Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers

Drilon, Alexander; Bergagnini, Isabella; Delasos, Lukas; Sabari, Joshua K.; Woo, Kaitlin M.; Plodkowski, Andrew J.; Wang, L.; Hellmann, Matthew D.; Joubert, Philippe; Sima, Cami S.; Smith, Roger S.; Somwar, Romel; Rekhtman, Natasha; Ladanyi, Marc; Riely, G.; Kris, Mark G.

doi:10.1093/annonc/mdw163

Cited by 103 publications

(69 citation statements)

References 20 publications

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“…Fortunately, TKIs with more potent anti-RET activity are in advanced stages of clinical development [ 46 , 47 ]. Faced with that concern, clinicians frequently prescribed pemetrexed-containing chemotherapy, in agreement with the valuable results that have been reported in fusion gene-driven NSCLC [ 48 ]. In addition, although studies have suggested little or no benefit of immune checkpoint inhibitors in oncogene-driven tumors [ 49 ], some patients were given nivolumab.…”

Section: Discussionmentioning

confidence: 79%

Clinicopathological characteristics of ROS1- and RET-rearranged NSCLC in caucasian patients: Data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations

et al. 2017

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Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine.We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients.Frequencies of ROS1 and RET rearrangements were 2.1% and 2.52%, respectively. Contrary to common belief, both ROS1 and RET rearrangements were detected in patients with a history of smoking, and the RET-positive patients were not younger than the negative patients. Moreover, RET but not ROS1 rearrangement was associated with the female gender. Nearly half of the ROS1-rearranged patients were successfully treated with ROS1 TKIs. In contrast, only 5/18 RET-positive patients received off-label RET TKIs. Two patients had stable disease, and three experienced disease progression. In addition to the 18 RET-positive cases, 10 showed isolated 5′ signals. The clinical relevance is unknown but if the frequency is confirmed by other groups, the question whether these patients are eligible to TKIs will arise. More potent RET TKIs are under development and may improve the response rate in RET-positive patients. Therefore, we recommend the routine implementation of RET testing in non-squamous NSCLC patients, including those with a history of smoking.

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Section: Discussionmentioning

confidence: 79%

Clinicopathological characteristics of ROS1- and RET-rearranged NSCLC in caucasian patients: Data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations

et al. 2017

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“…Reports have indicated that mutations in RET induce papillary carcinoma and familial medullary thyroid carcinoma in lung (27) and thyroid cancer (28). RET has been evidenced as an oncogene in a number of cancers, including head and neck squamous cell carcinoma (29), thyroid (30) and lung cancer (31). From the aspect mentioned above, targeting hNUDC with miR-449 may offer a novel strategy to prevent the oncogenic effect of RET in PTC.…”

Section: Discussionmentioning

confidence: 99%

miR-449 overexpression inhibits papillary thyroid carcinoma cell growth by targeting RET kinase-β-catenin signaling pathway

Huang

et al. 2016

International Journal of Oncology

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Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and represent approximately 80% of all thyroid cancers. The present study is aimed to investigate the role of microRNA (miR)-449 in the progression of PTC. Our results revealed that miR-449 was underexpressed in the collected PTC specimens compared with non-cancerous PTC tissues. Overexpression of miR-449 induced a cell cycle arrest at G0/G1 phase and inhibited PTC cell growth in vitro. Further studies revealed that RET proto-oncogene (RET) is a novel miR-449 target, due to miR-449 bound directly to its 3'-untranslated region and miR-449 mimic reduced the protein expression of RET. Similar to the effects of miR-449 overexpression, RET downregulation inhibited cell growth, whereas RET overexpression reversed the inhibitive effect of miR-449 mimic. Furthermore, miR-449 overexpression inhibited the nuclear translocation of β-catenin and reduced the expression of several downstream genes, including c-Myc, cyclin D1, T cell-specific transcription factor (TCF) and lymphoid enhancer-binding factor 1 (LEF-1), and inactivated the β-catenin pathway in TPC-1 cells. Moreover, overexpression of β-catenin prevented miR-449-reduced cell cycle arrest and cell viability. In xenograft animal experiments, miR-449 overexpression effectively suppressed the tumor growth of PTC. Taken together, our research indicated that miR-449 functions as an anti-oncogene by targeting RET, and that miR-449 overexpression inhibited the growth of PTC by inactivating the β-catenin pathway. Thus, miR-449 may serve as a potential therapeutic strategy for the treatment of PTC.

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“…In retrospective NSCLC series, RET rearrangement was significantly associated with increased levels of thymidylate synthase mRNA 67 and surprisingly high overall response rates (ORRs) (i.e., 40%) and progression-free survival (PFS) (i.e., 19 months) with pemetrexed-based chemotherapy. 74 However, a potential favorable prognosis associated with RET rearrangement or a generally higher chemosensitivity could be erroneously confounded with higher pemetrexed susceptibility. In terms of the prognostic value of RET rearrangement, in most retrospective series, RET did not significantly correlate with overall survival (OS) 10 or recurrence-free survival in resected lung cancer.…”

Section: Ret Inhibition In Nsclc: From Bench To Bedsidementioning

confidence: 99%

Clinical and Translational Implications of RET Rearrangements in Non–Small Cell Lung Cancer

Ferrara

Auger

Auclin

et al. 2018

Journal of Thoracic Oncology

176

151

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Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized. Unlike ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry (IHC), although fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage, potentially higher chemosensitivity (in particular, to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multitarget inhibitors with anti-rearranged during transfection proto-oncogene (RET) activity in patients with RET-rearranged lung cancer. In the clinical setting, the benefit in terms of response (16%-47%) and progression-free survival (2-7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multikinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn on account of discordant data coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET oncogene-addicted NSCLC underscores the clear need for development of more selective and potent RET inhibitors and for better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in patients with lung cancer.

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Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers

Abstract: Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

Cited by 103 publications

References 20 publications

Clinicopathological characteristics of ROS1- and RET-rearranged NSCLC in caucasian patients: Data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations

Clinicopathological characteristics of ROS1- and RET-rearranged NSCLC in caucasian patients: Data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations

miR-449 overexpression inhibits papillary thyroid carcinoma cell growth by targeting RET kinase-β-catenin signaling pathway

Clinical and Translational Implications of RET Rearrangements in Non–Small Cell Lung Cancer

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