FGFR2 Fusions Research Articles

Efficacy and safety of erdafitinib in adults with breast cancer and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial.

1088 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. The primary analysis results from the RAGNAR study demonstrated tumor agnostic efficacy in patients with advanced solid tumors with predefined FGFR alterations after failure of standard therapies (Pant 2023). Here, we report results on patients with breast cancer in the RAGNAR study. Methods: Patients with breast cancer and prespecified FGFR1-4 alterations (mutations or fusions) who had documented disease progression after exhausting standard therapies received oral erdafitinib 8 mg daily with optional up-titration until disease progression or intolerable toxicity. The primary end point was objective response rate by Independent Review Committee (IRC). Secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and safety. Results: At data cutoff (median follow up, 30.3 months), 16 patients with breast cancer received erdafitinib. Median age was 54 y (range 37-74); all (100%) patients were female and had visceral metastases. Patients had a median of 5 prior lines of systemic therapies (range 2-12); one (6%) patient had responded to the last line of therapy. Ten (63%) patients had FGFR fusions, and 6 (38%) had FGFR mutations. Mutations of TP53 and PIK3CA were found in 6/16 patients. Objective response rate and disease control rate by IRC were 31% (95% CI 11-59) and 69% (95% CI 41-89); objective response rate and disease control rate by investigator were 38% (95% CI 15-65) and 69% (95% CI 41-89), respectively. Median time to onset of response was 1.4 months. Responses were observed in patients with both FGFR2 fusions and with FGFR2/3 mutations. Median duration of response, progression free survival, and overall survival were 6.9 months, 5.7 months, and 8.9 months, respectively. Common adverse events (AEs) included stomatitis (81%), diarrhea (69%), and hyperphosphatemia (69%), dry mouth (63%), and palmar-plantar erythrodysesthesia (44%). Six (38%) patients had serious AEs. No patients discontinued erdafitinib due to AEs. No treatment-related deaths were observed. Conclusions: Erdafitinib demonstrated clinically meaningful activity in heavily pretreated patients with breast cancer and prespecified FGFR alterations. Safety data were consistent with the erdafitinib safety profile. Clinical trial information: NCT04083976 .

Association between somatic mutation pathways and treatment response in patients with biliary tract cancers (BTCs).

e16196 Background: Comprehensive somatic genomic profiling has become the standard of care for patients with BTCs, serving to identify targetable mutations and aiding in prognostication. While previous studies have identified individual somatic mutations such as TP53, CDKN1A, and KRAS as negative prognostic markers, little is known about their role as predictive biomarkers. This study aimed to investigate the predictive potential of somatic mutations and pathways using commercially available next-generation sequencing. Methods: We conducted a retrospective cohort study at Beth Israel Deaconess Medical Center (BIDMC) from January 2016 to January 2023, with data censoring in January 2024. Patient characteristics, including age, gender, race, stage, site of metastasis, performance status, and survival status, were collected. Somatic genomic alterations data were extracted from FoundationOneCDx, a commercially available NGS platform designed to capture 324 genetic alterations validated for therapy targets or unambiguous drivers of oncogenesis. Genetic alterations were classified into 14 oncogenic pathways constructed based on the TCGA and Reactome databases. Multivariate Cox proportional hazards regression analysis was performed between pathway alterations, progression-free survival and overall survival, accounting for selected covariates with p < 0.05 or potential known confounders. Results: Among 97 BTCs, 90 were successfully sequenced. Among these, 40 patients received gemcitabine and cisplatin, and 28 received fluorouracil and oxaliplatin (FOLFOX) therapy. Intrahepatic cholangiocarcinoma was present in 70% of cases, perihilar or distal cholangiocarcinoma in 27%, and gallbladder carcinoma in 3%. At presentation, 18% had stage I disease, and 44% had stage IV. The median follow-up time was 15 months. A total of 339 genomic alterations were identified, with 8% of samples harboring FGFR fusion or mutation, 9% IDH1 mutation, 6 % HER2 amplification, 30% KRAS mutation, and 32% with TP53 mutation. The most affected pathways were the cell cycle (66%) and DNA repair (50%). In multivariate regression analysis accounting for age, ECOG, and anatomical location, TP53 mutation was associated with shorter progression-free survival on gemcitabine and cisplatin treatment (n = 11, 2 vs. 6 months, HR 4.19, 95% CI 1.51 – 11.7, p < 0.01), whereas cell cycle pathway mutation was associated with longer progression-free survival (n = 14, 6 vs. 5 months, HR = 0.43, 95% CI 0.19-0.96, p < 0.05). No association was found between oncogenic pathways and treatment response to FOLFOX therapy. Conclusions: TP53 mutation is associated with a worse response, whereas cell cycle pathway mutations are associated with an improved response to gemcitabine and cisplatin therapy in patients with BTCs. Further research is needed to understand the mechanisms contributing to these observed effects.

Multifocal Papillary Thyroid Carcinomas With Discordant Molecular Drivers: Emphasizing the Morphology and Collision Tumors.

Multifocal papillary thyroid carcinomas (PTCs) are common and the majority of the tumors harbor mutual BRAF p.V600E mutation. This study aimed to investigate a contemporary series of multifocal PTCs with discordant molecular drivers. Consecutive thyroidectomies diagnosed with multifocal PTCs ≥0.5cm between 2019 and 2023 were reviewed. Immunohistochemistry (IHC) for BRAF VE1 was performed for all tumors. Cases with discordant BRAF IHC results or morphologic discrepancy were identified, and BRAF IHC-negative tumors were subjected to RAS Q61R IHC and/or targeted RNA next-generation sequencing. A total of 770 patients with a main PTC ≥0.5cm were identified; 255 (33.1%) had multifocal disease, and 142 (18.4%) had at least another PTC ≥0.5cm. Among them, 13 cases (9.2%, 13/142) had discordant molecular drivers. Twelve cases had one or more BRAF-positive PTCs accompanied by a BRAF-negative PTC (3 with CCDC6::RET fusion, 1 with NCOA4::RET fusion, 1 with ACBD5::RET fusion, 2 with ETV6::NTRK3 fusion, 1 with TG::FGFR1 fusion, 1 with LMTK2::BRAF fusion, 1 with AGK::BRAF fusion and RAS p.Q61R mutation, 1 with RAS p.Q61R mutation, and 1 without detectable molecular drivers). The last case had tumors with discordant fusion drivers (VIM::NTRK3 and TNS1::BRAF). Most cases showed tumors that were morphologically distinct (92.3%, 12/13) and occurred in the contralateral lobes (76.9%, 10/13). Notably, we identified 4 cases (30.8%) that presented as collision tumors and 6 cases (46.2%) that showed lymph node metastases, including 2 with simultaneous involvement by tumors with discordant molecular drivers, as novel findings. In summary, a subset (9.2%) of multifocal PTCs had discordant molecular drivers and 84.6% of them were a combination of BRAF-positive and kinase gene fusion-associated PTCs, most with distinct morphologies. Almost half of the cases had nodal metastasis and a third of them showed simultaneous involvement by tumors with discordant molecular drivers. The results highlight the clinical importance of identifying such cases, given the potentially different treatments.

The combination of gemcitabine plus an anti-FGFR inhibitor can have a synergistic antitumor effect on FGF-activating cholangiocarcinoma

Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50 = 19.3, 22.6 mg/dl, p = 0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50 = 7.18,7.60 nM, p = 0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.

Abstract B014: FGFR inhibition upregulates Nectin-4 expression in FGFR3 altered urothelial carcinoma

Abstract Bladder urothelial carcinoma (UC) is a common malignancy and remains a significant cause of mortality; however, in recent years there have been substantial advances in the treatment of metastatic UC (mUC). This includes the approval of the antibody drug conjugate (ADC) enfortumab vedotin, which targets Nectin-4, and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib (in FGFR2/3 altered tumors). Despite the impressive efficacy of these agents, most patients will ultimately develop progressive disease, underlining the need for further therapeutic development. Previous work has demonstrated that NECTIN4 expression and FGFR3 alterations are enriched in luminal subtypes of UC and NECTIN4 expression is higher in FGFR altered tumors. We validate these findings in scRNAseq from primary tumors as well as bulk RNAseq from murine models. Given the positive correlation between NECTIN4 and FGFR3 alterations we hypothesized that FGFR3 inhibition would downregulate Nectin-4 expression. To our surprise we found in vitro treatment with erdafitinib in cell lines with FGFR3 fusion proteins (RT112, RT4, SW780) lead to an increase in Nectin-4 protein levels. Additionally, in vitro FGFR inhibition in the UMUC-14 cell line which harbors an FGFR3S249C hotspot mutation, upregulates Nectin-4 protein levels. To further investigate this phenomenon, we engineered the FGFR3 WT cell line, 5637 to overexpress FGFR3-TACC3 or FGFR3S249C. We saw that FGFR3-TACC3 and FGFR3S249C overexpression both down regulated Nectin-4 indicating that FGFR3 activity negatively regulates Nectin-4 expression. We have also investigated the association between FGFR inhibition and Nectin-4 expression in two in vivo models: (1) in a xenograft model using the RT112 line we found an overall increase in Nectin-4 expression in tumors treated with a 5-day course of erdafitinib; (2) in a UPFL1 (a cell line derived from a genetically engineered mouse with a S249C mutation) syngeneic model we also saw an increase in Nectin-4 expression after erdafitinib treatment. We have observed that the increase in Nectin-4 expression persists in vitro even after withdrawal of erdafitinib treatment, indicating that intermittent dosing of erdafitinib maybe be sufficient to prime a tumor for Nectin-4 targeted therapy. Lastly, preliminary in vitro investigation of the combination of erdafitinib and enfortumab vedotin in RT112 cells showed synergy, particularly with lower doses of both agents, providing further support of our hypothesis that FGFR3 inhibition may act to sensitize UC to Nectin-4 ADC therapy. A potential synergistic relationship is further supported by the recent results of the phase 1 trial investigating the combination of erdafitinib plus enfortumab vedotin in which the objective response rate was 100% (9/9 patients: 8 PRs & 1CR). Citation Format: Sean Clark-Garvey, Mi Zhou, Michael Sturdivant, Wolfgang Beckabir, Lucia Kim, E. Drew Toomer, Ian McCabe, Akihiro Hamada, Daniel Crona, Jeffrey S. Damrauer, William Y. Kim. FGFR inhibition upregulates Nectin-4 expression in FGFR3 altered urothelial carcinoma [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 B014.

Advances in Immunooncology and Precision Medicine in Cholangiocarcinoma

AbstractCholangiocarcinoma (CCA) is an uncommon but morbid cancer arising from the intrahepatic or extrahepatic bile ducts. CCA is frequently asymptomatic at early stages and is often unresectable or metastatic at the time of initial diagnosis. While chemotherapy remains the mainstay of treatment for most patients with advanced disease, the addition of immunotherapy to frontline treatment has improved survival and provided an alternative to perpetual chemotherapy. Furthermore, a variety of targeted therapies have demonstrated benefit in patients with specific biomarkers including FGFR2 fusions, IDH1 mutations, HER2 overexpression, and tumor agnostic markers such as NTRK and RET fusions, among others. This review will summarize the established roles of immunotherapy, targeted therapies, and their combinations in CCA as well as treatment strategies that are under development with potential to impact clinical practice in the coming years.

Futibatinib: A Review in Locally Advanced and Metastatic Cholangiocarcinoma.

Futibatinib (LYTGOBI®) is an oral small molecule compound that selectively, irreversibly and potently inhibits the tyrosine kinase activity of fibroblast growth factor receptor (FGFR)1-4. It is approved in the EU, Japan and the USA for the treatment of adults with locally advanced or metastatic cholangiocarcinoma (CCA) harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy. In the phase II part (FOENIX-CCA2) of a multinational phase I/II study in this patient population, monotherapy with futibatinib 20mg once daily was associated with clinically meaningful and durable responses, sustained health-related quality of life (HR-QOL), and a manageable safety profile with supportive care and as-needed dose modifications. Indeed, hyperphosphataemia (the most common all grade and grade 3 treatment-related adverse event) was manageable with phosphate-lowering therapy and dose reductions or interruptions. Although further efficacy and tolerability data are expected, current evidence indicates that futibatinib is a valuable targeted therapy option for adults with locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy, a patient population with limited treatment options and poor life expectancy.

Are FGFR Fusions and Mutations the Next Tumor-Agnostic Targets in Oncology?

Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma.

We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.

Genomic landscape of glioblastoma without IDH somatic mutation in 42 cases: a comprehensive analysis using RNA sequencing data.

Glioblastoma is a malignant brain tumor with a poor prognosis. Genetic mutations associated with this disease are complex are not fully understood and require further elucidation for the development of new treatments. The purpose of this study was to comprehensively analyze genetic mutations in glioblastomas and evaluate the usefulness of RNA sequencing. We analyzed 42 glioblastoma specimens that were resected in routine clinical practice and found wild-type variants of the IDH1 and IDH2 genes. RNA was extracted from frozen specimens and sequenced, and genetic analyses were performed using the CLC Genomics Workbench. The most common genetic alterations in the 42 glioblastoma specimens were TP53 mutation (28.6%), EGFR splicing variant (16.7%), EGFR mutation (9.5%), and FGFR3 fusion (9.5%). Novel genetic mutations were detected in 8 patients (19%). In 12 cases (28.6%), driver gene mutations were not detected, suggesting an association with PPP1R14A overexpression. Our findings suggest the transcription factors SOX10 and NKX6-2 are potential markers in glioblastoma. RNA sequencing is a promising approach for genotyping glioblastomas because it provides comprehensive information on gene expression and is relatively cost-effective.

Recent Advances in Pathology of Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICCA) is a malignant epithelial neoplasm characterized by biliary differentiation within the liver. ICCA is molecularly heterogeneous and exhibits a broad spectrum of histopathological features. It is a highly aggressive carcinoma with high mortality and poor survival rates. ICCAs are classified into two main subtypes: the small-duct type and large-duct types. These two tumor types have different cell origins and clinicopathological features. ICCAs are characterized by numerous molecular alterations, including mutations in KRAS, TP53, IDH1/2, ARID1A, BAP1, BRAF, SAMD4, and EGFR, and FGFR2 fusion. Two main molecular subtypes-inflammation and proliferation-have been proposed. Recent advances in high-throughput assays using next-generation sequencing have improved our understanding of ICCA pathogenesis and molecular genetics. The diagnosis of ICCA poses a significant challenge for pathologists because of its varied morphologies and phenotypes. Accurate diagnosis of ICCA is essential for effective patient management and prognostic determination. This article provides an updated overview of ICCA pathology, focusing particularly on molecular features, histological subtypes, and diagnostic approaches.

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma.

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.

Molecular biology of cholangiocarcinoma and its implications for targeted therapy in patient management

Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of ‘druggable’ genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. As our understanding of the biology underpinning CCA continues to improve it is highly likely that additional targeted therapies will become available in the near future. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

Abstract 1755: Integrative genomic and transcriptomic profiles from a prospective cervical cancer study (RAIDs)

Abstract Background: Cervical cancer (CC) remains a leading cause of gynecological cancer related mortality worldwide and constitutes the third most common malignancy in women. We have previously reported a “metagene” of genomic markers in the PI3K pathway and epigenetic regulators associated with poor outcome. Immune therapy recently showed promising results yet new biomarkers for targeted therapeutic approaches in this type of cancer remain to be determined. Patients & Methods: Patients included in this study were enrolled in BioRAIDs [NCT02428842]. Whole exome sequencing (WES), shallow whole genome sequencing (sWGS) and RNA sequencing were performed on quality-controlled primary frozen tumor samples in 297, 306 and 280 patients, respectively who subsequently had received primary radio chemotherapy. Multi-omics bioinformatics analyses were performed to identify alterations representing new valid drug targets in CC. Tumor-stromal characteristics such as transcriptome deconvolution, CD8+, CD45+, CD68+ staining cells, PD-L1 expression, tumor infiltrating lymphocytes (TILs) together with the degree of tumor necrosis were assessed. Results: 273/306 were HPV positive (89%). Most frequently altered (≥10%) oncogenes were PIK3CA (30%) and TERT promoter (14%). Most frequently altered (≥10%) tumor suppressor genes were FBXW7 (14%), KMT2D (11%), KMT2C (11%) and FAT1 (11%).Microsatellite instability (MSI) was detected in 8/297 (3%) patients, homologous recombination deficiency (HRD)-high status in 8/297 (3%) patients and TMB-high (>10mut/Mb) in 32/297 (11%) patients. The most frequent mutational signatures were APOBEC, deaminase and MMR (DNA mismatch repair deficiency (74%, 28% and 11% respectively). Interestingly, FGFR3 fusions were detected in 8/297 patients (3%). Transcriptomic analyses showed 510 differentially expressed genes between HPV positive and HPV negative CC (adjusted p-value<0.01 and |log2FC|>1). No significantly differentially expressed genes were detected between FIGO 2018 stages (I/II vs III-IV). Both stages as well as tumor necrosis were highly significantly associated with progression-free survival (PFS), with tumor necrosis as an independent prognostic factor in a multivariable analysis (p<0.001).Presence or absence of CD8-positive lymphocytes, or CD68-positive cells of the myeloid cell compartment, histopathological subtype or number of TILs did not correlate with PFS. Conclusion: Our results confirm the high level of altered genes involved in chromatin remodeling with or without PI3K pathway mutations suggesting the relevance of epidrugs in CC. FGFR3 fusions and HRD tumors - although being rare (3%) - to be considered as new targeted approaches. Additionally, MSI and TMB high are of interest for immunotherapy beyond PD-L1 expression. Integrative analyses of omics and pathology data and correlation with PFS are ongoing and will be presented in the meeting. Citation Format: Maud Kamal, Solenn Barraud, Lolita Lecompte, Maral Halladjian, Emmanuelle Jeannot, Elodie Girard, Sylvain Baulande, Patricia Legoix, Fabrice Lecuru, Léa Pauly, Mathilde Saint-Ghislain, Stacy Cyrille, Célia Dupain, Constance Lamy, Olfa Chouchane-Mlik, Alexandra Oniga, Michel Mittelbronn, Christophe Le Tourneau, Aurélien Latouche, Nicolas Servant, Suzy Scholl, Ivan Bièche. Integrative genomic and transcriptomic profiles from a prospective cervical cancer study (RAIDs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1755.

Abstract 2857: Perspectives from a systematic review of kinase fusion oncogenes and access to corresponding kinase inhibitor clinical trials in pediatric, adolescent, and young adult solid malignancies

Abstract Oncogenic kinase fusions (KFs) have been reported in pediatric, adolescent, and young adult (P-AYA) brain tumors, sarcomas, and rare solid malignancies. Molecularly targeted therapy (MTT) matched to KFs generally produce objective responses even in advanced P-AYA malignancies. KFs occur across a broad age range of P-AYA cancer diagnoses (dx) so data on KF prevalence and the relationship between KFs and clinical characteristics including response and resistance to MTT is distributed across many studies. To address resulting knowledge gaps, we conducted a systematic review of KFs reported in P-AYA cancers and assessed the availability of clinical trials (CTs) for P-AYA patients with KF malignancies. A systematic literature search was conducted with PubMed using publication date 2013-2022, search terms for dx, age, and gene names of interest (BRAF, RAF1, NTRK1-3, ALK, FGFR1-4, MET, RET, ROS1). Known P-AYA cancer sequencing studies were also reviewed. Papers were included if they reported ≥1 patient <18 yo with a KF cancer of any type or ≤30 yo with a KF P-AYA cancer dx. Data abstracted included paper type, KF gene and partner, dx, fusion breakpoints, age, stage, MTT received, response to MTT, and CT enrollment. Clinicaltrials.gov was queried for interventional CTs in the U.S. assessing relevant MTTs. We identified 531 studies (299 case reports/series; 119 P-AYA sequencing studies) reporting 4,329 patients with a KF P-AYA solid tumor. Brain tumors had, in decreasing order of frequency, BRAF, NTRK, FGFR, ALK, ROS1, RAF1, MET, and RET fusions. Dx in which KFs were reported were LGG (n=2451), HGG (n=298), embryonal tumors (n=16), ependymomas (n=8), meningioma (n=1), and other (n=16). Extracranial solid tumors (EST) had, in decreasing order of frequency, NTRK, RET, ALK, BRAF, ROS1, MET, FGFR, and RAF1 fusions. Dx in which KFs were reported were thyroid cancer (n=607), sarcoma (n=546), melanoma and spitz tumor (n=183), renal tumor (n=90), carcinoma (n=57), rhabdomyosarcoma (n=12), neuroblastoma (n=11), osteosarcoma (n=9), and other (n=24). As of Aug 23, 2023, 476 CTs were assessing 65 inhibitors relevant for these KFs, of which only 20 are currently FDA-approved. Patients <18 yo were only eligible for 16% of CTs. RET (47%), RAF/BRAF (33%), and NTRK (32%) inhibitors had the highest percent of CTs enrolling patients <18 yo while ERK (4%) and FGFR (6%) inhibitors had the least. Notably, while 467 P-AYA patients identified in our review were <18 yo and had an ALK- or ROS1-fusion positive tumor, only 24% of ALK or ROS1 inhibitor CTs allowed enrollment of patients <18 yo. To our knowledge, this is the first systematic review of KFs in P-AYA solid tumors. Oncogenic KFs are common and occur across P-AYA solid and brain tumor dx demonstrating a need for CTs of relevant MTTs including patients <18 yo, particularly for drugs targeting ALK, ROS1, and FGFR. Citation Format: Lorena Lazo de la Vega, Sebastian K. Eder, Ellen Sukharevsky, Zachary A. Kahn, Michaela O'Connell, Franziska Wachter, Emily P. Anderson, Maria C. Trissal, Jenna J. LaBelle, Kendall Carpenter, Leo Kager, Mariella G. Filbin, Katherine A. Janeway. Perspectives from a systematic review of kinase fusion oncogenes and access to corresponding kinase inhibitor clinical trials in pediatric, adolescent, and young adult solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2857.

Abstract 6898: Cholangiocarcinoma patient-derived models in the NCI Patient-Derived Models Repository

Abstract Cholangiocarcinoma (CHOL) is an aggressive rare malignancy arising in the biliary tract with a 5-year relative survival rate of 10% and a 60-70% recurrence rate following surgical intervention. Advances in treatment strategies are hampered by the lack of well annotated and characterized preclinical models. The National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) has developed a national repository of Patient-Derived Models (PDMs) comprised of patient-derived xenografts (PDXs), in vitro patient-derived tumor cell cultures (PDCs) and cancer associated fibroblasts (CAFs) as well as patient-derived organoids (PDOrg). These PDMs are clinically annotated with molecular information available in an easily accessible database for the extramural community. To date, 94 patient CHOL tumor specimens (resections, biopsies, rapid autopsy) have been received from 55 unique patients with an overall PDX take rate of 36.3% (80 assessable specimens). There are currently 15 CHOL PDX models available for the research community to request with 14 more in final QC. Nine of the 15 public PDX models were generated from unique lesions in two rapid autopsy patients and while histo-morphologically consistent, some genomic heterogeneity is observed between the unique anatomical locations likely due to tumor evolution during metastasis. In addition, 27 in vitro PDOrgs, PDCs, and CAFs have been generated from patient or PDX material matched to most of the existing PDX models to allow for comparative translation research. The genetic landscape of the CHOL PDXs includes oncogenic drivers in NRAS, IDH1, ERBB2, TP53, KRAS and FGFR2 fusions; OncoKB likely oncogenic variants including ARID1A, AXIN1 and BAP1; and CDKN2A deep deletions representing most of the common alterations in CHOL. Early passage preclinical PDX and in vitro models for CHOL, and many other cancer types, with translational relevant features along with associated NextGen sequencing and patient treatment history are available from the NCI PDMR. Availability of preclinical models that can be used to study these cancers and improve preclinical drug screening is of high importance to better understand the biology of these cancers and prioritize novel therapeutics from bench to clinic. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yvonne A. Evrard, Cindy R. Timme, Biswajit Das, Gareth Bliss, Carrie Bonomi, Carley Border, Ting-Chia Chang, Alice Chen, Li Chen, Michelle A. Crespo-Eugeni, Kevin Cooper, Natalie Czarra, Isabella Czernia, Kelly Dougherty, Marion Gibson, Tara Grinnage-Pulley, Shahanawaz Jiwani, Keegan Kalmbach, Chris A. Karlovich, Chelsea McGlynn, Michael Mullendore, Matthew Murphy, Rini Pauly, Kevin Plater, Jessica Steed, Luke Stockwin, Shannon Uzelac, Peter I-Fan Wu, Dianne L. Newton, P. Mickey Williams, Melinda G. Hollingshead, James H. Doroshow. Cholangiocarcinoma patient-derived models in the NCI Patient-Derived Models Repository [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6898.

Abstract 1965: 3HP-2827-high selective inhibitor of FGFR2, a best-in-class therapy for FGFR2-driven solid tumors

Abstract FDA-approved pan-FGFR inhibitors bring encouraging results in solid tumors. However, resistance mechanisms and side effect profiles may limit their clinical utility. We designed 3HP-2827, a highly selective and potent small molecule inhibitor of FGFR2, to treat solid tumors harboring FGFR2 alterations, including amplifications, mutations, and fusions to overcome these limitations. 3HP-2827 inhibits FGFR2 enzyme activity with more than 1623-fold selectivity over FGFR1 and FGFR3. 3HP-2827 inhibits cell proliferation with IC50 <10 nM and 30 nM in FGFR2 amplified and FGFR2-mutant cancer cell lines, respectively. 3HP-2827 demonstrates high kinome selectivity for FGFR2 against a panel of 485 human kinases, resulting in 90.1% inhibition of FGFR2, and no other kinases showed greater than 75% inhibition. 3HP-2827 leads only modest activity at 10 µM against PDE4D2 and LCK in 44 distinct common adverse drug reaction targets, supporting its high degree of safety. 3HP-2827 also demonstrates a dose-dependent inhibition of phosphorylation of FGFR2 and FGFR2 signaling pathway nodes, including ERK and AKT, in the FGFR2-dependent cancer cell line. In vivo, 3HP-2827 demonstrates potent antitumor activity in cell- and patient-derived xenograft mouse models, including FGFR2-amplified gastric cancer, FGFR2-mutant (N549K) endometrial cancer, FGFR2 fusion ICC and gastric cancers. Strikingly, 3HP-2827 demonstrates superior activity in patient-derived ICC and gastric cancer, cell-derived endometrial cancer (CDX) in tumor and pFGFR2 inhibitions. In the ICC PDX model, 3HP-2827 also induces the regression of pemigatinib-resistant tumors. 3HP-2827 is well tolerated in the toxicology studies, and no hyperphosphatemia or tissue mineralization is observed at 150 mg/kg/kg/day in rats and 120 mg/kg/day in dogs. The data support that 3HP-2827, a potential to be a best-in-class selective FGFR2 inhibitor, will be studying clinically at the beginning of 2024. Citation Format: Susan S. Liu-Chen, Jufang Lin, Jingyu Hu, Yanchao Liu, Weibo Zhang, Zhixiong Zhang, Yan Ding, Jinqiu Liu, Kevin Chen, Shaojing Hu. 3HP-2827-high selective inhibitor of FGFR2, a best-in-class therapy for FGFR2-driven solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1965.

Abstract 1968: Discovery of a highly potent and selective FGFR2 inhibitor for FGFR2-driven cancers

Abstract Fibroblast growth factor receptor 2 (FGFR2) is a clinically validated target and frequently altered in many solid tumors. The resulting oncogenic driver alterations often drive multiple solid tumors. Therefore, targeting FGFR2 has broad therapeutic potential. Currently, only pan-FGFR inhibitors are approved for FGFR2-driven intrahepatic cholangiocarcinoma, but not for other FGFR2-driven cancers. Due to the severe on-target toxicity associated with inhibition of FGFR1 and FGFR4, the use of the pan-FGFR inhibitors has been very limited. Thus, developing a selective FGFR2 inhibitor addresses the unmet medical need as the treatment options for FGFR2-altered cancers remain limited. Here we report the discovery and characterization of a highly selective FGFR2 inhibitor, ACE-16229210. This molecule potently inhibits FGFR2 (IC50 = 6.2 nM) and exhibits excellent selectivity (>133-fold) over other FGFR1 and FGFR4 in biochemical assays. It also potently (IC50 <1 nM) and selectively (≥500-fold) inhibits FGFR2-induced ERK phosphorylation in multiple cancer cell lines harboring FGFR2 fusions, amplification, and mutations, but not those harboring FGFR1, FGFR3, or FGFR4 genetic alterations (IC50 > 460 nM). Furthermore, this molecule, when evaluated in a panel of 24 cell lines, demonstrates potent anti-proliferative activity against the cell lines harboring FGFR2, but not FGFR3, and especially FGFR1, or FGFR4 genetic alterations. Thus, ACE-16229210 is a potent and selective FGFR2 inhibitor. Interestingly, it exhibits the most potent activity against gatekeeper and molecular brake mutations followed by fusions, amplification, and activation loop mutations. This molecule shows a robust broad spectrum of antitumor activity with significant tumor regression at low doses (1-10 mg/kg) in several tumor xenograft and PDX models representing the major FGFR2 relevant tumor histologies including gastric, breast, ovarian, and endometrial cancers harboring clinically important FGFR2 driver alterations with a well-defined pharmacokinetic/pharmacodynamic relationship. This molecule also demonstrates strong synergistic effects when combined with irinotecan and fulvestrant in a gastric tumor model and a breast cancer PDX model harboring FGFR2 amplification, respectively. Finally, ACE-16229210 did not significantly affect serum phosphorus levels in animals at the exposure levels that are >100-fold higher than the efficacious AUC, further confirming its excellent selectivity over FGFR1. Taken together, these in vitro and in vivo studies show that ACE-16229210 is a potent and selective FGFR2 inhibitor with the potential to be developed into a more effective treatment option for multiple cancers harboring FGFR2 oncogenic driver alterations. Citation Format: Wenqian Li, Bin Liu, Junmei Wang, Tinggui Yin, Kuo-Long Yu, Sanjeev Kumar, Zhiming Wen, Genshi Zhao, Weitao Pan. Discovery of a highly potent and selective FGFR2 inhibitor for FGFR2-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1968.

The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations.

FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 and FGFR3 alterations are most prevalent in intrahepatic cholangiocarcinoma (ICC) and bladder cancers, respectively, and multiple selective reversible and covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved in these contexts. However, resistance, often due to acquired secondary mutations in the FGFR2/3 kinase domain, limits efficacy. Resistance is typically polyclonal, involving a spectrum of different mutations that most frequently affect the molecular brake and gatekeeper residues (N550 and V565 in FGFR2). Here, we characterize the activity of the next-generation covalent FGFR inhibitor, KIN-3248, in preclinical models of FGFR2 fusion+ ICC harboring a series of secondary kinase domain mutations, in vitro and in vivo. We also test select FGFR3 alleles in bladder cancer models. KIN-3248 exhibits potent selectivity for FGFR1-3 and retains activity against various FGFR2 kinase domain mutations, in addition to being effective against FGFR3 V555M and N540K mutations. Notably, KIN-3248 activity extends to the FGFR2 V565F gatekeeper mutation, which causes profound resistance to currently approved FGFR inhibitors. Combination treatment with EGFR or MEK inhibitors potentiates KIN-3248 efficacy in vivo, including in models harboring FGFR2 kinase domain mutations. Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers.

A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality.

The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.