumor cells with 2+/3+ FGFR2b IHC staining intensity. Randomized phase 3 trials focused on patients with ≥10% of tumor cells to confirm the observed clinical benefit of bemarituzumab are ongoing.

Greater clinical benefit was consistently observed with T-DXd vs TPC independent of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known CDK4/6i resistance marker status. Clinical trial information: NCT03734029. >aIncluded only pts with prior CDK4/6i and ≥1 gene alternation (CCND1, CCNE1, CDK6, FGFR1/2 amplification; RB1, PTEN, RAS, AKT1, ERBB2, FAT1 mutation).

Moreover, the key conformational intermediate states, dynamics, and driving forces of this transformation were uncovered. Overall, these findings not only provided a structural basis for understanding the closed P-loop conformation for therapeutic potential but also shed light on the design of selective inhibitors for treating specific types of cancer.

P2, N=168, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting

Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable antiproliferative activity in FGFR-aberrant cancer cell lines. In addition, the oral administration of 2e in the FGFR1-amplified H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models demonstrated potent antitumor efficacy, inducing tumor stasis or even tumor regression.

SB-PCCs may harbor RHOA mutations, which are reminiscent of the diffuse subtype of gastric cancers or appendiceal GCAs, while KRAS and PIK3CA mutations, commonly involved in colorectal and small bowel adenocarcinomas, are not typical of such cancers.

P2, N=168, Recruiting, Taiho Oncology, Inc. | Trial primary completion date: Dec 2022 --> Jun 2023

"FGFR2 is a validated target in GECs, and the contexture of FGFR2amp will be important to defining patient subgroups with responses to FGFR2-directed therapy. Here we define the FGFR2amp landscape which may help inform future combination strategies for this emerging biomarker. >"

Pairwise comparison of 4 tests based on the same patient population was performed: 3 IHC assays [Abcam clone EPR24075-418, R&D clone 98706, Santa Cruz clone C-8] and one FISH test... Among patients who were negative by FISH, 86%-93% of the patients were negative by IHC assay (Abcam). Among patients who were positive by FISH, 75-80% of them were positive by IHC. FISH should not be recommended as a substitute for a FGFR2 IHC assay due to high probability of false negative prediction as a result of intratumoral heterogeneity and low PCC.