Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab.
Camilla ZecchettoAlberto QuinziiSimona CasalinoMarina GauleCamilla PesoniValeria MerzSilvia PietrobonoDomenico MangiameliMartina PasquatoStefano MilleriSimone GiacopuzziMaria BencivengaAnna TomezzoliGiovanni de ManzoniDavide MelisiPublished in: Journal of personalized medicine (2023)
Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon's two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.
Keyphrases
- end stage renal disease
- ejection fraction
- newly diagnosed
- healthcare
- papillary thyroid
- randomized controlled trial
- peritoneal dialysis
- squamous cell carcinoma
- clinical trial
- epidermal growth factor receptor
- prognostic factors
- cancer therapy
- risk assessment
- palliative care
- stem cells
- free survival
- squamous cell
- patient reported outcomes
- drug delivery
- smoking cessation
- nucleic acid
- lymph node metastasis
- binding protein
- radiation therapy
- mesenchymal stem cells
- human health
- risk factors