Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic
Camilla Zecchetto1,2, Alberto Quinzii1,2, Simona Casalino1,2
1Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, Italy.
Abstract:
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.
Insights
Fibroblast Growth Factor Receptor (FGFR) inhibition showed limited efficacy in patients with advanced esophagogastric cancer resistant to trastuzumab. This study did not support FGFR targeting in this patient population.
Area of Science:
- Oncology
- Gastrointestinal Oncology
- Molecular Targeted Therapy
Background:
- Trastuzumab plus chemotherapy is standard first-line treatment for HER2+ advanced esophagogastric (EG) cancer.
- Acquired resistance to trastuzumab is a significant clinical challenge in advanced EG cancer.
- Fibroblast Growth Factor Receptor (FGFR) 3 overexpression is a potential mechanism of trastuzumab resistance.
Purpose of the Study:
- To evaluate the efficacy of pemigatinib, an FGFR inhibitor, as a second-line treatment in patients with advanced EG cancer refractory to trastuzumab-containing therapies.
- To explore potential mechanisms of resistance and identify predictive biomarkers.
Main Methods:
- A Simon's two-stage, single-arm, phase 2 study.
- Patients received pemigatinib after progression on trastuzumab-based regimens.
- Primary endpoint: 12-week progression-free survival rate.
- Translational analyses included tissue and plasma sample assessments.
Main Results:
- The study was discontinued in the first stage due to futility.
- Only one of eight enrolled patients achieved stable disease at 12 weeks.
- FGFR3 was expressed in 2/6 evaluable tumors; no FGFR amplification was detected.
- HER2 amplification was lost in 3/8 patients; high Tumor Mutational Burden (TMB) was observed in 3 patients, with 2 long-term survivors.
Conclusions:
- Targeting FGFR with pemigatinib is not therapeutically effective in unselected patients with advanced EG cancer resistant to trastuzumab.
- Further research is needed to identify patient subgroups who might benefit from FGFR inhibition.
- Tumor mutational burden may warrant further investigation as a potential predictive factor.
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