RET-rearranged Non-small Cell Lung Cancer Research Articles

Modeling RET-Rearranged Non-Small Cell Lung Cancer (NSCLC): Generation of Lung Progenitor Cells (LPCs) from Patient-Derived Induced Pluripotent Stem Cells (iPSCs).

REarranged during Transfection (RET) oncogenic rearrangements can occur in 1-2% of lung adenocarcinomas. While RET-driven NSCLC models have been developed using various approaches, no model based on patient-derived induced pluripotent stem cells (iPSCs) has yet been described. Patient-derived iPSCs hold great promise for disease modeling and drug screening. However, generating iPSCs with specific oncogenic drivers, like RET rearrangements, presents challenges due to reprogramming efficiency and genotypic variability within tumors. To address this issue, we aimed to generate lung progenitor cells (LPCs) from patient-derived iPSCs carrying the mutation RETC634Y, commonly associated with medullary thyroid carcinoma. Additionally, we established a RETC634Y knock-in iPSC model to validate the effect of this oncogenic mutation during LPC differentiation. We successfully generated LPCs from RETC634Y iPSCs using a 16-day protocol and detected an overexpression of cancer-associated markers as compared to control iPSCs. Transcriptomic analysis revealed a distinct signature of NSCLC tumor repression, suggesting a lung multilineage lung dedifferentiation, along with an upregulated signature associated with RETC634Y mutation, potentially linked to poor NSCLC prognosis. These findings were validated using the RETC634Y knock-in iPSC model, highlighting key cancerous targets such as PROM2 and C1QTNF6, known to be associated with poor prognostic outcomes. Furthermore, the LPCs derived from RETC634Y iPSCs exhibited a positive response to the RET inhibitor pralsetinib, evidenced by the downregulation of the cancer markers. This study provides a novel patient-derived off-the-shelf iPSC model of RET-driven NSCLC, paving the way for exploring the molecular mechanisms involved in RET-driven NSCLC to study disease progression and to uncover potential therapeutic targets.

Large-scale comparative analysis of clinico-genomic characteristics, treatment outcomes and resistant mechanisms of ALK/ROS1/RET-rearranged non-small cell lung cancer (NSCLC) in a nationwide genomic screening project (LC-SCRUM-Asia/TRY).

9026 Background: There is limited understanding of the clinico-genomic differences among ALK/ROS1/RET-rearranged NSCLC due to their low frequency. We aimed to characterize these fusions using a large-scale LC-SCRUM-Asia/TRY database. Methods: We conducted a prospective screening of treatment-naïve and refractory lung cancer to identify genomic alterations using RT-PCR and/or targeted next-generation sequencing (NGS) assays in LC-SCRUM-Asia/TRY. We compared clinico-genomic characteristics, treatment outcomes and resistant mechanisms among ALK/ROS1/RET-rearranged NSCLC. Results: Between February 2013 and December 2022, 18,616 lung cancer patients (pts) were enrolled in LC-SCRUM-Asia/TRY and 16,583 were NSCLC pts. ALK/ROS1/RET fusions were identified in 430 (2.6%)/240 (1.4%)/202 (1.2%) pts in NSCLC. The patient characteristics were as follows ( ALK/ROS1/RET): median age, 58/60/63 years; females, 53/54/54%; never-smokers, 57/55/59%; adenocarcinoma, 93/95/96%. The frequencies of brain metastasis at diagnosis were 26/20/19% (p = 0.15). Among pts tested by NGS, the frequencies of TP53, TET2 and NOTCH1 mutations were lower in ALK than in ROS1 and RET ( TP53; 23/34/27%, NOTCH1; 17/34/35%, TET2; 17/30/32%). Overall survival (OS) was significantly longer in ALK than in ROS1 (mOS [ ALK/ROS1/RET] 108.8 vs. 43.6 vs. not reached [NR] months, ALK vs. ROS1; p < 0.01, ALK vs. RET; p = 0.04) among stage IV pts underwent TKI therapy. TP53 mutation was associated with shorter OS in all three fusions (mOS [ TP53 mt+/mt-] ALK; 35.7 vs. 108.8, p < 0.01, ROS1; 26.4 vs. 47.4, p = 0.06, RET; 28.9 vs. 76.1 months, p = 0.05), shorter PFS with first line alectinib in ALK (mPFS [ TP53 mt+/mt-] 11.0 vs. 38.4 months, hazard ratio [HR] 2.5 [95% CI, 1.5-4.2], p < 0.01) and shorter PFS with initial crizotinib in ROS1 (mPFS [ TP53 mt+/mt-] 5.8 vs. 25.2 months, HR 2.6 [95% CI, 1.3-4.8], p < 0.01). There was no significant difference in PFS with first-line platinum plus pemetrexed among fusions (mPFS 12.6 vs. 10.7 vs. 9.2 months) and PFS with initial immune checkpoint inhibitors among fusions (mPFS 3.9 vs. 5.1 vs. 3.0 months). Among 60/13/10 re-biopsy samples refractory to TKI, on-target resistant mutations were identified in 14 (23%) /3 (23%) /1 (10%) samples. Conclusions: Pts with ALK/ROS1/RET-rearranged NSCLC shared similar characteristics, but the occurrence of concomitant mutations was lower in ALK than in ROS1 and RET. TP53 mutation was associated with worse prognosis in pts with ALK/ROS1/RET-rearranged NSCLC. Among those received TKI, pts with ALK-rearranged NSCLC had better prognosis than those with ROS1 and RET-rearranged NSCLC. The development of highly effective molecular targeted therapies for ROS1- and RET-rearranged NSCLC is warranted.

Expanded Access Program Pralsetinib in Advanced Non-Small Cell Lung Cancer with Rearranged during Transfection (RET) Gene Rearrangement.

Rearranged during transfection (RET) gene rearrangement is a well-known driver event in non-small cell lung cancer (NSCLC). Pralsetinib is a selective inhibitor of RET kinase and has shown efficacy in oncogenic RET-altered tumors. This study evaluated the efficacy and safety of expanded access program (EAP) use of pralsetinib in pretreated, advanced NSCLC patients with RET rearrangement. Patients who received pralsetinib as part of the EAP at Samsung Medical Center were evaluated through a retrospective chart review. The primary endpoint was overall response rate (ORR) per the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 guidelines. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and safety profiles. Between April 2020 and September 2021, 23 of 27 patients were enrolled in the EAP study. Two patients who were not analyzed due to brain metastasis and two patients whose expected survival was within 1 month were excluded from the analysis. After a median follow-up period of 15.6 months (95% confidence interval [CI], 10.0 to 21.2), ORR was 56.5%, the median PFS was 12.1 months (95% CI, 3.3 to 20.9), and the 12-month OS rate was 69.6%. The most frequent treatment-related adverse events (TRAEs) were edema (43.5%) and pneumonitis (39.1%). A total of 8.7% of patients experienced extra-pulmonary tuberculosis. TRAEs with a common grade of three or worse were neutropenia (43.5%) and anemia (34.8%). Dose reduction was required in nine patients (39.1%). Pralsetinib presents a clinical benefit when used in patients with RET-rearranged NSCLC, consistent with a pivotal study.

Clinical characteristics and targeted therapy of different gene fusions in non-small cell lung cancer: a narrative review.

Lung cancer is the most fatal malignant tumor in the world. Since the discovery of driver genes, targeted therapy has been demonstrated to be superior to traditional chemotherapy and has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The remarkable success of tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions has shifted the treatment from platinum-based combination chemotherapy to targeted therapy. Although the incidence rate of gene fusion is low in NSCLC, it is of great significance in advanced refractory patients. However, the clinical characteristics and the latest treatment progress of patients with gene fusions in lung cancer have not been thoroughly explored. The objective of this narrative review was to summarize the latest research progress of targeted therapy for gene fusion variants in NSCLC to improve understanding for clinicians. We conducted a search of PubMed database and American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and World Conference on Lung Cancer (WCLC) abstracts meeting proceedings from 1 January 2005 to 31 August 2022 with the following keywords "non-small cell lung cancer", "fusion", "rearrangement", "targeted therapy" and "tyrosine kinase inhibitor". We comprehensively listed the targeted therapy of various gene fusions in NSCLC. Fusions of ALK, ROS proto-oncogene 1 (ROS1), and rearranged during transfection proto-oncogene (RET) are relatively more common than others (NTRK fusions, NRG1 fusions, FGFR fusions, etc.). Among ALK-rearranged NSCLC patients treated with crizotinib, alectinib, brigatinib, or ensartinib, the Asian population exhibited a slightly better effect than the non-Asian population in first-line therapy. It was revealed that ceritinib may have a slightly better effect in the non-Asian ALK-rearranged population as first-line therapy. The effect of crizotinib might be similar in Asians and non-Asians with ROS1-fusion-positive NSCLC in first-line therapy. The non-Asian population were shown to be more likely to be treated with selpercatinib and pralsetinib for RET-rearranged NSCLC than the Asian population. The present report summarizes the current state of fusion gene research and the associated therapeutic methods to improve understanding for clinicians, but how to better overcome drug resistance remains a problem that needs to be explored.

Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients.

BackgroundRearranged during transfection (RET) rearrangement has been identified as one of the crucial oncogenic drivers in non-small cell lung cancer (NSCLC). Recently, two highly selective RET inhibitors have been approved by the US Food and Drug Administration and demonstrated remarkable responses. However, the clinical characteristics, outcomes and optimal diagnostic method of RET-rearrangements are not well understood. This study sought to evaluate the prevalence and characteristics of RET rearrangement, identify an effective diagnostic method for it, and correlate its presence with outcomes.MethodsA total of 9,431 Chinese NSCLCs from two cancer centers who have undertaken targeted DNA-NGS were enrolled and 167 RET-positive cases were screened. Non-canonical RET rearrangements were confirmed by targeted RNA-NGS. If material was sufficient, positive cases were analyzed by fluorescence in situ hybridization (FISH) (n=30) and immunohistochemistry (IHC) (n=57). Clinicopathologic characteristics, molecular profiling and treatment outcomes of RET rearrangement were evaluated.ResultsThe prevalence of RET rearrangement was 1.52% (138/9,101) in unfiltered cases and 8.79% (29/330) in EGFR/KRAS/BRAF/ALK-negative cases. RET rearrangement was common in females, never smokers, and lung adenocarcinoma patients. Additionally, 40.3% of stage IV RET-rearranged NSCLC patients developed brain metastases. TP53 was the most common concurrent mutation, and 8 patients harbored concurrent driver oncogenic alterations, including EGFR (N=5), KRAS (N=2), and ALK (N=1). Non-canonical fusion partners were identified in 13.8% (23/167) of cases by DNA-based NGS, and RNA-based NGS identified 3 new partners (EPS8, GOLGA5, and TNIP1). The concordance of FISH and NGS was 83.3% (25/30), while the concordance of IHC and NGS was only 28.1% (16/57). Both IHC and FISH demonstrated lower sensitivity for NCOA4-/other-RET fusions. The CCDC6-RET subgroup had significantly longer progression-free survival than the KIF5B-RET subgroup, both after chemotherapy (23 vs. 9.7 months; P=0.014).ConclusionsRET rearrangement occurs in 1.52% of Chinese NSCLCs and has identifiable clinicopathologic characteristics. RET IHC has a low sensitivity, disavowing its use in routine practice. While NGS and FISH has good performance in identifying RET rearrangement. Both IHC and FISH demonstrated lower sensitivity for NCOA4-/others-RET fusions. Clinical benefit with chemotherapy is different between CCDC6-RET and KIF5B-RET fusion patients, optimal treatment should be considered when selecting therapies for patients with RET-rearranged lung cancers.

Non-Small-Cell Lung Cancer Patients with Coexistence of High PD-L1 Expression and RET Fusion-Which Path Should We Follow? Case Reports and Literature Review.

Pembrolizumab is widely used in first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC) with high PD-L1 expression. The activity of pembrolizumab in NSCLC patients with rare molecular alterations is poorly characterised. RET gene rearrangements are identified in 1–2% of lung cancer patients. Here, we present two cases of RET-rearranged NSCLC patients with high PD-L1 expression (>50%), treated with pembrolizumab within routine clinical practice. Pembrolizumab was ineffective in both cases—single-agent immunotherapy seems to be of limited value in this group of patients. Selective RET-inhibitors, if available, are the optimal treatment for patients with RET fusion nowadays. The best sequence of the therapy is still not defined.

Molecular Testing and Treatment Strategies in RET-Rearranged NSCLC Patients: Stay on Target to Look Forward

RET alterations are recognized as key oncogenic drivers in different cancer types, including non-small cell lung cancer (NSCLC). Multikinase inhibitors (MKIs) with anti-RET activities resulted in variable efficacy with significant toxicities because of low target specificity. Selective RET kinase inhibitors, such as pralsetinib and selepercatinib, demonstrated high efficacy and favorable tolerability in advanced RET-rearranged NSCLC patients, leading to their introduction in the clinical setting. Among the different approaches available for the identification of RET rearrangements, next-generation sequencing (NGS) assays present substantial advantages in terms of turnaround time and diagnostic accuracy, even if potentially limited by accessibility issues. The recent advent of novel effective targeted therapies raises several questions regarding the emergence of resistance mechanisms and the potential ways to prevent/overcome them. In this review, we discuss molecular testing and treatment strategies to manage RET fusion positive NSCLC patients with a focus on resistance mechanisms and future perspectives in this rapidly evolving scenario.

RET Inhibitors in Non-Small-Cell Lung Cancer.

Simple SummaryNon-small cell lung cancer (NSCLC) remains a significant cause of death worldwide, despite the significant progresses to date. Multiple molecular alterations have been identified in NSCLC, leading to the development of target-based agents that have shown significant clinical benefits. Rearranged during Transfection (RET) fusions have recently emerged as a new potential target and a number of non-selective and selective RET inhibitors have been tested in RET positive NSCLC. In this review we analyse and summarise the characteristics of RET functions and its alterations in NSCLC. We then present the state of the art RET inhibitors in the treatment of NSCLC, discussing the ongoing trials and the future perspectives for RET positive (RET+) NSCLC patients.RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

Final survival results for the LURET phase II study of vandetanib in previously treated patients with RET-rearranged advanced non-small cell lung cancer

ObjectivesThe LURET phase II study evaluated the efficacy and safety of the multikinase inhibitor vandetanib in patients with previously treatedRET-rearranged advanced non-small cell lung cancer (NSCLC). Among the eligible patients included in the primary analysis, the objective response rate met the primary endpoint (53 %, 90 % confidence interval [CI]: 31–74). Here, we report final survival outcomes of the LURET study. Materials and methodsNineteen patients with previously treated RET-rearranged advanced NSCLC continuously received 300 mg of oral vandetanib daily. This final analysis provides updated data on progression-free survival (PFS), overall survival (OS) and safety. This study was registered with UMIN-CTR (number UMIN 000010095). ResultsAmong the 19 patients in the intention-to-treat population, 42 % had been heavily treated with 3 or more prior chemotherapy regimens. The median PFS was 6.5 months (95 % CI, 3.9–9.3) as determined by an independent radiology review committee. The median OS was 13.5 months (95 % CI, 9.8–28.1) and the overall survival rate at 12 months was 52.6 % (95 % CI 28.7–71.9). The most common adverse events were hypertension (84.2 %), diarrhea (78.9 %), and rash acneiform (63.2 %). Overall, 11 patients (57.9 %) had adverse events leading to a dose reduction, although the safety profile was consistent with that reported in previous studies. ConclusionOur results indicated that vandetanib enabled a prolonged and clinically meaningful PFS and OS in patients with previously treatedRET-rearranged advanced NSCLC at the updated final analysis. The safety profile was consistent with that reported in previous studies, although most of the patients experienced off-target adverse events besides RET.

P87.03 Characteristics and Outcomes of RET-Rearranged Non-Small Cell Lung Cancer from China: A Retrospective Study of Real-World

Rearranged during transfection (RET) proto-oncogene gene fusions are rare in non–small-cell lung cancer (NSCLC), about 1-2%. RET-rearranged tumours have been shown to respond to tyrosine kinase inhibitors, such as cabozantinib, vandetanib. Several clinical trials also has been undergoing. In the real word, RET fusion patients characteristics, treatment options and outcomes are still not clear. A retrospective, single center study of patients with pathologically confirmed NSCLC was conducted. RET rearrangements were detected using next generation sequencing (NGS). We analyzed the clinical characteristics of patients with RET-rearranged NSCLC and the efficacy of therapeutic regimens. We also evaluated the RET-rearranged patients survival outcomes, PFS of first-line therapy (PFS1), and second line therapy (PFS2). From 9/July/ 2017 to 25/Nov/2019, Total 3217 NSCLC patients were screened for RET-rearranged testing, only 41 (1.3%) patients had RET fusion gene, including 23 KIF5B-RET,10 CCDC6-RET and 8 other RET fusion gene. The average age was 60 years old (30-85). Of the 41 patients, 23(56%) females and 18 males, 36(87.8%) never smoker, 5 heavy smokers and no light smokers, 39(95%) adenocarcinoma and 2 squamous carcinoma. Most (33/41) of them had advanced stage (IIIB/IIIC/IV) . the majority (35/41) of patients had lymph node metastasis, especially in mediastinum, neck, supraclavicular, and axillary regions. Significantly, the axillary lymph node metastasis reached 12% (4/33). The common distant metastasis was still brain, bone, liver and adrenal gland. Unfortunately, 9 patients had no treatment records and failed to follow up. 20 patients with stage IIIB to stage IV had accepted first-line treatment, including 17chemotherapy, 2 target therapy, and 1 immunotherapy. The median progression-free survival (PFS1) of first-line chemotherapy was 9.3m (7.0m-11.6m), 2 patients with cabozantinib PFS1 were 3.9m and 6.0m respectively. the only one with duravalumab was 6.0m. There were few patients accepted second line therapy, The PFS2 was 3.0m(1.6m-6.5m). The median OS of all advanced (stage IIIB/IV) patients was 12.0 (6.5m-17.5m). Further analysis found that there were 20 patients accepted one or more lines treatment, while 4 patients had died through non-treatment. The OS of treated and non-treated advanced NSCLC patients were 14.0m and 2.0m respectively.Table 1RET-rearranged NSCLC characteristic and therapeutic outcometotal (n=41)N(%)Treatment outcomeAge,years60(30-85)First-linePFS1Sexchemotherapy9.3 (7.0m-11.6m)female23 (56.0%)target therapy3.9m/6.0mmale18 (44.0%)immunotherapy6.0mSmokeSecond-linePFS2never36 (87.8%)chemotherapy3.0m (1.4m-8.5m)light0target therapy3.0m (1.0m-3.6m)heavy5 (12.2%)OSRET-rearranged siteAll patients12.0m (6.5m-17.5m)KIF5B-RET23 (56.1%)treated14.0m (1.7m-26.2m)CCDC6-RET10 (24.4%)non-treated2.0m (0.4m-3.6m)others8 (19.5%)Pathology typeadenocarcinoma38 (92.7%)sqmous carcinoma2 (4.9%)neuroendocrine tumor1 (2.4%)Lymph node metastasismediastinum20 (47.8%)supraclavicular15 (36.6%)axillary4 (9.8%) Open table in a new tab RET-rearranged NSCLC was more likely to have lymph node metastasis. Because of poor access to target drug of cabozantinib and vandetanib in China, most of RET rearranged non-small cell lung cancer had chosen chemotherapy as first-line therapy, even so, they had a quite acceptable PFS, and overall survival was prolonged.

Frontline pembrolizumab for the treatment of RET-rearranged non-small cell lung cancer: A case report

RET-rearrangement occurs in 1 to 2% of patients with non-small cell lung cancer (NSCLC), typically among non-smokers, and it is associated with an increased incidence of brain metastasis. While selpercatinib and pralsetinib are active for RET-rearranged NSCLC, the optimal standard frontline regimen for this clinical setting remains undefined. Here, we report on a patient with RET-rearranged NSCLC who received frontline pembrolizumab and achieved a complete tumor response lasting for 29 months and ongoing. Single-agent ICI can be an effective frontline treatment for RET-rearranged NSCLC.

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

BackgroundRearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared.MethodsPatients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs).ResultsAmong 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10).ConclusionsRET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

Characteristics and outcomes of RET-rearranged Korean non-small cell lung cancer patients in real-world practice.

Since the first discovery of rearranged during transfection (RET) fusion in lung adenocarcinoma in 2011, two tyrosine kinase inhibitors, namely vandetanib and cabozantinib, are currently available. Despite favorable outcomes in systemic control, the intracranial therapeutic response remains insufficient. In this study, the clinical characteristics and outcomes of non-small cell lung cancer (NSCLC) patients with RET rearrangements were analyzed. Patients with NSCLC harboring RET fusion who received treatment between January 2006 and January 2018 were analyzed. RET rearrangement was identified by FISH or NGS. A total of 59 patients were identified. About half of the patients were female (47.5%) and never smokers (50.9%). Most patients had adenocarcinoma (89.8%). A total of 17 patients (28.8%) had an intracranial lesion at the initial diagnosis of stage IV disease, and 11 additional patients (18.6%) developed intracranial metastases during follow-up. The median time to development of intracranial metastases was 19.0months (95% CI: 9.6-28.5), resulting in a >60% cumulative incidence of brain metastasis at 24months. The systemic efficacy of pemetrexed-based regimens was favorable with progression-free survival of 9.0 (95% CI: 6.9-11.2) and OS of 24.1 (95% CI: 15.2-33.0) months. The median progression-free survival for vandetanib and immunotherapy was 2.9 (95% CI: 2.0-3.8) and 2.1 (95% CI: 1.6-2.6) months, respectively. Given the likelihood of RET-rearranged NSCLC progressing to intracranial metastases and the absence of apparent clinical benefit of currently available targeted or immunotherapeutic agents, development of novel treatment with higher selectivity and better penetration of the blood-brain barrier remains a priority.

Association Between RET Fusions and Efficacy of Pemetrexed-based Chemotherapy for Patients With Advanced NSCLC in China: A Multicenter Retrospective Study

BackgroundRearranged during transfection (RET) proto-oncogene gene fusions are rare in non–small-cell lung cancer (NSCLC). We compared the efficacy of pemetrexed-based chemotherapy with other chemotherapy regimens in patients with NSCLC with different RET fusion subtypes. Patients and MethodsA retrospective, multicenter study of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas was conducted. RET rearrangements were detected using next generation sequencing. We analyzed the clinical characteristics of patients with RET-rearranged NSCLC and the efficacy of chemotherapy regimens. We also evaluated the efficacy between groups of patients with and without KIF5B-RET–rearranged lung cancer. ResultsWe evaluated 62 patients with NSCLC and RET rearrangements, including 41 with KIF5B-RET, 15 with CCDC6-RET, and 6 with other rare fusion subtypes. Of these 62 patients, 50 had stage IIIB/IV. We also evaluated 40 patients with first-line chemotherapy information available. The median progression-free survival was significantly different between those receiving pemetrexed-based chemotherapy and those receiving other chemotherapy regimens (9.2 vs. 5.2 months; P = .007). The median progression-free survival for patients with KIF5B-RET fusion and non–KIF5B-RET fusion was not significantly different statistically (7.8 vs. 11.2 months; P = .847). For second-line chemotherapy, a statistically significant difference was found between the chemotherapy regimens (4.9 vs. 2.8 months; P = .049). Survival follow-up data were available for 38 patients with advanced NSCLC. The median overall survival was 26.4 months. The overall survival of the patients with RET-rearranged NSCLC who had received pemetrexed-based chemotherapy versus no pemetrexed-based chemotherapy was 35.2 versus 22.6 months (P = .052). No difference in survival was observed between the patients with KIF5B-RET and non–KIF5B-RET rearrangements. ConclusionsPemetrexed-based treatment should be considered first when selecting the chemotherapy regimen for patients with NSCLC and RET rearrangements.

Novel targeted therapy beyond EGFR and ALK: ROS1, BRAF, RET and MET

Abstract Non-small-cell lung cancer (NSCLC) has recently been recognized as a heterogeneous set of diseases at the molecular level. Targeted therapy based on driver oncogenes such as EGFR and ALK has become standard of care in patients with advanced NSCLC. ROS1 rearrangements, BRAF V600E mutation, RET rearrangements and MET exon 14 skipping mutation are reported to be effective therapeutic targets for patients with advanced NSCLC. To date, crizotinib as ROS1 inhibitor and dabrafenib plus trametinib as BRAF and MEK inhibitors are also approved as driver oncogenes guided targeted therapy for patients with advanced NSCLC. However, the incidence of each driver oncogenes is low except for EGFR mutations in East-Asian patients. A nationwide lung cancer genomic screening project in Japan, so called LC-SCRUM-Japan has been operated since February 2013 for the development of targeted therapy for NSCLC patients with rare driver oncogenes. In 2012, RET rearrangements were identified as new driver oncogenes occurring in 1% to 2% of patients with NSCLC. Several phase 2 trials to evaluate single-agent multi-targeted RET inhibitors including cabozantinib, vandetanib, or lenvatinib, have demonstrated clinical antitumor activity in patients with RET-rearranged NSCLC. However, this efficacy was lower than that of targeted therapy in NSCLC patients harboring EGFR and ALK. Development of highly selective RET inhibitors might help to have greater antitumor activity. More recent investigations focusing on MET exon 14 skipping mutation have been notable for meaningful clinical responses to MET inhibitor in patients with MET-mutated NSCLC. MET exon 14 skipping mutation are also rare occurrence in NSCLC. Several clinical trials to evaluate MET inhibitors such as crizotinib, tepotinib, or capmatinib are ongoing in patients with MET-mutated NSCLC. Patients with NSCLC harboring rare driver oncogenes as ROS1, BRAF, RET and MET, will derive more effective benefit from specific targeted therapy.

Targeted Therapy For RET-Rearranged Non-Small Cell Lung Cancer: Clinical Development And Future Directions.

Approximately 1–2% of unselected patients with Non-small Cell Lung Cancer (NSCLC) harbor RET rearrangements resulting in enhanced cell survival and proliferation. The initial treatment strategy for RET rearranged NSCLC has been multi-target tyrosine kinase inhibition. With overall response rates (ORR) of 16–53% and a median progression-free survival (PFS) of 4.5–7.3 months these outcomes are clearly inferior to the efficacy outcomes of selective tyrosine kinase inhibitors (TKI) in other oncogene-addicted NSCLC. Additionally, multi-kinase inhibition in RET-driven NSCLC patients showed concerning rates of high-grade toxicity, mainly induced by anti-VEGFR-kinase activity. Novel selective RET inhibitors like BLU-667, LOXO-292 and RXDX-105 have been recently investigated in early phase clinical trials showing promising efficacy with a manageable toxicity profile.

1487P - LURET: Final survival results of the phase II trial of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer

1487P - LURET: Final survival results of the phase II trial of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer

Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: Update.

Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLC). Notably, new molecular profiling technologies have permitted dynamic growth in the identification of actionable driver oncogenes including RET rearrangements. RET oncogenes cannot be adequately detected by immunohistochemistry, although fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction and next-generation sequencing are complementary diagnostic tools. In the clinical setting, the benefit of the most developed RET inhibitors, i.e., cabozantinb, vandetanib and lenvatinb, in terms of response and median progressionfree survival has been demonstrated. The absence of striking clinical results of RET inhibitors underscores the clear need for development of more selective and potent RET inhibitors. This paper reviews the clinical data available on RET inhibitors in RET-associated NSCLC.

Characterization of Computed Tomography Imaging of Rearranged During Transfection-rearranged Lung Cancer

BackgroundRearranged during transfection (RET)-rearranged non–small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented. Patients and MethodsWe identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics. ResultsIn 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%). ConclusionAdvanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed.

The importance of RET-directed therapy in patients with RET-rearranged non-small cell lung cancer

The importance of RET-directed therapy in patients with RET-rearranged non-small cell lung cancer