RET Fusion Research Articles

EP08.02-174 RET Fusions as Primary Oncogenic Drivers and Secondary Acquired Resistance to EGFR TKI in a Large Cohort of Non-Small-Cell Lung Cancers

RET fusions occur in 1-2% of non-small-cell lung cancers (NSCLCs), which are associated with unique clinical features and poor prognosis and may contribute to resistance to EGFR-TKIs. Despite the development of highly potent RET inhibitors, the genetic architecture of primary and secondary RET fusions in NSCLCs remains to be systematically elucidated.

980P Continuation of selpercatinib beyond progression in RET fusion-positive NSCLC: Data from LIBRETTO-001 study

Selpercatinib, a first-in-class highly selective RET kinase inhibitor with CNS activity, is approved in various regions for patients (pts) with RET fusion+ NSCLC. In other oncogene-addicted NSCLC settings, targeted treatment beyond RECIST progression (PD) in the case of solitary site or oligoprogression is commonly utilized and endorsed by guidelines.

1170P Updated efficacy and safety data from the phase I/II ARROW study of pralsetinib in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC)

Pralsetinib is FDA/EMA approved for the treatment of advanced RET fusion+ NSCLC based on the global multicohort, open-label, Phase 1/2 ARROW study. Prior results from ARROW show that pralsetinib has promising anti-tumour activity with a manageable safety profile in advanced RET fusion+ NSCLC (Gainor JF, et al. Lancet Oncol 2021). We present updated data from the RET fusion+ NSCLC cohort after an additional 16 months of follow-up since the previous analysis.

1007P Mechanisms of primary and secondary resistance to RET inhibitors in patients with RET-positive advanced NSCLC

RET fusions are found in 1-2% of patients (pts) with advanced non-small cell lung cancer (aNSCLC). Targeted therapy with RET inhibitors (RETi) significantly improved prognosis. Molecular mechanisms of resistance are still incompletely characterized.

72P Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET+ colorectal carcinoma as a unique molecular subset of CRC

Two selective RET tyrosine kinase inhibitors have been approved to treat RET fusion-positive (RET+) non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusions have been reported in other solid tumors.

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.

EP08.02-073 Clinical and Genomic Analysis of Primary and Secondary MET Fusions with Intact Kinase Domain in Lung Cancer

Several kinase gene fusions, including MET, have been uncovered as oncogenic alterations in lung cancer beyond the well-studied ALK, RET, and ROS1 fusions. As amplification and exon 14 skipping were the two most frequent MET alterations, MET fusions are rarely reported and less investigated. Though the potential role of MET fusions as a resistance mechanism to tyrosine kinase inhibitors (TKIs) has been proposed in a series of case reports, comprehensive studies remain to be performed in large cohorts.

EP08.02-120 MET Alterations at Presentation in NSCLC Patients Harboring EGFR Mutations and ALK, RET and ROS1 fusions

Although EGFR-mut and ALK, RET and ROS1 fusion-positive NSCLC patients are treated first-line with tyrosine kinase inhibitors (TKIs), some present intrinsic resistance and could benefit from combined treatments.To determine the frequency of MET gene amplification, MET mutations and MET mRNA high expression baseline in a large cohort of EGFR-mut and ALK, ROS1 and RET fusion-positive NSCLC patients; (ii) To analyze paired biopsies of EGFR and fusion positive patients showing MET amplification at progression to targeted therapies.

EP08.02-037 Small Cell Transformation in a Patient with RET Fusion Positive Lung Adenocarcinoma on Pralsetinib.

Approximately 1-2% of non-small cell lung cancers harbor activating fusions between the 3’ end of RET and the 5’ end of various partner genes. Tumors with RET fusions respond to RET tyrosine kinase inhibitors, however secondary resistance to RET inhibitors invariably ensues.

P2.07-02 RET Fusion Testing with FISH and Real-Time PCR: a Comparison with RNA-Based Next-Generation Sequencing in RET Positive NSCLC

Although next-generation sequencing (NGS) is now the gold-standard for lung cancer biomarker testing, single-gene assays are still used for different reasons. Therefore, we were intrigued by the perfomance of commonly used fluorescence in situ hybridization (FISH) and real-time PCR assays in a cohort of RET fusion-positive non-small cell lung carcinoma (NSCLC) patients.

Cystic Salivary Gland Neoplasms: Diagnostic Approach With a Focus on Ancillary Studies.

Cystic salivary gland cytology can be challenging due to the fact that a cystic mass can be the clinical presentation of both non-neoplastic and neoplastic conditions. Neoplastic lesions consist of both benign and malignant neoplasms. The cytomorphologic features of these entities can overlap and the cystic background may additionally contribute to the complexity of these lesions and their interpretation. Ancillary studies have been reported in several studies to be beneficial in further characterization of the cellular components and subsequent diagnosis of the cystic lesions of the salivary gland. Fluorescence in situ hybridization, real-time polymerase chain reaction, and next-generation sequencing are now being utilized to detect molecular alterations in salivary gland neoplasms. MALM2 rearrangement is the most common gene fusion in mucoepidermoid carcinoma. PLAG1 rearrangement is present in more than half of pleomorphic adenomas. AKT1:E17K mutation is the key diagnostic feature of the mucinous adenocarcinoma. NR4A3 overexpression is highly sensitive and specific for the diagnosis of acinic cell carcinoma. MYB fusion is noted in adenoid cystic carcinoma. ETV6:NTRK3 fusion is helpful in diagnosis of secretory carcinoma. p16 and human papillomavirus (HPV) studies differentiate HPV-related squamous cell carcinoma from non-HPV-related neoplasms with overlapping features. NCOA4:RET fusion protein is the main fusion in intraductal carcinoma.

Profiling of gene fusion involving targetable genes in Chinese gastric cancer.

BACKGROUNDApproximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIMTo identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODSWe retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTSWe found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB.CONCLUSIONWe characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.

Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial

RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n= 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Molecular testing in fine-needle aspiration of thyroid nodules.

Thyroid nodules are commonly faced by clinicians as palpable nodules or incidentally identified on imaging. Nodules that are found to be suspicious by imaging can be biopsied by fine needle aspiration, which can yield material for molecular testing to refine the diagnosis. The current literature concerning molecular testing in thyroid nodules including available commercial assays was reviewed and summarized. Commonly encountered alterations include mutations in RAS, BRAF, TERT promoter, PTEN, and DICER1 as well as fusions of RET, ALK, PAX8-PPARγ, and NTRK. This article provides a summary of these molecular alterations, commercially available molecular assays, and general considerations for thyroid epithelial malignancies and benign thyroid nodules.

Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial

Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW (NCT03037385, ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion–positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35–77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib’s potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion–positive solid tumors.

Indeterminate Thyroid Fine-Needle Aspirations in Pediatrics: Exploring Clinicopathologic Features and Utility of Molecular Profiling

Introduction: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis. Methods: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children’s Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics. Results: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) Pediatric Guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration. Conclusions: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.

Selpercatinib (Retevmo)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses selpercatinib (Retevmo), 40 mg and 80 mg, capsules, oral. Indication: As monotherapy for the treatment of metastatic RET fusion–positive non–small cell lung cancer in adult patients.

Molekular zielgerichtete Therapien beim radiojodrefraktären differenzierten Schilddrüsenkarzinom – Update 2022

BackgroundThe individualized use of systemic molecularly targeted therapies in radioiodine refractory differentiated thyroid cancer (DTC) should be limited to patients with large tumor burden and progressive, metastatic disease that is not amenable to other local palliative approaches or a “watch and wait” strategy. In addition to the two approved multityrosine kinase inhibitors lenvatinib and sorafenib, cabozantinib has recently been approved for second-line treatment. The identification of specific gene alterations, such as BRAFV600E mutation, RET or NTRK fusions as well as ALK fusions allows the very effective use of the respective selective inhibitors within tumor-agnostic approval or off-label use, or if available preferably within a clinical trial. The specific targeting of driver mutations has also been demonstrated to very effectively re-induce tumoral radioiodine uptake thereby re-establishing radioiodine therapy that has been successfully used in DTC for more than 80 years.ConclusionIn order to make use of targetable mutations within an individualized therapy concept, we highly recommend timely molecular analysis of tumor tissue in patients with radioiodine refractory DTC. Patients with advanced radioiodine refractory DTC should be referred to experienced centers that offer interdisciplinary expertise in the individualization of treatment including participation in clinical trials.

Non-small-cell lung cancer: how to manage RET-positive disease.

Targeted therapy has dramatically changed the history and outcomes of oncogene-addicted non-small-cell lung cancer (NSCLC). RET rearrangements are typically observed in about 1–2% of NSCLC, resulting in constitutive activation of downstream signalling pathways commonly involved in cell growth and survival. RET-positive NSCLCs are generally associated with young age, non-smoking history, a high rate of brain metastases at diagnosis and an immunologically ‘cold’ tumour microenvironment. Multi-kinase inhibitors, such as cabozantinib, lenvatinib and vandetanib, showed limited efficacy but significant toxicity mainly linked to off-target effects. In contrast, two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, demonstrated high response rates and manageable safety profiles, and have received FDA approval for the treatment of advanced RET-positive NSCLC regardless of previous lines of treatment. Despite the initial high response rate to RET-TKIs, most patients inevitably develop disease progression due to acquired resistance mechanisms by both on-target or off-target mechanisms. To date, new potent and selective next-generation RET-TKIs are currently being evaluated in ongoing clinical trials in order to overcome resistance and improve efficacy and blood–brain barrier crossing. Genomic recharacterization at progression could help guide treatment choice or enrolment in clinical trials of specific next-generation RET inhibitors. Here, we review the biology, clinicopathological characteristics, targeted therapies and mechanisms of resistance of advanced NSCLC harbouring RET fusions to provide treatment guidance for these patients.

Abstract 4019: RET-MAP: An international multi-center study of patients with advanced non-small cell lung cancer and RET fusions

Abstract Introduction: RET fusions (RET+) are identified in nearly 1% of advanced NSCLC (aNSCLC). We evaluated characteristics and outcomes of patients (pts) with RET+ aNSCLC. Methods: This is an international, multicenter, retrospective study evaluating clinical, biological, pathological and radiological data of pts with RET+ aNSCLC. Objective response rates (ORR), duration of response (DOR) and progression-free survival (PFS) were evaluated under double or single agent chemotherapy (CT), immunotherapy (ICI), CT-ICI, multityrosine kinase inhibitors (MTKi) and RET inhibitors (RETi). Overall survival (OS) was calculated from the start of first line therapy and compared between pts treated or not by RETi, after stratification by number of treatment lines. Results: A total of 71 pts was included from 11 centers. Median age was 60 [IQR 47-69], 58% were female, 93% had adenocarcinoma, 2 pts (3%) had squamous and 2 (3%) neuroendocrine carcinoma, 38 (53.5%) were tobacco consumers (median 18.5 PY [7.8-31.3]), 50 (70%) had stage IV disease at diagnosis. Fusion partners were KIF5B (35/49, 71%), CCDC6 (9/49, 18%), others (5/49, 10%). Median TMB was 2.76 [2.0-8.5], median PD-L1 5% [0-29]. The most frequent co-mutation was TP53 (18/58 cases, 31%). Median number of metastatic sites was 2 [1-3], most commonly lung (48%), bone (45%), pleura (41%) and nodes (35%). Brain metastases were found in 18% of cases at diagnosis and in 31% at last follow-up or death. Table reports outcomes by treatment. mOS was 50.6 months [95%CI 37.6 - NR]. Fifty-two pts received 1st generation RETi. The use of RETi improved OS in pts treated with ≤2 lines of therapy (NR vs 17.8 months, p=0.024) and in those receiving &amp;gt;2 lines (50.6 vs 12.7 months, p=0.0037). Pts responding to ICI had a median PD-L1 of 85% [15.5-90]. Conclusions: Pts with RET+ aNSCLC have mainly thoracic and bone disease. Despite smoking history, median TMB and PD-L1 expression are low. ICI may have a significant activity in selected cases. RETi improve OS. Outcomes by treatment First use of Doublet CT (N=46) Single agent CT (N=12) CT-ICI (N=9) ICI (N=19) MTKi (N=9) RETi (N=52) Line of treatment (median, range) 1 [1-1] 2 [2-3] 1 [1-2] 2 [2-3] 3 [1.5-3.5] 2 [1-3] ORR (N,%) 25/40 (62.5%) 3/12 (25%) 3/9 (33%) 7/17 (41%) 4/8 (50%) 36/45 (80%) mPFS (months, 95%CI) 7.89 [6.18-14] 2.81 [2.43-NR] 5.62 [2.79-NR] 3.71 [2.99-11.5] 2.76 [1.51-NR] 24.7 [16.2-NR] mDOR (months,95%CI) 11.83 [7.06-15.6] 8.90 [4.21-NR] 14.47 [10.25-NR] 20.47 [11.3-NR] 8.18 [1.64-NR] 24.74 [17.12-NR] Stopped for toxicity (N,%) 7/46 (15%) 1/12 (8%) 2/9 (22%) 4/18 (22%) 1/9 (11%) 14/50 (28%) Citation Format: Mihaela Aldea, Arianna Marinello, Wael Zrafi, Fabrizio Tabbo, Florian Guisier, Damien Vasseur, Vincent Fallet, Clarisse Audigier-Valette, Laura Mezquita, Antonio Calles, Giannis Mountzios, Marco Tagliamento, Judith Raimbourg, Safae Terrisse, Silvia Novello, Maria-Rosa Ghigna, Fabrice Barlesi, David Planchard, Benjamin Besse. RET-MAP: An international multi-center study of patients with advanced non-small cell lung cancer and RET fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4019.