RET alterations were first identified in the late 1980s with the detection of an oncogenic RET fusion in papillary thyroid carcinomas (33). Since then, additional RET rearrangements have been identified by multiple groups in a number of solid tumors (34). Oncogenic gene fusions arise from juxtaposition of two otherwise independent genes, resulting from structural rearrangements such as inversions or translocations, transcriptional reading of adjacent genes (35–37), or splicing of pre-mRNA sequences (38, 39). Most RET fusions lack the transmembrane domain, giving rise to chimeric, cytosolic proteins that exert their oncogenic influence through constitutive activation of RET kinase domain ( Figure 2A ). Since discovery of the first RET fusion in thyroid cancers, at least 13 fusion partners have been identified in papillary thyroid cancers, the most common of which are coiled-coil domain containing 6 (CCDC6-RET) and nuclear receptor co-activator 4 (NCOA4)-RET (40). Similarly, at least 45 RET fusion partners have been identified in lung cancers (34), with the most common being kinesin family member 5B (KIF5B)-RET (70-90%) and CCDC6-RET (10-25%). While RET fusions are detected in other cancers, such as breast cancer and salivary gland carcinomas (discussed later), RET fusions occur in these cancer types at much lower frequencies (0.16% and 3.2%, respectively) (41). Thus, RET fusions present as a clinical and therapeutic challenge in multiple tumor types ( Table 1 ).

In addition to oncogenic fusions, germline mutations, such as activating point mutations, in RET are also associated with neoplasia and tumorigenesis, namely in multiple endocrine neoplasia type 2 (MEN2; described in 4.2). For example, mutations in the cysteine residues (C609, C611, C618, C620, C630, C634) within the extracellular domain of RET promotes formation of intermolecular disulfide bridges, resulting in constitutive dimerization and activation of RET that is GDNF-independent ( Figure 2B ) (76). Additionally, mutations in the RET tyrosine kinase domain elicits steric conformations that regulate access to the ATP binding pocket of RET (E768X, V804X) (81–83, 88), alters hinge or inter-lobe flexibility (L790X, Y791X), promotes activation of RET monomers (S891X, M918T) (85), or destabilizes the inactive form of RET (A883X) (7, 84, 89), all of which confer constitutive activation albeit with varying activities (90) ( Table 1 ). Taken together, oncogenic RET alterations can promote constitutive activation of RET signaling, driving tumorigenesis in these affected tissues ( Figure 2C ).

Papillary thyroid carcinomas (PTCs) are the most common form of differentiated thyroid cancers, the most common form of radiation exposure-induced thyroid neoplasm, and represents up to 85% of all thyroid cancer cases (91). PTC occurrence was initially associated with activating mutations of RAS and subsequent activation of the RAS/MAPK/ERK pathway (92–94). This paradigm was challenged when Fusco et al. (95) identified oncogenic RET as an unknown transforming oncogene in metastatic PTC and, while the oncogene was analyzed for homology with known kinase genes, including ret, the identity of this novel gene remained unclear and was therefore named ‘PTC’. A follow-up study by the same group determined that PTC is a rearranged form of RET, and rearranged RET DNA sequences were readily detectable in PTC-positive papillary thyroid tumors (33). These findings were corroborated by a study by Ishizaka and colleagues (96), in which they identified aberrant RET transcripts in PTC tumor samples. Further analysis by Lanzi et al. identified two additional RET rearrangements in PTC, named RET/PTC1 and RET/PTC2, which were constitutively activated, tyrosine-phosphorylated, and apparently not bound to the cell membrane (42). Santoro et al. identified a third RET rearrangement, which they named RET/PTC3 (43). In RET/PTC1, RET is fused with a then-unknown gene named H4 (D10S170), which is now known as CCDC6 (33, 97, 98), whereas RET/PTC2 and RET/PTC3 are products of RET kinase domain fusing to the N-terminus of RIα (now known as PRKAR1A) (63, 64) and ELE1 (now known as NCOA4) (43, 99, 100) genes, respectively ( Figure 3 ).

While RET/PTC1-3 are considered unique forms of RET/PTC fusions, they share common features such as ubiquitous expression of the 5’ fusion partner (44, 99), altered subcellular localization of RET kinase activity (101), and constitutive activation of RET kinase arising from ligand-independent dimerization of the RET (63, 100, 101). Transgenic overexpression of RET/PTC1 is indeed oncogenic and induces spontaneous and metastatic murine thyroid carcinomas that are histologically similar to human PTC tumors (45, 102), though whether RET/PTC1 overexpression is an initiating factor in human thyroid carcinogenesis remained unclear. Analysis of 26 occult thyroid carcinomas, which are small papillary carcinomas with clinically apparent node metastases but are often microscopic or overlooked by ultrasonograms, determined that RET/PTC activation is found in 42% (11/26) of samples analyzed, suggesting that RET/PTC activity contributes to early papillary thyroid carcinogenesis (103). Importantly, additional studies determined that RET rearrangements are frequently found in individuals exposed to radiation (104), such as the children who experienced the Chernobyl nuclear plant incident (105–107), suggesting an association between radiation and emergence of RET rearrangements. To date, there are at least 12 oncogenic RET fusions identified in PTC (108), suggesting that RET alterations contribute significantly to initiation and progression of PTC. Further characterization of PTC tumors determined that RET proto-oncogene expression is primarily found in PTC subtype of thyroid cancers (109). It is important to note, however, that clonal RET/PTC rearrangements occur in 10-20% of PTC patients and may be induced by varying causative factors (110). For example, RET/PTC rearrangements are found in up to 70% of pediatric PTC cases in areas of high radioisotope contamination (46). However, Rhoden and colleagues showed that RET/PTC rearrangements are found in over 25-30% of spontaneous PTC (47, 111). Additionally, a comparative study by Zhu and colleagues determined that the method by which RET/PTC rearrangements are assessed may alter the reported frequency within the sample cohort (46). Thus, considerations must be made when assessing frequency of RET/PTC rearrangements in PTC patient samples.

In contrast to PTC, medullary thyroid carcinomas (MTCs) are a rare type of thyroid tumor that arises in parafollicular C cells and represent 2-4% of malignant thyroid neoplasms (91, 112). While the majority of MTC tumors are spontaneous, up to 30% of MTCs are hereditary. MTCs are classified into one of the following major clinical subtypes: classical MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease, FMTC, and MEN2B. Familial MTC (FMTC) subtype is characterized by occurrence of only MTC, which has relatively delayed latency and is clinically less aggressive compared to MEN2A and MEN2B subtypes (91). MEN2A was first characterized in 1961 by J.H. Sipple after identifying an association between pheochromocytoma and occurrence of a thyroid carcinoma (113). MEN2A subtype represents 70-80% of hereditary MTCs and is characterized by co-occurrence of MTC, pheochromocytoma, and/or primary hyperparathyroidism (may include Hirschsprung’s disease or CLA) (114, 115). MEN2B subtype is characterized by co-occurrence of aggressive MTC and pheochromocytoma, along with intestinal tumors, neuromas, and Marfanoid body habitus (114). The major MTC variants are summarized in Table 2 .

RET rearrangements were first associated with MTC tumors when Santoro et al. detected RET fusion products in pheochromocytomas and MTC samples (123). The following year, a study by Yamamoto and colleagues demonstrated that the mapped chromosomal location of RET is in close proximity with the MEN2A gene locus (116), suggesting a potential genetic correlation between RET expression and MEN2A occurrence. However, Donis-Keller and colleagues proposed a strict association between exon 7/8-specific RET mutations and occurrence of MEN2A and FMTC since these mutations were strictly detected in families with MEN2A and FMTC, not MEN2B (77). These findings were supported by Mulligan et. al, in which they identified germline missense mutations within the RET proto-oncogene in 87% (20/23 cases) of the MEN2A families but not in families without MEN2A (8). Additionally, the Mulligan et al. found that, of the 20 families with germline missense RET mutations, 19 of these families shared a mutation in one of the cysteine residues in the RET extracellular domain, suggesting that mutation of this cysteine residue may predispose patients to MEN2A or FMTC (8). A follow-up study analyzed 118 unrelated families with MEN2A, MEN2B, or FMTC and determined that over 95% of MEN2A families and 86% of FMTC families possessed RET-C634 mutation, which is in the immediate proximity of the transmembrane domain (78). In agreement with their earlier study (8), Mulligan and colleagues (1994) did not detect the RET-C634 mutation in the MEN2B families assessed in this study, however the frequency of RET-C634 mutation was significantly higher in MEN2A families than those with FMTC (84% vs. 50%, respectively) (78). As MEN2A patients develop hyperparathyroidism and/or pheochromocytoma that is not typically detected in FMTC, these findings suggest that the RET-C634 mutation is correlated with increased predisposition to develop MEN2A due to enhanced RET activity.

While MEN2A cases frequently acquire RET-C634 mutations, MEN2B families also share common RET mutations. RET-M918T was first detected in 1994 upon DNA sequence analysis of 9 unrelated MEN2B patients (124), which was corroborated by a separate study that detected the mutation in 34 unrelated MEN2B patients (89). RET-M918T mutation is detected in 95% of MEN2B cases (122) and elicits oncogenic signaling by stabilizing monomeric RET, enhancing binding with ATP, and is activated in absence of GDNF ligand (9, 85, 125). Additionally, RET-A883F (7, 84, 86) is a strongly activating RET mutation that is hypothesized to destabilize the inactive conformation of RET by altering the local conformation of the protein (10).

Until recently, only activating RET mutations were cited as oncogenic events in MTC. However, a 2015 case report identified an MTC patient with Myosin Heavy Chain 13 (MYHC13)-RET fusion (68), suggesting that oncogenic RET rearrangements also occur in MEN2B albeit at lower frequencies. Taken together, MTC subtypes present with unique, activating RET mutations that induce thyroid tumorigenesis.

Lung cancers are the second most-commonly diagnosed cancer and the leading cause of cancer-related deaths in American men and women (126). Non-small cell lung cancer (NSCLC) constitutes up to 80-85% of all lung cancers and can further categorized into one of three major subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (127). NSCLC subtypes are frequently grouped together due to the similarities in treatment options, namely surgical resection, neoadjuvant or adjuvant chemotherapies, and immunotherapy (for a full review of NSCLC epidemiology and treatments, see Duma et. al) (128).

RET rearrangements occur in 1-2% of NSCLC cases (58, 59, 65). Since identification of the first RET fusion (KIF5B-RET) in lung cancer (51, 65–67), significant efforts have been made to identify additional novel RET fusions in NSCLC. While RET fusions occur in 1-2% of NSCLC cases, there are at least 48 unique RET fusion partners identified in NSCLC, which have been catalogued by Ou and Zhou (34), with the most common being KIF5B-RET and CCDC6-RET. While most NSCLC cases do not present with additional driver mutations, analysis of over 4,871 samples by Kato and colleagues identified co-occurrence of RET fusions with other genetic alterations, such as PI3K-associated genes or MAPK effector genes, in up to 82% (72/88) of NSCLC patients (41). Thus, the clinical and pathological features of RET fusion-positive NSCLC may differ from those observed in NSCLC cases driven by alternative oncogenic aberrations. Indeed, an analysis by Wang and colleagues determined that RET fusion-positive lung carcinomas had more poorly differentiated tumors compared to those with ALK or EGFR alterations, indicating that RET fusions define a unique molecular and clinicopathological subtype of NSCLC (58).

Distant metastases are of a particular concern in NSCLC, with 30-40% of cases metastasizing to the bone, lungs, brain, and adrenal glands (129). At the time of diagnosis, 10% of NSCLC patients present with brain metastases, with 30% of NSCLC patients developing brain metastases over the course of their disease (130). Baseline incidence of brain metastases in RET fusion-positive NSCLC is 27% and is independent of age, smoking status, or 5’ fusion partner status, and this proportion increases to 49% throughout the lifetime of disease (131). Thus, identifying molecular targets in brain-metastatic NSCLC and developing therapeutic compounds with blood-brain-barrier (BBB) permeability is a topic of recent investigation. Multi-kinase inhibitors (MKIs) targeting commonly altered oncogenic drivers, such as EGFR, MET, KIT, and VEGFR2, have shown moderate selectivity against altered RET in NSCLC and were thus repurposed as RET inhibitors (discussed below) (132–136), with many of these inhibitors displaying intracranial activity against brain metastases (137–139). However, a multi-institutional study by Drilon and colleagues determined that 25% of RET fusion-positive stage IV lung cancer patients presented with brain metastases at diagnosis, and less than 20% experienced intracranial response upon treatment with RET-targeting MKIs, suggesting that MKI inhibitors are inadequate for treatment of brain-metastatic lung cancers (140).

While aberrant RET activity is primarily associated with thyroid carcinomas and NSCLC, abnormal RET signaling is also found in other tumor types, albeit at lower frequencies. This section of the review will briefly summarize the role of RET signaling in other solid tumor types and the implications of RET inhibition in these cancers.

Cabozantinib (XL184, sold as Cometriq ^® and Cabometyx ^®) is an orally available ATP-competitive MKI that can inhibit c-MET, VEGFR2, and a number of other kinases including RET, FLT3, TRK, and KIT (200). Cabozantinib effectively inhibits cell proliferation, growth, migration, and invasion in vitro, and promotes tumor cell and endothelial cell apoptosis in vivo in a number of cancer cell lines (200). Cabozantinib was well-tolerated in a number of clinical trials including MTC (201) and renal cell carcinoma (202). Cabozantinib received FDA approval in 2012 for treatment of MTC, as second line of treatment in kidney cancer in 2016, treatment of renal cell carcinoma in 2017, and again in 2019 for treatment of hepatocellular carcinoma. A phase II clinical trial (NCT01639508) reported that RET-fusion positive lung cancer patients receiving cabozantinib (60mg, p.o. daily) demonstrated partial response (28%; 7/25 patients) and fortifies the notion that RET is actionable in lung cancers (132, 203). Similarly, daily oral administration of cabozantinib (140mg) enhanced overall survival (26.6 vs. 21.1 months in treatment vs. placebo group, respectively) and progression-free survival in phase III clinical trial (NCT00704730) for treatment of metastatic MTC cases harboring RET-M918T with an acceptable safety profile (204, 205). The overall ORR for patients who received cabozantinib was 28%, but increased to 34% when assessing only patients with RET-M918T mutations. While data is limited for use of cabozantinib in treatment of central nervous system (CNS) tumors, such as BCBM, cabozantinib penetrates the BBB and may prove to be effective in targeting brain malignancies arising from RET-altered cancers (137, 206). While cabozantinib received FDA approval for treatment of MTC (207), ongoing clinical trials aim to assess cabozantinib safety and efficacy in RET fusion-positive NSCLC (NCT01639508, NCT04131543).

Lenvatinib (E7080; Lenvima ^®) is an oral ATP-competitive MKI with activity against FLT-1, FLT-4, KIT, FGFR1, PDGFR, VEGFR1-3, and can inhibit angiogenesis and growth of SCLC and breast cancer cells in vitro and in vivo (208–211). When evaluated in RET fusion-positive preclinical models, lenvatinib effectively inhibits RET fusion kinases and RET pathway activity in vitro, and inhibits growth of RET fusion-positive tumor cells in vivo (212, 213). While a phase II clinical trial (NCT01877083) determined that once-daily oral administration of lenvatinib (24mg) induces relatively low response in RET fusion-positive NSCLC patients (ORR 16%, 4/25 patients), this effect was adequate to improve the median progression-free survival (214). Lenvatinib received FDA approval in 2015 for treatment of differentiated thyroid cancer (215) and 2018 for treatment of unresectable hepatocellular carcinoma (216). Lenvatinib has also received FDA approval as part of combination therapies in renal cell carcinoma (with mTOR inhibitor everolimus) (217) and endometrial carcinoma (with anti-PD-1 antibody pembrolizumab) (218).

Vandetanib is an orally available inhibitor of KDR/VEGFR-2 tyrosine kinase with moderate activity against FLT-1/VEGFR-1, EGFR, and PDGFRβ (219, 220). Vandetanib potently inhibits VEGF signaling and angiogenesis, resulting in reduced growth of varying tumor cell xenografts, namely human lung, prostate, breast, ovarian, and colon cancer cells, with little to no acute toxicity (221). Within the same year, Carlomagno and colleagues showed that vandetanib potently inhibited kinase activity of RET/PTC, RET/MEN2A, and RET/EGFR in transformed NIH3T3 cells, reverted the morphological phenotype of transformed cells to that of parental cells, and inhibited anchorage-independent growth (222). Vandetanib selectivity for RET was further validated in a D. melanogaster model of MEN2 syndromes and papillary thyroid carcinomas, suggesting that vandetanib can inhibit multiple RET isoforms to treat RET-dependent carcinomas (223). However, a follow-up study by Carlomagno et al. identified RET-V804L or RET-V804M gatekeeper mutations which confer resistance to vandetanib (83), suggesting that vandetanib may not yield clinical efficacy in cases with RET gatekeeper mutations. Clinical trials determined that vandetanib is well-tolerated when administered once daily (300mg, p.o.), elicits anti-tumor response in patients with advanced or metastatic hereditary MTC (224, 225), demonstrated improved therapeutic efficacy, and was predicted to enhance progression-free survival (PFS) in advanced MTC (19.3 months vs. 30.5 months in placebo vs. treatment, respectively) in phase III clinical trial (NCT00410761) (226). As with other MKIs, vandetanib can inhibit many kinases (220–223), thus the anti-tumor effects observed in MTC may not strictly be due to inhibition of RET kinase activity. Nevertheless, vandetanib received FDA approval for treatment of non-resectable advanced or metastatic MTC in 2011 (227).

Sorafenib (Nexavar ^®) is an orally available ATP-competitive inhibitor of Raf kinase (228) with activity against other kinases, such as BRAF, VEGFR-2 and -3, and PDGFRβ, to impede tumor growth and angiogenesis in vivo (229). Subsequent studies illustrated that sorafenib inhibits activity of wild-type RET and oncogenic altered RET with some degree of selectivity to abrogate PTC tumor cell proliferation and growth in vitro and in vivo (230–232). Moreover, RET inhibition by sorafenib is not affected by the RET-V804M gatekeeper mutation, suggesting that sorafenib may yield clinical benefit in MTC patients bearing RET-V804 mutation (231). In addition to being an ATP-competitive inhibitor, Plaza-Menacho and colleagues demonstrated that sorafenib treatment promotes degradation of RET protein independently of proteosomal targeting (231), which suggests a secondary mechanism by which RET activity is depleted upon treatment with this inhibitor. Interestingly, a 2012 study by Mao et al. corroborated the finding that sorafenib affects RET expression and concurrently alters VEGFR2 expression, although these findings are cell-line dependent and require additional mechanistic studies (233). Sorafenib received FDA approval in 2005 for treatment of advanced renal cell carcinoma (234), and was subsequently approved for treatment of unresectable hepatocellular carcinomas (235) and iodine-refractory, metastatic differentiated thyroid cancers (236). Interestingly, an exploratory study by Horiike and colleagues determined that NSCLC patients do not exhibit response to sorafenib (136), suggesting that RET fusion-positive NSCLC patients may not gain clinical benefit from this compound, though this requires additional testing in RET-altered NSCLC patients and other RET-altered cancers.

Regorafenib (BAY 73-056; Stivarga ^®) is an orally bioavailable ATP-competitive inhibitor that targets VEGFR1-3, TIE2, PDGFRβ, KIT, and RET in vitro and in vivo, effectively functioning as an anti-angiogenic, anti-tumorigenic, and pro-apoptotic compound (237). Regorafenib is well-tolerated when administered as a single agent and elicited a partial response or stable disease in patients with advanced or non-resectable solid tumors (238–240), though renal cell carcinoma patients experienced adverse events with prolonged treatment (241). Chen and colleagues illustrated that regorafenib potently inhibits RET activity and RET-mediated PI3K/AKT signaling in neuroblastoma cells to inhibit their growth in vitro and in vivo (242). Additionally, regorafenib targets the RET-Src signaling axis to inhibit JAK1/2-STAT1 and MAPK signaling and concurrently inhibits PD-L1 expression, suggesting inhibition of RET-Src axis may impact immune response to tumor cells in vivo (243). While regorafenib is currently in numerous clinical trials for use in various cancer types (ClinicalTrials.gov), it has not entered trials for use in RET-altered cancers.

Sunitinib (SU11248; Sutent ^®) was developed in 2003 as an orally bioavailable ATP-competitive inhibitor of VEGFR, PDGFR, KIT, and FLT3 receptor tyrosine kinases, and effectively inhibits tumor growth of multiple cancer cell types, namely breast, NSCLC, colon cancer, glioma, and melanoma when administered daily as a single agent (244–247). As a VEGF inhibitor, sunitinib effectively inhibits angiogenesis of tumor cells, reduces endothelial cell migration, and inhibits tubule formation in vivo (248). Sunitinib is potent against PTC tumors harboring RET/PTC3 fusions and effectively inhibits downstream MAPK signaling (249). While sunitinib received FDA approval in 2006 for treatment of GI stromal tumors and advanced renal cell carcinomas, a pilot clinical trial to test safety and efficacy of sunitinib (50mg, p.o. daily) in RET fusion-positive solid tumors (NCT02450123) was placed on hold in 2020 and is of unknown status at the time of this publication.

Alectinib (CH5424802; Alecensa ^®) is an orally bioavailable, small molecule competitive ATP inhibitor developed to inhibit ALK alterations and gatekeeper mutations while sparing MET activity (250). Alectinib effectively reduces ALK activation in vitro and in vivo, inhibits activation of STAT3, PI3K/AKT, and MAPK pathways, inhibits growth of tumors harboring ALK alterations (250), and even inhibited ALK-L1196M, a gatekeeper mutation that conferred resistance to earlier generations of ALK inhibitors (251). Alectinib was well-tolerated and highly active in patients with NSCLC patients with ALK alterations (252). Kodama et al. showed that alectinib inhibits wild-type RET and the constitutively active RET-M918T NSCLC cells in vitro and in vivo, and exhibits selectivity against RET with gatekeeper mutations (V804L and V804M) (134). However, while clinical assessment determined that alectinib was well-tolerated in treatment-naïve patients, twice-daily oral administration of alectinib (600mg) exerts minimal activity in RET fusion-positive NSCLC patients (133) and yielded an overall response rate (ORR) of 4% (1/25 patients) and PFS of 3.4 months (135). These findings were corroborated by a recent clinical trial (NCT03131206) in which RET fusion-positive thyroid cancer and NSCLC patients showed minimal to no response to alectinib. Alectinib received accelerated FDA approval in 2015 for treatment of patients with ALK fusion-positive metastatic NSCLC that were unresponsive to crizotinib, an ALK and ROS1 inhibitor (253), and is currently in clinical trials to test efficacy against other solid tumors alone (NCT04116541, NCT02314481, NCT03194893) or in combination with other compounds (NCT03944772).

In an effort to overcome the suboptimal clinical benefit of MKIs in RET-altered cancers, agerafenib (CEP-32496; RXDX-105) was developed as an orally available, ATP-competitive, selective inhibitor of RET and BRAF (262). Preclinical assessment in multiple RET-altered cancer types showed that RXDX-105 potently inhibits wild-type and altered RET more potently and selectively than MKIs with non-selective RET activity, and elicited rapid response in the primary tumor and brain metastases of a RET fusion-positive lung cancer patient (262). These findings strongly suggested RXDX-105 as a promising new anti-cancer compound with BBB penetrance. However, a phase I/Ib trial (NCT01877811) revealed that daily oral administration of agerafenib (275mg) does not elicit response in RET fusion-positive NSCLC patients (0/20) and conferred multiple treatment-related adverse events such as diarrhea, fatigue, and hypophosphatemia (263). Ultimately, this clinical trial was discontinued due to lack of clinical response.

Selpercatinib (LOXO-292, LY3527723; Retevmo ^®) is an orally available RET inhibitor that competitively binds to its ATP binding pocket (264). In vitro studies reveal that selpercatinib selectively inhibits both wild-type and altered RET, spares KDR/VEGFR2 activity, and selectively targets RET-altered cancer cells (264). Selpercatinib also abrogates tumor growth of lung cancer and MTC xenografts in a dose-dependent manner in vivo, highlighting its therapeutic utility in RET-dependent cancers. Further in vitro and in vivo characterization confirms that selpercatinib is selective against RET alterations, including fusions and activating mutations, is well-tolerated upon daily oral administration, and elicited rapid clinical response in two patient cases (MTC and NSCLC) (265). Selpercatinib entered a phase I/II clinical trial (NCT03157128) in patients bearing RET alterations (fusions, mutations, and other alterations). This clinical trial, LIBRETTO-001, remains ongoing but recently reported an objective response of 64% (67/105 patients), with treatment-naïve patients reporting 85% objective response (33/39 patients) with daily oral administration of 20-240mg selpercatinib (266). Since lung cancers frequently metastasize to the brain, effective therapeutic agents should also display BBB penetrance. In the LIBRETTO-001 trial, the authors reported that NSCLC patients with CNS metastases had over 82% objective intracranial response rate (18/22 patients), with two patients undergoing complete response, indicating that selpercatinib can penetrate the BBB to act upon brain metastases of RET-altered lung cancers (265, 267). The same clinical trial also determined an objective response of 69-79% in MTC patients bearing RET alterations (268). Many of these patients (NSCLC or MTC) reported improved or maintained quality of life during treatment with selpercatinib (269, 270). Taken together, these results indicate that selpercatinib elicits durable efficacy, including intracranial activity, with primarily low-grade toxicity effects in patients with RET-altered cancers. Selpercatinib received accelerated approval from the FDA in 2020 for patients with metastatic RET fusion-positive NSCLC, and patients with RET-mutant aggressive or metastatic MTC (271, 272), making it the first FDA approval for RET fusion-positive NSCLC and MTC. In addition to the LIBRETTO-001 trial, ongoing clinical trials are underway to test efficacy of selpercatinib in multiple tumor types, such as pediatric solid tumors (NCT03899792, NCT04320888) and advanced NSCLC (NCT04268550).

As with selpercatinib, pralsetinib (BLU-667; Gavreto ^®) is an orally available, ATP-competitive inhibitor that selectively inhibits wild-type and altered RET while sparing KDR/VEGFR2 activity (273). Pralsetinib entered Phase I/II clinical trial in 2017 (NCT03037385) to assess safety and efficacy in patients with RET fusion-positive thyroid and lung cancers (274). This clinical trial, entitled ARROW, is a multi-cohort, open-label, first-in-human study that involved 75 sites in 11 countries. An ORR of 61% was observed in NSCLC patients who previously received platinum chemotherapy (53/87 patients), 70% (19/27) in treatment-naïve patients, with a small percentage undergoing complete response (255). Additionally, pralsetinib showed robust intracranial activity in 78% (7/9) of NSCLC patients with CNS metastases and mitigated progression of new CNS lesions, suggesting that pralsetinib crosses the BBB to act on brain metastases (274). Pralsetinib was granted accelerated approval by the FDA in 2020 for adults with metastatic RET fusion-positive NSCLC, and patients with metastatic RET-mutant MTC that may or may not be radioactive iodine-refractory (275). While pralsetinib is well-tolerated in patients included within the ARROW clinical trial, a recent report characterized leptomeningeal progression in a NSCLC patient despite durable extracranial response to pralsetinib, though this patient exhibited clinical CNS response following selpercatinib treatment (276), suggesting that selpercatinib may improve on the intracranial therapeutic efficacy of pralsetinib. In addition to ARROW, another ongoing clinical trial aims to assess efficacy of pralsetinib compared to first-line treatments of advanced NSCLC (NCT04222972), as well as test efficacy compared to standard-of-care therapies in NSCLC (NCT04222972) and MTC (NCT04760288).