RET inhibitors

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 alterations^2–4

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.

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

RET kinase is encoded by the RET gene, which is located on chromosome 10^5,7. RET is made up of 3 domains: an extracellular ligand-binding domain consisting of four cadherin-like repeats (CLD1–4) and a cysteine-rich domain (CRD), a transmembrane domain, and an intracellular tyrosine kinase domain (Figure 2)⁸.

Figure 2. The structure of RET protein and its ligands (Adapted⁵). CLD, cadherin-like domain; CRD, cysteine-rich domain; EC, extracellular region; GDNF, glial-derived neurotrophic factor; GFR, GDNF family receptor; JM, juxtamembrane segment; TKD, tyrosine kinase domain; TM, transmembrane segment.

RET is activated by ligands belonging to the glial-derived neurotrophic factor (GDNF) family, including GDNF, neurturin, persephin and artemin⁵. GDNF family ligands first bind to co-receptors located on the cell surface, called GDNF family receptors (GFRα1–4). These ligand-receptor complexes in turn associate with RET, leading to homodimerisation and kinase activation (Figure 2)⁵. This results in the phosphorylation of several tyrosine residues located in the intracellular portion of RET, and activation of downstream signalling cascades involved in cellular proliferation and differentiation^5,9.

Inhibiting RET

Hyperactivation of tyrosine kinases such as RET is a central driving force in multiple cancers, and agents that inhibit these proteins are widely used in cancer therapy. Drugs such as vandetanib and cabozatinib are multi-kinase inhibitors (MKIs) that can be used in patients that have cancers driven by RET alterations¹⁰.

Toxicity due to ‘off-target’ effects is a major limitation of multi-kinase inhibitors

MKIs block receptor activation and downstream signalling, usually by competing with ATP, thereby inhibiting phosphorylation⁸. However, while MKIs have demonstrated improvements in progression-free survival (PFS) in patients with thyroid cancer, MKIs are not specific for RET, and also inhibit additional receptors⁵. This lack of specificity results in ‘off-target’ effects which can lead to dose limiting, and potentially life-threatening, adverse events including hypertension, and cardiovascular complications⁵.

Recently, selective RET inhibitors have been developed to address some of the limitations associated with MKIs.

Selpercatinib and pralsetinib have been specifically designed to target RET and its alterations commonly seen in NSCLC and thyroid cancer^11,12

Both selpercatinib and pralsetinib exhibit a novel binding mechanism whereby they wrap around RET, binding to both the front and back portions of the drug-binding pocket, while avoiding ‘gatekeeper’ sites that are liable to mutations associated with drug resistance¹³.

In vitro testing of both selpercatinib and pralsetinib revealed very high selectivity for RET.

In pre-clinical studies, selpercatinib was over 250-fold more selective for RET than 98% of other kinases tested, while pralsetinib was 100-fold more selective for RET than 96% of other kinases tested^5,11

Based on early clinical results, the FDA and European Medicines Agency (EMA) granted approval for selpercatinib for use in selected non-small cell lung cancer (NSCLC) and thyroid cancer patients who harbour RET alterations^2,3. The FDA has also granted approval for use of pralsetinib in these patients⁴.

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

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 (Adapted^14,15). CI, confidence intervals; CR, complete response; ORR, overall response rate; PR, partial response; RET, rearranged during transfection.

Both the LIBRETTO-001 and ARROW trials stipulated that patients must possess alterations to RET, so eligibility hinged on the results of molecular testing^14,15

LIBRETTO-001¹⁴:

• Patients aged 12 years and older with a diagnosis of advanced or metastatic solid tumour of any type, and who harboured an activating RET alteration, received twice daily doses of 160 mg oral selpercatinib
• Among NSCLC patients, the overall response rate (ORR) was 64% in patients who had previously received platinum-based chemotherapy (n = 105), including two patients (2%) with a complete response (CR) and 65 (62%) with a partial response (PR)
• The median duration of response was 17.5 months, and 66% of patients were progression-free after 12 months
• An ORR of 85% was reported in 39 previously untreated patients, with no CRs and 33 (85%) PRs
• At 6 months, 90% of responses were ongoing, while 75% of patients were progression-free after 12 months with median duration of response not yet reached

ARROW¹⁵:

• Patients aged 18 and over with locally advanced or metastatic tumours, including RET-positive NSCLC, received 400 mg oral pralsetinib once daily
• The ORR was 61% among the 87 patients who had previously received platinum-based chemotherapy, including five patients (6%) who demonstrated a CR
• Median duration of response was not reached, although 83% and 74% of previously treated patients had a response at 6 and 12 months, respectively
• An ORR of 70%, including three (11%) CRs, was reported in 27 treatment-naïve patients, with 74% and 26% of patients exhibiting a response at 6 and 12 months, respectively

Overall, these data indicate that selpercatinib and pralsetinib demonstrated durable efficacy in RET fusion-positive NSCLC, both in patients who had received previous treatment with platinum-based chemotherapy, and in previously untreated patients^14,15.

National Comprehensive Cancer Network guidelines for RET-positive non-small cell lung cancer

Selpercatinib and pralsetinib are recommended by the National Comprehensive Cancer Network (NCCN) guidelines for use as first-line therapy for patients with RET rearrangement-positive metastatic NSCLC. Both drugs are also recommended as preferred subsequent therapy options in this setting if RET inhibitors have not been previously used as first-line therapy¹⁶.

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 FDA has approved selpercatinib and pralsetinib for use in RET-altered thyroid cancer patients; in Europe, only selpercatinib is currently licensed for use (Figure 4)^2–4

Figure 4. RET inhibitor thyroid cancer indications in the US (FDA) and Europe (EMA)^2–4. MTC, medullary thyroid cancer; RET, rearranged during transfection.

RET-mutant medullary thyroid cancer

Data from the LIBRETTO-001 and ARROW trials supported the approval of selective RET inhibitors in patients with RET-altered thyroid cancers (see Table 2).

Patients with RET-mutant medullary thyroid cancer (MTC), with or without prior treatment with vandetanib or cabozantinib were eligible to join the LIBRETTO-001 study¹⁷. Patients were treated with oral selpercatinib at a dose of 160 mg twice daily in 28-day cycles¹⁷. Overall response rate (ORR) was 69% in patients (n = 55) previously treated with vandetanib and/or cabozantinib, with 5 patients (9%) demonstrating a complete response (CR)¹⁷. Responses persisted for 12 months in 86% of patients, with 82% remaining progression-free at this timepoint¹⁷. In 88 patients who had not received previous multi-kinase inhibitor (MKI) therapy, the ORR was 73%, with 10 patients (11%) showing CRs. At Year 1, 91% of responses were ongoing and 92% of patients remained progression-free¹⁷.

Data from the ARROW trial showed pralsetinib treatment was associated with an ORR of 60% in 55 RET-mutant MTC patients previously treated with MKI, with one patient (2%) showing a CR¹⁸. A cohort of treatment-naïve patients (n = 21) showed an ORR of 71%, with CR again seen in one patient (5%)¹⁸.

Table 2. Clinical trials investigating selpercatinib and pralsetinib in RET-altered MTC^17,18. CR, complete response; MTC, medullary thyroid cancer; ORR, overall response rate; PR, partial response, RET, rearranged during transfection.

National Comprehensive Cancer Network guidelines for RET-positive medullary thyroid cancer

Selpercatinib and pralsetinib are recommended by the NCCN as systemic therapy for MTC patients who are RET mutation positive with unresectable disease that is symptomatic or progressing according to RECIST (Response Evaluation Criteria in Solid Tumours) criteria¹⁹.

RET fusion-positive thyroid cancer

The LIBRETTO-001 and ARROW trials also included patients with RET fusion-positive thyroid cancer, including papillary, poorly differentiated, anaplastic and Hurthle-cell thyroid cancer, all of whom had received prior treatment^17,18. In 19 previously treated patients in LIBRETTO-001, an ORR of 79% was seen in response to selpercatinib, with 71% of responses ongoing and 64% of patients remaining progression free at 12 months¹⁷. A comparable ORR of 89% was also seen following pralsetinib treatment in ARROW, with almost all patients showing PRs (Table 3)¹⁸.

Table 3. Clinical trials investigating selpercatinib and pralsetinib in RET fusion-positive thyroid cancer^17,18. CR, complete response; ORR, overall response rate; PR, partial response.

National Comprehensive Cancer Network guidelines for RET-positive thyroid cancer

Selpercatinib and pralsetinib are recommended by the National Comprehensive Cancer Network Guidelines (NCCN) as systemic therapy for patients with RET-positive thyroid cancer that is structurally persistent/recurrent, locoregional or with distant metastatic disease that is not amenable to radioactive iodine ablation therapy¹⁹.

See the next section for more information regarding the safety of selpercatinib and pralsetinib and how to manage side effects.

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).

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 cancer^15,18. 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).

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

Among NSCLC patients receiving pralsetinib in the ARROW trial, dose reductions owing to treatment-related adverse events were required in 38% of patients, while treatment was discontinued in 6% of patients¹⁵. Treatment-related dose reductions were more common in patients with thyroid cancer (46%), with treatment-related adverse events leading to treatment discontinuation occurring in five patients (4%)¹⁸.

The most common adverse reactions associated with selpercatinib and pralsetinib were fatigue, hypertension, constipation, and diarrhoea. During the LIBRETTO-001 and ARROW studies, dose reductions due to adverse reactions occurred in approximately a third of patients^2,4

RET inhibitor side effect management

The labels for selpercatinib and pralsetinib allow three dose reductions in the event of adverse reactions. If the patient is still unable to tolerate treatment after three dose reductions, it is recommended that selpercatinib and pralsetinib are discontinued permanently^2,4. The approved product labelling for each agent provides specific guidance, including dosage reductions and withholding of medication, in the event of certain adverse reactions such as hepatotoxicity, hypertension and haemorrhagic events^2,4.

RET inhibitors: Drug-drug interactions

A major consideration with tyrosine kinase inhibitors is drug-drug interaction, particularly as patients often face multiple comorbidities²⁰. Factors such as changes in stomach pH or metabolism can alter drug bioavailability²⁰. These interactions may lead to a reduction in the plasma concentration of a drug, impairing its anti-tumour activity, or to an increase, potentially increasing the risk of adverse events^2,20. Alternatively, a synergistic, additive or antagonistic effect can result from interactions between the active agents of multiple drugs²⁰. It is therefore essential to assess all the products a patient is treated with prior to prescribing tyrosine kinase inhibitors²⁰.

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 chemotherapy^23,24.

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.

The primary outcome of both trials is progression‑free survival, with study completion for AcceleRET-Lung and AcceleRET-MTC expected in 2024 and 2028, respectively^23,25.

Other studies are assessing the safety and efficacy of RET inhibitors for RET-altered advanced solid or primary central nervous system (CNS) tumours in patients as young as 6 months

RET alterations are reported in paediatric patients with a variety of cancers, including 22%–45% of papillary thyroid cancers (PTCs)²⁶. The LIBRETTO-121 study (NCT03899792) is assessing the safety and efficacy of selpercatinib in paediatric patients as young as 6 months with RET-altered thyroid cancer, with preliminary findings appearing to align with results from adult trials^27,28. Additionally, the A LUNG-MAP study (NCT04268550) is assessing efficacy of selpercatinib in adults and children with RET fusion-positive NSCLC²⁹.

Tables 7 and 8 provide an overview of the ongoing trials of selpercatinib and pralsetinib, respectively.

Table 7. Ongoing clinical trials of selpercatinib relevant to thyroid cancer and non-small cell lung cancer^{21,22,27,29–33}. CNS, central nervous system; EFS, event free survival; EGFR, epidermal growth factor receptor; MTC, medullary thyroid cancer; NSCLC, non-small cell lung cancer; ORR, overall response rate; PFS, progression free survival; PTC, papillary thyroid cancer; RET, rearranged during transfection; SoC, standard of care; TFFS, treatment failure free survival.

Table 8. Ongoing clinical trials of pralsetinib^23,25,34. MKI, multi-kinase inhibitor; MTC, medullary thyroid cancer; NSCLC, non-small cell lung cancer; ORR, overall response rate; PFS, progression free survival; RET, rearranged during transfection; SoC, standard of care.

RET inhibitor resistance mechanisms

Patients with RET-driven cancers may be resistant to certain tyrosine kinase inhibitors due to either intrinsic or acquired mechanisms^5,10. 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.

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 resistance^5,35. 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 trials^11,12,17,18.

In addition to gatekeeper mutations, mutations in the solvent-front area of the kinase may also lead to acquired resistance³⁵. Acquired mutations at glycine 810, including G810R, G810S or G810C, have been identified in RET fusion-positive NSCLC and RET-mutant MTC patients³⁶. However, unlike common gatekeeper mutations, RET inhibitors remain vulnerable to resistance from solvent-front and other non-gatekeeper mutations^18,36. Indeed, after an initial response to selpercatinib, patients harbouring acquired solvent-front mutations at the G810 position later developed drug resistance and disease progression³⁶.

Mutations associated with acquired resistance to RET inhibitors can be detected in circulating tumour DNA (ctDNA)³⁶. With this in mind, early monitoring of ctDNA may identify patients who will progress on RET inhibitors and therefore allow for alternative treatment strategies to be initiated³⁶. This may involve multi-drug combination strategies, several of which are currently being investigated³⁵.

Patient stratification for RET inhibition

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