About RET+ mNSCLC

The importance of obtaining complete biomarker test results prior to initiating first-line therapy in mNSCLC

About 1 in 2
About 1 in 2 patients with mNSCLC have biomarkers with approved, emerging, or evolving therapeutics.4,5

RET fusions are 1 of 9 driver alterations with FDA-approved therapies4,5*

1 of 9 alterations

*Current as of May 2024.
Emerging Therapeutics=currently being studied in clinical trials; Evolving Therapeutics=either proof-of-concept studies or in a very early clinical stage.
ALK=anaplastic lymphoma kinase; BRAF=B-Raf proto-oncogene; EGFR=endothelial growth factor receptor; ERBB2=erb-b2 receptor tyrosine kinase 2; HER2=human epidermal growth factor receptor 2; KRAS=Kirsten rat sarcoma; MET=MET proto-oncogene; mNSCLC=metastatic non–small cell lung cancer; NTRK=neurotrophic tyrosine receptor kinase; RET=rearranged during transfection; ROS1=ROS proto-oncogene 1.

Test for RET in mNSCLC

Talk to your pathologist or lab partners to determine how to best test comprehensively for all biomarkers in mNSCLC, including RET

Comprehensive biomarker testing can assess most actionable biomarkers with one test—so you can identify which biomarker may be responsible for driving disease6

The National Comprehensive Cancer Network® (NCCN®) NSCLC Panel recommends that eligible patients with metastatic NSCLC receive routine biomarker testing for2:

  • EGFR mutations
  • ALK fusions
  • ROS1 fusions
  • BRAF mutations
  • HER2 (ERBB2) mutations
  • KRAS G12C mutations
  • MET exon 14 skipping mutations
  • RET rearrangements
  • NTRK1/2/3 gene fusions
  • PD-L1 expression levels

ALK=anaplastic lymphoma kinase; BRAF=B-Raf proto-oncogene; EGFR=endothelial growth factor receptor; KRAS=Kirsten rat sarcoma; MET=MET proto-oncogene; mNSCLC=metastatic non–small cell lung cancer; NTRK=neurotrophic tyrosine receptor kinase; PD-L1=programmed death-ligand 1; RET+=rearranged during transfection positive; ROS1=ROS proto-oncogene 1.

Insufficient tissue (or QNS) is not a conclusive result and may lead to an uninformed treatment decision2

NGS-based tissue genotyping and plasma ctDNA testing are considered accurate, reliable, and complementary approaches to test for actionable biomarkers, including RET alterations.7

  • Testing of plasma ctDNA may overcome some of the limitations of tumor tissue genotyping due to faster turnaround time and a less invasive procedure7
  • Plasma ctDNA testing is recommended by both IASLC and NCCN under certain circumstances2,7

International Association for the Study of Lung Cancer Guidelines (IASLC)7

Plasma ctDNA can now be considered a valid tool for genotyping of newly diagnosed patients with advanced NSCLC and should be performed using a clinically validated NGS platform

NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®)2

NCCN Guidelines® recommend plasma ctDNA testing as an option when there is limited tissue availability or the patient is unfit for invasive tissue sampling

ctDNA=circulating tumor DNA; NGS=next-generation sequencing.

Use biomarker test results to help guide treatment decisions in mNSCLC4,8,9

Reviewing biomarker test results before initiating treatment could help determine an appropriate treatment plan9

targeted therapy

Targeted therapies may lead to better outcomes in patients with actionable biomarkers.9-12

  • Although many mNSCLC patients have derived benefit from immunotherapy (IO), some biomarker-driven cancers may respond poorly to IO treatment13-16
    • mNSCLC patients with biomarkers are often excluded from IO clinical trials14,17
    • In a retrospective study of 551 advanced NSCLC patients, IO response rates in select biomarker-driven NSCLC were13:
      • ALK (n=23): 0%
      • RET (n=16): 6%
      • EGFR (n=125): 12%
      • HER2 (ERBB2) (n=29): 7%
      • KRAS (n=271): 26%
      • BRAF (n=43): 24%
      • ROS1 (n=7): 17%
      • MET (n=36): 16%
NCCN Guidelines

NCCN Guidelines state that, for eligible patients with metastatic NSCLC who have actionable genetic variants, targeted therapy2:

  • is recommended as a first-line and/or second-line treatment option, depending on the biomarker*
  • for the oncogenic driver should take precedence over treatment with an immune checkpoint inhibitor, even when PD-L1 expression is elevated in patients with an oncogenic driver

*Targeted therapy is recommended as second-line treatment for KRAS G12C and HER2 (ERBB2) mutations.
PD-L1=programmed death-ligand 1.
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.

DNA Icon

Select patients for treatment based on the presence of a RET gene fusion. Consider a selectively designed RET inhibitor.1

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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efficacy data

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References:

 

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

 

2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed July 2, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.

 

4. VanderLaan PA, Rangachari D, Costa DB. The rapidly evolving landscape of biomarker testing in non-small cell lung cancer. Cancer Cytopathol. 2021;129(3):179-181.

 

5. Morton C, Sarker D, Ross P. Next-generation sequencing and molecular therapy. Clin Med (Lond). 2023;23(1):65-69.

 

6. 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. Arch Pathol Lab Med. 2018;142(3):321-346.

 

7. Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021:S1556-0864(21)02284-X. doi:10.1016/j.jtho.2021.06.017.

 

8. Drusbosky LM, Rodriguez E, Dawar R, Ikpeazu CV. Therapeutic strategies in RET gene rearranged non-small cell lung cancer. J Hematol Oncol. 2021;14(50):1-8.

 

9. Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients. Lancet. 2016;387(10026):1415-1426. doi:10.1016/S0140-6736(16)00004-0.

 

10. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006.

 

11. Solomon BJ, Kim DW, Wu YL, et al. J Clin Oncol. 2018;36(22):2251-2258.

 

12. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non–small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651-659.

 

13. Mazières J, Drilon A, Lusque A. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328.

 

14. Addeo A, Malapelle U, Luigi Banna G, Subbiah V, Friedlaender A. Immunotherapy in non-small cell lung cancer harbouring driver mutations. Cancer Treat Rev. 2021;96:102179. doi:10.1016/j.ctrv.2021.102179.

 

15. Chen R, Tao Y, Xu X, et al. Discover Med. 2018;26(143):155-166.

 

16. Lisberg A, Cummings A, Goldman JW, et al. J Thorac Oncol. 2018;13(8):1138-1145.

 

17. Offin M, Guo R, Wu SL, et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers. JCO Precis Oncol. 2019;3:PO.18.00386. doi:10.1200/PO.18.00386.

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.