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


NCCN recommends testing for RET in eligible patients

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend testing for RET alterations in appropriate patients with advanced and/or metastatic NSCLC and thyroid carcinoma* to determine if they are eligible for RET inhibitors such as selpercatinib (Retevmo)2,3


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.


Next-generation sequencing (NGS) can be an accurate and tissue-efficient method to test for driver RET alterations and other targetable biomarkers4-7†

An FDA-approved test for the detection of RET gene fusions and RET gene mutations is not currently available for Retevmo.1

Retevmo may affect both healthy cells and tumor cells, which can result in side effects, some of which can be serious.1

Testing methods for NSCLC, Thyroid cancers other than medullary and medullary thyroid cancer

  • Immunohistochemistry (IHC) is not preferred for detecting RET alterations due to low sensitivity and variable specificity15,16
  • Test the tissue: molecular testing of FFPE tumor tissue specimens is preferred for detecting RET fusions and point mutations8,17-19
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
  • IHC testing was not used in LIBRETTO-0011


Why NGS?

Broad molecular profiling to identify appropriate targeted therapies can improve outcomes in NSCLC20


  • NCCN Guidelines for NSCLC recommend that, when feasible, molecular testing of NSCLC specimens be performed via a broad, panel-based approach, most typically performed by NGS2
  • Because of potential tissue limitations in metastatic NSCLC and the increased number of actionable biomarkers, NGS testing is part of the most comprehensive strategy to identify appropriate targeted therapies7
  • Consider NGS testing to identify the 69% of patients with lung adenocarcinoma who have a potentially actionable oncogenic driver alteration and may benefit from appropriate approved or investigational targeted therapy21,22
Biomarkers in lung cancer

Emerging=biomarkers with therapies under investigation but not approved.
Other=unknown oncogenic driver detected.22
EGFR=EGFR sensitizing mutations including exon 20 insertions.22,29
EGFR other=secondary EGFR mutations, including Thr790Met and Cys797Ser, and other less common EGFR mutations.22
KRAS other=all KRAS mutations other than KRAS G12C.22,28

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)



For NSCLC:

  • recommend testing for RET fusions in eligible patients with metastatic non-small cell lung cancer2
  • recommend molecular testing and strongly advise broad molecular profiling for multiple biomarkers, including RET, in eligible patients with metastatic NSCLC2*‡

*The NCCN Guidelines provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.
†Through design and validation, the test has established high sensitivity, specificity, and reproducibility for the detection of genomic alterations.
‡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.

For Thyroid Carcinoma:

  • recommend molecular testing for RET fusions and RET point mutations for certain patients with advanced or metastatic thyroid carcinomas3
RET FUSIONS: Test for RET fusions in NSCLC and thyroid cancers (non-MTC)

Consider waiting for RET test results before making therapeutic decisions1

NGS testing

  • NGS testing for RET fusions: when properly designed, NGS testing is able to detect known and unknown fusion events6
  • A combination of RNA- and DNA-based NGS testing may be a more comprehensive approach to identify oncogenic drivers missed by DNA-based NGS alone30

Fluorescence in situ hybridization (FISH)

  • FISH testing allows for detection of fusions regardless of fusion partner15
  • Testing for RET fusions using FISH has demonstrated the potential to generate false negative results due to close proximity to partner genes15,31

Reverse transcription polymerase chain reaction (PCR)

  • Reverse transcription PCR testing provides sensitive detection of known RET fusions with relatively fast turnaround time15,16,32
  • Reverse transcription PCR testing does not detect unknown fusion partners and therefore may underestimate the prevalence of RET fusions15

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

NSCLC33:

  • 59% KIF5B
  • 22% CCDC6
  • 11% Unknown§
  • 6% Otherǁ
  • 2% NCOA4

Thyroid cancer other than MTC34:

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

§Unknown includes positive by FISH or PCR.
ǁOthers included KIAA1468(2), ARHGAP12, CCDC88C, CLIP1, DOCK1+RBPMS, ERC1, PRKAR1A, and TRIM24 (all 1 each).33
¶Others included CCDC1686, ERC1, KTN1, and RUFY (all 1 each).34

RET POINT MUTATIONS: Test for RET point mutations in MTC

While germline testing in MTC is well established, the majority of cases are not inherited, highlighting the importance of testing the tumor tissue to identify somatic RET point mutations35,36

Medullary thyroid cancer KCD Testing

NGS testing

  • NGS allows for multiplex testing on a small amount of tissue for the detection of rare, as well as common, cancer-related biomarkers4,7,38
  • RET point mutations can be detected by NGS4-6

Quantitative PCR (qPCR)

  • Established option that can detect RET-activating point mutations in MTC12-14

Sanger sequencing

  • Can detect driver RET mutations; however, the sensitivity may be lower than NGS testing39

Most common RET mutations identified in the LIBRETTO-001 phase I/II clinical trial34:

  • 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).34

The role of liquid biopsy in molecular profiling and clinical decision making

  • While not recommended as a replacement for a diagnostic tissue biopsy, consider liquid biopsy when FFPE tumor tissue is unavailable or insufficient for molecular profiling17
  • While a positive liquid biopsy result is considered reliable, a negative result requires confirmation with tumor tissue testing17
  • NCCN Guidelines: principles of molecular and biomarker analysis in metastatic NSCLC2
    • Plasma ctDNA (liquid biopsy) should not be used in lieu of a histologic tissue diagnosis
    • Studies have demonstrated liquid biopsy to generally have very high specificity but significantly compromised sensitivity, with a false-negative rate of up to 30%
    • Standards and guidelines for liquid biopsy testing for genetic alterations have not been established

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.

Tissue Biopsy Tests

Laboratory
Contact Info
Caris Life Sciences® Contact Info: T: 888-979-8669
E: CustomerSupport@carisls.com
carismolecularintelligence.com
Exact Sciences Contact Info: T: 844-870-8870
exactsciences.com
Foundation Medicine® Contact Info: T: 888-988-3639
E: client.services@foundationmedicine.com
foundationmedicine.com
Integrated Oncology (LabCorp)/OmniSeq® Contact Info: T: 800-710-1800
E: support@omniseq.com
omniseq.com
Mayo Clinic Laboratories Contact Info: T: 800-533-1710
E: mcl@mayo.edu
mayocliniclabs.com
NeoGenomics Laboratories Contact Info: T: 866-776-5907
E: client.services@neogenomics.com
neogenomics.com
PathGroup Contact Info: T: 888-474-5227
pathgroup.com
Quest Diagnostics™/Med Fusion Quest Diagnostics™:
Contact Info: T: 866-697-8378
questdiagnostics.com

Med Fusion:
Contact Info: T: 844-966-7050
E: clientservices@medfusionsvs.com
medfusionservices.com
Tempus Contact Info: T: 800-739-4137
E: support@tempus.com
tempus.com


Liquid Biopsy Tests

Laboratory
Contact Info
Biocept Contact Info: T: 888-332-7729
E: customerservice@biocept.com
biocept.com
Biodesix® Contact Info: T: 866-432-5930
biodesix.com
Foundation Medicine® Contact Info: T: 888-988-3639
E: client.services@foundationmedicine.com
foundationmedicine.com
Guardant Health® Contact Info: T: 855-698-8887
E: clientservices@guardanthealth.com
guardant360cdx.com
Inivata™ Contact Info: T: 844-464-8282
E: client.services@inivata.com
inivata.com
Integrated Oncology (LabCorp) Contact Info: T: 800-710-1800
integratedoncology.com
NeoGenomics Laboratories Contact Info: T: 866-776-5907
E: client.services@neogenomics.com
neogenomics.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

ALK=anaplastic lymphoma kinase; BRAF=v-raf murine sarcoma viral oncogene homolog B; DNA=deoxyribonucleic acid; EGFR=epidermal growth factor receptor; FFPE=formalin-fixed paraffin-embedded; HER2=human epidermal growth factor receptor 2; KRAS=Kirsten rat sarcoma; MEK1=dual specificity mitogen-activated protein kinase kinase 1; METex14=mesenchymal-epithelial transition exon 14 skipping; MTC=medullary thyroid cancer; NCCN=National Comprehensive Cancer Network; NSCLC=non-small cell lung cancer; NTRK=neurotrophic receptor tyrosine kinase; PIK3CA=phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTC=papillary thyroid cancer; RET=rearranged during transfection; RNA=ribonucleic acid; ROS1=reactive oxygen species 1.

Savings & support

References: 1. Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V5.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed June 15, 2021. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V1.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed April 9, 2021. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 4. 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. 5. 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. 6. Mertens F, Johansson B, Fioretos T, et al. The emerging complexity of gene fusions in cancer. Nat Rev Cancer. 2015;15(6):371-381. 7. 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. 8. 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. 9. Lee M-Y, Ku BM, Kim HS, et al. Genetic alterations and their clinical implications in high-recurrence risk papillary thyroid cancer. Cancer Res Treat. 2017;49(4):906-914. 10. Prescott JD, Zeiger MA. The RET oncogene in papillary thyroid carcinoma. Cancer. 2015;121(13):2137-2146. 11. Elisei R, Tacito A, Ramone T, et al. Twenty-five years experience on RET genetic screening in hereditary MTC: an update on the prevalence of germline RET mutations. Genes (Basel). 2019;10(9). doi:10.3390/genes10090698. 12. 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. 13. 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;7:42074. doi:10.1038/srep42074. 14. 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. 15. 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. 16. Naidoo J, Drilon A. Molecular diagnostic testing in non-small cell lung cancer. Am J Hematol Oncol. 2014;10(4):4-11. 17. Rolfo C, Mack PC, Scagliotti GV, et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): a statement paper from the IASLC. J Thorac Oncol. 2018;13(9):1248-1268. 18. Dietel M, Bubendorf L, Dingemans A-M, et al. Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group. Thorax. 2016;71(2):177-184. 19. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358. 20. Singal G, Miller PG, Agarwala V, et al. Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database. JAMA. 2019;321:1391-1399. 21. Fernandes MGO, Jacob M, Martins N, et al. Targeted gene next-generation sequencing panel in patients with advanced lung adenocarcinoma: paving the way for clinical implementation. Cancers (Basel). 2019;11(9):1229. 22. Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389:299-311. 23. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. 24. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. doi:10.1136/esmoopen-2015-000023. 25. Vansteenkiste JF, Van De Kerkhove C, Wauters E, et al. Capmatinib for the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 2019;19(8):659-671. 26. FDA approves first targeted therapy to treat aggressive form of lung cancer. News release. FDA. May 6, 2020. Accessed May 21, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-aggressive-form-lung-cancer. 27. Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984-993. 28. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed June 17, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug. 29. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed June 30, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-subset-non-small-cell-lung-cancer. 30. 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. 31. 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. 32. Bustin SA, Nolan T. Pitfalls of quantitative real-time reverse-transcription polymerase chain reaction. J Biomol Tech. 2004;15(3):155-166. 33. 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. 34. 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. 35. Nosé V. Familial thyroid cancer: a review. Mod Pathol. 2011;24(Suppl 2):S19-S33. 36. Mohammadi M, Hedayati M. A brief review on the molecular basis of medullary thyroid carcinoma. Cell J. 2017;18(4):485-492. 37. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. 38. 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. 39. 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.

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 prednisone (or equivalent). 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.

Tumor lysis syndrome (TLS) occurred in 1% of patients with medullary thyroid carcinoma receiving Retevmo. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

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 (35%), 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. Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing Retevmo if abnormalities occur.

No dosage modification is recommended for patients with mild to severe renal impairment (estimated Glomerular Filtration Rate [eGFR] ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease [MDRD] equation). A recommended dosage has not been established for patients with 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.

SE HCP ISI All_25MAR2021

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