Biomarker Consortium

GI Cancer

Hepatocellular Carcinoma

The rearranged during transfection (RET) protein is a tyrosine kinase involved in multiple cellular processes, including proliferation, differentiation, survival, motility, and migration.

There are 4 known endogenous ligands, including glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin.

 Ligands bind to glycosylphosphatidylinositol-anchored co-receptor molecules, called GFRα, and the co-receptor complex presents to RET, inducing homodimerization.

Homodimerized RET causes autophosphorylation, which activates signal transduction pathways RAS-MAPK, JAK-STAT, PKC, PI3K-AKT, PLCγ, and PKC.

gene is located on chromosome 10 and encodes a transmembrane tyrosine kinase and proto-oncogene.

RET contains intracellular, transmembrane, and extracellular domains.

The extracellular region contains cysteine-rich domains and cadherin-like domains (involved in dimerization and are, thus, mutation targets.

Hepatocellular carcinoma (HCC) patients with 

 gene fusion have a poorer duration of response and overall survival compared to wild-type tumors.

 rearrangement likely occurs because of broken repair mechanisms after DNA double-strand breaks, which can occur via cell-extrinsic or cell-intrinsic factors.

Breakpoints occur more frequently at intron 11, but some involve introns 7 and 10.

In some cases, the partner fusion gene is constitutively expressed, so RET tyrosine kinase activity is increased.

In other cases, the fusion contains a dimerization domain that activates RET in a ligand-independent manner.

RET alterations are rare in hepatocellular carcinoma (HCC), with an occurrence rate of less than 0.1%.

RNA-sequencing next-generation sequencing (NGS) has high sensitivity and specificity and can detect RET expression, while other testing modalities currently have limited utility.

In cases where NGS is unavailable, the European Society for Medical Oncology (ESMO) recommends fluorescence in situ hybridization or reverse transcription polymerase chain reaction (RT-PCR).

National Comprehensive Cancer Network guidelines currently have no established indication for molecular profiling in HCC, but it may be warranted in some instances with unusual or atypical presentation.

Selpercatinib is FDA-approved for the treatment of patients with locally advanced or metastatic HCC solid tumors with a 

gene fusion who have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

Selpercatinib is approved under accelerated approval based on the results of the phase I/II study LIBRETTO-001 (NCT03157128).

 Among 41 patients with advanced solid tumors, the overall response rate was 44% with a median duration of response of 24.5 months, and 67% of patients had a response at 6 months or longer.

 Selpercatinib was well tolerated, with only 8% of patients discontinuing permanently due to an adverse reaction.

Adult patients with locally advanced or metastatic solid tumors with a 

 gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Selpercatinib is a kinase inhibitor that inhibits wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3. Selpercatibib also inhibits FGFR 1, 2, and 3 at higher concentrations.

Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines.

In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T.

https://retevmo.lilly.com/savings-support

Zhao L, Wang N, Zhang D, Jia Y, Kong F. A comprehensive overview of the relationship between RET gene and tumor occurrence. 

. 2023;13:1090757. doi:10.3389/fonc.2023.1090757

Belli C, Penault-Llorca F, Ladanyi M, et al. ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. 

. 2021;32(3):337-350. doi:10.1016/j.annonc.2020.11.021

Carlomagno F. Thyroid cancer: role of RET and beyond. 

Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. 

. 2018;15(3):151-167. doi:10.1038/nrclinonc.2017.175

Hua S. Physiological and pharmaceutical considerations for rectal drug formulations. 

. 2019;10:1196. doi:10.3389/fphar.2019.01196

Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. 

. 2017;23(8):1988-1997. doi:10.1158/1078-0432.CCR-16-1679

Ye S, Zhao XY, Hu XG, et al. TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in hepatocellular carcinoma. 

. 2017;37(4):2215-2226. doi:10.3892/or.2017.5494

Shi M, Wang W, Zhang J, Li B, Lv D, Wang D, Wang S, Cheng D, Ma T. Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing. 

 2022;113(1):308-318. doi: 10.1111/cas.15181

National Comprehensive Cancer Network. NCCN guidelines version 1.2024: hepatocellular carcinoma. 

https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf

RETEVMO (selpercatinib). Prescribing information. Eli Lilly and Company; 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213246s008lbl.pdf

Subbiah V, Wolf J, Konda B, et al. 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 trial. 

. 2022;23(10):1261-1273. doi:10.1016/S1470-2045(22)00541-1

FDA D.I.S.C.O. burst edition: FDA approvals of Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive solid tumors, and Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive non-small cell lung cancer. FDA. Updated November 7, 2022. Accessed April 1, 2024. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approvals-retevmo-selpercatinib-adult-patients-locally-advanced-or

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