Fibroblast Growth Factor Receptor Alterations Research Articles

Abstract A004: Clinical test design affects tumor tissue and ctDNA FGFR gene status in metastatic urothelial cancer: a prospective study

Abstract Fibroblast growth factor receptor (FGFR) gene alterations are common in urothelial cancer (UC) and targetable with erdafitinib. The co-approved companion diagnostic is an amplicon-based tumor tissue test that detects a limited number of recurrent FGFR alterations. However, FGFR status may change during disease progression, and rare FGFR alterations not typically covered by existing tests may be of clinical importance. Therefore, in a prospective pan-Canadian study (NCT06129084), we compared standard archival tissue testing to broad targeted sequencing of cell-free circulating tumor DNA (ctDNA) to detect FGFR alterations in UC. Eligible patients had progressing metastatic UC and were undergoing tissue FGFR testing. Blood was drawn at study enrollment and plasma cell-free DNA and matched white blood cell DNA underwent deep-targeted sequencing with a hybridization capture panel including the introns and exons of FGFR1-4 and the common breakpoint region of TACC3. Archival tissue selection and testing was initiated by the treating physician and typically used the Oncomine Focus assay. 210 patients were enrolled across 12 sites, and 140 patients have tissue and ctDNA results available for concordance assessment. 43/140 (31%) of cell-free DNA samples had low tumor fraction (<0.5%) and were considered inconclusive. For the remaining 97 same-patient tissue and ctDNA pairs, FGFR status was identical in 88 (91%). In 7 of 9 discordant cases, the tissue was negative, but ctDNA was positive for FGFR alterations: these were enriched for FGFR3-TACC3 fusions (4/7). Two discordant fusions had canonical breakpoints that can be identified by current amplicon-based companion diagnostics, indicating potential spatiotemporal heterogeneity in somatic FGFR status. The other two discordant (ctDNA-only) fusions had non-canonical breakpoints that are not amenable to detection by current amplicon-based companion diagnostics. In two mutation discordant cases (S249C positive in ctDNA only), lack of signal in tumor tissue could be explained by the presence of additional FGFR3 variants within 25bp of S249 and in cis - disrupting primer binding sites. There were only two cases of tissue-only FGFR alterations among the 97 evaluable pairs (FGFR3-TACC3 fusion, S249C). ctDNA testing of metastatic UC with a broad capture-based approach covering all exons and introns of FGFR genes can identify additional alterations not detected with current amplicon-based companion diagnostics applied to archival tissue. Our results support ctDNA testing as a valuable adjunct to tissue testing, but not as a replacement due to the high frequency of inconclusive ctDNA results, secondary to tumor fraction below the threshold. Assay design, including target enrichment technique, is a significant source of variability in tissue and ctDNA FGFR status and should be carefully considered in future clinical biomarker testing strategies. Citation Format: David C. Müller, Gillian Vandekerkhove, Andrew J. Murtha, Jack V.W. Bacon, Carlos Vasquez-Rios, Maria Stephenson, Kimia Rostin, Elena Schönlau, Connor Wells, Sunil Parimi, Krista Noonan, Naveen S. Basappa, Jenny J. Ko, Daygen Finch, Nimira Alimohamed, Tarek A. Bismar, Gang Wang, Andreas Papadakis, Lucia Nappi, Matti Annala, Cecily Q. Bernales, Alan Spatz, Kim N. Chi, Alexander W. Wyatt, Bernhard J. Eigl. Clinical test design affects tumor tissue and ctDNA FGFR gene status in metastatic urothelial cancer: a prospective study [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A004.

The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. Inaddition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Abstract LB162: Tinengotinib in patients with advanced solid tumors harboring actionable FGFR1-3 mutations

Abstract Background: Fibroblast growth factor receptor (FGFR) alterations occur across various malignancies and are potent oncogenic drivers in multiple tumor types. FGFR inhibitors have demonstrated efficacy in several cancers with FGFR alterations. Tinengotinib is a novel kinase inhibitor with high potency to a variety of FGFR 1/2/3 kinase domain mutations and has shown promising efficacy in several ongoing clinical studies. Here, we present pooled data of tinengotinib in previously treated solid tumor patients (pts) with actionable FGFR1-3 mutations from four trials (NCT03654547, NCT04742959, NCT04919642, NCT05253053). Methods: Eligible pts received tinengotinib orally once daily (daily dose ranging from 5-12mg) until disease progression. Analyses of best overall response (BOR) rate, disease control rate (DCR), median progression-free survival (mPFS), median duration of response (mDOR) and treatment-related adverse events (TRAEs) were performed. Results: As of 3-Aug-2023, 53 solid tumor pts with actionable FGFR1-3 mutations were enrolled between Dec-2019 to Aug-2023 in the US and China. The median follow-up time was 14.5 (range, 3.3-43.8) months. Median age was 58 years (range, 29-83). Most pts were female (62%), had ECOG of 1 (68%) and were heavily pretreated with 55% having ≥3 lines of prior antitumor therapy. The most frequent FGFR mutation enrolled was in FGFR2 (77%) followed by FGFR1 (19%) and FGFR3 (11%). 25 pts (47%) had received prior therapy with FGFR inhibitor. A total of 45 pts were efficacy-evaluable, including cholangiocarcinoma (CCA, n=25), colon cancer (n=5), breast cancer (n=3), prostate cancer (n=3), head and neck cancer (n=3), urothelial cancer (n=3), pancreatic cancer (n=1), gastric cancer (n=1) and leiomyosarcoma (n=1). mPFS reached 6.83 (95% CI, 4.90-8.34) months. Partial responses were observed in 16/45 (35.6%) pts across 6 distinct tumor types, including CCA, breast, prostate, urothelium, colon and head and neck cancer. mDOR was 6.74 (95% CI, 3.52-9.46) months. For 44 pts with measurable target lesions per RECISTv1.1, the BOR rate and DCR were 36.4% and 86.4%, respectively. For 22 pts with prior FGFR inhibitor, mPFS was 5.98 (95% CI, 3.75-9.10) months and their BOR rate and DCR were 40.9% and 86.4%. TRAEs were reported in 46 (86.8%) pts, with 13 (24.5%) Grade (G) 1-2, 30 (56.6%) G3, 2 (3.8%) G4, and no G5. The most common TRAEs (≥20%) were hypertension, stomatitis, diarrhea, nausea, blood thyroid stimulating hormone increased, fatigue and anemia. Side effects were manageable and reversible with dose hold and/or dose reduction. Conclusions: We observed promising clinical benefit with tinengotinib in heavily pretreated solid tumor pts with FGFR1-3 mutations. The side effects profile was manageable and no new safety signals have been identified. Further research is planned to evaluate the safety and efficacy of tinengotinib in pts with FGFR1-3 mutations across a wider variety of tumor types. Citation Format: Sarina A. Piha-Paul, Chih-Yi "Andy" Liao, Lionel Fonkoua, Amit MahipaI, Sanjay Goel, Christos Fountzilas, Lin Shen, Daneng Li, Dustin Deming, Farshid Dayyani, Weiqing Han, Zuoxing Niu, Jean Fan, Peng Peng, Hui Wang, Peng Huang, Frank Wu, Milind Javle. Tinengotinib in patients with advanced solid tumors harboring actionable FGFR1-3 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB162.

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to tumor development. Targeting these FGFR alterations has shown to be effective in treating cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms, and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments in multiple agents targeting the FGFR pathway, including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody-drug conjugates. However, most of these agents have variable and low responses, with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments in agents targeting the FGFR pathway, and will also discuss future directions for FGFR-targeting agents.

Abstract A165: FGFR alterations in pediatric cancers: Opportunity for targeted therapy

Abstract Introduction: The Fibroblast Growth Factor Receptor (FGFR) family consists of four members, FGFR1–4, and is involved in regulating cell proliferation, survival, and differentiation. FGFR alterations, such as fusions, mutations and amplification, have been found in multiple adult cancers, for which several FGFR inhibitors are in clinical development. Although cancer is a leading cause of death in children, the understanding of genetic causes of pediatric cancers is urgently lacking and the progress in developing targeted therapy in children significantly lags that in adults. This study aimed to uncover the FGFR alterations in pediatric cancers and provide preclinical rationale for FGFR inhibitors as potential therapy in children with cancer. Methods: The prevalence of FGFR alterations in pediatric cancers such as neuroblastoma (NB) , gliomas and sarcomas was calculated based on systematic queries of multiple cancer databases that house real-world molecular profiling data. A pan-FGFR inhibitor, BGJ398, was used as a tool compound for FGFR inhibition. Effect of BGJ398 on cell proliferation was tested by Incucyte in a panel of 12 NB cell lines. Cell migration, survival and signaling pathway modulation were carried out in a subset of NB lines. Results: The overall rates of genomic alterations (fusions, mutations and amplification) of FGFR1, 2, 3 and 4 in pediatric cancers are 0.5%, 0.1%, 1.1% and 0.8%, respectively, with pediatric gliomas exhibiting higher rates in all subtypes. Although FGFR genomic alterations are rare (<0.1%) in neuroblastoma and rhabdoid sarcoma, overexpression of FGFR1-4 is observed in subsets of these tumors. In pediatric glioma, FGFR1, 2, 3 and 4 alterations are found in 1%, 1.6%, 2.1% and 0.9% tumor samples, respectively, and the mutation profile substantially differs from that of adult glioma. Dose-dependent inhibition of cell proliferation and migration, as well as induction of cell death, were achieved with BGJ398 treatment in a panel of NB cells, accompanied by inhibition of MAPK pathway and induction of apoptosis. Conclusions: Adult and pediatric cancers share common mechanisms of FGFR activation, but differ in overall alteration rates and in relative abundance of specific aberrations. Preliminary preclinical data indicates the therapeutic potential of FGFR inhibitors in the treatment of certain pediatric cancers. Citation Format: Ivan Li, Yuchen Huo, Gary Li, Peter Zage. FGFR alterations in pediatric cancers: Opportunity for targeted therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A165.

The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer

BackgroundCurrently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA).MethodsA multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months.ResultsFGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases.ConclusionsDifferential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR: 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR: 5%), indicating promising avenues for precision immunotherapy for BLCA.

Pemigatinib for metastatic or surgically unresectable urothelial carcinoma with FGF/FGFR genomic alterations: final results from FIGHT-201

Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714). Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 260 patients were enrolled and treated (A-CD, n= 101; A-ID, n= 103; B, n= 44; unconfirmed FGF/FGFR status, n= 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n= 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n= 3; V553M, n= 1; N540K/S, n= 2; M528I, n= 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each). Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.

208O Asian subgroup analysis of the THOR phase III study: Erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer and selected fibroblast growth factor receptor alterations

208O Asian subgroup analysis of the THOR phase III study: Erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer and selected fibroblast growth factor receptor alterations

LBA102 THOR-2 cohort 1: Results of erdafitinib (ERDA) vs intravesical chemotherapy (chemo) in patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) with select fibroblast growth factor receptor alterations (FGFRALT) who received prior bacillus calmette-guérin (BCG) treatment

LBA102 THOR-2 cohort 1: Results of erdafitinib (ERDA) vs intravesical chemotherapy (chemo) in patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) with select fibroblast growth factor receptor alterations (FGFRALT) who received prior bacillus calmette-guérin (BCG) treatment

1621P Efficacy and safety of erdafitinib in adults with pancreatic cancer and prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase II open-label: Single-arm RAGNAR trial

1621P Efficacy and safety of erdafitinib in adults with pancreatic cancer and prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase II open-label: Single-arm RAGNAR trial

2359O Phase III THOR study: Results of erdafitinib (erda) vs pembrolizumab (pembro) in pretreated patients (pts) with advanced or metastatic urothelial cancer (muc) with select fibroblast growth factor receptor alterations (FGFRalt)

2359O Phase III THOR study: Results of erdafitinib (erda) vs pembrolizumab (pembro) in pretreated patients (pts) with advanced or metastatic urothelial cancer (muc) with select fibroblast growth factor receptor alterations (FGFRalt)

FGFR3 alterations in bladder cancer stimulate serine synthesis to induce immune-inert macrophages that suppress T-cell recruitment and activation.

Fibroblast growth factor receptor 3 (FGFR3) alterations are common in patients with bladder cancer (BCa). While the FGFR tyrosine kinase inhibitor erdafitinib has been approved as a targeted therapy for FGFR3-altered (aFGFR3) BCa patients, the response rate remains suboptimal, prompting development of strategies to improve treatment response. Here, we observed an immune-desert tumor microenvironment (TME) phenotype in human aFGFR3 BCa and demonstrated that mutant FGFR3 indirectly induces a "cold" TME in mouse BCa models. Single-cell RNA sequencing (scRNA-seq) revealed the central role of macrophages in inducing the cold TME of aFGFR3 tumors. Macrophages in aFGFR3 tumors exhibited reduced T cell recruitment and antigen presentation capabilities. Increased serine synthesis in BCa cells that was induced by mutant FGFR3 activated the PI3K/Akt pathway in macrophages, shifting them to an immune-inert phenotype. Targeting PI3K in aFGFR3 tumors with duvelisib achieved promising efficacy by reversing the macrophage phenotype, and combination therapy with duvelisib and erdafitinib demonstrated increased antitumor activity. Overall, these findings reveal the critical role of enhanced serine synthesis efflux from cancer cells with mutant FGFR3 in shifting macrophages to an immune-inert phenotype. Reversing the macrophage phenotype holds promise for enhancing erdafitinib efficacy.

Phase 3 THOR study: Results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt).

LBA4619 Background: FGFRalt are observed in ~20% of pts with mUC. Erda is an oral selective pan-FGFR tyrosine kinase inhibitor granted accelerated approval to treat locally advanced or mUC in adults with susceptible FGFR3/2alt who have progressed after platinum-containing chemo. THOR (NCT03390504), a randomized phase 3 study, assessed whether erda provided a survival advantage vs investigator’s choice of chemo in pts with mUC who progressed after 1 or 2 prior treatments, including an anti-PD-(L)1 agent. Methods: Pts (≥18 y) with unresectable advanced/mUC and select FGFR3/2alt (mutations/fusions), ECOG performance status 0-2, adequate organ function, progression on/after prior systemic therapy (tx) that included an anti-PD-(L)1 agent, and ≤2 prior lines of tx were randomized 1:1 to receive erda (8 mg with pharmacodynamically guided uptitration to 9 mg on day 14) QD or investigator’s choice of chemo (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results: 266 pts were randomized: 136 pts assigned to erda, 130 to chemo. In all pts, median age was 67 y; 30% had 1 prior line of tx, 70% had 2 prior lines; 74% had visceral metastases; 90% were PD-L1 low (CPS <10). Median follow-up was 15.9 mo. The primary endpoint of the study was met, with erda significantly increasing OS and reducing the risk of death by 36%; median OS was 1 y (Table). These data met predefined stopping criteria for superiority. Erda also significantly improved median PFS (5.6 vs 2.7 mo) and ORR (46% vs 12%) vs chemo. No new safety signals were seen. Serious treatment-related adverse events (TRAEs) were observed in 13% and 24% of pts with erda and chemo, respectively, and grade (Gr) 3/4 TRAEs were observed in 46% and 46% of pts with erda and chemo, respectively. TRAEs leading to death were reported in 1 and 6 pts with erda and chemo, respectively. More TRAEs leading to dose reduction were observed with erda (66%) vs chemo (21%); 8% and 13% of pts had TRAEs leading to discontinuation of erda and chemo, respectively. Central serous retinopathy occurred in 23 pts (17%) with erda (Gr 1-2, 20 pts). Conclusions: In pts with FGFRalt advanced/mUC after prior treatment with PD-(L)1, erda significantly improved OS, PFS, and ORR vs investigator’s choice of chemo. Erda toxicity was consistent with the known safety profile. These results support the role of erda to treat pts with FGFRalt mUC after PD-(L)1 tx. Clinical trial information: NCT03390504 . [Table: see text]

Evaluating the use of circulating tumor DNA (ctDNA) in patients with urothelial cancer in the context of FGFR-targeted therapy.

4577 Background: Fibroblast growth factor receptor (FGFR) inhibitors (e.g., erdafitinib) are increasingly important in the management of FGFR-mutated urothelial carcinoma. FDA-approved archival tissue testing for specific FGFR alterations was implemented as a companion diagnostic for erdafitinib. However, longitudinal sequencing studies indicate variable tumor FGFR status over time, and erdafitinib resistance mechanisms in metastatic urothelial carcinoma (mUC) are underreported. This ongoing study aims to evaluate the accuracy of cell-free DNA (cfDNA) compared to archival tissue testing in mUC for FGFR alterations detection, and to evaluate genomic mechanisms of erdafitinib resistance in cfDNA at progression. Methods: Patients with progressing mUC who were undergoing archival tissue testing for FGFR1-3 mutations and/or fusions and who had blood samples drawn during the management of their metastatic disease were eligible. Plasma cfDNA and matched leukocyte DNA were subjected to deep targeted sequencing with a custom panel including UC-specific gene loci and all clinically approved hotspots in FGFR1+2 and all exons and introns of FGFR3. Results: As of January 2023, 109 patients from 6 sites were enrolled. Median age at diagnosis was 71, 33% had upper urinary tract primaries, and 76% were male. Tissue and cfDNA results for comparison were available for 69 patients to date. Actionable somatic FGFR alterations were found in the tissue of 15 patients (31%); the most common alteration was the FGFR3 p.S249C mutation (67%). 50 of the analyzed cfDNA samples had detectable somatic circulating tumor DNA (ctDNA) variant allele fraction of 0.5% (72%). Of those, 49 had an evaluable tissue test result. Analysis of this subset revealed high concordance (92%) between the two test methods. With the assumption that archival tissue testing is considered the ‘gold standard’, sensitivity is 93% and specificity is 91%. The four discordant results comprised one cfDNA test with undetectable FGFR3-TACC3 fusion, which was detected in tissue and three positive ctDNA test results in patients with FGFR wild-type tissue tests. In one case at erdafitinib progression, ctDNA revealed multiple subclonal populations with distinct FGFR3 gatekeeper mutations suggesting polyclonal resistance. Conclusions: This ongoing study suggests cfDNA is a valuable minimally invasive adjunct to tissue-based assays for the detection of FGFR alterations to identify patients for FGFR inhibitor therapy and to monitor for mechanisms of resistance.

Use of an artificial intelligence (AI) –based pre-screening tool for patients with bladder cancer with fibroblast growth factor receptor (FGFR) alteration.

e13580 Background: Over 25% of urothelial carcinoma have actionable genetic alterations in FGFR. The clinical trial of the pan-FGFR inhibitor requires thousands of patients with FGFR alterations to be screened; however, the cost is prohibitively expensive. A deep learning model can help predict the occurrence of specific genetic alterations and effectively screen patients with FGFR actionable alterations in bladder cancer. Methods: The prediction model of FGFR oncogenic alterations was trained by using 440 H&E-stained bladder cancer diagnostic slides (from 373 patients) from the OrigiMed Database and validated with 448 slides (from 376 patients) from the additional TCGA-BLCA dataset. The model employs an attention-based, weakly supervised learning method to identify tissue subregions most likely to have the mutations of FGFR1-4, so as to classify the entire slide. Every patch is assigned an attention score, which represents the corresponding contribution to slide classification. The slide-level aggregation rule of attention-based pooling computes a final attention score by weighted average. Results: The FGFR oncogenic alteration predictive AI (FGFRonaP) model was trained, validated and tested on the OrigiMed real-world cohort. The FGFRonaP model could identify patients with FGFR1-4 gene oncogenic aberration on the test set accurately (Precision = 60.0%, Recall = 69.2%, AUROC = 0.839). When the model was tested on the additional TCGA independent cohort, 11 negative samples were included mistakenly while 323 true negative slide and 19 true positive slides were identified correctly. The FGFRonaP model showed an acceptable classification precision (63.3%), much higher than the occurrence rate (26.9%) of FGFR oncogenic alterations, in spite of an imperfect AUROC (0.636) and recall (0.167). Conclusions: FGFRonaP is feasible to serve as an in-house or monocentric application to pre-screen the potential FGFR-altered patients. It could be useful and efficient in preliminary screening to reduce workloads of genetic testing, and thus help pharmaceutical companies improve the proportion of candidates with FGFR-alterations in all patients who undergo genetic testing and cut expensive costs for enrolling patients.

Abstract CT119: A first-in-human phase 1 study of LOXO-435, a potent, highly isoform-selective FGFR3 inhibitor in advanced solid tumors with FGFR3 alterations (trial in progress)

Abstract Background: Alterations in the fibroblast growth factor receptor 3 (FGFR3) have been identified as oncogenic drivers in several solid tumor malignancies, including urothelial carcinoma (UC). Available pan-FGFR inhibitors target all 4 isoforms of FGFR (FGFR1 - 4) and consequently their efficacy can be limited by off-target toxicity (i.e. inhibition of other non-altered FGFR isoforms) including gastrointestinal, oral mucositis, and cutaneous/nail disorders, as well as FGFR1-mediated hyperphosphatemia. Moreover, clinical studies of pan-FGFR inhibitors have reported the development of drug resistance through acquired gatekeeper mutations (e.g. V555M and V565F) at the time of disease progression. LOXO-435 is a potent, highly isoform-selective FGFR3 inhibitor that is designed to preserve activity in the setting of gatekeeper resistance mutations. Preclinically, LOXO-435 has demonstrated potent in vitro and in vivo activity as a selective inhibitor of both wild-type and oncogenically activated FGFR3, including FGFR3 fusions, point mutations, and acquired gatekeeper resistance mutations without evidence of FGFR1-mediated hyperphosphatemia. Methods: LOXO-FG3-22001 is a multicenter, open-label, first-in-human phase 1a/b study of LOXO-435 in patients (pts) with FGFR3-altered advanced solid tumors, including metastatic UC (mUC) (NCT05614739). Eligible pts (≥ 18 years) must have an advanced or metastatic solid tumor with an FGFR3 alteration detected in tumor or ctDNA, ECOG PS of 0-1, and have received all standard therapy or have no known available options to provide benefit. The study will be conducted in 2 phases: phase 1a dose escalation and phase 1b dose expansion. Dose escalation (cohort A) will begin as a single-patient accelerated design, allowing intra-patient dose escalation, followed by the modified toxicity probability interval-2 method. Additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. Dose escalation will assess safety, PK/PD, and antitumor activity of LOXO-435 as monotherapy to determine the recommended phase 2 dose (RP2D). Dose expansion will include 4 cohorts of pts with prespecified activating FGFR3 alterations. Cohort B will enroll pts with mUC and include 2 cohorts to evaluate LOXO-435 as monotherapy (B1, B2) and 1 cohort to evaluate LOXO-435 in combination with pembrolizumab (B3). Cohort C will enroll pts with non-UC advanced solid tumors and will evaluate LOXO-435 as monotherapy (C1). Pts in cohort B1 must have progressed on or were intolerant to a prior FGFR inhibitor, and pts in cohorts B2, B3, and C1 must be FGFR inhibitor treatment naive. Dose expansion will evaluate the safety, PK/PD, and antitumor activity (per RECIST v1.1) of LOXO-435 at the RP2D. Citation Format: Gopa Iyer, Arlene Siefker-Radtke, Matthew Milowsky, Neal Shore, Xin Gao, Melissa A. Reimers, Noah Hahn, Rasha Cosman, Nobuaki Matsubara, Andrea Necchi, Debbie Robbrecht, Armelle Vinceneux, Enrique Grande, Jae-Lyun Lee, Tian Zhang, Tormod Guren, Ulrich M. Lauer, Michal Sarfaty, Bernhard Eigl, Syed Hussain, Xiang Zhao, Arjun V. Balar, Kaitlyn Francese, Ryan Widau, Benjamin Garmezy. A first-in-human phase 1 study of LOXO-435, a potent, highly isoform-selective FGFR3 inhibitor in advanced solid tumors with FGFR3 alterations (trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT119.

Efficacy and safety of erdafitinib in adults with cholangiocarcinoma (CCA) with prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase 2 open-label, single-arm RAGNAR trial: Expansion cohort results.

610 Background: Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2alt who have progressed during or after ≥1 line of platinum-containing chemotherapy . Interim results from the ongoing phase 2 RAGNAR study (NCT04083976) demonstrated tumor agnostic efficacy and safety of erda in adults with advanced solid tumors harboring prespecified FGFRalt after failure of standard therapies (Loriot Y, et al. J Clin Oncol 2022;40(suppl 16):3007). Here we report results from an expansion cohort of the RAGNAR study that enrolled only patients (pts) with CCA. Methods: Adults (aged ≥18 y) with advanced or metastatic CCA with predefined FGFR1-4alt (mutations/fusions [excluding amplifications] based on local/central test) and documented disease progression on ≥1 prior line of systemic therapy received oral erda until disease progression or intolerable toxicity. The primary end point is objective response rate (ORR) by independent review committee (IRC). Secondary end points include duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), investigator-assessed efficacy end points, and safety. Results: At data cutoff (median follow-up 20.4 mo), 35 pts with CCA received erda (median age 57 y [range 40-74], median 2 prior systemic therapy [range 1-6]); 90.9% had visceral metastasis, and 17.1% responded to last line of therapy. ORR by IRC was 60.0% (95% CI 42.1-76.1). Median time to onset of response was 1.5 mo (range 1.1-8.2). Responses were observed in pts harboring FGFR mutations and fusions and in pts with co-occurring genomic alterations. Median DCR and CBR were 100.0% (95% CI 90.0-100.0) and 71.4% (95% CI 53.7-85.4), respectively. Median DOR, PFS, and OS were 5.6 mo (95% CI 2.8-8.3), 8.4 mo (95% CI 5.5-9.7), and 18.7 mo (95% CI 8.9-not evaluable), respectively. Investigator-assessed efficacy end points were aligned with IRC results. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (82.9%), diarrhea (80.0%), and stomatitis (74.3%). The majority of pts (80.0%) had grade ≥3 TEAEs, the most common being anemia (22.9%), stomatitis (20.0%), and acute kidney injury (11.4%); 42.9% had serious TEAEs; 11.4% discontinued treatment due to TEAEs. No treatment-related deaths were observed. Conclusions: Data from the CCA expansion cohort of the phase 2 RAGNAR study demonstrate robust efficacy of erda in heavily pretreated adults with CCA harboring prespecified FGFR fusions or mutations, irrespective of co-occurring genomic alterations. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04083976 .

Outcomes of Patients with Advanced Urothelial Carcinoma after Anti–programmed Death-(ligand) 1 Therapy by Fibroblast Growth Factor Receptor Gene Alteration Status: An Observational Study

BackgroundClinical outcomes of anti–programmed death‑(ligand) 1 (anti–PD-[L]1) therapy in patients with locally advanced or metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa+) remain unclear; recent studies have reported either comparable or poorer outcomes versus patients without FGFR alterations (FGFRa–). ObjectiveTo analyze the outcomes of patients with mUC and any FGFRa (mutations or fusions) who received anti–PD-(L)1 therapy. Design, setting, and participantsIn this noninterventional, retrospective, multicenter study, clinical practice data were collected from FGFRa+/– patients who received prior immunotherapy between May 2018 and July 2019. Outcome measurements and statistical analysisInvestigator‑determined overall response rate (ORR), disease control rate (DCR), and overall survival (OS) were assessed in multivariate and unadjusted analyses. Results and limitationsNinety-four patients (66% men; median age, 63 yr) with mUC and known FGFR status were included; 38 (40%) were FGFRa+ and 56 (60%) were FGFRa–. In FGFRa+ versus FGFRa– patients who received any line of anti–PD-(L)1 therapy (n = 92), ORR, DCR, and OS were 16% versus 26%, 29% versus 52% (relative risk: 1.14 [95% confidence interval {CI}, 0.92–1.40]; p = 0.3), and 8.57 versus 13.2 mo (hazard ratio [HR]: 1.33 [95% CI, 0.77–2.30]; p = 0.3), respectively. A multivariate analysis provided some evidence supporting shorter OS in FGFRa+ versus FGFRa– (any line of anti–PD-L[1] therapy; HR: 1.81 [95% CI, 0.99–3.31]; p = 0.054). Limitations include this study’s retrospective nature and a potential selection bias from small sample size. ConclusionsSome evidence of lower response rates and shortened OS following anti–PD-(L)1 therapy was observed in FGFRa+ patients. The phase 3 THOR study (NCT03390504) will prospectively compare FGFRa+ patients with advanced mUC treated with erdafitinib versus pembrolizumab. Patient summaryPatients with metastatic urothelial carcinoma and prespecified fibroblast growth factor receptor alterations (FGFRa) potentially have worse clinical outcomes when treated with anti–PD-(L)1 therapy than those without FGFRa.

Targeting Fibroblast Growth Factor Receptor Alterations in Cholangiocarcinoma and Other Solid Tumours: A New Frontier in Personalised Medicine

Cholangiocarcinoma (CCA) is a cancer of the bile duct with poor prognosis and increasing incidence. Filippo de Braud gave an overview of CCA and its classification and highlighted key unmet needs in both diagnosis and treatment. Juan Valle explained that intrahepatic CCA (iCCA) accounts for 11% of the entire cancer of unknown primary (CUP) population, as well as 33% of patients with liver-inclusive disease. It is, therefore, vital that CUP with a ‘liver-dominant lesion’ is reviewed by a specialist team familiar with iCCA management. Angela Lamarca emphasised that managing CAA requires a multidisciplinary approach to both diagnosis and treatment. Precision medicine is now a reality in biliary tract carcinoma (BTC), particularly iCCA, so molecular testing is essential to ensure targeted therapy options are considered. David Malka explored existing and emerging standard-of-care (SOC) treatments for advanced BTC, which represents a target-rich disease. Updated guidelines now recommend targeted treatment for second-line iCCA in patients with appropriate alterations, underscoring the importance of systematic and early molecular profiling. A wide range of malignancies harbour FGFR alterations at varying frequencies, and the FGFR inhibitor pemigatinib is already approved for the treatment of CCA with FGFR2 fusions or rearrangements. Antoine Hollebecque highlighted the final results from the Phase II FIGHT-202 study, in which pemigatinib achieved an overall response rate (ORR) of 37% in the target population with a manageable safety profile.

Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations

Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape. Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA). FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Mostcommon FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations. Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.