Erdafitinib for tumors with FGFR3 mutation: A promising targeted therapy

• DOI: 10.4103/crst.crst_176_23
• Publication Date: 2023-08-02T08:00:40Z
• Authors: Jaspreet Kaur; Ajaykumar Singh; Minit Shah; Pratik Chandrani; Anuradha Chougule; Omshree Shetty; Trupti Pai; Santosh Menon; Subhash Yadav; Akhil Kapoor; B. K. Mishra; Amit Dutt; Vanita Noronha; Kumar Prabhash
• Keywords: Past medical history; Outpatient clinic; Urinary retention

CASE SUMMARY History and examination A 77-year-old gentleman, with no prior comorbidities or a family history of malignancy, presented in October 2021 to the outpatient department Tata Memorial Hospital, Mumbai, India, complaints loss appetite unintentional weight (of approximately 12 kgs) over past 5 months. In May 2021, he experienced an episode acute urinary retention, which required catheterization. He was prescribed tablet tamsulosin for this. view persistent repeated lower tract symptoms (burning micturition increased frequency), patient underwent further evaluation. At time presentation had Eastern Cooperative Oncology Group Performance Status 1 systemic revealed significant findings. Investigations diagnosis The undergone ultrasonography kidney bladder (USG KUB) consultation his general physician, heterogeneous echotexture left few hypoechoic areas associated cystic lesion third peripheral rim calcifications (maximum diameter 2.4 cm), grade 2 prostatomegaly [Figure 1]. then referred our center. Repeat USG at center diffusely measuring 8.6 × 4.9 cm echogenic endophytic causing distention proximal ureter, infiltration renal pelvis. Contrast-enhanced computed tomography (CECT) thorax, abdomen pelvis (TAP) [Figures 3] heterogeneously hypoenhancing mass interpolar region pole perinephric fat stranding extending into upper ureter. There were least four hypodensities segments VIII, VII, VI liver (largest 1.1 multiple enlarged enhancing irregular lesions both lungs right lobe 6.5 5.6 pre- paratracheal, hilar subcarinal nodes paratracheal node 1.8 cm).Figure 1: Ultrasonography showing (arrow) size cmFigure 2: stranding. – Anterior, P Posterior, R Right, L - LeftFigure 3: New onset exophytic soft tissue response contrast enhanced CT scan done December 2022 on erdafitinib therapyThe CT-guided biopsy lung November reported histopathology as carcinoma squamous differentiation. Immunohistochemistry (IHC) showed diffuse positivity p40, GATA binding protein 3 (GATA-3); it negative thyroid transcription factor (TTF1) paired-box gene 8 (PAX8). pathological metastatic urothelial differentiation considered. Additional IHC markers estrogen (ER), progesterone (PR), androgen receptors (AR) negative. tumor cells programmed death ligand (PD-L1) antibody by SP263 Ventana clone. sent next-generation sequencing (NGS). After thorough clinical, radiological histopathological evaluation, final (with differentiation) liver, non-regional nodal metastases made. Next-generation excerpts from discussion molecular board NGS using targeted panel (SOPHiA solid plus solution),[1] identified single nucleotide variants (SNVs), indels 44 genes, 139 ribonucleic acid (RNA) fusions, amplification events 24 genes microsatellite instability (MSI) status (6 unique loci). test has been standardized validated pathology laboratory institution. data analyzed annotation sources: dbSNP (Version 1), 1000 genomes ClinVar 4), COSMIC 3), EXAC 1).[2] Extracted deoxyribonucleic (DNA) RNA subjected library preparation, followed paired-end synthesis technology Illumina MiSeq platform.[3] Data analysis performed SOPHiA data-driven medicine (DDM) software. mutations according American College Medical Genetics Genomics (ACMG) guidelines, 2018, Human Genome Variation Society (HGVS) nomenclature. Genes < 500X coverage not interpreted. paraffin block (reports available February 2022, Table Tier I mutation Fibroblast Growth Factor Receptor (FGFR3) [Tier c.746C>G, p.(Ser249Cys) amino change, variant allele frequency (VAF)= 11.20] II likely pathogenic phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) [c.1633G>A p.(Glu545Lys) VAF=11.40]. FGFR3 S249C[4] is highly activating type seen carcinoma. This oncogenic sensitive tyrosine kinase inhibitors (TKI), hence considered I. Targeted therapy erdafitinib[5] recommended. Other possible options discussed infigratinib,[6] rogaratinib,[7] pemigatinib.[8]PIK3CA also targetable resistance mechanism FGFR inhibitors, but clinical rates PIK3CA inhibition have disappointing patients non-breast cancer (objective ([ORR] 3-6%, and, median progression-free survival [PFS] 3.4-5.5 months), recommended be used after exhaustion standard lines if rapid progression inhibition.[9] incidence 25% per Cancer Atlas (TCGA), 18% having hotspot alleles.[10]Table Next generation report 2021Treatment While awaiting results NGS, planned chemotherapy. evaluation frailty means geriatric assessment, started reduced dose chemotherapy (three-weekly gemcitabine 75% [days 8] carboplatin dosed area under free plasma concentration versus curve [AUC] 4).[11] three cycles interval increase number 2.3 1.5 segment VII), decrease 4.8 2.2 lobe), mediastinal cm) suggestive disease Response Evaluation Criteria Solid tumors version (RECIST, v1.1). Based (February 3, 2022), that point, India only compassionate basis platinum-based therapy. As patient's progressed + chemotherapy, treatment planned. Erdafinitib tolerance starting mg orally once daily, developed Grade hyperphosphatemia, correction close monitoring serum phosphate levels. there minimal reduction levels despite use oral binders, 7 September 2022. Patient could tolerate either hand-foot syndrome (HFS) temporarily withheld conservative management given. Erdafitinib restarted daily Progression CECT new 2.1 3], bilobar 4.7 3.3 cm, 4]), para-aortic lymph (measuring 1.3 patchy opacities Figure nodules bilateral parenchyma, paratracheal/subcarinal location), focal short segmental eccentric wall thickening involving sigmoid colon maximal thickness mm adjacent meso-colonic mesenteric nodes.Figure 4: contrast-enhanced therapy, well hepatic metastasisDue progressive disease, weekly paclitaxel 80 mg/m2 intravenously January 2023, continued. decision continue one, interruptions while solely attributed development (sub-optimal therapeutic exposure). One presence mutation. However, receiving second cycle paclitaxel, hospitalization mucositis HFS, following permanently discontinued. recovery, continued agent alone. Early 2023 lesions, changed atezolizumab, however, lost follow up subsequently. timeline shown 5.Figure 5: Timeline course mutations; = growth receptor Phosphatidyl inositol-4,5-bisphophate alpha, AUC Area curve, Generation Sequencing, Contrast-Enhanced Computed Tomography, TAP Thorax, Abdomen PelvisDISCUSSION Introduction FGFR3, belonging family, exhibits high expression chondrocytes osteoblasts, thereby playing critical role processes osteogenesis bone maintenance. Its governed gene, located chromosome 4.[12,13] Germline this are linked various disorders, including achondroplasia, chondrodysplasia, thanatophoric dysplasia.[14] These paternally inherited increasing paternal age.[12,15] signaling pathway fibroblast factors (FGF) FGF implicated tumoral epithelial-to-mesenchymal transition (EMT). overlaps mitogen-activated (MAPK) PI3-AKT pathways, influencing cellular such proliferation, differentiation, angiogenesis, metabolism, mobility, invasion.[16] protein, acts kinase, transmembrane single-pass structure. It consists immunoglobulin-like domains (IgI, IgII, IgIII) its extracellular region, domain intracellular domain.[17] Dimerization leads transphosphorylation sites, subsequently recognized src homology-2 (SH2) phosphotyrosine (PTB) adaptor proteins.[16,18,19] phosphorylation event triggers proteins, initiating downstream through major cascades: MAPK pathway, PI3K/AKT phospholipase C gamma signal transducer activator (STAT) pathway. carcinogenesis alterations transformation resulting genetic abnormalities. hyperactivation promotes cell metastasis, drug resistance.[20] context advanced carcinomas, detected 20% cases.[21-24] most commonly occurring cancers missense in-frame fusions transforming coiled coil (FGFR3-TACC3), occur 2% cases cancers.[22] Mutations Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) proteins responsible recurrent mutation, S249C (TCC→TGC). other types demonstrating APOBEC signature raising possibility target APOBEC-mediated ability generate clinically relevant driver mutations.[25] potential observed pre-translational level, circular (circRNA) product known Has_circ_0068871. circRNA proliferation migration.[26] Furthermore, tumors, antisense transcript FGFR3-AS1 stabilizes mRNA. This, turn, invasiveness, motility.[26,27] Bladder involves FGFR, EGFR, PI3/AKT/mTOR, RAS-MAPK, checkpoints, DNA damage repair. TCGA classified 4 subtypes as: Luminal cluster (consisting 30-35% total carcinomas) express FGFR3; (comprising carcinomas), HER2-, ER pattern; Basal III, similar basal-like breast carcinoma, head-and-neck carcinomas (20–25% carcinomas); IV, III 10–15% additional features surrounding stroma muscle).[27] clusters GATA3 whereas KRT5/6 IHC. double phenotype exists small proportion (4%) neither Tumors aggressive higher activation EMT early metastasis.[28] Treatment particularly directed towards luminal I, TCGA. Of note, subtype lowest anti PD-L1 atezolizumab nivolumab when compared lack immune marker expression.[29] classification prognostic value[30] non-muscle-invasive (associated conventional morphology), less expression, favorable outcomes terms overall survival. basal greater muscle invasive (variant histology), checkpoint inhibitor (ICI) mortality related cancer. Immunomodulatory effect study conducted genetically engineered p53 mutated mouse model statistically improvement (OS, OS 19.7 weeks vs 13.4 weeks, ≤ 0.01) combined immunotherapy (10 mg/kg, Bio X Cell, RMP1-14) Prior exposure, micro-environment cold immunosuppressive abundance i.e. T-regulatory (Tregs). Following exposure erdafitinib, CD4+ CD8+ T-cell noted can deduced study, monotherapy immunomodulatory potentiating benefit combination.[31] To strengthen hypothesis, ongoing phase Ib/II NORSE trial evaluating safety efficacy combination cetrelimab (immunoglobulin G4 monoclonal specific PD-1) cisplatin-ineligible participants locally select disease.[32,33] Previous vitro assays demonstrated enhancement function PD-1 mediated suppression reversal anti-PD-1 antibody. addition, drives clone expansion, microenvironment immunologic changes which, turn supports antitumor immunity survival.[26] Updated promising confirmed objective rate (ORR) 55% 11 evaluable control (including unconfirmed complete response, partial stable disease) 100%.[34] indicator Aberrations grades stages. Approximately 49–84% non-muscle muscle-invasive carcinomas.[35-37] Despite their association disease-specific rates.[30–32] Although more common T1 luminal-papillary cancers, currently evidence validate claim stage correlate phenotype. fact, aberrations chemotherapy.[29,38,39] Erdafitinib: pan-FGFR oral, (1-4) TKI potent all activity.[40] granted accelerated approval United States Food Drug Administration (FDA) second-line adults FGFR2/3 (mutations/fusions) whose one line platinum-containing approved based BLC2001 open-label, arm led 40% ORR (95% CI, 30–49) unresectable fusion.[5,41] follow-up months, PFS 5.5 months 4.2–6.0), 13.8 9.8–not reached). Given (mutations/fusions), trials different settings. Additionally, may heightened responses sensitivity interventions.[33] studies effects microenvironment, research solidify hypothesis.[33] beyond targets Alteration (FGFRalt), malignancies. single-arm called RAGNAR (NCT04083976): alterations," being investigated pre-treated adult pediatric harboring FGFRalt.[33,42] aims explore benefits broad range malignancies (beyond carcinoma) alterations. profile daily. two long remain below mg/dL. Hyperphosphatemia class 76 (77%) study.[5] toxicities included stomatitis (n 57; 58%), diarrhea 50; 51%), dry mouth 45; 46%). ≥ 10, 10%), hyponatremia 11; 11%) asthenia 7; 7%). 3% 2) enrolled subjects retinal pigment epithelium detachment, discontinuation drug.[33,42,43] Close phosphorus essential erdafitinib. plays pivotal regulation levels, hyperphosphatemia might lead mineralization, cutaneous calcinosis, non-uremic calciphylaxis, and/or vascular calcification. Increased Median documented 20 days (range, 8-116). Cutaneous calcification 0.3% patients. avoid concurrent agents potassium phosphate, vitamin D supplements, antacids, phosphate-containing enemas laxatives, medications excipients before initial (days 14-21) period. Phosphate intake should restricted 600-800 exceed mg/dL, binder until fall well, (tablet sevelamer carbonate 400 times day antacid syrup) added level 6.8 When did respond normalize, decreased mg. Our reductions due toxicities, namely, fatigue, mucositis, requiring in-patient hospital admission, parenteral nutrition, anti-mucositis measures, topical emollients, therefore never escalated full dose. sub-therapeutic blood reasons PFS. whom successfully 9 numerically 48.8%.[41] Central serous retinopathy (CSR) another important class-specific adverse inhibitors. disruption normal ocular FGFR–MAPK leading accumulation fluid between neural retina resultant epithelial dysfunction central retinopathy. first retinopathy/retinal detachment 50 days, resolution 13% CSR/retinal study. discontinued.[41,43,44] toxicity generally presents visual impairment , asymptomatic edema limited fovea. For (or any inhibitor), monthly ophthalmological examinations during visits ophthalmologist. Dry eyes about quarter patients, eye lubricants used. needs immediately discontinued worsening acuity than 20/40 (Grade Common Terminology Adverse Events v4.03).[45] date, pemigatinib FGFR-altered cholangiocarcinoma, respectively. marketed non-selective nintedanib, regorafenib (metastatic colorectal cancer, gastrointestinal stromal hepatocellular carcinoma), pazopanib sarcoma) sunitinib lieu selective CONCLUSION evolved alteration (mutation/fusion) positive however almost half prompt effects. Overall, represents advancement offering renewed hope improved previously scenario. With better understanding underlying mechanisms, will expected population. Declaration consent authors certify they obtained appropriate forms. form, given images information journal. understands name initials published, efforts made conceal identity, anonymity cannot guaranteed. Financial support sponsorship Nil. Conflicts interest Vanita Noronha, Anuradha Chougule, Kumar Prabhash members editorial Research, Statistics Treatment. such, access participated decisions perceived publication manuscript. recused themselves peer review, editorial, decision-making process manuscript, ensure content unbiased.