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Abstract

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.

Keywords

LOXO292 precision oncology selpercatinib targeted therapy

RET biology

The rearranged during transfection (RET) gene is a protooncogene that is located on chromosome 10. It encodes for a receptor tyrosine kinase that initiates a cellular signaling cascade leading to cell proliferation and growth. The RET receptor is composed of three distinct parts: an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain includes four cadherin-like domains, a calcium-binding site, and a cysteine-rich region. The intracellular domain features a tyrosine kinase enzyme, which can have variable isoforms of the c-terminal tail due to alternative splicing.^1–4 Ligand binding to the RET co-receptors leads to the activation of multiple downstream cellular signaling pathways including RAS/MAPK/ERK, PI3K/AKT, and JAK/STAT; all with resulting increase in cellular proliferation and differentiation.^5–9

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.^10–14 RET mutations are relatively more frequent, but RET fusion-positive cancers represent a distinct molecular entity that defines a unique clinical subtype.^15,16

Figure 1.

RET fusions can lead to ligand-independent activation of the RET pathway, which leads to downstream signaling of multiple other cellular pathways associated with cellular proliferation and survival.

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.^15,17–22 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.^{19,26,28–31}

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 analysis of cell-free DNA (cfDNA) from 32,989 samples collected from patients with diverse cancers revealed the presence of 176 RET alterations (mostly fusions) in 170 patients (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 fusion-positive cancers and led to their inclusion in standard of care treatment guidelines⁴⁰ (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.

Table 1.

Summary of data on FDA and EMA-approved selective RET inhibitors in RET fusion-positive solid tumors.

Drug	Clinical trial	FDA indication	EMA indication	Data
Selpercatinib	LIBRETTO-001, NCT03157128	Adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options		ORR = 43.9%⁴¹
		Adult patients with locally advanced or metastatic NSCLC with a RET gene fusion	Advanced RET fusion-positive NSCLC not previously treated with a RET inhibitor	ORR = 84% and 61% in untreated and previously treated patients^42,43
		Adult and pediatric patients 12 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)	Advanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or levatinib	ORR = 79%⁴⁴
Pralsetinib	ARROW, NCT03037385	Adult patients with metastatic RET fusion-positive NSCLC	Adult patients with RET fusion-positive advanced NSCLC not previously treated with a RET inhibitor	ORR = 70% and 61% in untreated and previously treated patients⁴⁵
		Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)		ORR = 89%⁴⁶

EMA = European Medicines Agency; FDA = Food and Drug Administration; NSCLC, non-small cell lung cancer; ORR, objective response rate; RET, Rearranged during Transfection.

Selpercatinib

Mechanism of action and preclinical data

Selpercatinib is a selective small molecule inhibitor of RET kinase via ATP competitive mechanism. Preclinical studies have shown that selpercatinib possesses high selective potency against different RET alterations, including fusions and mutations.^47,48

Clinical development in NSCLC

Evidence in favor of using selpercatinib in RET fusion-positive NSCLC came from the LIBRETTO-001 trial. LIBRETTO-001 was an open-label phase 1–2 clinical trial including patients with advanced or metastatic solid tumors who harbor RET alterations (fusions and mutations). Patients in the phase 2 portion received 160 mg twice daily and were allowed to continue treatment beyond progression per investigator’s evaluation of clinical benefit.

A total of 247 patients with heavily pretreated and 69 patients with treatment naïve RET fusion-positive NSCLC were included as part of LIBRETTO-001. ORR was 61% (95% Cl: 55–67) in pretreated patients—including 18 patients with complete response, and 84% (95% CI: 73–92) in previously untreated patients – including four patients with complete response. The median PFS was 24.9 months (95% CI: 19.3–not reached) and 22 months (95% CI: 13.8–not reached) in previously treated and previously untreated patients, respectively.^42,43 Intracranial activity was quite impressive in 22 patients with measurable central nervous system (CNS) metastasis who showed an ORR of 82% (95% CI: 60–95)—including 23% complete responses. In 80 patients with NSCLC and intracranial disease, the median intracranial PFS was 13.7 months (95% CI: 10.9–not reached).⁴⁹ In an updated analysis including 106 patients with baseline intracranial disease, intracranial ORR was 85% (95% CI: 65–96) with a median PFS of 19.4 months (95% CI: 13.8–not reached). The calculated probability of CNS progression in brain metastasis-free patients who received selpercatinib was only 0.7% at 2 years.⁴³ Based on results from the NSCLC cohort analysis in LIBRETTO-001, selpercatinib received its FDA approval for treatment of metastatic RET fusion-positive NSCLC in 2020.⁵⁰

Since LIBRETTO-001 was a single-arm study, an effort to explore the comparative effectiveness of selpercatinib by pooling patient-level data from matched patients in real world, pemetrexed/platinum arm of the KEYNOTE-189 trial, and docetaxel arm of REVEAL trial. PFS was significantly longer for selpercatinib (median not reached) versus pemetrexed and platinum in KEYNOTE-189 (median 12 months) and docetaxel (median 9 months) using targeted maximum likelihood estimation.⁵¹

Selpercatinib maintained its efficacy in NSCLC and tolerable safety profile when tested in different patient populations and different disease settings. For example, in a population with Japanese patients (n = 44 previously treated and 4 previously untreated), the ORR was 55.4%. Another study (LIBRETTO-321; NCT04280081) included Chinese patients with RET-altered cancers. In 47 patients with RET fusion-positive NSCLC, ORR was 69.2% (95% CI: 48.2–85.7).⁵² Beyond clinical trials, in a real-world retrospective study, selpercatinib was demonstrated to achieve an ORR of 68% and a disease control rate of 92% in 50 patients with RET fusion-positive NSCLC. This was quite interesting given the inclusion of 14 patients (28%) who had a performance status of ⩾2 who would classically be excluded from clinical trials.⁵³

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 fusion-positive 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 In 45 patients with RET fusion-positive non-lung and non-thyroid cancers (12 pancreatic cancer, 10 colon cancer, 4 salivary gland cancer, 3 sarcoma, 3 cancer of unknown primary, 2 breast cancer, 2 skin cancer, 2 cholangiocarcinoma, 2 xanthogranuloma, 1 carcinoid syndrome, 1 ovarian cancer, 1 pulmonary carcinosarcoma, 1 rectal neuroendocrine tumor, and 1 small intestinal cancer), the ORR was 43.9% (95% CI: 28.5–60.3)—including two patients with complete response (Figure 2). The median PFS assessed by independent reviewers was 13.2 months (95% CI: 7.4–26.2).⁴¹

Figure 2.

Pan-cancer efficacy of selpercatinib in RET fusion-positive solid tumors.

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 non-gatekeeper 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

Table 2.

Examples of ongoing clinical trials for selpercatinib in RET fusion-positive cancers.

Clinical trial	Phase	Setting	Population
LIBRETTO-432	3	Adjuvant	Patients with early-stage NSCLC after curative intent surgery or radiation therapy
NCT04759911	2	Neoadjuvant	Patients with thyroid cancer
LIBRETTO-431	3	Advanced	Patients with advanced or metastatic RET fusion-positive nonsquamous NSCLC
Lung-MAP	2	Advanced	Patients with RET fusion-positive recurrent or metastatic NSCLC
ORCHARD	2	Advanced	Patients with advanced NSCLC who progressed after treatment with first-line osimertinib
FINPROVE	2	Advanced	Patients with advanced solid tumors that harbor a RET alteration
LIBRETTO-121	1/2	Advanced	Pediatric patients with advanced solid tumors and primary CNS tumors not including lung cancer that harbor a RET alteration
Pediatric-MATCH	2	Advanced	Pediatric patients with RET-altered cancers

NSCLC, non-small cell lung cancer; RET, Rearranged during Transfection.

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 RET-altered 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.

Footnotes

Acknowledgements

Figures were created using tools from Biorender.com.

Declarations

ORCID iD

Vivek Subbiah

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

Abstract

Keywords

RET biology

RET fusions

Detection of RET fusions

Development of RET inhibitors: A historical perspective

Selpercatinib

Mechanism of action and preclinical data

Clinical development in NSCLC

Clinical development beyond NSCLC

Drug-induced toxicities

Resistance to selpercatinib

Clinical trials with selpercatinib in multiple settings and future perspectives

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References