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  • Review Article
  • OPEN ACCESS

The Efficacy and Safety of RET-selective Inhibitors for Cancer Patients

  • Fu-Bin Zhu1,#,
  • Qi-Heng Gou1,# and
  • Lin-Yong Zhao2,* 
 Author information  Cite
Journal of Exploratory Research in Pharmacology   2021;6(1):16-22

doi: 10.14218/JERP.2020.00035

Abstract

The rearrangement during transfection (RET) encodes a receptor tyrosine kinase (RTK), which is involved in the development of various tissues and cells. The rearrangements and mutations of RET contribute to the development of a variety of human malignancies. Therefore, RET alterations are novel therapeutic targets. Inhibitors for RET and other kinases have been approved for the treatment of RET-altered tumors and have demonstrated their benefits for some types of cancer patients in clinics. However, due to off-target effects, these inhibitors have some adverse effects and dose-limiting toxicity. Therefore, long-term treatment with these inhibitors has potential limitations. Novel highly selective inhibitors (pralsetinib and selpercatinib) that target the RET pathway are well tolerated and have significant and long-lasting antitumor activity. They have been accelerated for approval by the FDA. This article will focus on the role of highly selective inhibitors targeting the RET and their efficacy and safety in therapy for RET-associated cancers.

Keywords

Efficacy, Pralsetinib, Rearrangement during transfection alteration, Safety, Selpercatinib, Tyrosine kinase inhibitor

Introduction

Rearrangements in the rearrangement during transfection (RET) genes that encode transmembrane receptor tyrosine kinases (RTK) are associated with tumorigenesis. The RET protein forms a heterodimer complex after it is engaged by a ligand in the glial cell line-derived neurotropic factor (GDNF) family that causes autophosphorylation of the tyrosine kinase domain in the cells and activates downstream signaling, regulating the processes of cell differentiation, cell migration, and proliferation.1–4RET can regulate the development of multiorgans, cell survival, death, and migration and its mutations or gene fusion can promote spontaneous tumor proliferation, activation, and migration.

Alterations in the RET gene are associated with the pathogenesis of many human diseases, including multiple endocrine neoplasia type 2 (MAN-2), papillary thyroid cancer, Hirschsprung’s disease, colon adenocarcinoma, invasive breast cancer, non-small cell lung cancer (NSCLC), and others.5CDCC6-RET and KIF5B-RET, two RET fusions are common in papillary thyroid carcinoma and NSCLC, respectively. A germline mutation in the RET can cause MAN-2 syndrome.6 Germline-activated RET mutations are found in 95–98% of hereditary medullary thyroid cancer (MTC) and somatic RET mutations are found in 25–40% of sporadic MTC. In addition, RET mutations are associated with the aggressiveness of MTC, such as distant metastasis.7 The RET fusions are detected in 1–2% of NSCLC,8 particularly for lung adenocarcinoma and RET rearrangements, are found in other histological types of NSCLC, including malignant neuroendocrine tumor and squamous cell carcinoma.9 It was found that the RET fusion genes were detected in lung cancer, thyroid cancer, colon adenocarcinoma (CCDC6-RET) and invasive breast cancer (ERC1-RET).10

The biology and function of RET

The RET, a transforming gene, was first discovered in mouse embryonic fibroblast cells that were established by the National Institutes of Health (NIH) transfected with DNA from human T cell lymphoma.11 The RET gene is located at 10q11.2 and contains 21 exons.12 The RET encodes an RTK, a type of transmembrane glycoprotein, which mediates signal transduction during various processes, such as cell migration, proliferation, and differentiation. It is required for the development and maturation of various organs and cells.13 Studies have confirmed that RET is crucial for the formation and development of the kidneys and nervous system. In addition, the RET supports the survival of hematopoietic stem cells and early spermatogenesis.14,15 Structurally, RET contains three domains; an extracellular domain, a transmembrane domain, and an intracellular domain that contains the tyrosine kinase domain adjacent to the transmembrane region. The large extracellular region contains a domain of four cadherin-like repeats, a calcium-binding site, and a conserved cysteine-rich portion at the proximal end of the membrane.16 The C-terminal of RET has two main forms, which are formed by alternate splicing of G1063 residue to exon 3. There are 9 or 51 amino acids at the end of the C-terminal, respectively called RET 9 and RET 51.17 Unlike other RTKs, RET protein does not directly transmit signals after it is engaged by its ligand. The ligands of RET are members of the GDNF family, which include neuroturin, artemin, and persephin.2 These GDNF family ligands (GFLs) can bind to four types of GDNF family growth factor receptor-alfa (GFR-α) to form a coreceptor. This GFL-GFR-α binary complex can bind to the intracellular tyrosine kinase domain of RET and induce dimerization of RET.18 The formation of a homodimer between two RET will cause transphosphorylation of intracellular tyrosine residues of RET and create a docking site for the signal adapter molecule. The phosphorylated RET will then recruit key signal adapter molecules and activate a variety of cellular signal cascades, including the MAPK, PI3K, JAK-STAT, PKA, and PKC pathways.3,16 (Fig. 1)

The RET structure and signaling network.
Fig. 1  The RET structure and signaling network.

RET, rearrangement during transfection; GDNF, glial cell line-derived neurotrophic factor; GFRα, growth factor receptor-alfa; ART, artemin; NTN, neurturin; PSP, persephin; Ca++, calcium ion.

Multikinase inhibitors

Multikinase inhibitors for thyroid cancer

Multikinase inhibitors (MKIs) that target the RET pathway have been tested for their antitumor activity in patients with thyroid cancer. Some drugs have shown clinical efficacy, such as vandetanib, cabozantinib, lenvatinib, alectinib, and sorafenib.19 Between them, cabozantinib and vandetanib have been approved for the treatment of locally advanced or metastatic MTC. Vandetanib, an oral RET kinase inhibitor, has shown therapeutic potential in a Phase III trial (ZETA, ClinicalTrials.gov number NCT00410761) in patients that have locally advanced or metastatic MTC. The results of the ZETA study indicated that treatment with vandetanib significantly prolonged the progression-free survival (PFS) in patients that had locally advanced or metastatic MTC (30.5 versus 19.3 months for patients with placebo).20 Similarly, treatment with cabozantinib significantly prolonged the PFS (11.2 versus 4.0 months) of MTC patients in a Phase III trial (EXAM, NCT00704730) with a higher objective response rate [ORR (28% versus 0%)].21 The retrospective analysis of the EXAM trial in two studies revealed that treatment with cabozantinib for MTC patients with the RET M918T mutation achieved a better median PFS (61 versus 17 weeks).22,23

MKIs for NSCLC

MKIs have made some progress in the treatment of RET-associated NSCLC. A multicenter Phase II clinical trial (LURET, UMIN-CTR, UMIN000010095) revealed that treatment with vandetanib achieved an ORR of 53% [95 confidence interval (CI)% 28–77], and a median PFS of 4.7 months (95% CI 2.8–8.5) in previously treated NSCLC patients that harbored RET rearrangements. Further subgroup analysis indicated that treatment with vandetanib resulted in ORRs of 83% and 20% in patients with CCDC6-RET and KIF5B-RET fusion genes, respectively.24 Furthermore, a Phase II clinical trial (NCT01639508) reported that treatment with cabozantinib led to an ORR of 28% (95% CI 12–49) with a median PFS of 5.5 months (95% CI 3.8–8.4) in NSCLC patients.25 This data indicated that MKIs are effective for NSCLC patients with RET fusion, particularly for the common CCDC6-RET and KIF5B-RET fusions. However, whether the efficacy of MKIs is a result of their inhibition of these specific biomarkers needs to be further explored.

Limitations of MKIs

MKIs are usually not selective for targeting RET, and they can target other kinases, such as EGFR, VEGFR-2, KIT, and MET.26 In particular, because the domain of VEGFR-2 kinase has a high degree of homology with RET, several tyrosine kinase inhibitors that target VEGFR-2 (e.g., cabozantinib, vandetanib, and lenvatinib) have shown therapeutic potential for cancer patients with RET alterations to a certain extent.8,27–29 Due to the off-target effect, the inhibitory effect of these MKIs specifically on RET might be limited. Moreover, these MKIs have drug-related toxicity, and increase the dose-reduction rates and treatment-discontinuation rates of drugs, further reducing their clinical applications.17 In addition, these MKIs have developed intrinsic resistance that has limited their clinical application in targeted therapy for RET-altered cancers. The intrinsic resistance might be caused by the fusion between the upstream partner gene KIF5B and RET.16,30 Treatment with MKIs had less efficacy in NSCLC patients that carried KIF5B-RET fusion genes than those without the KIF5B-RET fusion in the LURET study and the Phase I/Ib trail of RXDX-105.31 The acquired resistance to MKIs is probably from specific RET alterations, which result in gatekeeper mutations V804M and V804L on RET.32,33 Particularly, cabozantinib and vandetanib are not effective for NSCLC patients with V804M and V804L mutations.34,35

Selective RET inhibitors

Because traditional MKIs have limitations, including off-target effects, treatment-related toxicity, and acquired resistance new and potent inhibitors that selectively inhibit RET have recently been developed and approved for clinical applications for some types of cancers. For example, selpercatinib (RETEVMO or LOXO-292) and pralsetinib (BLU-667) are two small molecule inhibitors with highly selective inhibition of RET and have been approved by the FDA.36,37

Selpercatinib (RETEVMO or LOXO-292)

Compared with MKIs, preclinical studies have shown that LOXO-292 can selectively target the RET mutants, including gatekeeper resistance mutations and RET fusions compared with MKIs; LOXO-292 exhibits lower toxicity and has low activity against non-RET gene alterations (i.e., VEGFR-2).37 Several clinical studies have been carried out on the treatment of cancer patients.

Selpercatinib for thyroid cancer

Selpercatinib was approved for the treatment of NSCLC and MTC patients with RET-alteration by the FDA on 8 May 2020.38 The multicohort, Phase I/II clinical trial (LIBRETTO-001, NCT03157128) reported that selpercatinib had a significant and long-lasting antitumor activity with an ORR of 69% (n = 38, 95% CI 55–81) and low-grade toxicity in advanced thyroid cancer patients with RET alterations, including patients with RET-mutant MTC resistant to vandetanib or cabozantinib (Table 1). Of interest, some patients with RET mutations or gatekeeper resistance responded to selpercatinib although they were resistant to one or two MKIs previously. Treatment with selpercatinib for the patients with MTCs that harbored RET-alteration without previous MKI treatment achieved an ORR of 73% (n = 64, 95% CI 62–83), the median duration of response (DOR) of 22 months (95% CI Not-Estimable NE–NE) and a PFS of 23.6 months (95% CI NE–NE). Furthermore, treatment with selpercatinib for patients with thyroid cancer bearing the RET fusion observed an ORR of 79% (95% CI 54–94), median DOR of 18.4 months (95% CI 7.6–NE) and a PFS of 20.1 months (95% CI 9.4–NE). Of interest, treatment with selpercatinib for patients with newly diagnosed thyroid cancer without previous systemic treatment resulted in an ORR of 100% (95% CI 63–100).39,40 Selpercatinib appeared to be safe for humans and there was only grade 1 and 2 of treatment-related adverse effect in a population of 162 patients. There were few cases with a low adverse effect or discontinuer event following selpercatinib treatment.39 The low adverse effect of selpercatinib might be attributed to its high selectivity against the RET.

Table 1

Key Clinical trials of selpercatinib and pralsetinib

AgentConditionPhaseStatusLocationsNCT no.
selpercatinibRET fusion-positive solid tumors, MTC, and other tumors with RET activationIIActiveChinaNCT04280081
selpercatinibAdvanced solid tumors, lymphomas, or histiocytic disorders with RET activation in pediatric patients( a pediatric MATCH treatment trial)IIRecruitingUSNCT04320888
selpercatinib, cabozantinib, vandetanibRET-mutant MTCIIIRecruitingMultiple countriesNCT04211337
selpercatinibRET fusion-positive solid tumors, MTC, and other tumors with RET activationI/IIRecruitingMultiple countriesNCT03157128
selpercatinib, carboplatin,
cisplatin, pemetrexed, pembrolizumab		Advanced or metastatic RET fusion-positive NSCLCIIIRecruitingMultiple countriesNCT04194944
selpercatinibRET fusion-positive advanced NSCLCIIRecruitingUSNCT04268550
selpercatinibSolid
tumors with RET activation (expanded access)		N/AAvailableMultiple countriesNCT03906331
selpercatinibAdvanced solid or primary CNS tumors in pediatric patientsI/IIRecruitingUSNCT03899792
selpercatinib,osimertinib,savolitinib,
gefitinib,necitumumab,durvalumab,
carboplatin,pemetrexed,alectinib		Advanced NSCLCIIRecruitingMultiple countriesNCT03944772
pralsetinibThyroid cancer, NSCLC, and other advanced solid tumorsI/IIRecruitingMultiple countriesNCT03037385
pralsetinibUnresectable or metastatic MTC or NSCLCN/AAvailableN/ANCT04204928
pralsetinib,carboplatin,cisplatin,
pemetrexed,pembrolizumab, gemcitabin		Advanced NSCLCIIIRecruitingMultiple countriesNCT04222972

N/A, not applicable; CNS, central nervous system; MTC, medullary thyroid carcinoma; NSCLC, non-small cell lung cancer; NCT, National Clinical Trials

Selpercatinib for NSCLC

In the Phase I/II clinical trial, LIBRETTO-001 (NCT03157128), the therapeutic efficacy of selpercatinib in patients with NSCLC bearing advanced RET fusion was evaluated (Table 1).41 Treatment with selpercatinib 105 NSCLC patients with previous platinum-based chemotherapy obtained an ORR of 64% (n = 67, 95% CI 54–73), median DOR of 17.5 months (95% CI 12.0–NE) and a PFS of 16.5 months (95% CI 13.7–NE). In addition, treatment with selpercatinib benefited 55% of NSCLC patients who received immunotherapy and 56% of NSCLC patients who had received ≥3 systemic therapies. Of note, 38 out of 105 patients had brain metastases, and 11 of them had measurable lesions. The intracranial ORR was 91% (n = 10, 95% CI 95–100), and the median central nervous system (CNS) DOR was 10.1 months (95% CI 6.7–NE). Treatment with selpercatinib obtained an ORR of 85% (n = 33, 95% CI 70–89) in 39 patients with newly diagnosed NSCLC.41 Selpercatinib has a higher therapeutic efficacy in newly diagnosed NSCLC patients than in those with NSCLC refractory common therapies.

Similar to thyroid cancer, selpercatinib treatment resulted in grade 1 and 2 drug-related adverse effects in NSCLC patients. There were a few patients that needed to reduce drug doses or treatment termination.41 Because the most common grade 3 adverse reactions are reversible after dose adjustment, long-term treatment with selpercatinib is feasible. Further analysis of selpercatinib safety supported that selpercatinib was relatively safe in a population of 531 patients with NSCLC and thyroid cancer. The most common adverse events during selpercatinib treatment were at grade 1–2, where 30% (n = 160) of patients reduced the drug dose, and 2% (n = 12) discontinued treatment.

Selpercatinib for other cancers with RET-alteration

Preliminary studies have shown that selpercatinib benefits pediatric cancer patients bearing RET-alterations. A study reported that treatment with selpercatinib for 1–2 cycles achieved a partial response in four pediatric patients with cancers harboring RET fusions (including papillary thyroid cancer and soft-tissue sarcomas).42 Similarly, treatment with selpercatinib resulted in a partial response in four out of five pediatric cancer patients and the remaining one achieved stable disease. Several clinical trials are ongoing, for example, LIBRETTO-431 (NCT04194944), LIBRETTO-121 (NCT03899792), and LIBRETTO-321 (NCT04280081), and might extend selpercatinib to other types of cancers that have RET alterations (Table 1).

Pralsetinib (BLU-667)

A preclinical study has shown that BLU-667 can selectively target RET with higher efficiency.36 The Phase I/II study (ARROW study) (ClinicalTrials.gov number NCT03037385) indicated that BLU-667 has better therapeutic efficacy than other MKIs in advanced thyroid cancer and NSCLC.43,44 Pralsetinib was approved by the FDA for the treatment of NSCLC with RET fusion on 4 September 2020.45

Pralsetinib for thyroid cancer

According to the available data from the ARROW study, treatment with pralsetinib achieved an ORR of 65% (95% CI 53–75) in 79 MTC patients with RET mutations. Similarly, pralsetinib treatment resulted in an ORR of 60% (95% CI 46–74), 71% (95% CI 58–85) with 18 month PFS and 90% (95% CI 77–100) with DOR in 53 MTC patient’s resistant to cabozantinib, or vandetanib, or both. Furthermore, treatment with pralsetinib resulted in 74% (95% CI 49–91) of patients with ORR, 85% with 18-month PFS, and 86% with DOR in patients newly diagnosed MTC.46 Finally, 9 out of 12 patients with thyroid cancer achieved ORR and a median DOR of 14.5 months following pralsetinib treatment.47

Pralsetinib for lung cancer

In the ARROW trial, pralsetinib treatment was effective for patients with NSCLC bearing RET fusion, including an ORR of 57% (95% CI 46–68) in patients with previous cisplatin chemotherapy. Furthermore, treatment with pralsetinib achieved an ORR of 59% (95% CI 42–74) in a cohort of 39 patients without anti-PD-1 or anti-PD-L1 treatment. Similarly, pralsetinib treatment resulted in an ORR of 70% (95% CI 50–86), a median DOR of 9.0 months (95% CI 6.3–NE) in the untreated cohort (n = 2 7). After 8 weeks of treatment with pralsetinib, 90% of NSCLC patients eliminated plasma ctDNA of the RET variant and 90% of them reduced plasma ctDNA levels by ≥50%.48

Pralsetinib for other solid tumors with RET-alteration

In addition to thyroid cancer and NSCLC, pralsetinib has been used for the treatment of other solid tumors with RET alterations. Following pralsetinib treatment, three out of five patients responded, including two advanced pancreatic cancer patients with a partial response and a DOR of 5.5 months; two colon cancer patients with stable disease; an intrahepatic bile duct carcinoma patient with a DOR of 7.5 months.47 Several clinical trials, such as the ARROW trial and AcceleRET Lung study (NCT04222972), are ongoing to test the therapeutic efficacy and safety of pralsetinib. The analysis of 438 patients that received pralsetinib showed that the treatment-related adverse effects of pralsetinib were in grades 1–2, and only 4% of patients discontinued treatment, similar to that of selpercatinib.46

Future directions

Several problems need to be solved urgently. The emergence of potent and highly selective RET inhibitors has led to the development of acquired resistance. The mechanisms underlying the resistance of these inhibitors need to be explored. Precise therapy for cancers that harbor RET alterations requires accurate diagnosis. Therefore, the detection of RET alterations in tumors faster and accurately (including RET structural variants of unknown significance and uncommon RET-alteration) is a challenge for future research. In addition, the exploration of the next-generation of selective RET inhibitors and the combination of existing RET inhibitors and agents that target other pathways might provide new strategies for the clinical treatment of RET-altered tumors.

Conclusions

In the last few decades, the role of RET proto-oncogene mutations and rearrangements in the development of several malignancies have been clarified. Treatment with MKIs has achieved certain efficacy in tumor patients with RET alterations. However, due to their off-target effects, the inhibition of non-RET targets, including the VEGFR-2, leads to significant dose toxicity, limiting their long-term administration. Selpercatinib and pralsetinib are new selective RET inhibitors, which are well tolerated and have reproducible and significant antitumor activity. Therefore, these drugs have been approved for clinical application.

Abbreviations

RET: 

rearrangement during transfection

MAN-2: 

multiple endocrine neoplasia type 2

NSCLC: 

non-small cell lung cancer

MTC: 

medullary thyroid cancer

NIH: 

National Institutes of Health (USA)

RTK: 

receptor tyrosine kinase

CNS: 

central nervous system

GDNF: 

glial cell line-derived neurotrophic factor

GFL: 

GDNF Family Ligands

GFRα: 

growth factor receptor-alfa

MKI: 

multi-kinase inhibitors

PFS: 

progression-free survival

ORR: 

overall response rate

DOR: 

duration of response

FDA: 

Food and Drug Administration

Declarations

Acknowledgement

We apologize for not being able to cite all the publications related to this topic due to a space limitation.

Funding

This work was supported by the Sichuan Science and Technology Program (No.2019YJ0070; 2021YFS0111).

Conflict of interest

The authors declare no conflict of interest.

Authors’ contributions

All the listed authors made substantial contributions to: conception and design, and/or acquisition of data, and/or analysis and interpretation of data; and all the authors gave final approval of the version to be published. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content. The details are listed as follows: study concept and design and obtained funding (LYZ); draft manuscript and analysis and interpretation of data (FBZ, QHG).

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Copyright © 2021 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Exploratory Research in Pharmacology
  • pISSN 2993-5121
  • eISSN 2572-5505

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The Efficacy and Safety of RET-selective Inhibitors for Cancer Patients

Fu-Bin Zhu, Qi-Heng Gou, Lin-Yong Zhao
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