Precision oncology with selective RET inhibitor selpercatinib in RET-rearranged cancers

Rearranged during transfection (RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways. Activating RET alterations can occur and lead to uncontrolled cellular proliferation as a hallmark of cancer development. Oncogenic RET fusions are present in nearly 2% of patients with non-small cell lung cancer (NSCLC), 10–20% of patients with thyroid cancer, and <1% across the pan-cancer spectrum. In addition, RET mutations are drivers in 60% of sporadic medullary thyroid cancers and 99% of hereditary thyroid cancers. The discovery, rapid clinical translation, and trials leading to FDA approvals of selective RET inhibitors, selpercatinib and pralsetinib, have revolutionized the field of RET precision therapy. In this article, we review the current status on the use of the selective RET inhibitor, selpercatinib, in RET fusion-positive tumors: NSCLC, thyroid cancers, and the more recent tissue-agnostic activity leading to FDA approval.

RET fusions RET can be aberrantly activated by mutations and chromosomal rearrangements ( Figure 1); both of which has been linked to the process of oncogenesis in different tumor types. 2 Initial discoveries were made in patients with thyroid cancer who had multiple endocrine neoplasia syndrome, but later evidence suggested a role of RET alterations in other sporadic cancers as well. [10][11][12][13][14] RET mutations are relatively more frequent, but RET fusionpositive cancers represent a distinct molecular entity that defines a unique clinical subtype. 15,16 In a study including 96,324 samples from AACR Project GENIE, 223 RET fusions (0.23%) were identified. Nearly half of RET fusions (54.3%) were identified in patients with non-small cell lung cancer (NSCLC). The second most common tumor type with frequent RET fusions was papillary thyroid cancer (22.8%). Frequently encountered fusion partners were KIF5B, CCDC6, and NCOA4 . 16 In disease-specific analysis, RET fusions are estimated to occur in 2% of NSCLC patients. 15,[17][18][19][20][21][22] Such prevalence might be perceived as infrequent, but the fact that lung cancer is estimated to hit nearly a quarter million new patients a year in the United States alone makes the number of patients who might benefit from targeted treatment substantial. 23 RET fusion-positive cancers usually present with distinct clinicopathological characteristics including young age, never smokers, early nodal metastasis, and poorly differentiated histology. 15 A study by Drilon et al. 24 also suggested that RET-rearranged lung cancers commonly present with brain metastasis (present in 25% of patients with stage IV at the time of diagnosis with a lifetime prevalence of 46%) and have suboptimal response to multikinase inhibitor (MKI) therapy. In NSCLC samples with RET fusion, co-occurring alterations were found in KRAS, SETD2, PBRL4, EZH1, and RRAGC genes. 16 In addition to NSCLC, RET fusions have also been implied as part of the molecular profile in various other tumor types. 17

Detection of RET fusions
There are multiple methods that can be used to detect RET fusions which vary in their advantages and disadvantages. 25 For example, immunohistochemistry has been long used as a cheap technology for the detection of RET aberrations but is limited by its low sensitivity and specificity. 15,19,20,26,27 Fluorescence in situ hybridization (FISH) can be used to achieve higher sensitivity and specificity, but it cannot identify fusion partners unless the specific fusion partner probe is used. 15,26 Polymerase Chain Reaction (PCR) is another alternative that can inform about the exact fusion partner, but it can only evaluate specimens based on known molecular profile which is used to select the used primers and limits its ability to discover new or unknown partners. 19,26,[28][29][30][31] Therefore, next-generation sequencing emerges as the optimum tool for the detection of RET fusion variants, given its high sensitivity and specificity as well as its ability to overcome most of the previously mentioned limits. The cost will remain a challenging concern, especially in low-resource settings but it will hopefully be cheaper with wider applications of genomic testing and more advances in technologies that will characterize the era of personalized cancer medicine. 3,31 One promising approach is the use of liquid biopsy for the detection of RET fusions. 25 This has gained lots of interest in the past decade given its minimally invasive nature. In a study by Rich et al., 32   (0.5%). In NSCLC, this is particularly important given the challenges of obtaining repeated tissue samples. Liquid biopsy in that setting can allow for the detection of originally present RET fusions at baseline samples and emerging fusions during longitudinal monitoring, which offers patients a chance for real-time assessment of therapeutic targetability in an era with the expanded availability of targeted therapy. 33,34 Development of RET inhibitors: A historical perspective Treatment of RET-altered cancers has been quite challenging since response rates to chemotherapy were relatively low. Moreover, limited response and progression-free survival (PFS) benefit has been shown with immunotherapy, possibly due to low levels of Programmed Death Ligand 1 (PDL1) expression and low mutation burden. 35 The first potential for targeting RET alterations came historically from studies that were done on MKIs. 2 Cabozantinib and vandetanib have emerged, among other MKIs, in that regard as key players with evidence of their activity in RET-altered cancers. For example, an objective response rate (ORR) of 28% was observed with cabozantinib in patients with previously treated RET fusion-positive NSCLC. 36 Vandetanib has also demonstrated an ORR of 17% in a similar patient population. Nevertheless, the wide spectrum of toxicities primarily attributed to nonselective inhibition of tyrosine kinases including non-target ones was quite devastating. Moreover, the durability of the response was also another concern. 2,37 With that in mind, further efforts have led to the introduction of more selective RET-targeting agents. 38,39 So far, two agents, selpercatinib and pralsetinib, have shown promising results in treating RET-driven cancers. Data from clinical trials suggested a potential for both drugs in RET fusionpositive cancers and led to their inclusion in standard of care treatment guidelines 40 (Table 1). This review will primarily focus on selpercatinib and its activity in RET fusion-positive cancers starting with NSCLC and expanding beyond that to tissue-agnostic activity.

Clinical development beyond NSCLC
In addition to NSCLC, the initial FDA approval for selpercatinib included patients with advanced or metastatic RET mutant medullary thyroid carcinoma and patients with advanced or metastatic RET fusion-positive thyroid cancer; based on reports with promising results in those other two other cohorts of LIBRETTO-001. 44 For example, the RET fusionpositive thyroid cancer group showed an ORR of 79% (95% CI: 54-94). 44 This cohort had patients with variable thyroid cancer histologies including papillary, poorly differentiated, hurthle cell, and anaplastic carcinomas. 44 Interestingly, selpercatinib use has been demonstrated to enhance radioactive iodine uptake in RET-rearranged thyroid cancer, probably via a drug-induced histological redifferentiation. 54,55 An updated report was published for other cohorts of LIBRETTO-001 and was the basis for the tissue-agnostic approval in 2022. 50

Drug-induced toxicities
Despite having a tolerable toxicity profile, the use of selpercatinib has been linked to the occurrence of multiple toxicities that can be quite distinct. For example, chylous effusions have been described in patients treated with selpercatinib. 56 Hypersensitivity reactions have also been reported in selpercatinib-treated patients regardless of prior use of immunotherapy. 57 Other common adverse events include fatigue, hypertension, rash, dry mouth, nausea, abdominal pain, diarrhea, constipation, edema, and headache. 50 Resistance to selpercatinib Multiple mechanisms of acquired resistance, which commonly limits the durability of response with tyrosine kinase inhibitors, are also being increasingly reported with selpercatinib. While selpercatinib can structurally evade the gatekeeper mutations of RET by wrapping around the tyrosine kinase, 58 resistance to first-generation RET inhibitors, including selpercatinib, has been reported to occur as a result of acquired mutation at the nongatekeeper sites; namely, solvent front and hinge sites of RET kinase; including RET Y806 and RET G810 mutations. 58,59 These form the basis for the design of second-generation RET inhibitors. For example, Solomon et al. demonstrated using cfDNA samples from a patient with CCDC6-RET NSCLC with prior dramatic response to selpercatinib the emergence of RET G810C mutation at the time of progression. 59,60 In addition to G810 mutations, other RET-independent resistance mechanisms have also been reported in RET inhibitor-treated patients including amplifications of MET and KRAS genes. 61,62 NTRK3 fusion as a mechanism of resistance has also been reported in RET fusion-positive lung cancer. 63 Different approaches have been suggested to overcome such resistance including combination with other targeted agents, for example, crizotinib. 61 Moreover, second-generation drugs are currently being explored in early-phase trials and will hopefully delay the emergence of these mutations with a benefit in expanding PFS.

Clinical trials with selpercatinib in multiple settings and future perspectives
The tissue-agnostic approval of selpercatinib was a landmark in biomarker-driven precision oncology. However, multiple studies are currently ongoing to explore the expanded potential of selpercatinib in RET fusion-positive cancers ( Table 2). These are primarily focused on testing in different disease settings and patients' populations. For example, a phase 3 trial (LIBRETTO-432; NCT04819100) is investigating the use of selpercatinib in the adjuvant setting compared to placebo when given to patients with early-stage NSCLC after curative intent surgery or radiation therapy. 64 In the neoadjuvant setting, NCT04759911 is a phase 2 trial that is evaluating preoperative selpercatinib in patients with thyroid cancer and RET alterations. 65 In the advanced and metastatic setting, LIBRETTO-431 (NCT04194944) continues to evaluate the efficacy of selpercatinib in patients with advanced or metastatic RET fusion-positive non-squamous NSCLC. Patients are randomized to receive either selpercatinib or standard platinum-based and pemetrexed-based therapy with or without pembrolizumab as first-line treatment. 60 Selpercatinib is also tested as part of the Lung-MAP lung cancer Master Protocol which is an umbrella trial that includes patients with advanced NSCLC for the purpose of testing various therapeutic regimens including selpercatinib. For example, phase 2 Lung-MAP (NCT05364645) investigates carboplatin and pemetrexed with or without selpercatinib in patients with RET fusion-positive recurrent or metastatic NSCLC. Another arm of Lung-MAP evaluates selpercatinib as a single-agent in the same disease setting. 66 Selpercatinib is also being studied as part of the phase 2 platform study (ORCHARD; NCT03944772) in patients with advanced NSCLC who progressed after treatment with first-line osimertinib. 67 This is also the case in the phase 2 Finnish trial (FINPROVE) which includes patients with advanced solid tumors that harbor a RET alteration. 68 In the pediatric patient population, LIBRETTO-121 (NCT03899792) is a phase 1/2 trial evaluating selpercatinib in patients with advanced solid tumors and primary CNS tumors, not including lung cancer, that harbors a RET alteration. Moreover, the phase 2 pediatric MATCH trial (NCT04320888; NCT03155620) is studying selpercatinib in RETaltered cancers in the pediatric patient population (⩽21 years).

Conclusion
Selpercatinib has led to a paradigm change in the management of RET fusion-positive solid tumors including NSCLC and thyroid cancer. Its current tissue-agnostic approval highlights the potential it has in different tumor types. Multiple studies are ongoing with the aim of exploring selpercatinib use in other disease settings and different patients' populations.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.