Fusion-positive Tumors Research Articles

Real-world Experience With Neurotrophic Tyrosine Receptor Kinase Fusion-positive Tumors and Tropomyosin Receptor Kinase Inhibitors in Veterans.

Neurotrophic tyrosine receptor kinase 1-3 (NTRK1-3) gene fusions are found in a broad range of tumor types. Clinical trials demonstrated high response rates to tropomyosin receptor kinase (TRK) inhibitors in NTRK fusion-positive cancers, but few reports have described real-world experience with these targeted agents. We evaluated the prevalence of NTRK fusions and the outcomes with TRK inhibitor therapy in a real-world population of patients in the Veterans Health Administration. Patients with NTRK fusions or rearrangements were identified from the Veterans Affairs (VA) National Precision Oncology Program (NPOP), and patients who were prescribed TRK inhibitors were identified from the Corporate Data Warehouse. Baseline data and clinical outcomes were obtained by retrospective review of medical records. A total of 33 patients with NTRK fusions or rearrangements were identified, including 25 patients comprising 0.12% of all patients with solid tumors sequenced through VA NPOP. Twelve patients with NTRK fusions or rearrangements were treated with TRK inhibitors, none of whom had objective responses. Eight patients experienced toxicities leading to drug interruption, dose reduction, or discontinuation. In this retrospective study of VA patients, NTRK fusions and rearrangements were less common than in previous studies, and objective responses to TRK inhibitors were not observed. Real-world experience with TRK inhibitors differs markedly from clinical trial findings, possibly due to differences in patient demographics, tumor types, and sequencing methods. Our findings highlight the need to study TRK inhibitors in the real-world setting and in populations underrepresented in clinical trials.

Entrectinib dose confirmation in pediatric oncology patients: pharmacokinetic considerations

PurposeEntrectinib is a central nervous system-active potent inhibitor of tropomyosin receptor kinase (TRK), with anti-tumor activity against neurotrophic NTRK gene fusion-positive tumors. This study investigates the pharmacokinetics of entrectinib and its active metabolite (M5) in pediatric patients and aims to understand whether the pediatric dose of 300 mg/m2 once daily (QD) provides an exposure that is consistent with the approved adult dose (600 mg QD).MethodsForty-three patients aged from birth to 22 years were administered entrectinib (250–750 mg/m2 QD) orally with food in 4-week cycles. Entrectinib formulations included capsules without acidulant (F1) and capsules with acidulant (F2B and F06).ResultsAlthough there was interpatient variability with F1, entrectinib and M5 exposures increased dose dependently. Lower systemic exposures were observed in pediatric patients receiving 400 mg/m2 QD entrectinib (F1) versus adults receiving either the same dose/formulation or the recommended flat dose of 600 mg QD (~ 300 mg/m2 for a 70 kg adult) due to suboptimal F1 performance in the pediatric study. The observed pediatric exposures following 300 mg/m2 QD entrectinib (F06) were comparable to those in adults receiving 600 mg QD.ConclusionsOverall, the F1 formulation of entrectinib was associated with lower systemic exposure in pediatric patients compared with the commercial acidulant formulation (F06). Systemic exposures achieved in pediatric patients with the F06 recommended dose (300 mg/m2) were within the known efficacious range in adults, confirming the adequacy of the recommended dose regimen with the commercial formulation.

Exploring the binding characteristics of bovine serum albumin with tyrosine kinase inhibitor entrectinib: Multi-spectral analysis and theoretical calculation

Entrectinib (ENB) is one of multi-target tyrosine kinase inhibitors, which is mainly used for treating neurotrophic tyrosine receptor kinase gene fusion positive solid tumors. The binding characteristics of ENB and bovine serum albumin (BSA) were studied by experiments and theoretical calculations. The steady-state fluorescence showed that ENB quenched the fluorescence of BSA through mixed quenching, and ENB was dominated by static quenching at low concentration. ENB and BSA had a moderate affinity, formed a complex with a stoichiometric ratio of 1:1 and the binding constant of about 105 M−1 at 298 K, and Förster non-radiative energy transfer occurs. According to the driving force competition experiment, thermodynamic parameter analysis and theoretical calculation, hydrogen bond, van der Waals force and hydrophobic force were the main factors affecting the stability of the ENB-BSA complex. Molecular docking and site markers competition showed that ENB spontaneously bound to the Site III of BSA so that ENB could make the skeleton of BSA loose, the spatial structure of BSA changed (α-helix decreased by 3.1%, random coil increased by 1.7%), and the microenvironment of Tyr and Trp residues changed. The existence of Co2+ metal ions can enhance the binding effect, thus prolonging the half-life of ENB in vivo, which may improve the efficacy of ENB, while Ca2+, Cu2+ and Mg2+ metal ions will reduce the efficacy of ENB.

Genomic landscape of 891 RET fusions detected across diverse solid tumor types

In this study, we report the clinicopathologic and genomic profiles of 891 patients with RET fusion driven advanced solid tumors. All patient samples were tested using a tissue-based DNA hybrid capture next generation sequencing (NGS) assay and a subset of the samples were liquid biopsies tested using a liquid-based hybrid capture NGS assay. RET fusions were found in 523 patients with NSCLC and in 368 patients with other solid tumors. The two tumor types with the highest number of RET fusion were lung adenocarcinoma and thyroid papillary carcinoma, and they had a prevalence rate 1.14% (455/39,922) and 9.09% (109/1199), respectively. A total of 61 novel fusions were discovered in this pan-tumor cohort. The concordance of RET fusion detection across tumor types among tissue and liquid-based NGS was 100% (8/8) in patients with greater than 1% composite tumor fraction (cTF). Herein, we present the clinicopathologic and genomic landscape of a large cohort of RET fusion positive tumors and we observed that liquid biopsy-based NGS is highly sensitive for RET fusions at cTF ≥1%.

Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1, or RET Fusions

Neurotrophic tyrosine receptor kinase (NTRK) fusions define infantile fibrosarcomas in young children and NTRK-rearranged spindle-cell tumors in older children and adults, which share characteristic spindle-cell histology and CD34 or S100 protein expression. Similar phenotypes were identified in tumors with BRAF, RAF1, or RET fusions, suggesting a unifying concept of “spindle-cell tumors with kinase gene fusions.” In this study, we investigated CD30 expression in 38 mesenchymal tumors with kinase gene fusions using immunohistochemistry. CD30 was expressed in 15 of 22 NTRK-rearranged tumors and 12 of 16 tumors with BRAF, RAF1, or RET fusions. In total, CD30 was expressed in 27 of the 38 tumors (71%), with >50% CD30-positive cells in 21 tumors and predominantly moderate or strong staining in 24 tumors. CD34 and S100 protein were also expressed in 71% and 69% of the tumors, respectively. In contrast, CD30 was significantly less frequently expressed in other mesenchymal tumor types that histologically mimic kinase fusion–positive tumors (9 of 150 tumors, 6%), of which none showed >50% or predominantly strong staining. Among these mimicking tumors, malignant peripheral nerve sheath tumors occasionally (30%) expressed CD30, albeit in a weak focal manner in most positive cases. CD30 was also expressed in 3 of 15 separately analyzed ALK- or ROS1-positive inflammatory myofibroblastic tumors. Frequent expression of CD30 enhances the shared phenotype of spindle-cell tumors with NTRK and other kinase gene fusions, and its sensitivity seems similar to that of CD34 and S100 protein. Although moderate sensitivity hampers its use as a screening tool, CD30 expression could be valuable to rapidly identify high-yield candidates for molecular workup, particularly in communities that lack routine genetic analysis and/or for tumors with BRAF, RAF1, or RET fusions.

Precision oncology with selective RET inhibitor selpercatinib in RET-rearranged cancers.

Rearranged during transfection (RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways. Activating RET alterations can occur and lead to uncontrolled cellular proliferation as a hallmark of cancer development. Oncogenic RET fusions are present in nearly 2% of patients with non-small cell lung cancer (NSCLC), 10-20% of patients with thyroid cancer, and <1% across the pan-cancer spectrum. In addition, RET mutations are drivers in 60% of sporadic medullary thyroid cancers and 99% of hereditary thyroid cancers. The discovery, rapid clinical translation, and trials leading to FDA approvals of selective RET inhibitors, selpercatinib and pralsetinib, have revolutionized the field of RET precision therapy. In this article, we review the current status on the use of the selective RET inhibitor, selpercatinib, in RET fusion-positive tumors: NSCLC, thyroid cancers, and the more recent tissue-agnostic activity leading to FDA approval.

Metastatic rhabdomyosarcoma with exclusive distant lymph node involvement: A European Pediatric Soft tissue sarcoma Study Group (EpSSG) report.

The prognosis of patients with metastatic rhabdomyosarcoma (RMS) is not uniformly poor. Tumors with nodal involvement beyond the first lymph node station are currently considered to have distant metastases. The aim of this study is to evaluate the characteristics and outcome of RMS patients with distal nodal involvement as the only site of metastasis. This study included all patients with a diagnosis of RMS and distant nodal involvement as the only metastatic site, enrolled in the European Pediatric Soft tissue sarcoma Study Group (EpSSG) protocols. Treatment comprised chemotherapy, surgery, and/or radiotherapy. The main outcome measures were event-free survival (EFS) and overall survival (OS). A total of 22 patients (median age 7.1years, range 1.4-16.7) fit the inclusion criteria. The extremities were the most common primary tumor site (59%). Twenty-one patients had regional and distant nodal involvement, 12 were PAX3/7-FOXO1 positive. Twenty patients had radiotherapy including 16 to the nodal metastatic area. After a median follow-up of 53.9months (range 22.8-110.5), 15 patients remain in complete remission, seven had progressive disease or relapse, and six of them died. The 3-year EFS and OS were 67.1% (95% confidence interval [CI]: 42.9-82.9) and 71.9% (95% CI: 47.7-86.3), respectively. Patients with fusion-negative tumors had better outcomes than those with fusion-positive tumors (3-year EFS 100% vs. 46.6%; p=.04). In our experience, patients with RMS and distant lymph node involvement as the only site of metastasis present an outcome superior than other metastatic patients and comparable to patients with locoregional nodal involvement. In particular, excellent outcomes were seen in the limited number of patients with fusion-negative tumors.

CO118 TRK Inhibitor Treatment Patterns in Patients with NTRK Fusion-Positive Solid Tumors: A Multi-Site Cohort Study at U.S. Academic Cancer Centers

Neurotrophic receptor tyrosine kinase (NTRK) gene fusions are rare in solid tumors (<0.35%) yet incidence varies widely across cancer types. The first TRK inhibitor (TRKi) was approved by the FDA in November 2018 (larotrectinib) with a second TRKi (entrectinib) approved August 2019. This research aims to describe the TRKi treatment patterns in patients with NTRK-fusion positive solid tumors.

EE242 Cost-Effectiveness Analysis of Entrectinib for Treatment NTRK Fusion-Positive Tumors in Czech Republic

EE242 Cost-Effectiveness Analysis of Entrectinib for Treatment NTRK Fusion-Positive Tumors in Czech Republic

Çocukluk Çağı Kanserlerinde NTRK Somatik Füzyonları ve Tümör Agnostik Tedavi

Neurotrophic tyrosine receptor kinase (NTRK) gene rearrangements have been recently identified and developed as one of the biomarkers that have been utilized as new targets for cancer therapy. NTRK gene fusions have taken their place in individualized targeted therapy by being used as a predictive (diagnostic) biomarker as well as a treatment target. Selective inhibitors of NTRK fusion proteins have potent efficacy in the treatment of NTRK fusion-positive solid tumors. Detection of these fussions have become important since the finding of new drugs for which U.S. Food and Drug Administration (FDA) granted approval are used on the treatment of patients who has NTRK fussions positive cansers. Clinical trials have shown that first generation tyrosine receptor kinase (TRK) inhibitors, larotrectinib (Vitrakvi, Bayer HealthCare Pharmaceutical Inc, New Jersey, U.S.) and entrectinib (Rozlytrek, Genentech Inc, California, U.S.), have potent efficacy in the treatment of NTRK fusion positive cancers. In the future, with the increase in the number of comprehensive studies on these drugs further information will become available and beneficial.

Best of ASCO 2022—central nervous system tumors

SummaryIn this article, updates on novel therapy approaches in central nervous system tumors presented at the ASCO 2022 meeting are summarized. Promising outcome results on targeted therapies in rare entities such as neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors [1] and in v‑RAF murine sarcoma viral oncogene homolog (BRAF)V600 mutant pediatric glioma are reported [2, 3]. Furthermore, we shortly review data on additional administration of polyADP-ribose polymerase (PARP) inhibitor veliparib (Alliance A071102 trial) [4] and on a combinatorial immunotherapy regime (consisting of intramuscular administration of two synthetic DNA plasmids in combination with cemiplimab) in newly diagnosed glioblastoma patients [5].

NTRK Gene Fusions in Solid Tumors and TRK Inhibitors: A Systematic Review of Case Reports and Case Series

The approval of larotrectinib and entrectinib for cancer patients harboring an NTRK gene fusion has represented a milestone in the era of "histology-agnostic" drugs. Among the clinical trials that led to the approval of these two drugs, most of the enrolled patients were affected by soft tissue sarcomas, lung, and salivary gland cancer. However, as next-generation sequencing assays are increasingly available in the clinical setting, health care professionals may be able to detect NTRK gene fusions in patients affected by tumor types under or not represented in the clinical trials. To this aim, we systematically reviewed MEDLINE from its inception to 31 August 2022 for case reports and case series on patients with NTRK gene fusion-positive tumors treated with TRK inhibitors. A virtual cohort of 43 patients was created, excluding those enrolled in the above-mentioned clinical trials. Although our results align with those existing in the literature, various cases of central nervous system tumors were registered in our cohort, confirming the benefit of these agents in this subgroup of patients. Large, multi-institutional registries are needed to provide more information about the efficacy of TRK inhibitors in cancer patients affected by tumor types under or not represented in the clinical trials.

390P Entrectinib in Japanese patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC and NTRK-fp solid tumours

Entrectinib is a ROS1/TRK tyrosine kinase inhibitor (TKI) with CNS activity. In an integrated analysis of three phase I/II trials (ALKA-372-001 EudraCT 2012-000148-88; STARTRK-1 NCT02097810; STARTRK-2 NCT02568267), entrectinib showed overall response rates (ORRs) of 67% in pts with ROS1-fp NSCLC and 61% in pts with NTRK-fp solid tumours (data cutoff: 2 Aug 2021). We present primary data for the subset of Japanese pts from STARTRK-2.

264P Updated analysis of entrectinib in a subset of Chinese (mainland China, Hong Kong, Taiwan) patients (pts) with NTRK fusion-positive (fp) solid tumours and ROS1-fp non-small cell lung cancer (NSCLC)

Entrectinib is a CNS-active tyrosine kinase inhibitor that showed efficacy in pts with NTRK-fp solid tumours and ROS1-fp NSCLC from three phase 1/2 clinical trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267), including in a subset of Chinese (mainland China, Hong Kong, Taiwan) pts from STARTRK-2 (objective response rate [ORR]: 81% [NTRK-fp] and 63% [ROS1-fp]; data cutoff: 17 June 2021). We report updated data for this subset of patients, with a longer follow-up (enrolment/data cutoff: 17 Dec 2020/17 Dec 2021).

Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies

Intrahepatic cholangiocarcinoma (ICC) remains a deadly malignancy lacking systemic therapies for advanced disease. Recent advancements include selective FGFR1–3 inhibitors for the 15% of ICC patients harboring fusions, although survival is limited by poor response and resistance. Herein we report generation of a patient-derived FGFR2 fusion-positive ICC model system consisting of a cell line, organoid, and xenograft, which have undergone complete histologic, genomic, and phenotypic characterization, including testing standard-of-care systemic therapies. Using these FGFR2 fusion-positive ICC models, we conducted an unbiased high-throughput small molecule screen to prioritize combination strategies with FGFR inhibition, from which HDAC inhibition together with pemigatinib was validated in vitro and in vivo as a synergistic therapy for ICC. Additionally, we demonstrate broad utility of the FGFR/HDAC combination for other FGFR fusion-positive solid tumors. These data are directly translatable and justify early phase trials to establish dosing, safety, and therapeutic efficacy of this synergistic combination.

FGFR mRNA Expression in Cholangiocarcinoma and Its Correlation with FGFR2 Fusion Status and Immune Signatures.

Selective FGFR inhibitors are effective against cholangiocarcinomas that harbor gene alterations in FGFR2. Clinical trials suggest that expression of wild-type FGFR mRNA can predict sensitivity to FGFR inhibitors, but this biomarker has not been well characterized in cholangiocarcinoma. This study explores the prevalence of FGFR mRNA overexpression in cholangiocarcinoma, its role in predicting sensitivity to FGFR inhibitors, and its association with immune markers. Tissue microarrays of intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC) resected between 2004 and 2015 were used to evaluate FGFR1-4 mRNA expression levels by RNA in situ hybridization (ISH). Expression levels of FGFR2 mRNA were correlated with FGFR2 fusion status and with patient outcomes. Immune markers expression was assessed by IHC and CSF1 and CSF1 receptor expression were examined by RNA ISH. Among 94 patients with resected cholangiocarcinoma, the majority had ICC (77%). FGFR2 fusions were identified in 23% of ICCs and 5% of ECCs. High levels of FGFR mRNA in FGFR2 fusion-negative ICC/ECC were seen for: FGFR1 (ICC/ECC: 15%/0%), FGFR2 (ICC/ECC: 57%/0%), FGFR3 (ICC/ECC: 53%/18%), and FGFR4 (ICC/ECC: 32%/0%). Overall, 62% of fusion-negative cholangiocarcinomas showed high levels of FGFR mRNA. In patients with advanced FGFR2 fusion-positive ICC, high levels of FGFR2 mRNA did not correlate with clinical benefit. FGFR2 fusion-positive tumors showed a paucity of PD-L1 on tumor cells. FGFR mRNA overexpression occurs frequently in cholangiocarcinoma in the absence of genetic alterations in FGFR. This study identifies a molecular subpopulation in cholangiocarcinoma for which further investigation of FGFR inhibitors is merited outside currently approved indications.

8 Oral - Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors

8 Oral - Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors

209 (PB089) - Update from the ongoing phase 1/2 registrational trial of repotrectinib: results in TKI-naïve and TKI-pretreated patients with NTRK fusion-positive advanced solid tumors (TRIDENT-1)

Background: Repotrectinib is a selective, highly potent, next-generation ROS1 and TRK inhibitor that is currently under evaluation in the global registrational phase 1/2 TRIDENT-1 trial. Early clinical data from the TRIDENT-1 trial was presented in a plenary session at the 2021 AACR-NCI-EORTC conference. Repotrectinib was generally well tolerated. In NTRK fusion-positive tyrosine kinase inhibitor (TKI)-naïve (expansion cohort [EXP]-5) and TRK TKI-pretreated (EXP-6) patients with advanced solid tumors, confirmed overall response rates (cORR) per investigator assessment were 41% (95% CI: 18–67) and 48% (95% CI: 27–69), respectively.

Tissue-agnostic RET inhibition: can you trust your target?

The field of oncology has changed vastly over the past two decades with the advent of immunotherapy and the expansion of targeted agents. The basket trial design has emerged as a means to evaluate novel treatments in a tissue-agnostic fashion. To date, tissue-agnostic approvals exist for anti-PD-1 antibodies in the setting of mismatch repair deficiency or high microsatellite instability or high tumour mutational burden, as well as TRK inhibitors for NTRK fusions and dabrafenib plus trametinib for BRAFV600E mutations (table). Approvals of several of these drugs were based on analyses of not only so-called anchor malignancies (those in which a given mutation is most prevalent), but also those belonging to the long tail, meaning cancer types less commonly associated with the alteration of interest. FDA=US Food and Drug Administration. EMA=European Medicines Agency. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trialSelpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib. Full-Text PDF

110P Characteristics and survival outcomes of patients (pts) with RET fusion-positive (RET-fp) solid tumours receiving non-RET inhibitor (RETi) therapy in a real-world setting

RET alterations are oncogenic drivers in multiple solid tumours and can be targeted with effective and well tolerated RETis. The genomic landscape and natural history of pts whose tumours harbour RET fusions is unknown. We describe the clinical and demographic profiles of pts with RET-fp metastatic solid tumours receiving non-RETi therapy in a real-world setting and assess the value of RET fusions as prognostic biomarkers.