|REVIEW ARTICLE: BIOMARKER SERIES
|Year : 2021 | Volume
| Issue : 4 | Page : 702-708
RET in non-small cell lung carcinoma: A narrative review
Shrinidhi Nathany1, Himanshi Diwan1, Ullas Batra2
1 Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
|Date of Submission||01-Nov-2021|
|Date of Decision||24-Nov-2021|
|Date of Acceptance||07-Dec-2021|
|Date of Web Publication||29-Dec-2021|
Sector 5 Rohini, Sir Chhotu Ram Marg, New Delhi - 110 085
Source of Support: None, Conflict of Interest: None
The advent of stratified medicine and tailored therapies has caused non-small cell lung cancer (NSCLC) to become a subject of keen interest, with an emphasis on comprehensive genomic testing for driver mutations and biomarkers. The rearranged during transfection (RET) gene rearrangement has been observed in 1%–2% of all NSCLCs. In this edition of the biomarker series, we have reviewed the available literature on RET and its biology, along with the clinical features and therapeutic options for RET-rearranged NSCLC. For the purpose of this review, we performed a detailed search of the PubMed, Scopus, and My Cancer Genome databases using the keywords “RET,” “NSCLC,” “pralsetinib,” and “selpercatinib.” We included 42 articles in the final review. Studies suggest that RET rearrangement has emerged as a new biomarker of interest in NSCLC owing to the development and approval of selective RET inhibitors. Newer trials comparing RET inhibitors with chemotherapy and immune checkpoint inhibitors are underway. However, more studies are required to lucidly explain the underlying biology, including newer mechanisms of resistance to selective RET inhibitors, to guide drug development in future.
Keywords: Precision medicine, NSCLC, pralsetinib, rearranged during transfection, selpercatinib
|How to cite this article:|
Nathany S, Diwan H, Batra U. RET in non-small cell lung carcinoma: A narrative review. Cancer Res Stat Treat 2021;4:702-8
| Introduction|| |
Our evolving understanding of molecular alterations that drive myriad cancers has unveiled the path to targeted therapies, which, in turn, has resulted in a substantial change in the prognostic portrait of various malignancies. Oncogene addiction is a common phenomenon in malignancies such as gastrointestinal stromal tumors, chronic myelogenous leukemia, breast cancers, and non-small cell lung cancer (NSCLC), for which safe and effective targeted therapies have been developed and approved.
This narrative review depicts the structure, molecular biology, clinical characteristics, and the most recent advances in therapeutic strategies available for rearranged during transfection (RET) gene alterations in NSCLC. RET gene alterations including single nucleotide variants, fusions, and gene rearrangements have been described in the literature. RET rearrangements are reported to occur in 1–2% of all NSCLCs, with KIF5B being the most common fusion partner. RET-rearranged NSCLCs are more common among young non-smokers, and those with histomorphological evidence of the solid variant of adenocarcinoma. There are limited prognostic data in the literature, owing to the rarity of this entity. However, few studies have revealed that patients with a RET fusion have a worse prognosis than those without. The United States Food and Drug Administration (FDA) has approved selective RET inhibitors such as selpercatinib and pralsetinib in the first and subsequent lines of treatment for the management of metastatic RET-rearranged NSCLC.
| Methods|| |
For the purpose of this narrative review, we sought articles from databases such as PubMed Central, Scopus, and My Cancer Genome, using the keywords “RET,” “NSCLC,” “pralsetinib,” and “selpercatinib.” There were no specific filters and inclusion or exclusion criteria for selection of articles. A total of 42 articles were selected and reviewed.
| Historical Perspectives|| |
RET, a proto-oncogene, was first identified in 1985 by Takahashi et al. in the 3T3 fibroblast cell line transfected with DNA from human lymphoma cells. This was followed by the discovery of RET-rearrangement in papillary thyroid carcinomas by Grieco et al. in 1990. In 2012, a novel KIF5B-RET fusion was first reported by four groups from Japan, Korea, and the United States.,,,
| Molecular Biology|| |
RET is located on the long arm of chromosome 10 (10q11.21) and encodes a tyrosine kinase receptor comprising extracellular, transmembrane, and intracellular domains., The N-terminal extracellular domain contains four cadherin-like domains and cysteine-rich regions. The ligand-binding domain prompts the autophosphorylation of the intracellular domain of the tyrosine kinase receptor, which then embarks on a cascade of downstream signaling pathways including the mitogenic activated protein kinase (MAPK) and phosphoinositide-3-kinase-protein kinase B (Akt) pathways. The activation of these pathways leads to uninhibited cellular proliferation with an added survival advantage for the cells [Figure 1].
Somatic rearrangement of RET is well described in NSCLC, papillary thyroid carcinoma, colorectal carcinoma, breast cancer, ovarian tumors, and skin cancer., The 3' kinase region of RET coded by exons 12–18 fuses with the 5' region of a ubiquitously expressed partner gene, resulting in the formation of a chimeric protein, which causes constitutive expression of RET. Breakpoints are most frequent in the intron 11 of RET, followed by introns 7 and 10. Unlike the wild-type RET protein, the chimeric protein is usually localized to the cytosol, thus escaping protein degradation mechanisms.,
NCOA4-RET and CCD6-RET fusions are the most commonly occurring fusions in papillary thyroid cancers. RET rearrangements are exclusive of other driver mutations. KIF5B is the most common fusion partner seen in 70–90% of cases of RET-rearranged NSCLC, followed by CCDC6 seen in 10%–25% of cases., Other less common upstream RET fusion partners observed in NSCLC include MYO5C, NCOA4, FRMD4A, EPHA5, TRIM33, ERC1, CLIP1, PICALM, and RUFY2 [Table 1]. Owing to the rarity of occurrence, the geographical distribution of the various less common fusion partners is not available.
Germline RET mutations are more commonly discerned in the extracellular and kinase domains. Multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinomas often harbor point mutations in the cysteine-rich domain of the RET protein, with p.C634R in exon 11 being the most common mutation. The above point mutation and others (C609, C611, C618, C620, and C630) cause dimerization of the RET protein in the absence of any ligand, leading to its constitutive activation. As the focus of this review is RET alterations in NSCLC, a detailed description of RET alterations in other malignancies is beyond the scope of this review.
Patients with MEN2B syndrome have mutations in the kinase domain of RET, and p.M918T in exon 16 is the most frequently encountered mutation, followed by p.A883F. These mutations enhance the ATP binding ability, thus resulting in the activation of the receptor.
| Clinical Characteristics|| |
RET gene rearrangement in NSCLC is commonly observed in young non-smokers with a median age of 57.5 years and histomorphological evidence of poorly differentiated adenocarcinoma with aggressive clinical behavior. These patients usually present with lymph node metastases. Although RET rearrangements are reported to occur independently of other driver mutations, a contrary view exists. Song et al. have described concomitant EGFR and CTNNB1 mutations in a few RET-rearranged cases of NSCLC. CCDC6-RET fusions are associated with adenocarcinoma with evidence of extracellular or intracellular mucin.
Limited literature is available regarding the outcome of patients with NSCLC harboring RET rearrangements. Sarfaty et al. described the clinical profiles and prognosis of RET-rearranged NSCLC in their study on 14 patients with lung cancer harboring RET fusions. The median overall survival (OS) of these patients was 22.8 months. Patients harboring CCDC6–RET fusion have been reported to have better survival than those harboring the KIF5B–RET fusion. Cai et al. studied 392 patients with NSCLC, of which 6 had KIF5B-RET fusions. Patients with KIF5B-RET fusions had a worse prognosis than those without fusion (median survival, 21 months vs. 52.6 months; P = 0.06).
Tsai et al. studied the prognostic implications of RET rearrangements in metastatic lung adenocarcinoma. They also compared the survival of those harboring RET rearrangement with that of those harboring EGFR, Kirsten rat sarcoma virus (KRAS), and anaplastic lymphoma kinase (ALK) gene alterations. The median OS of patients with RET fusion (n = 17) was 22.4 months, while that of patients with EGFR mutations (n = 451) was 21.3 months. The median OS for patients with KRAS mutations (n = 13) was 5.4 months, while that of those with EML4–ALK fusion (n = 51) was 18.9 months. For the 190 patients with mutation-negative tumors, the OS was 12 months.
| Detection of RET Alterations|| |
The understanding of RET alterations has improved significantly over the last decade, with a plethora of tests now available for the detection of RET alterations, based on the type of alteration to be detected as well as the clinical context.
Immunohistochemistry (IHC) is used as a screening test and is not the gold standard test for the detection of RET alterations. The monoclonal antibodies used for IHC, as cited in the literature, include the mouse recombinant monoclonal RET antibody clone 3F8 (Novocastra, Newcastle, United Kingdom) and the rabbit recombinant monoclonal RET antibody clone EPR287.,,,,,,,, Recently, Furugaki et al. demonstrated that IHC cannot be relied upon for the detection of RET fusions, owing to its high false-positive rates and lack of specificity. Hence, the use of IHC is discouraged and surmounted by fluorescence in situ hybridization (FISH).
Fluorescence in situ hybridization
The FISH assay is considered the gold standard for the detection of RET rearrangements. Both break apart and fusion probes can be used; break apart probes detect the gene rearrangement and fusion probes detect the RET fusions, but one needs to have the knowledge of the fusion partner. Break apart probes are currently recommended. The recommended threshold for the detection of RET fusion is more than 15% cells with break apart signals or a single 3' signal (the latter requires confirmation by orthogonal testing). FISH offers both high sensitivity and specificity. However, novel RET fusion partners cannot be detected using FISH. FISH requires a lucid understanding of the genes involved in the rearrangement, in addition to the probe design and type. Another drawback specific to RET rearrangement is that break apart signals may not be discernible owing to the proximity of the fusion partners in some cases.
Single nucleotide variants can be detected by DNA-based assays, including Sanger sequencing, polymerase chain reaction (PCR), real-time PCR, allele-specific PCR, and next-generation sequencing (NGS). DNA-based NGS assays have the advantages of detecting somatic mutations with low variant allele frequencies; however, they are less sensitive in detecting fusion genes.
Other methods for RET fusion detection
Reverse transcriptase-PCR and RNA-NGS can also be used for the detection of RET fusions. Recently, circulating cell-free total nucleic acid-based testing has emerged as a seminal molecular test for patients in whom tumor tissue is not available. A positive test on liquid biopsy should be deemed positive irrespective of the detected allele frequency in view of the high sensitivity of NGS-based testing of cell-free total nucleic acid. Furthermore, the NGS performed on a liquid biopsy may unravel the resistance mechanism to RET inhibitors in the near future. [Table 2] summarizes the various tests used for the detection of RET fusions.
| Therapeutic Options|| |
Until the development and approval of selective RET inhibitors, multikinase inhibitors were recommended by the National Comprehensive Cancer Network (NCCN) with a category 2A recommendation for the treatment of RET-rearranged NSCLC. Drugs in this category include cabozantinib, vandetanib, and others such as lenvatinib and sorafenib. The lack of response to multikinase inhibitors can be attributed to the off-target kinase inhibition and increased toxicities due to the inhibition of non-RET targets. In addition, resistance mechanisms to these multikinase inhibitors, both on-target and off-target, emerge during treatment, thus limiting their therapeutic potential. Commonly acquired resistance mechanisms include missense mutations in the RET kinase domains such as G810A, and V804L and off-target activation of other bypass mechanisms such as MAPK, RAS mutations, and AKT amplification.
Vandetanib is an FDA-approved multikinase inhibitor for the treatment of medullary thyroid carcinoma. However, many trials have been conducted and several are underway to assess its efficacy in NSCLC as well. A Japanese trial, which enrolled 18 patients, has reported the highest objective response rate (ORR) of 53% along with a progression-free survival (PFS) of 6.5 months and an OS of 13.5 months., In a study by Gautschi et al., the ORR was only 18% with a median PFS of 2.9 months and OS of 10.2 months. Conflicting data from controlled trials and real-world settings have limited the use of vandetanib in the treatment of NSCLC.
Cabozantinib was the first multikinase inhibitor to be used in RET-rearranged NSCLC in a trial in 2013. In this trial, 28% of patients achieved a partial response, and 36% demonstrated stable disease. The median PFS was 5.5 months and OS was 9.9 months. Gautschi et al. studied 19 patients with RET-altered NSCLC in 2016, and demonstrated a median PFS of 3.6 months, an ORR of 37%, and OS of 4.9 months. However, resistance to cabozantinib develops, and post the development of selective RET inhibitors, the relevance of this drug in NSCLC is uncertain. A detailed account of the real-world evidence and trials is provided in [Table 3].
Selective RET inhibitors inhibitors
Selpercatinib (LOXO-292) is a new ATP-competitive small molecule RET inhibitor and has been extensively studied in the LIBRETTO-001 trial (NCT03157128). This trial enrolled 105 patients with RET-rearranged NSCLC who were pre-treated with chemotherapy and 39 previously untreated patients. For the treatment-naive patients, the median PFS and OS have not been reached at a follow-up of 7.4 and 9.2 months, respectively. The ORR was found to be 85%. In the pre-treated group, the ORR was 68%, with a median duration of response of 20.3 months and median PFS of 18.4 months. Selpercatinib has been shown to be efficacious in patients with intracranial metastases as well. In 11 patients with intracranial metastases included in the LIBRETTO-001 trial, the ORR was 91%. With regard to the safety profile, most adverse events were low-grade, with dry mouth being the most common adverse event reported in 27 patients. The most common severe adverse events were hypertension (14%), elevated alanine transferase (12%), raised aspartate transferase (10%), and hyponatremia (6%). An Indian series included five patients with RET-positive NSCLC. of which four were treated with pemetrexed–carboplatin-based chemotherapy and one was treated with selpercatinib after failing on several lines of therapy. The median PFS was not reached for selpercatinib in this study. The drug was discontinued in only 2% of patients due to adverse events. Selpercatinib was approved by the FDA on May 08, 2020, for NSCLC and thyroid cancers, and the NCCN recommends its use in the first as well as subsequent lines of treatment for metastatic RET-rearranged NSCLC.
Pralsetinib, earlier known as BLU-667, a selective RET tyrosine kinase inhibitor, has been shown to have intracranial activity in mouse models. In the ARROW trial (NCT03037385) which enrolled 120 patients with RET-rearranged NSCLC, 91 patients were pre-treated with platinum-based chemotherapy, and the rest were treatment-naive. The ORR in the pre-treated group was 61% compared to 73% in the treatment-naive group. The disease control rate was 95% and 88%, respectively, in the two groups. With regard to the safety profile, there were no significant severe adverse drug reactions. The grade 3 adverse events included neutropenia (13%) and hypertension (10%). The drug was discontinued in 7% of the patients due to treatment-related toxicities. Pralsetinib received FDA approval on September 04, 2020, for RET-rearranged NSCLC and has been included as a category 2A recommendation in the NCCN guidelines for first/subsequent-line treatment of metastatic RET-rearranged NSCLC.
The Global, Multicenter RET Registry (GLORY) registry included 84 patients with RET-positive NSCLC and reported sensitivity to platinum-based chemotherapy. About 51% of patients showed a partial or complete response to first-line chemotherapy, with a median OS of 24.8 months and median PFS of 7.8 months. Shen et al. in their study observed a higher PFS (9.2 months) in patients who received pemetrexed-based chemotherapy compared to those who received non-pemetrexed-based chemotherapy. Drilon et al. in 18 patients with RET-rearranged NSCLC reported a better ORR (45%) and PFS (19 months) with pemetrexed-based chemotherapy when compared to the KRAS mutant lung cancer group. In the five-patient series from India by Batra et al., four patients showed a partial response to first-line pemetrexed–carboplatin-based chemotherapy with an ORR of 80%. There have been anecdotal cases demonstrating almost 2 years of therapeutic advantage with single-agent pemetrexed in RET-positive cases.
| Resistance Mechanism to RET Inhibition|| |
As expected, resistance to targeted therapy eventually emerges, and so is the case with selective RET inhibitors as well. In a series, G810R/S/C mutation in the RET solvent front has been reported in two patients progressing on selpercatinib.
These have been demonstrated to cause steric hindrance to inhibitor binding. To overcome this, a new drug, named TPX-0046 which is a RET/SRC inhibitor, is under development, and a phase I trial is underway for the same (NCT04161391).
The G810 mutation has been described in only two patients thus far. Due to the scarcity of data, this has not been detailed in this review.
| Role of immunotherapy|| |
RET-rearranged tumors are usually noted to have a low expression of programmed death-ligand 1 and low tumor mutation burden (TMB). Thus, patients harboring RET fusions are not ideal candidates for immunotherapy. However, in the IMMUNOTARGET study, 16 RET-positive patients were enrolled, and received immune checkpoint inhibitors in the second line or beyond; these patients were noted to have a 6% response rate, with a median PFS of 2.1 months. Another retrospective series from the Memorial Sloan Kettering Cancer Center showed no response to RET inhibitors in 16 patients. However, combinations of chemotherapy and immunotherapy have not been lucidly studied and published in the literature. The LIBRETTO-431 trial (NCT04194944) was launched in early 2020 to compare selpercatinib to platinum- and pemetrexed-based chemotherapy, with or without pembrolizumab. This trial is still recruiting. The TMB is generally low in RET-rearranged NSCLC, as described in the literature and the IMMUNOTARGET study.,
| Conclusion|| |
RET rearrangement has emerged as a new biomarker of interest in NSCLC owing to the development and approval of selective RET inhibitors. Newer trials comparing RET inhibitors with chemotherapy and immune checkpoint inhibitors are underway. However, more comprehensive studies and trials are required to lucidly explain the underlying biology of RET, including newer mechanisms of resistance to selective RET inhibitors, to guide future drug development in this area.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]