Abstract CT326: Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors

Sequist, Lecia V.; Cassier, P. A.; Varga, Andréa; Tabernero, Josep; Schellens, Jan H.M.; Delord, Jean‐Pierre; LoRusso, Patricia; Camidge, D. Ross; Medina, Manuel Hidalgo; Schüler, Martin; Campone, Mario; Tian, G. Gary; Wong, Steven; Corral, J.; Isaacs, Randi; Sen, Suman; Porta, Diana Graus; Kulkarni, Swarupa G.; Lefèbvre, Caroline; Wolf, Jürgen

doi:10.1158/1538-7445.am2014-ct326

Cited by 71 publications

(46 citation statements)

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“…For example, preliminary analysis of a phase I trial of BGJ398, a potent, selective pan-FGFR inhibitor, showed tumor regression in four of five patients with urothelial carcinomas with FGFR3-activating mutations (with tumor reductions ranging from 27% to 48%; ref. 44).…”

Section: Discussionmentioning

confidence: 99%

The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing

Helsten

Elkin²,

Arthur

et al. 2016

Clinical Cancer Research

596

612

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Purpose: Molecular profiling may have prognostic and predictive value, and is increasingly used in the clinical setting. There are more than a dozen fibroblast growth factor receptor (FGFR) inhibitors in development. Optimal therapeutic application of FGFR inhibitors requires knowledge of the rates and types of FGFR aberrations in a variety of cancer types.Experimental Design: We analyzed frequencies of FGFR aberrations in 4,853 solid tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One.Results: FGFR aberrations were found in 7.1% of cancers, with the majority being gene amplification (66% of the aberrations), followed by mutations (26%) and rearrangements (8%). FGFR1 (mostly amplification) was affected in 3.5% of 4,853 patients; FGFR2 in 1.5%; FGFR3 in 2.0%; and FGFR4 in 0.5%. Almost every type of malignancy examined showed some patients with FGFR aberrations, but the cancers most commonly affected were urothelial (32% FGFR-aberrant); breast (18%); endometrial ($13%), squamous lung cancers ($13%), and ovarian cancer ($9%). Among 35 unique FGFR mutations seen in this dataset, all but two are found in COSMIC. Seventeen of the 35 are known to be activating, and 11 are transforming.Conclusions: FGFR aberrations are common in a wide variety of cancers, with the majority being gene amplifications or activating mutations. These data suggest that FGFR inhibition could be an important therapeutic option across multiple tumor types.

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Section: Discussionmentioning

confidence: 99%

The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing

Helsten

Elkin²,

Arthur

et al. 2016

Clinical Cancer Research

596

612

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“…Third, evidence of oncogene addiction has been reported with highly specific inhibitors in patients with lung cancer and bladder carcinoma presenting FGFR alterations (18,71,74). Clinical benefit and tumor reduction were also reported in patients with glioblastoma and cholangiocarcinoma harboring FGFR translocations, and ongoing trials may help to validate the relevance of these targets.…”

Section: Lessons Learned From the Clinical Development Of Fgfr Inhibimentioning

confidence: 96%

“…Preliminary results (in 94 patients) of the ongoing phase I trial documented clinical benefit in 8 patients with tumors harboring FGFR signaling alterations (4 patients with FGFR1-amplified squamous-NSCLC achieved PRs, and 4 of 5 patients with FGFR3-mutant bladder carcinoma had tumor reductions), 4 of which lasted for more than 16 weeks. In addition, tumor reductions were observed in patients with cholangiocarcinoma with FGFR2 fusion and FGFR1-amplified breast cancer (41,74). AEs were generally mild (grade 2) and included dose-dependent hyperphosphatemia, diarrhea, fatigue, and nausea.…”

Section: Small-molecule Tkis Targeting Fgfrsmentioning

confidence: 99%

“…First, proof-ofconcept of an effective inhibition of FGFR signaling by TKIs in patients with cancer has been achieved, and increased serum FGF23, phosphate, and vitamin D levels have been identified as potential pharmacodynamic markers associated with on-target effect (18,71,74). Second, the safety and feasibility of FGFR targeting have been demonstrated, with several phase I/II trials reporting manageable toxicities.…”

Section: Lessons Learned From the Clinical Development Of Fgfr Inhibimentioning

confidence: 99%

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Targeting FGFR Signaling in Cancer

Touat

Ileana

Postel-Vinay

et al. 2015

Clinical Cancer Research

412

369

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The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents. Clin Cancer Res; 21(12); 2684-94. Ó2015 AACR.

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“…Recent genomic analyses of lung SCC have also given the first set of potentially targetable driver mutations, including FGFR1, FGFR2, FGFR3, DDR2 and PI3K 20 . Clinical trials that aim to target these subsets of patients who have Stage I-IIIA lung cancers are currently underway; preliminary results were presented at the 2014 American Association for Cancer Research Annual Meeting 86 , and these showed responses to an FGFR inhibitor (BGJ398) in a subset of patients with SCC who have FGFR1 amplification.…”

Section: Current Treatments For Nsclcmentioning

confidence: 99%

Erratum: Non-small-cell lung cancers: a heterogeneous set of diseases

Chen¹,

Fillmore²,

Hammerman³

et al. 2015

Nat Rev Cancer

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Non-small-cell lung cancers (NSCLCs), the most common lung cancers, are known to have diverse pathological features. During the past decade, in-depth analyses of lung cancer genomes and signalling pathways have further defined NSCLCs as a group of distinct diseases with genetic and cellular heterogeneity. Consequently, an impressive list of potential therapeutic targets was unveiled, drastically altering the clinical evaluation and treatment of patients. Many targeted therapies have been developed with compelling clinical proofs of concept; however, treatment responses are typically short-lived. Further studies of the tumour microenvironment have uncovered new possible avenues to control this deadly disease, including immunotherapy.Lung cancer results in the largest number of cancer-related deaths worldwide 1,2 . More than 85% of those cases are currently classified as non-small-cell lung cancer (NSCLC), for which the predicted 5-year survival rate is 15.9% -a figure that has only marginally improved during the past few decades 3 . Technological advances during the past decade, including the introduction of next-generation sequencing (NGS), the generation of multiple genetically engineered mouse models (GEMMs) of lung cancer and the construction of large databases characterizing the molecular features of human tumours, have transformed our view of NSCLC from histopathological descriptions to precise molecular and genetic identities that can be resolved to the single-cell level. In parallel, approaches and concepts from fields such as developmental biology, stem cell biology and immunology have deepened our knowledge of tumour development, cellular heterogeneity and interactions between the lung tumour and its surrounding microenvironment. These multidisciplinary Correspondence to P.S.H., C.F.K. and K.-K.W. phammerman@partners.org; carla.kim@childrens.harvard.edu; kwong1@partners.org. * These authors contributed equally to this work. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Cancer. Author manuscript; available in PMC 2017 December 04. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript efforts have enhanced our understanding of molecular disease mechanisms, thereby forming the rationales for targeting different cellular compartments simultaneously. Scientists and physicians have better tools than ever to pursue answers to two provocative questions: first, how can we define the specific subsets of NSCLC that differ by cellular and molecular composition? Second, how can we effectively control lung cancer growth for each specific subset of NSCLC? In this Review, we discuss how data that are derived from technological advances in lung cancer genomics, mouse modelling of cancers and tumour microenvironment studies might be used to improve the survival of patients with NSCLC through the development of novel therapeutic strategies. Defining NSCLC subsetsNSCLC is currently defined by pathological characteristics. The two...

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Abstract CT326: Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors

Cited by 71 publications

References 0 publications

The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing

The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing

Targeting FGFR Signaling in Cancer

Erratum: Non-small-cell lung cancers: a heterogeneous set of diseases

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