FGFR3-TACC3 fusion

Findings were validated in in vivo experiments. This study suggests that iPSC-derived CTLs targeting FGFR3-TACC3 hold promise for personalized immunotherapy against osteosarcoma.

Received 3 cycles of pembrolizumab and enfortumab vedotin...Treatment with Erdafitinib, gemcitabine and cisplatin resulted in a partial response...Pembrolizumab with gemcitabine and cisplatin was administered for 4 cycles, but the disease progressed with liver metastasis...Over one year he received many lines of treatment, including sorafenib, gemcitabine and cisplatin, , ramucirumab, nivolumab, and liposomal doxorubicin, lenvatinib durvalumab, and ramucirumab... In clinical practice, ctDNA or tumor NGS can detect rare and actionable FGFR3-TACC fusions in patients with advanced solid tumors that have progressed on standard therapy. Targeted therapy for such fusions can result in clinical benefit.

The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.

We developed an effective AI system for detecting phenotypes associated with FGFR3 abnormalities that may be targetable by FGFR inhibitors. This system may allow cost and time savings in comparison to existing assays to screen bladder carcinomas for additional diagnostic testing.

A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

Recent studies associated clear cell morphology with FGFR3-TACC3 fusion, suggesting that patients with this diagnosis may be potentially eligible for FGFR inhibitors. We described, for the first time, the pseudoangiosarcomatous pattern in a case of lung adenocarcinoma; to our knowledge this aspect has only been described until now in the context of squamous cell carcinomas.

Several FGFR inhibitors were tested in FGFR3-TACC3 fusion-positive gliomas and proved some efficacy, although inferior to the results seen in other FGFR3-TACC3 fusion-driven cancers. In this review, we summarize and discuss the state-of-the-art knowledge resulting from a 10-year research effort in the field, its clinical implications for glioma patients, the potential reasons for targeted therapy failures, and the perspective of emerging treatments.

Extended genomic profiling of his tumor at time of biopsy revealed a FGFR3-TACC3 fusion and MGMT promoter methylation, and the decision was made to pursue a single patient IND for anlotinib for use in combination with temozolomide. As first point of contact for the patient and family, the APP plays a key role in glioma research within the multidisciplinary team by providing ongoing symptom management, education, and monitoring for patients receiving investigational drugs.

Three patients recurred after first-line therapy: 1 with BRAF mutated GBM, 1 with GBM harboring FGFR3-TACC3 fusion, and 1 with NTRK1 fusion positive glioneuronal tumor received specific BRAF/MEK inhibitor (dabrafenib/trametinib), FGFR inhibitor (pemigatinib), and NTRK inhibitor (larotrectinib), respectively. The incidence of actionable molecular alterations in IDH wt gliomas and glioneuronal/neuronal tumors was low. However, the use of targeted therapies may lead to significant impact on the outcome.

FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. In our cohort, 100% of the patients with F3T3-positive glioblastomas also had an associated TERT promoter mutation. To our knowledge, this is one of the larger cohorts showing the association between FGFR3 and TERT promoter alterations in glioblastomas.

Catequentinib in combination with metronomic temozolomide was well tolerated in this single patient. This patient’s response shows the promise of intentional, patient-specific care at the intersection of molecular testing and rational drug design. The patient will continue therapy and updated clinical and radiographic outcomes will be presented.

FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. In our cohort, 100% of the patients with F3T3-positive glioblastomas also had an associated TERT promoter mutation. To our knowledge, this is one of the larger cohorts showing the association between FGFR3 and TERT promoter alterations in glioblastomas.

Conclusions According to the first stage results of the two-stage Simon's design, erdafitinib showed preliminary efficacy in NSCLC with FGFR translocations. Further molecular, pharmacological and clinical data are needed to evaluate the efficacy of FGFR inhibition in NSCLC, especially in pts with FGFR mutations.

Conclusions IDH wild-type glioblastomas have a poor prognosis. Identifying patients with FGFR3-TACC3 fusion can potentially provide a targeted treatment.

This ongoing study suggests cfDNA is a valuable minimally invasive adjunct to tissue-based assays for the detection of FGFR alterations to identify patients for FGFR inhibitor therapy and to monitor for mechanisms of resistance.

AMB302/GR1017 showed robust anti-tumor efficacies in F3-T3 fusion and FGFR3 overexpression models derived from GBM and BC in vitro and in vivo. In addition, AMB302/GR1017 was well tolerated with no adverse effects in rodent model. Our data suggest AMB302/GR1017 has a potential therapeutic option as a first-in-class FGFR3 targeting ADC for GBM, BC, and other solid tumors with FGFR3 overexpression or alterations.

These results demonstrate that clinically identified FGFR3-TACC3 fusion proteins differ in their biological activity, depending upon the specific breakpoint. This study further suggests the TACC3 dimerization domain of FGFR3-TACC3 as a novel target in treating FGFR translocation driven cancers.

Among gliomas with FGFR3::TACC3 fusion, age, TERT promoter mutation, pathological features, DNA-methylation profiling and fusion subtype are of interest to determine patients' risk.

Derazantinib showed signals of clinical activity in some patients with mUC and FGFR1-3 GA but the observed ORR and PFS did not meet contemporary benchmarks that would support further clinical development of derazantinib as monotherapy in this indication. Derazantinib showed a well-manageable safety profile with low rates of hand-foot syndrome, stomatitis, nail toxicity and retinal side effects. Clinical trial information: NCT04045613.

We demonstrated that glioblastomas with F3T3 fusion were peculiar molecular subgroup of IDH-wildtype glioblastoma with female preference and relatively located in subcortical region with well-demarcated. Curvilinear capillary proliferation is the most characteristic morphological feature and CDKN2A deletion was accompanied in half of the cases.

Histologic features correlate with FGFR alterations in IGs. FGFR3-TACC3 fusion and FGFR3 amplification are the most common FGFR alterations in IGs. FGFR alterations are a rare, but potentially viable, therapeutic target in asubset of IGs.

One patient received erdafitinib, a targeted FGFR inhibitor, for 3 months at late disease recurrence and no response was seen...However, further research is needed to examine whether IDH1/2-wild-type tumors with FGFR3-TACC3 fusion should be classified as a subtype on the basis of this molecular fusion. Because patients with IDH1/2-wild-type GBM with FGFR3-TACC3 fusion have improved survival, routine molecular testing for this mutation in patients enrolled in clinical trials and subsequent stratification may be warranted.

The subgroup of FGFR3-TACC3 fusion-positive glioblastomas presents with recurrent clinical and histomolecular characteristics, defining a distinctive subtype of IDH-wildtype glioblastoma. This review aims to provide an overview of the available literature on FGFR3-TACC3 fusions in glioblastoma and possible implications for actual clinical practice.

FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3‑TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.

Over 23% of FGFR2/3 fusions in aNSCLC may be associated with acquired resistance following treatment with EGFR TKIs. In this clinical scenario, a combination of EGFR TKIs and FGFR TKIs represents a promising treatment strategy.

No abstract available

We demonstrate that increased expression of pERBB3 is a key mechanism of adaptive resistance to FGFR inhibitors in FGFR3-fusion driven bladder cancers, and that this also occurs rapidly following FGFR inhibitor treatment. Our findings demonstrate that resistance can be overcome by combination treatment with a pan-ERBB inhibitor and suggest that upfront combination treatment with FGFR and pan-ERBB inhibitors warrants further investigation for FGFR3-fusion harbouring bladder cancers.

This novel cfRNA assay can detect actionable gene fusions and exon skipping events in liquid biopsies with high sensitivity. Combining cfRNA with more routine cfDNA testing can increase the total actionable diagnostic information from non-invasive testing in NSCLC patients where tissue samples are lacking, especially for gene fusions not amenable to detection in cfDNA.

Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment...HSP90 inhibitors sensitized F3-T3 glioma cells to TMZ via inhibition of F3-T3 activation and potentiated TMZ-induced DNA damage. These results demonstrate that F3-T3 oncogenic function is dependent on the HSP90 chaperone system and suggests a new clinical option for targeting this genetic aberration in cancer.

Conclusions : Infigratinib shows substantial activity in patients with localized UTUC bearing FGFR3 mutations, consistent with previous data in the metastatic setting. Enrollment continues, and based on these promising initial results, a phase 2 expansion evaluating additional cycles is planned.

The majority of the FGFR-positive tumors are low-grade CNS tumors. Further, the identification of FGFR alterations can significantly improve the tumor diagnosis and provide genomic evidence for potential targeted treatment with FGFR inhibitors.

There was a high level of analytical concordance in detection of FGFR alterations indicated for erdafitinib between the Qiagen companion diagnostic assay and 2 commercially available NGS platforms. >

Based on this unusual morphology, molecular analyses were performed and an FGFR3 exon17-TACC3 exon 10 fusion was found. The present case contributes to widening the morphologic spectrum of FGFR3-TACC3-fused GBM, IDHwt and emphasizes that pathologists, in the presence of a GBM, IDHwt with unconventional morphology, should promptly search for this fusion gene.

Increasing detection of gene fusions in glioma along with basket trials have helped define different fusion phenotypes and paved the way for targeted kinase inhibitor-based therapies. Targeting NTRK fusions has been the most successful fusion-guided therapy to date and evaluating all patients for these fusions may be warranted.

CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.