Bemarituzumab With Modified Folfox6 For Advanced Fgfr2-Positive Gastroesophageal Cancer: Fight Phase Iii Study Design

Catenacci, Daniel V.T.; Tesfaye, Anteneh; Tejani, Mohamed; Cheung, Eric; Eisenberg, Peter D.; Scott, Aaron J.; Eng, Clarence; Hnatyszyn, James; Marina, Neyssa; Powers, Janine; Wainberg, Zev A.

doi:10.2217/fon-2019-0141

Cited by 60 publications

(58 citation statements)

References 45 publications

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“…FPA-114 (bemarituzumab, FivePrime) is currently being developed for solid tumours (NCT02318329) and gastric cancer (NCT03694522) with FGFR2 protein overexpression or FGFR2 gene amplification. 164 FP-1039 (FivePrime) is a soluble fusion protein consisting of the extracellular domain of FGFR1 linked to the Fc portion of human IgG1 able to inhibit FGFR1 ligands from binding to the receptor 165 which is currently under clinical development. 166 Anti-FGFR3 antibodies have also been developed for treatment of urothelial malignancies (Vofatamab (B-701, BioClin Therapeutics/Rainier Therapeutics) 167 ).…”

Section: Gene Transcriptionmentioning

confidence: 99%

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

Lamarca

Barriuso

McNamara

et al. 2020

Journal of Hepatology

275

221

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The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and-2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

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Section: Gene Transcriptionmentioning

confidence: 99%

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

Lamarca

Barriuso

McNamara

et al. 2020

Journal of Hepatology

275

221

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“…In this study, patients are being selected based on FGFR2-IIIb protein overexpression or FGFR2 genetic amplification. Encouragingly, in a preliminary dose-finding study with this antibody, 4/21 patients with FGFR2-IIIb overexpression (gene amplification or protein overexpression) presented partial response to treatment [42] (clinical trial #NCT02318329). This shows that other mechanisms triggering aberrant FGFR2 isoform expression in GC, may also be relevant for patient stratification.…”

Section: Introductionmentioning

confidence: 99%

Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

Teles

Oliveira

Ferreira

et al. 2019

Cancers

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Gastric Cancer (GC) is one of the most common and deadliest types of cancer in the world. To improve GC prognosis, increasing efforts are being made to develop new targeted therapies. Although FGFR2 genetic amplification and protein overexpression in GC have been targeted in clinical trials, so far no improvement in patient overall survival has been found. To address this issue, we studied genetic and epigenetic events affecting FGFR2 and its splicing regulator ESRP1 in GC that could be used as new therapeutic targets or predictive biomarkers. We performed copy number variation (CNV), DNA methylation, and RNA expression analyses of FGFR2/ESRP1 across several cohorts. We discovered that both genes were frequently amplified and demethylated in GC, resulting in increased ESRP1 expression and of a specific FGFR2 isoform: FGFR2-IIIb. We also showed that ESRP1 amplification in GC correlated with a significant decreased expression of FGFR2-IIIc, an alternative FGFR2 splicing isoform. Furthermore, when we performed a survival analysis, we observed that patients harboring diffuse-type tumors with low FGFR2-IIIc expression revealed a better overall survival than patients with FGFR2-IIIc high-expressing diffuse tumors. Our results encourage further studies on the role of ESRP1 in GC and support FGFR2-IIIc as a relevant biomarker in GC.

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“…Early safety data suggest that bemarituzumab combined with oxaliplatin, fluorouracil, and leucovorin (mFOLFOX6) is tolerable in patients with advanced-stage GI cancers, 39 and a randomized, placebo-controlled, phase III study of mFOLFOX6 with bemarituzumab in patients with newly diagnosed advanced-stage GEA, the FIGHT trial (ClinicalTrials.gov identifier: NCT03694522 ), initiated enrollment in September 2018. 40 …”

Section: Discussionmentioning

confidence: 99%

Phase I Escalation and Expansion Study of Bemarituzumab (FPA144) in Patients With Advanced Solid Tumors and FGFR2b-Selected Gastroesophageal Adenocarcinoma

Catenacci

Rasco

Lee

et al. 2020

JCO

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PURPOSE To evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA). PATIENTS AND METHODS FPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer. RESULTS Seventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of ≥ 10 mg/kg every 2 weeks for ≥ 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade ≥ 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response. CONCLUSION Overall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA.

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Bemarituzumab With Modified Folfox6 For Advanced Fgfr2-Positive Gastroesophageal Cancer: Fight Phase Iii Study Design

Cited by 60 publications

References 45 publications

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

Phase I Escalation and Expansion Study of Bemarituzumab (FPA144) in Patients With Advanced Solid Tumors and FGFR2b-Selected Gastroesophageal Adenocarcinoma

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