This site is intended for healthcare professionals
Molecular diagnostics for RET inhibition in NSCLC and thyroid cancers

RET inhibitors

Read time: 75 mins
Last updated:10th Sep 2021
Published:10th Sep 2021

Discover how aberrant rearranged during transfection (RET) tyrosine kinase signalling drives thyroid cancer and non-small cell lung cancer (NSCLC). 

  • Understand RET kinase physiology and the mode of action (MOA) of RET inhibitors
  • Find out how RET mutations can be targeted effectively to manage NSCLC and thyroidcancer
  • Explore the clinical evidence for RET inhibitors
  • Understand mechanisms of RET inhibitor resistance

RET inhibitor mode of action

Recent developments in our understanding of the key oncogenic drivers of various types of cancers has facilitated a transition in oncology, from a ‘one size fits all’ approach to precision medicine, whereby treatment is directed by the patient’s individual molecular profile1. Central to precision medicine is the ability to characterise specific molecular features of a patient’s cancer. Such information can inform diagnosis and prognosis, and importantly, help oncologists to match individual patients to the treatment most likely to produce a favourable outcome1.

This approach is particularly relevant to patients with non-small cell lung cancer (NSCLC) and thyroid cancer who harbour particular defects in a gene called rearranged during transfection (RET). A faulty RET gene leads to the production of a dysfunctional RET protein and two drugs, selpercatinib and pralsetinib, specifically targeting this defective protein have been approved by the Food and Drug Administration (FDA) for use in patients with these conditions.

Two RET inhibitors – selpercatinib and pralsetinib – have been approved for use in NSCLC and thyroid cancer patients harbouring RET alterations2–4

The RET gene was first discovered in 1985. Over the subsequent decades, substantial progress has been made in our understanding of RET as a driver of various cancers5.

RET is a proto-oncogene, which when mutated gives rise to a constitutively active RET protein that triggers downstream signalling pathways implicated in cancer. RET is therefore a logical anti-cancer target, and in recent years RET inhibitors have been developed (Figure 1)5.

RET_T1_Fig_1_Aug2021-01.png

Figure 1. Timeline of major developments in research on RET and RET inhibition (Adapted5). EMA, European Medicines Agency; FDA, Food and Drug Administration; GDNF, glial cell line-derived neurotrophic growth factor; LADC, lung adenocarcinoma; MTC, medullary thyroid cancer; PTC, papillary thyroid cancer; RET, rearranged during transfection; TKD, tyrosine kinase domain; TKI, tyrosine kinase inhibitor.

RET kinase structure and physiology

RET is a type of cell surface receptor called a tyrosine kinase receptor. Tyrosine kinase receptors play an important role in the regulation of cell growth, differentiation and survival6

Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

RET inhibition in non-small cell lung cancer

Dr Alexander Drilon outlines the evidence which led to the regulatory approvals of rearranged during transfection (RET) inhibitors for RET fusion-positive non-small cell lung cancers (NSCLC).

 

Selpercatinib and pralsetinib have been approved for use in adult patients with metastatic RET fusion-positive NSCLC (Figure 3)2–4

RET_T1_Fig_3_Aug2021.png

Figure 3. RET inhibitor non-small cell lung cancer indications in the US (FDA) and Europe (EMA)2–4.

Selpercatinib is licensed in Europe as a second-line therapy for the treatment of adult patients with advanced RET fusion-positive NSCLC who require systemic therapy following prior immunotherapy and/or platinum-based chemotherapy3. The indication is broader in the US, where it can be used as a first-line therapy for metastatic RET fusion-positive NSCLC2.

Pralsetinib is licensed in the US for adult patients with metastatic RET fusion-positive NSCLC as detected by a Food and Drug Administration (FDA) approved test4.

The approval of both drugs was based largely on the efficacy and safety results of the LIBRETTO-001 (NCT03157128: selpercatinib)14 and ARROW (NCT03037385: pralsetinib)15 clinical trials (Table 1).

Table 1. Clinical trials investigating selpercatinib and pralsetinib in RET-altered NSCLC (Adapted14,15). CI, confidence intervals; CR, complete response; ORR, overall response rate; PR, partial response; RET, rearranged during transfection.

*105 previously treated, 39 treatment-naïve.
†87 previously treated, 27 treatment-naïve.
Study Study population and treatment regimen Outcomes in previously treated patients Outcomes in previously untreated patients
LIBRETTO-001
Phase 1/2

NCT03157128
(Drilon, 2020)
144 patients with RET fusion-positive NSCLC* treated with oral selpercatinib (160 mg) twice daily ORR: 64%
(95% CI 54–73)

CR: 2%

PR: 62%
ORR: 85%
(95% CI 70–94)

CR: 0%

PR: 85%
ARROW
Phase 1/2

NCT03037385
(Gainor, 2021)
121 patients with RET fusion-positive NSCLC† treated with oral pralsetinib (400 mg) once daily ORR: 61%
(95% CI 50–71)

CR: 6%

PR: 55%
ORR: 70%
(95% CI 50–86)

CR: 11%

PR: 59%

Both the LIBRETTO-001 and ARROW trials stipulated that patients must possess alterations to RET, so eligibility hinged on the results of molecular testing14,15

Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

RET inhibition in thyroid cancer

Professor Lori Wirth, an international authority in advanced thyroid cancer and head and neck oncology, discusses the importance of molecular testing for the application of rearranged during transfection (RET) inhibitors in the clinic.

The importance of molecular testing for RET inhibition in thyroid cancer

Evidence of the effectiveness of RET inhibitors for treating thyroid cancer

5
Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

RET inhibitor safety

In the following video Dr Alexander Drilon discusses the main side effects of rearranged during transfection (RET) inhibitors to be aware of, noting the differences between the adverse event profiles of the approved first-generation selective RET inhibitors in non-small cell lung cancer (NSCLC).

 

The greater selectivity for RET and reduced affinity for other kinases provided by selective RET inhibitors provides the potential for reduced toxicity compared to other treatment options5

Selpercatinib clinical trial safety data

The safety profile of selpercatinib was broadly similar among all 702 patients recruited to the LIBRETTO-001 trials, regardless of cancer subtype17. Serious adverse reactions occurred in 33% of patients, the most frequent of which was pneumonia in ≥2% of patients. Fatal adverse reactions occurred in 3% of patients, and included sepsis, cardiac arrest and respiratory failure2. The most frequently reported adverse reactions from LIBRETTO-001 can be seen in Table 4.

Table 4. Adverse reactions in ≥15% of patients who received selpercatinib in LIBRETTO-001 (n = 702) (Adapted2).

*Only includes a grade 3 adverse reaction.
Adverse reaction Grades 1–4 (%) Grades 3–4 (%)
Gastrointestinal
Dry mouth 39 0
Diarrhoea 37 3.4*
Constipation 25 0.6*
Nausea 23 0.6*
Abdominal pain 23 1.9*
Vomiting 15 0.3*
Vascular
Hypertension 35 18
General
Fatigue 35 2*
Oedema 33 0.3*
Skin
Rash 27 0.7*
Nervous system
Headache 23 1.4*
Respiratory
Cough 18 0
Dyspnoea 16 2.3
Investigations
Prolonged QT interval 17 4*
Blood and lymphatic system
Haemorrhage 15 1.9

Among the entire study population receiving selpercatinib in the LIBRETTO-001 trial, treatment-related adverse events led to a dose reduction in 30% of patients, and necessitated treatment discontinuation in 2% of patients17.

Pralsetinib clinical trial safety data

Safety data from the ARROW trial also indicated pralsetinib is generally well tolerated in patients with NSCLC and thyroid cancer15,18. The adverse reactions were stratified according to the patient populations and shown below in Table 5 and Table 6.

Table 5. Adverse reactions in ≥15% of patients with RET fusion-positive non-small cell lung cancer who received pralsetinib in ARROW (n = 220) (Adapted4).

*Only includes a Grade 3 adverse reaction.
Adverse reaction Grades 1–4 (%) Grades 3–4 (%)
General
Fatigue 35 2.3*
Oedema 20 0
Pyrexia 20 0
Gastrointestinal
Constipation 35 1*
Diarrhoea 24 3.2*
Dry Mouth 16 0
Musculoskeletal disorders
Musculoskeletal pain 32 0
Vascular
Hypertension 28 14*
Respiratory, thoracic and mediastinal
Cough 23 0.5*
Infections
Pneumonia 17 8

Table 6. Adverse reactions in ≥15% of patients with RET-altered thyroid cancer who received pralsetinib in ARROW (n = 138) (Adapted4).

*Only includes a Grade 3 adverse reaction.
Adverse reaction Grades 1–4 (%) Grades 3–4 (%)
Musculoskeletal
Musculoskeletal pain 42 0.7*
Gastrointestinal
Constipation 41 0.7*
Diarrhoea 34 5*
Abdominal pain 17 0.7*
Dry mouth 17 0
Stomatitis 17 0.7*
Nausea 17 0.7*
Vascular
Hypertension 40 21*
General
Fatigue 38 6*
Oedema 29 0
Pyrexia 22 2.2*
Nervous system
Headache 24 0
Peripheral neuropathy 20 0
Dizziness 19 0.7*
Dysgeusia 17 0
Respiratory
Cough 27 1.4*
Dyspnea 22 2.2*
Skin and subcutaneous
Rash 24 0
Metabolism and Nutrition
Decreased appetite 15 0
Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

Ongoing clinical trials for RET inhibitors

In the following video Professor Lori Wirth provides an overview of ongoing clinical trials for rearranged during transfection (RET) inhibitors in the treatment and management of medullary thyroid cancer (MTC).


There are a number of ongoing clinical trials that are exploring the efficacy and safety of RET inhibitors in different patient populations with varied types of cancer and treatment histories.

Ongoing studies are comparing RET inhibitors to standard of care (SoC) in patients with NSCLC and medullary thyroid cancer

Investigations into selpercatinib are continuing, with the LIBRETTO-431 (NCT04194944) trial comparing selpercatinib to chemotherapy in patients with metastatic RET fusion‑positive non-small cell lung cancer (NSCLC) and the LIBRETTO-531 (NCT04211337) study randomising patients with RET-mutant medullary thyroid cancer (MTC) to either selpercatinib or SoC (cabozantinib or vandetanib)21,22.

The AcceleRET-Lung (NCT04222972) and AcceleRET-MTC (NCT04760288) trials are comparing pralsetinib to SoC in patients with NSCLC and MTC, respectively. During AcceleRET-Lung, adult patients with RET fusion-positive metastatic NSCLC who have not been treated previously with systemic anti-cancer therapy for metastatic disease, will be randomised to receive either once-daily oral pralsetinib or platinum-based chemotherapy23,24.

Meanwhile, AcceleRET-MTC will randomise patients with RET-mutant MTC who have not been treated previously with MKI, to either pralsetinib or MKI (cabozantinib or vandetanib)25.

Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

RET inhibitor resistance mechanisms

Patients with RET-driven cancers may be resistant to certain tyrosine kinase inhibitors due to either intrinsic or acquired mechanisms5,10. Acquired resistance can develop following modification of the target kinase, whereby somatic mutations occur in response to selective pressure from tyrosine kinase inhibitors, resulting in constitutive signal activation35.

Certain RET alterations are associated with resistance to MKIs and RET inhibitors5

Mutation of residues V804, Y806 and G810 in the hinge segment, and S904 in the activation segment of RET kinase can mediate resistance to various MKIs (Figure 5)5.

RET_T1_Fig_5_Aug2021.png

Figure 5. Structure of the RET protein, showing mutation sites that are implicated in resistance (Adapted5). AS, activation segment; CLD, cadherin-like domain; CRD, cysteine-rich domain; EC, extracellular region; G, glycine-rich loop mediating binding to the nucleotide; H, hinge; I, kinase insert; JM, juxtamembrane segment; TM, transmembrane segment.

Residue V804 is particularly important for signalling due to its ‘gatekeeper’ position in RET, where it controls ATP and drug binding5. Single amino acid substitutions in this region frequently occur both as a germline mutation in sporadic MTC and a somatic mutation that develops in response to MKI therapy, mediating drug resistance5,35. Importantly, both selpercatinib and pralsetinib have been shown to inhibit gatekeeper RET kinase V804 mutants in preclinical models, and patients harbouring V804 mutations have responded to treatment in clinical trials11,12,17,18.

Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

References

  1. Malone E, Oliva M, Sabatini P, Stockley T, Siu L. Molecular profiling for precision cancer therapies. Genome medicine. 2020;12(1). doi:10.1186/S13073-019-0703-1.
  2. Selpercatinib. Highlights of Prescribing Information. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf.
  3. Selpercatinib® Summary of Product Characteristics. https://www.medicines.org.uk/emc/product/12196/smpc#gref. Accessed 14 July 2021.
  4. Pralsetinib. Highlights of Prescribing Information. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214701s000lbl.pdf. Accessed 27 August 2021.
  5. Salvatore D, Santoro M, Schlumberger M. The importance of the RET gene in thyroid cancer and therapeutic implications. Nature Reviews Endocrinology. 2021;17(5):296–306.
  6. RTK | Learn Science at Scitable. https://www.nature.com/scitable/topicpage/rtk-14050230/. Accessed 31 August 2021.
  7. Klubo-Gwiezdzinska J. Targeting RET-mutated thyroid and lung cancer in the personalised medicine era. The Lancet Diabetes and Endocrinology. 2021;9(8):473–474.
  8. Santoro M, Carlomagno F. Central role of RET in thyroid cancer. Cold Spring Harbor Perspectives in Biology. 2013;5(12). doi:10.1101/cshperspect.a009233.
  9. Choudhury NJ, Drilon A. Decade in review: A new era for RET-rearranged lung cancers. Translational Lung Cancer Research. 2020;9(6):2571–2580.
  10. Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discovery. 2020;10(4):498–505.
  11. Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Cabanillas ME, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Annals of Oncology. 2018;29(8):1869–1876.
  12. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, et al. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discovery. 2018;8(7):836–849.
  13. Subbiah V, Shen T, Terzyan SS, Liu X, Hu X, Patel KP, et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Annals of Oncology. 2021;32(2):261–268.
  14. Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, et al. Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2020;383(9):813–824.
  15. Gainor JF, Curigliano G, Kim DW, Lee DH, Besse B, Baik CS, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. The Lancet Oncology. 2021;22(7):959–969.
  16. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, et al. Non-small cell lung cancer, Version 2.2021 featured updates to the NCCN guidelines. JNCCN Journal of the National Comprehensive Cancer Network. 2021;19(3):254–266.
  17. Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. New England Journal of Medicine. 2020;383(9):825–835.
  18. Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. The Lancet Diabetes and Endocrinology. 2021;9(8):491–501.
  19. NCCN. Clinical Practice Guidelines in Oncology for Thyroid Carcinoma. Version 1.2021. www.nccn.org. Accessed 31 August 2021.
  20. van Leeuwen RWF, van Gelder T, Mathijssen RHJ, Jansman FGA. Drug-drug interactions with tyrosine-kinase inhibitors: A clinical perspective. The Lancet Oncology. 2014;15(8).
  21. A Study of Selpercatinib (LY3527723) in Participants With Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04194944. Accessed 12 July 2021.
  22. A Study of Selpercatinib (LY3527723) in Participants With RET-Mutant Medullary Thyroid Cancer - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04211337. Accessed 12 July 2021.
  23. A Study of Pralsetinib Versus Standard of Care for First-Line Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC) - ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04222972. Accessed 12 July 2021.
  24. Besse B, Felip E, Clifford C, Louie-Gao M, Green J, Turner CD, et al. AcceleRET Lung: A phase III study of first-line pralsetinib in patients (pts) with RET-fusion+ advanced/metastatic non-small cell lung cancer (NSCLC). Journal of Clinical Oncology. 2020;38(15_suppl):TPS9633–TPS9633.
  25. A Study of Pralsetinib Versus Standard of Care (SOC) for Treatment of RET-Mutated Medullary Thyroid Cancer (MTC) - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04760288. Accessed 13 July 2021.
  26. Ortiz M v., Gerdemann U, Raju SG, Henry D, Smith S, Rothenberg SM, et al. Activity of the Highly Specific RET Inhibitor Selpercatinib (LOXO-292) in Pediatric Patients With Tumors Harboring RET Gene Alterations. JCO Precision Oncology. 2020;(4):341–347.
  27. A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03899792. Accessed 12 July 2021.
  28. Morgenstern DA, Mascarenhas L, Campbell M, Ziegler DS, Nysom K, Casanova M, et al. Oral selpercatinib in pediatric patients (pts) with advanced RET -altered solid or primary CNS tumors: Preliminary results from the phase 1/2 LIBRETTO-121 trial. Journal of Clinical Oncology. 2021;39(15_suppl):10009–10009.
  29. Targeted Treatment for RET Fusion-Positive Advanced Non-Small Cell Lung Cancer (A LUNG-MAP Treatment Trial) - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04268550. Accessed 12 July 2021.
  30. A Study of Selpercatinib After Surgery or Radiation in Participants With Non-Small Cell Lung Cancer (NSCLC) - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04819100. Accessed 12 July 2021.
  31. Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD) - ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03944772. Accessed 12 July 2021.
  32. A Study of Selpercatinib (LY3527723) in Participants With Advanced Solid Tumors Including RET Fusion-positive Solid Tumors, Medullary Thyroid Cancer and Other Tumors With RET Activation - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04280081. Accessed 12 July 2021.
  33. Selpercatinib Before Surgery for the Treatment of RET-Altered Thyroid Cancer - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04759911. Accessed 12 July 2021.
  34. A Study of Alectinib, Entrectinib, Vemurafenib Plus Cobimetinib, or Pralsetinib in Patients With Resectable Stages II-III Non-Small Cell Lung Cancer With ALK, ROS1, NTRK, BRAF V600, or RET Molecular Alterations - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04302025. Accessed 13 July 2021.
  35. Fancelli S, Caliman E, Mazzoni F, Brugia M, Castiglione F, Voltolini L, et al. Chasing the target: new phenomena of resistance to novel selective ret inhibitors in lung cancer. Updated evidence and future perspectives. Cancers (Basel). 2021;13(5):1–23.
  36. Solomon BJ, Tan L, Lin JJ, Wong SQ, Hollizeck S, Ebata K, et al. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. Journal of Thoracic Oncology. 2020;15(4):541–549.
Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

Welcome: