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How to test for RET

Testing for RET alterations is essential to identify patients who may be eligible for Retevmo1


Next-generation sequencing (NGS) can be an accurate and tissue-efficient method to test for driver RET alterations and other targetable biomarkers2-5*

An FDA-approved test for the detection of RET gene fusions and RET gene mutations is not currently available.

How to Test for RET

  • Immunohistochemistry (IHC) is not preferred for detecting RET alterations due to low sensitivity and variable specificity10,11
Discover more about RET alterations
In the LIBRETTO-001 clinical trial, NGS testing was used to identify driver RET alterations in 86% of patients

  • In the clinical trial, identification of a RET gene alteration was prospectively determined in local laboratories using NGS, PCR, or FISH1
  • Immunohistochemistry (IHC) testing was not used in LIBRETTO-0011


NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)



For NSCLC:

  • recommend testing for RET fusions in patients with metastatic non-small cell lung cancer12
  • recommend molecular testing and strongly advise broad molecular profiling for multiple biomarkers, including RET, in eligible patients with metastatic NSCLC12†‡§

†The NCCN Guidelines for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays.
‡It is recommended at this time that, when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS. For patients who, in broad panel testing, don’t have identifiable driver oncogenes (especially in never smokers), consider RNA-based NGS, if not already performed, to maximize detection of fusion events.
§Testing should include NTRK gene fusion.

For Thyroid Carcinoma:

  • recommend molecular testing for RET fusions and RET point mutations for patients with thyroid carcinomas13

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Detection of RET fusions in NSCLC and thyroid cancer other than medullary

NGS Testing

  • NGS testing for RET fusions: When properly designed, NGS testing is able to detect known and unknown fusion events4
  • A combination of RNA- and DNA-based NGS testing may be a more comprehensive approach to identify oncogenic drivers missed by DNA-based NGS alone14

Fluorescence in situ hybridization (FISH)

  • FISH testing allows for detection of fusions regardless of fusion partner10
  • Testing for RET fusions using FISH has demonstrated the potential to generate false negative results due to close proximity to partner genes10,21

Reverse transcription polymerase chain reaction (PCR)

  • Reverse transcription PCR testing provides sensitive detection of known RET fusions with relatively fast turnaround time10,11,15
  • Reverse transcription PCR testing does not detect unknown fusion partners and therefore may underestimate the prevalence of RET fusions10

Most common RET fusion partners identified in the LIBRETTO-001 phase I/II clinical trial:

NSCLC16:

  • 59% KIF5B
  • 22% CCDC6
  • 11% Unknown||
  • 6% Other¶
  • 2% NCOA4

Thyroid cancer other than MTC17:

  • 52% CCDC6
  • 33% NCOA4
  • 15% Other#

||Unknown includes positive by FISH or PCR.
¶Others included KIAA1468(2), ARHGAP12, CCDC88C, CLIP1, DOCK1+RBPMS, ERC1, PRKAR1A, and TRIM24 (all 1 each).16
#Others included CCDC1686, ERC1, KTN1, and RUFY (all 1 each).17

Detection of RET point mutations in MTC

  • RET testing in germline is well established18
  • When germline testing is negative or unknown, the tumor should be tested for somatic RET point mutations18,19

NGS testing

  • NGS allows for multiplex testing on a small amount of tissue for the detection of rare, as well as common, cancer-related biomarkers2,5,22
  • RET point mutations can be detected by NGS2-4

Quantitative PCR (qPCR)

  • Established option that can detect RET-activating point mutations in MTC7-9

Sanger sequencing

  • Can detect driver RET mutations; however, the sensitivity may be lower than NGS testing20

Most common RET mutations identified in the LIBRETTO-001 phase I/II clinical trial17:

  • 57% M918T
  • 19% Extracellular cysteine mutations
  • 16% Other**
  • 8% V804M/L

**Others included D631-L633delinsE(5), E632-L633del(4), A883F(4), D631-L633delinsV(2), L790F(2), D898-E901del(2), D898_E901del + D903_S904delinsEP, K666N, T636-V637insCRT, D378-G385delinsE (all 1 each).17

Select testing that can detect driver RET fusions and point mutations in the appropriate tumors

The following commercial reference laboratories may offer testing for driver RET fusions and point mutations:

This list is not all-inclusive and does not represent all laboratories and tests. This list is intended for informational purposes and your consideration only, and is based on publicly available information for these organizations. Eli Lilly and Company (Lilly) makes no representations regarding the clinical or analytical validity, manufacturing quality, or design of the testing offered by the laboratories included on this list. Inclusion on this list does not represent an endorsement, referral, or recommendation by Lilly. Contact the laboratory for more information.

Laboratory Contact Info
Aurora Diagnostics Contact Info: T: 866-420-5512
auroradx.com
Bioreference Laboratories/GenPath Contact Info: T: 800-627-1479
genpathdiagnostics.com
Caris Life Sciences® Contact Info: T: 888-979-8669
E: CustomerSupport@carisls.com
carismolecularintelligence.com
CSI Laboratories Contact Info: T: 800-459-1185
E: clientservice@csilaboratories.com
csilaboratories.com
Foundation Medicine Contact Info: T: 888-988-3639
E: client.services@foundationmedicine.com
foundationmedicine.com
Genomic™ Testing Cooperative Contact Info: T: 949-450-9421
E: gtc@genomictestingcooperative.com genomictestingcooperative.com
Integrated Oncology (LabCorp)/OmniSeq® Contact Info: T: 800-710-1800
E: support@omniseq.com
omniseq.com
Intermountain Precision Genomics Contact Info: T: 435-251-5780
E: genomics@imail.org
navican.com
Knight Diagnostic Laboratories Contact Info: T: 855-535-1522
E: KDLClientServices@ohsu.edu
knightdxlabs.com
Mayo Clinic Laboratories Contact Info: T: 800-533-1710
E: mcl@mayo.edu
mayocliniclabs.com
Michigan Medicine Laboratories Contact Info: T: 800-862-7284
mlabs.umich.edu
NeoGenomics Laboratories Contact Info: T: 866-776-5907
E: Client.Services@neogenomics.com
neogenomics.com
Exact Sciences Contact Info: T: 844-232-4719
paradigmdx.com
Pathgroup Contact Info: T: 888-474-5227
pathgroup.com
Quest Diagnostics™/Med Fusion Quest Diagnostics™:
T: 866-697-8378
questdiagnostics.com

Med Fusion:
T: 844-966-7050
medfusionservices.com
Sema4 Contact Info: T: 800-298-6470
E: billing@sema4.com
sema4.com
Tempus Contact Info: T: 800-739-4137
E: support@tempus.com
tempus.com


Test for RET1
Ensure your test can detect driver RET fusions in NSCLC and non-medullary thyroid cancer and driver RET mutations in MTC

*Through design and validation, the test has established high sensitivity, specificity, and reproducibility for the detection of genomic alterations.

Savings & support

References: 1. Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 2. Gregg JP, Li T, Yoneda KY. Molecular testing strategies in non-small cell lung cancer: optimizing the diagnostic journey. Transl Lung Cancer Res. 2019;8(3):286-301. 3. Suh JH, Schrock AB, Johnson A, et al. Hybrid capture-based comprehensive genomic profiling identifies lung cancer patients with well-characterized sensitizing epidermal growth factor receptor point mutations that were not detected by standard of care testing. Oncologist. 2018;23(7):776-781. 4. Mertens F, Johansson B, Fioretos F, et al. The emerging complexity of gene fusions in cancer. Nat Rev Cancer. 2015;15(6):371-381. 5. Suh JH, Johnson A, Albacker L, et al. Comprehensive genomic profiling facilitates implementation of the National Comprehensive Cancer Network Guidelines for lung cancer biomarker testing and identifies patients who may benefit from enrollment in mechanism-driven clinical trials. Oncologist. 2016;21(6):684-691. 6. Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. 7. Matsuda K. PCR-based detection methods for single-nucleotide polymorphism or mutation: real-time PCR and its substantial contribution toward technological refinement. Adv Clin Chem. 2017;80:45-72. 8. Oczko-Wojciechowska M, Swierniak M, Krajewska J, et al. Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations. Sci Rep. 2017;7. doi:10.1038/srep42074. 9. Agrawal N, Jiao Y, Sausen M, et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab. 2013;98(2):E364-E369. 10. Ferrara R, Auger N, Auclin E, et al. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol. 2018;13(1):27-45. 11. Naidoo J, Drilon A. Molecular diagnostic testing in non-small cell lung cancer. Am J Hematol Oncol. 2014;10(4):4-11. 12. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.6.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed June 15, 2020. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 13. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.2.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed July 15, 2020. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 14. Benayed R, Offin M, Mullaney K, et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res. 2019;25(15):4712-4722. 15. Bustin SA, Nolan T. Pitfalls of quantitative real-time reverse-transcription polymerase chain reaction. J Biomol Tech. 2004;15(3):155-166. 16. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET fusion-positive lung cancers. Presented at: 2019 World Conference on Lung Cancer, September 7-10, 2019; Barcelona, Spain. 17. Wirth L, Sherman E, Drilon A, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET-altered thyroid cancers. Presented at: 2019 ESMO Congress. September 27- October 1, 2019; Barcelona, Spain. 18. Santoro M, Carlomagno F. Central role of RET in thyroid cancer. Cold Spring Harb Perspect Biol. 2013;5(12):1-17. 19. Elisei R, Alevizaki M, Conte-Devolx B, et al. 2012 European thyroid association guidelines for genetic testing and its clinical consequences in medullary thyroid cancer. Eur Thyroid J. 2013;1(4):216-231. 20. Simbolo M, Mian C, Barollo S, et al. High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas. Virchows Arch. 2014;465(1):73-78. 21. Lee SE, Lee B, Hong M, et al. Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma. Mod Pathol. 2015;28(4):468-479. 22. Yu TM, Morrison C, Gold EJ, et al. Multiple biomarker testing tissue consumption and completion rates with single-gene tests and investigational use of Oncomine Dx target test for advanced non—small-cell lung cancer: a single-center analysis. Clin Lung Cancer. 2019;20(1):20-29.e8.

Indications

Retevmo is a kinase inhibitor indicated for the treatment of:

  • adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC)
  • adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy
  • adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

These indications are approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR). Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information for Retevmo™ (selpercatinib)

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased aspartate aminotransferase (AST) occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased alanine aminotransferase (ALT) occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years). Monitor ALT and AST prior to initiating Retevmo, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Retevmo based on the severity.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity.

Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo. Grade ≥3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivity occurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg. Upon resolution of the event, resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing. Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequently reported serious adverse reaction (in ≥ 2% of patients) was pneumonia.

Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (33%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) ≥20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Concomitant use of strong and moderate CYP3A inhibitors increases selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently.

Concomitant use of strong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older.

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] ≥30 mL/Min, estimated by Cockcroft-Gault). A recommended dosage has not been established for patients with severe renal impairment or end-stage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

Please see full Prescribing Information for Retevmo.

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