Central Nervous System Response to Selpercartinib in Patient With RET-rearranged Non-small Cell Lung Cancer After Developing Leptomeningeal Disease on Pralsetinib

Tsui, David Chun Cheong; Kavanagh, Brian D.; Honce, Justin M.; Rossi, Candice; Patil, Tejas; Camidge, D. Ross

doi:10.1016/j.cllc.2021.06.005

Cited by 14 publications

(13 citation statements)

References 11 publications

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“…The case depicted the robust activity of selpercatinib in a patient with RET fusion-positive lung cancer, resulting in a reduction in 65% from baseline at 21 weeks of treatment and subsequent scans showed resolution of leptomeningeal enhancement. A recent anecdotal case report showed subsequent clinical response to selpercatinib in a patient with RET fusion-positive NSCLC, who had a durable extracranial response to pralsetinib, but had leptomeningeal progression [ 100 ]. It will be interesting to see if these agents can be used sequentially, especially in these special situations, potentially opening up more options for patients.…”

Section: Treating Ret -Altered Cancersmentioning

confidence: 99%

Precision therapy for RET-altered cancers with RET inhibitors

et al. 2021

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Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks. HighlightsRearranged during transfection (RET) is an oncogenic driver activated by either RET fusions or mutations. RET fusions occur predominantly in 2% of lung cancers and 10-20% of thyroid cancers and in low frequency in an increasing number of diverse cancers.Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been successfully translated to the clinic and are FDA approved.Data on acquired resistance to RETspecific inhibitors are rapidly emerging but not fully understood. However recent studies have suggested on-target mutations at non-gatekeeper sites or emergence of off-target alterations such as MET amplification or NTRK fusion as mechanisms of acquired resistance.

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Section: Treating Ret -Altered Cancersmentioning

confidence: 99%

Precision therapy for RET-altered cancers with RET inhibitors

et al. 2021

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“…Only two case reports revealed efficacy of selective RET TKIs on meningeal metastasis for patients with RET -rearranged NSCLC up to now. 13 , 14 According to the two reported cases, selective RET inhibitors posed a positive effect to the patient’s meningeal symptoms owing to the remission of the symptoms caused by intracranial hypertension, which suggests RET TKIs might have a potential effect on the meningeal metastasis, confirmed by the higher cerebrospinal fluid concentration to blood concentration ratio we measured for pralsetinib.…”

Section: Discussionmentioning

confidence: 63%

“…In conclusion, this case together with the previous two papers 13 , 14 might serve as the basis for another possible choice for the meningeal metastasis of advanced EGFR -mutated NSCLCs with acquired RET mutations.…”

Section: Discussionmentioning

confidence: 67%

Response to Pralsetinib Observed in Meningeal-Metastatic EGFR-Mutant NSCLC With Acquired RET Fusion: A Brief Report

Zhao¹,

Su²,

Xiu³

et al. 2022

JTO Clinical and Research Reports

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“…Especially, genetic alterations that cause ligandindependent dimerization of RET kinase in lung and thyroid cancers, such as RET fusion and hotspot cysteine mutations (11,13,43,44), are strongly associated with a good therapeutic response to inhibitory drugs specifically targeting RET kinase (5,45). These RET alterations are present in several cancers other than lung and thyroid cancers (19,46), and the therapeutic effects of RET kinase inhibitors have been observed in a tumor agnostic manner (47)(48)(49). The RET-CaLM mutations identified in this study are present in multiple types of cancers, such as lung, colorectal, central nervous system, and blood cancers.…”

Section: Discussionmentioning

confidence: 99%

Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis

Tabata

Nakaoku²,

Araki

et al. 2022

Cancer Research

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Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71,756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca2+ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico–driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations. Significance: Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene.

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Central Nervous System Response to Selpercartinib in Patient With RET-rearranged Non-small Cell Lung Cancer After Developing Leptomeningeal Disease on Pralsetinib

Cited by 14 publications

References 11 publications

Precision therapy for RET-altered cancers with RET inhibitors

Precision therapy for RET-altered cancers with RET inhibitors

Response to Pralsetinib Observed in Meningeal-Metastatic EGFR-Mutant NSCLC With Acquired RET Fusion: A Brief Report

Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis

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