About RET+ Advanced Thyroid Cancer

Biomarkers are known to drive oncogenic growth in papillary thyroid cancer1-7

RET fusions are present in ~10%-20% of all papillary thyroid cancers8,9

RET fusionsNTRK
rearrangements		BRAF v600E
mutations		ALK
fusions
ALL PTC~10%-20%8,9~2%-3%5~45%1~1%-3%6
PTC
(≤18 years of age)		~22%7~26%7~48%7—

ALK=anaplastic lymphoma kinase; BRAF=B-Raf proto-oncogene; neoplasia type 2; NTRK=neurotrophic tyrosine receptor kinase; PTC=papillary thyroid cancer; RET+=rearranged during transfection positive.

Test for RET in Advanced Thyroid Cancer

Comprehensive biomarker testing is important in advanced thyroid cancers due to the prevalence of actionable biomarkers1,2,5

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend genomic testing to identify actionable mutations for structurally persistent/recurrent locoregional or distant metastatic DTC not amenable to radioiodine therapy that is advanced, progressive or threatening1

  • Somatic testing includes RET fusions, ALK fusions, NTRK fusions, BRAF mutations, dMMR/MSI, and TMB1

DNA- or RNA-based comprehensive profiling may be appropriate.10

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.

RET alterations can be identified via various testing methodologies, including NGS, PCR, and FISH2

It is important to consider that not every laboratory test can detect RET fusions.

Talk to your pathologist to determine the most appropriate lab for testing your patient for biomarkers.

dMMR/MSI=mismatch repair deficient/microsatellite instability-high; DTC=differentiated thyroid cancer; FISH=fluorescence in situ hybridization; NCCN=National Comprehensive Cancer Network® (NCCN®); NGS=next-generation sequencing; PCR=polymerase chain reaction; RET+=rearranged during transfection positive; TMB=tumor mutational burden.

DNA Icon

Select patients for treatment based on the presence of a RET gene fusion. Consider a selectively designed RET inhibitor.11

Information on FDA-approved tests for RET gene fusions is available at http://www.fda.gov/CompanionDiagnostics

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Efficacy data for GAVRETO
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References:

 

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed May 7, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org.

 

2. Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167.

 

3. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997.

 

4. Santoro M, Porta GP, Berger N, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest. 1992;89(5):1517-1522.

 

5. Lee YC, Chen JY, Huang CJ, et al. Detection of NTRK1/3 rearrangements in papillary thyroid carcinoma using immunohistochemistry, fluorescent in situ hybridization, and next-generation sequencing. Endocr Pathol. 2020;31(4):348-358.

 

6. Panebianco F, Nikitski AV, Nikiforova MN, et al. Characterization of thyroid cancer driven by known and novel ALK fusions. Endocr Relat Cancer. 2019;26(11):803-814.

 

7. Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in Northeast United States. Cancer. 2016:1097-1107.

 

8. Prescott JD, Zeiger MA. The RET oncogene in papillary thyroid carcinoma. Cancer. 2015;121(13):2137-2146.

 

9. Bulanova Pekova B, Sykorova V, Mastnikova K, et al. RET fusion genes in pediatric and adult thyroid carcinomas: cohort characteristics and prognosis. Endocr Relat Cancer. 2023;30(12):e230117. Published October 26, 2023. doi:10.1530/ERC-23-0117

 

10. Belli C, Penault-Llorca F, Norman N, et al. ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. Ann Oncol. 2021;32(3):337-350.

 

11. GAVRETO® [Package insert], South San Francisco, CA: Rigel Pharmaceuticals, Inc.

Indications & Important Safety Information

INDICATIONS

GAVRETO (pralsetinib) is indicated for the treatment of:

  • Adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test
  • 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)*

*This indication is approved under accelerated approval based on 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).

IMPORTANT SAFETY INFORMATION

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal ILD/pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD.

Hypertension: Occurred in 35% of patients, including Grade 3 hypertension in 18% of patients. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. 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 GAVRETO based on the severity.

Hepatotoxicity: Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased aspartate aminotransferase (AST) occurred in 49% of patients, including Grade 3 or 4 in 7% and increased alanine aminotransferase (ALT) occurred in 37% of patients, including Grade 3 or 4 in 4.8%. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and increased ALT was 24 days (range: 7 days to 3.7 years). Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity.

Hemorrhagic Events: Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥3 events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event. Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage.

Tumor Lysis Syndrome (TLS): Cases of TLS have been reported in patients with medullary thyroid carcinoma receiving GAVRETO. 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.

Risk of Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing. Withhold GAVRETO for at least 5 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 GAVRETO after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose.

Common adverse reactions (≥25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. Common Grade 3/4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium, and increased bilirubin.

Avoid coadministration of GAVRETO with strong or moderate CYP3A inhibitors, P-gp inhibitors, or combined P-gp and strong or moderate CYP3A inhibitors. If coadministration cannot be avoided, reduce the GAVRETO dose. Avoid coadministration of GAVRETO with strong or moderate CYP3A inducers. If coadministration cannot be avoided, increase the GAVRETO dose.

Lactation: Advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose.

Pediatric Use: Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing GAVRETO if abnormalities occur.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please click here to see the full Prescribing Information and Patient Information for GAVRETO.