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Selpercatinib
Clinical data
Trade namesRetevmo, Retsevmo
Other namesLOXO-292
AHFS/Drugs.comMonograph
MedlinePlusa620036
License data
Pregnancy
category
  • AU: D[1]
  • Use should be avoided
Routes of
administration		By mouth
Drug classTyrosine kinase inhibitor
ATC code
Legal status
Legal status
Identifiers
  • 6-(2-hydroxy-2-methylpropoxy)-4- (6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC29H31N7O3
Molar mass525.613 g·mol−1
3D model (JSmol)
  • COc1ccc(CN2C3CC2CN(c2ccc(-c4cc(OCC(C)(C)O)cn5ncc(C#N)c45)cn2)C3)cn1
  • InChI=1S/C29H31N7O3/c1-29(2,37)18-39-24-9-25(28-21(10-30)13-33-36(28)17-24)20-5-6-26(31-12-20)34-15-22-8-23(16-34)35(22)14-19-4-7-27(38-3)32-11-19/h4-7,9,11-13,17,22-23,37H,8,14-16,18H2,1-3H3
  • Key:XIIOFHFUYBLOLW-UHFFFAOYSA-N

Selpercatinib, sold under the brand name Retevmo among others, is a targeted medication for the treatment of cancers in people whose tumors have an alteration (mutation or fusion) in a specific gene (RET which is short for "rearranged during transfection").[6][7][9] Before beginning treatment, the identification of a RET gene alteration must be determined using laboratory testing.[6][9] Selpercatinib is taken by mouth.[6]

The most common side effects include changes in laboratory tests (including increased liver enzymes, increased blood sugar, decreased white cell and platelet counts, decreased protein level, decreased calcium, increased total cholesterol, increased creatinine, and decreased sodium) dry mouth, diarrhea, high blood pressure, fatigue, edema, rash, and constipation.[6][9][10]

Selpercatinib is a RET kinase inhibitor, meaning it inhibits the protein RET receptor kinase, which is mutated in the cancer cells and provides them with growth signals. Blocking the RET kinase blocks the main growth signal for cancer cells and thereby prevents them from dividing.[6][9]

Selpercatinib is the first therapy approved specifically for people with cancer harboring RET gene alterations.[9] Selpercatinib received accelerated approval for this indication for patients aged twelve years of age and older in 2020.[9][11][12][10] In June 2024, the US Food and Drug Administration granted traditional approval to selpercatinib for people aged two years of age and older.[13]

Medical uses

[edit]

In the United States, selpercatinib is indicated for the treatment of:[6]

  • adults with locally advanced or metastatic non-small cell lung cancer with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.[6][9][10][14]
  • people aged twelve years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.[6][9][10]
  • people aged twelve years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).[6][9][10]
  • adults with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.[6][15]

In the European Union, selpercatinib, as monotherapy, is indicated for the treatment of adults with:[7]

  • advanced RET fusion-positive non-small cell lung cancer who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy[7]
  • advanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or lenvatinib[7]

and for the treatment of people aged twelve years of age and older with advanced RET-mutant medullary thyroid cancer (MTC) who require systemic therapy following prior treatment with cabozantinib and/or vandetanib.[7]

In September 2024, the FDA granted traditional approval to selpercatinib for people aged two years of age and older with advanced or metastatic medullary thyroid cancer with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.[16] Selpercatinib received accelerated approval for this indication for people 12 years of age and older in 2020.[16][17] In May 2024, the FDA granted accelerated approval for this indication to people aged two years of age and older.[16]

Adverse effects

[edit]

Selpercatinib can cause serious side effects including liver toxicity, high blood pressure, heart rhythm changes due to prolongation of heart electrical activity (QT prolongation), bleeding, allergic reactions and impaired wound healing.[6][9][10]

Selpercatinib may also cause harm to a developing fetus or a newborn baby.[6][9]

The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium.[13]

History

[edit]

Selpercatinib received accelerated approval for this indication for patients aged twelve years of age and older in 2020.[9][18][12][10]

Selpercatinib was approved based on the results of the LIBRETTO-001 clinical trial (NCT03157128) involving 702 participants aged 15–92 years with each of the three types of tumors.[9][12][10] During the clinical trial, participants received 160 mg selpercatinib orally twice daily until disease progression or unacceptable toxicity.[9] The major efficacy outcome measures were overall response rate (ORR), which reflects the percentage of participants that had a certain amount of tumor shrinkage, and duration of response (DOR).[9] The trial was conducted at 84 sites in the United States, Canada, Australia, Hong Kong, Japan, South Korea, Singapore, Taiwan, Switzerland, Germany, Denmark, Spain, France, the United Kingdom, Italy and Israel.[10] The conversion to regular approval for non-small cell lung cancer was based on data from an additional 172 participants and 18 months of additional follow-up to assess durability of response.[14]

Efficacy for non-small cell lung cancer was evaluated in 105 adult participants with rearranged during transfection (RET) fusion-positive non-small cell lung cancer who were previously treated with platinum chemotherapy.[9] Sixty-four percent of the 105 participants with previously treated non-small cell lung cancer, experienced complete or partial shrinkage of their tumors which lasted more than six months for 81% of them.[10] Out of 39 participants who had never undergone treatment, 84% experienced complete or partial shrinkage of their tumors which lasted more than six months for 58% of them.[10]

Efficacy for medullary thyroid cancer (MTC) was evaluated in participants aged twelve years of age and older with RET-mutant MTC .[9] The study enrolled 143 participants with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib, vandetanib or both (types of chemotherapy), and participants with advanced or metastatic RET-mutant MTC who had not received prior treatment with cabozantinib or vandetanib.[9] Sixty-nine percent of the 55 previously treated participants for MTC experienced complete or partial shrinkage of their tumors which lasted more than 6 months for 76% of them.[10] Out of 88 participants who had never undergone treatment with an approved drug, 73% experienced complete or partial shrinkage of their tumors which lasted more than six months for 61% of them.[10]

Efficacy for rearranged during transfection (RET) fusion-positive thyroid cancer was evaluated in participants aged twelve years of age and older.[9] The study enrolled 19 participants with RET fusion-positive thyroid cancer who were radioactive iodine-refractory (RAI, if an appropriate treatment option) and had received another prior systemic treatment, and eight participants with RET fusion-positive thyroid cancer who were RAI-refractory and had not received any additional therapy.[9] Seventy-nine percent of the 19 previously treated participants with thyroid cancer experienced complete or partial shrinkage of their tumors which lasted more than six months for 87% of them.[10] All eight participants who had not received therapy other than radioactive iodine therapy experienced complete or partial shrinkage of their tumors which lasted more than six months for 75% of them.[10]

Efficacy for locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options was demonstrated in LIBRETTO-001 (NCT03157128), a multicenter, open-label, multi-cohort trial that evaluated 41 participants with RET fusion-positive tumors (other than non-small cell lung cancer and thyroid cancer) with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options.[15] The efficacy evaluation was supported by data in 343 participants with RET fusion-positive non-small cell lung cancer and thyroid cancer enrolled in the same trial already described in product labeling.[15] Participants received selpercatinib until disease progression or unacceptable toxicity.[15]

Society and culture

[edit]
[edit]

The US Food and Drug Administration (FDA) granted the application for selpercatinib priority review, orphan drug, and breakthrough therapy designations;[9][19] and granted approval of Retevmo to Loxo Oncology, Inc., a subsidiary of Eli Lilly and Company.[9]

In December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Retsevmo, intended for the treatment of cancers that display rearranged during transfection (RET) gene alterations: RET-fusion positive non-small cell lung cancer, RET-fusion positive thyroid cancer and RET-mutant medullary-thyroid cancer (MTC).[20] The applicant for this medicinal product is Eli Lilly Nederland B.V. Selpercatinib was approved for medical use in the European Union in February 2021.[7]

In June 2024, the Food and Drug Administration granted traditional approval to selpercatinib for people aged two 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). The applicant was Eli Lilly and Company.[13]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Selpercatinib

View on Grokipedia
from Grokipedia
Selpercatinib, sold under the brand name Retevmo, is an oral medication that acts as a selective inhibitor of the RET proto-oncogene receptor, targeting cancers driven by RET fusions or mutations. Developed by Loxo Oncology and later co-developed by after its 2019 acquisition of Loxo, selpercatinib received its initial accelerated approval from the U.S. (FDA) on May 8, 2020, for two specific indications in adults: metastatic RET fusion-positive non-small cell (NSCLC) and advanced or metastatic RET-mutant (MTC). On the same date, it was also granted accelerated approval for advanced or metastatic RET fusion-positive in patients aged 12 years and older. Subsequent expansions included accelerated approval in September 2022 for locally advanced or metastatic RET fusion-positive solid tumors in adults and pediatric patients 12 years and older weighing at least 40 kg, as well as full FDA approval on June 12, 2024, for RET fusion-positive and on September 27, 2024, for RET mutation-positive MTC, both in adults and pediatric patients 2 years and older; an accelerated approval on May 29, 2024, further expanded use to pediatric patients 2 years and older for RET-altered cancers and solid tumors requiring systemic treatment. The drug's mechanism of action involves highly selective binding to RET , inhibiting its activity and thereby disrupting downstream signaling pathways that promote uncontrolled in RET-altered tumors, such as those in approximately 1-2% of NSCLC cases and 50-60% of MTC cases. Clinical trials, including the LIBRETTO-001 study, demonstrated objective response rates of 64% in RET fusion-positive NSCLC and 69% in RET-mutant MTC, supporting its efficacy with a manageable safety profile dominated by side effects like dry mouth, , and . Selpercatinib is administered orally at 160 mg twice daily for adults and patients 12 years and older weighing 50 kg or more, with adjusted doses based on body weight or surface area for smaller pediatric patients 2 years and older, with ongoing research exploring its role in earlier treatment lines and combination therapies.

Medical uses

Indications

Selpercatinib is a approved for use in patients with certain advanced cancers driven by RET fusions or , which play a key role in oncogenesis by constitutively activating signaling pathways that promote tumor growth. It is indicated for the treatment of adult patients with locally advanced or metastatic (NSCLC) that is RET fusion-positive, as confirmed by an FDA-approved test. Selpercatinib is also indicated for adult and pediatric patients 2 years of age and older with advanced or metastatic RET-mutant (MTC) that requires , detected by an FDA-approved test. Additionally, it is approved for adult and pediatric patients 2 years of age and older with advanced or metastatic RET fusion-positive that requires and is radioactive iodine-refractory (if applicable), as detected by an FDA-approved test. For broader application, selpercatinib is indicated in adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors that are RET fusion-positive, have progressed following prior , or for which there are no satisfactory alternative treatments, confirmed by an FDA-approved test; this indication received accelerated approval, with continued approval dependent on confirmatory trials. These approvals are limited to locally advanced or metastatic disease settings where curative surgery is not feasible. In 2024, the FDA expanded selpercatinib's indications to include pediatric patients as young as 2 years across the MTC, , and solid tumor approvals, converting several from accelerated to traditional approval and broadening access for younger patients with RET alterations. Prior to initiating treatment, confirmation of RET gene alterations (fusions or ) is required using an FDA-approved companion diagnostic test.

Dosage and administration

Selpercatinib is administered orally at a recommended dose of 160 mg twice daily for adult patients and pediatric patients weighing 50 kg or more, while patients weighing less than 50 kg receive 120 mg twice daily. For pediatric patients aged 2 to less than 12 years, dosing is based on (BSA): 40 mg three times daily for BSA 0.33 to 0.65 , 80 mg twice daily for BSA 0.66 to 1.08 , 120 mg twice daily for BSA 1.09 to 1.52 , and 160 mg twice daily for BSA 1.53 or greater; it is not recommended for BSA less than 0.33 . Treatment continues until disease progression or unacceptable toxicity. Capsules or tablets should be swallowed whole with , with or without , and must not be crushed, chewed, or opened. Patients should avoid concomitant use of grapefruit products, , or oranges, as these are strong CYP3A inhibitors that may increase selpercatinib exposure. If a dose is missed and it is less than 6 hours until the next dose, the missed dose should be skipped; if occurs after administration, no additional dose should be taken. For patients requiring acid-reducing agents, concomitant inhibitors should be avoided; if unavoidable, selpercatinib should be taken with at least 2 hours before or 10 hours after an , or 2 hours before or after a locally acting . Dose modifications are recommended for adverse reactions, with reductions typically to 120 mg or 80 mg twice daily (or equivalent for lower-weight patients), and further to 80 mg or 40 mg twice daily if needed. Treatment should be interrupted for severe toxicities such as Grade 3 or 4 hepatotoxicity (withhold until resolution to Grade 1 or baseline, then resume at a reduced dose), Grade 3 hypertension (withhold until recovery to Grade 0 or 1 or baseline, then resume reduced), or Grade 3 QT prolongation (withhold until recovery to less than 481 ms or baseline, then resume reduced). For concomitant strong CYP3A inhibitors, the dose should be reduced (e.g., from 160 mg to 80 mg twice daily); treatment with strong CYP3A inducers should be avoided. In patients with severe hepatic impairment (Child-Pugh C), the dose should be reduced by 50% (e.g., 160 mg to 80 mg twice daily). Upon resolution of toxicities, treatment may resume at the next lower dose level. Monitoring requirements include baseline and periodic assessments of (ALT, AST, and total ) every 2 weeks for the first 3 months, then monthly thereafter, or more frequently as clinically indicated. should be monitored approximately 1 week after initiation and monthly thereafter, with more frequent checks for patients with . Electrocardiograms (ECG) for assessment, along with serum electrolytes and (TSH), are recommended at baseline and periodically during treatment, with increased frequency if concomitant CYP3A inhibitors or QT-prolonging drugs are used. should be monitored before initiation and as clinically indicated.

Pharmacology

Mechanism of action

Selpercatinib is a potent, selective small-molecule inhibitor that specifically targets the RET (rearranged during ) proto-oncogene, a involved in cellular signaling. It functions as an ATP-competitive inhibitor, binding directly to the domain of RET and preventing its autophosphorylation, which is essential for activation. This inhibition disrupts the RET signaling pathway, blocking downstream activation of key oncogenic cascades such as the MAPK/ERK, PI3K/AKT, and PLCγ pathways, which promote , survival, and tumor growth in cancers harboring RET alterations. The selectivity of selpercatinib for RET is notable, with over 250-fold greater potency against RET compared to other kinases, including VEGFR2 and FGFR1, as demonstrated in biochemical and cellular assays. This high selectivity minimizes off-target effects on unrelated kinases, distinguishing it from multikinase inhibitors. Selpercatinib is effective against various RET alterations, including common gene fusions such as KIF5B-RET, which are prevalent in non-small cell lung cancer (NSCLC), and point mutations like M918T, frequently associated with medullary thyroid cancer (MTC). RET alterations, including gene fusions and activating point , result in ligand-independent RET activation through constitutive dimerization or enhanced activity, driving oncogenesis in tumors such as NSCLC and MTC. By targeting these aberrant RET proteins, selpercatinib restores control over dysregulated signaling, thereby inhibiting tumor progression specifically in RET-altered malignancies.

Pharmacokinetics

Selpercatinib is absorbed rapidly following , with a time to maximum plasma concentration (Tmax) of 2 hours. The absolute is 73% (range: 60% to 82%). Administration with a high-fat meal (approximately calories) has no clinically significant effect on the area under the plasma concentration-time curve (AUC) or maximum plasma concentration (Cmax) of selpercatinib. Distribution
The steady-state apparent of selpercatinib is approximately 203 L, indicating moderate tissue distribution. Selpercatinib is 96% bound to plasma proteins, primarily , in a concentration-independent manner. The blood-to-plasma concentration ratio is 0.7. Selpercatinib exhibits limited penetration into the but has demonstrated anti-tumor activity in preclinical models of intracranial RET fusion-positive tumors. Metabolism
Selpercatinib undergoes hepatic metabolism predominantly via the enzyme CYP3A4. Following a single radiolabeled 160 mg oral dose, approximately 86% of the circulating radioactivity in plasma is represented by unchanged selpercatinib, with minor metabolites such as LOXO-292-N-oxide identified in trace amounts. Elimination
The effective of selpercatinib is 32 hours, supporting once- or twice-daily dosing. The apparent oral clearance is 6 L/h. Following administration of a single radiolabeled dose, 69% of the dose is recovered in (with 14% as unchanged ) and 24% in (with 12% as unchanged ), indicating primary elimination via biliary/fecal routes with minimal renal of unchanged parent compound. No clinically significant differences in selpercatinib pharmacokinetics are observed based on age (ranging from 2 to 92 years), sex, or mild to moderate hepatic impairment (Child-Pugh A or B) or renal impairment (eGFR 15 to 89 mL/min). Severe hepatic impairment (Child-Pugh C) increases selpercatinib AUC by 1.77-fold. Exposure to selpercatinib is altered by strong CYP3A modulators; for example, coadministration with ketoconazole (a strong CYP3A inhibitor) increases AUC by 2.33-fold and Cmax by 1.3-fold, while rifampin (a strong CYP3A inducer) decreases AUC by 87% and Cmax by 70%.

Adverse effects

Common adverse effects

The most common adverse effects of selpercatinib, based on data from the LIBRETTO-001 trial (n=796 adults), occur in at least 25% of patients and are primarily grade 1 or 2 in severity. These include (49%), (47%), (46%), dry mouth (43%), (41%), (34%), (33%), (33%), (31%), and (28%).
Adverse EffectIncidence (All Grades)Grade 3-4 Incidence
49%0.8%
47%5%
46%3.1%
Dry mouth43%0%
41%20%
34%2.5%
33%0.8%
33%0.6%
31%1.1%
28%1.4%
Edema is typically peripheral and managed with supportive measures such as and compression; it rarely requires dose interruption. is usually mild and responsive to antidiarrheal agents like , with most cases resolving without discontinuation. is nonspecific and often improves with rest, while dry mouth can be alleviated with hydration and substitutes. is generally maculopapular and treated topically with corticosteroids if needed. necessitates regular monitoring and may require initiation of antihypertensive therapy, such as ACE inhibitors. and are commonly managed with antiemetics (e.g., ) and laxatives (e.g., ), respectively. and are typically managed supportively. Common laboratory abnormalities include increased AST (59%), decreased calcium (59%), increased ALT (56%), increased glucose (53%), and decreased (28%), most of which are grade 1 or 2 and monitored through routine blood tests. These abnormalities often reflect transient effects and are reversible with dose adjustments or supportive care, such as calcium supplementation for . Most common adverse effects and laboratory abnormalities onset within the first few months of treatment and are reversible upon dose interruption or discontinuation, though long-term data indicate persistent or late-onset events such as (63%) and (61%) in patients treated ≥24 months. Dose modifications, as outlined in the dosage and administration guidelines, are frequently employed to manage these effects while maintaining therapeutic benefit. Drug-related discontinuations due to adverse effects remain low at 4.3%.

Serious adverse effects

Selpercatinib is associated with several serious adverse effects that require careful monitoring and potential dose adjustments or discontinuation. manifests as elevated liver enzymes, with increased AST occurring in 59% of patients (grade 3-4 in 11%) and increased ALT in 56% (grade 3-4 in 12%). , including ALT and AST, should be assessed prior to initiating treatment, every 2 weeks for the first 3 months, and then monthly thereafter. For grade 3 or 4 elevations, selpercatinib should be withheld until recovery to grade 1 or baseline, with weekly monitoring during interruption; resume at a reduced dose upon recovery, and permanently discontinue if grade 3 or 4 elevations recur or persist despite dose reduction. QT interval prolongation is reported in approximately 20% of patients with an increase of 60 ms or more from baseline and in 7% with QTcF exceeding 500 ms. Risk factors include congenital , concomitant use of QT-prolonging drugs, and imbalances. Baseline ECG and levels (including , calcium, magnesium, and TSH) are recommended prior to treatment initiation, with periodic monitoring during therapy. For grade 3 prolongation, withhold selpercatinib until resolution to grade 1 or less, correcting electrolytes as needed; permanently discontinue for grade 4 events. Hemorrhagic events, including , occur in 3.1% of patients as grade 3 or higher, with fatal outcomes in 0.5%. Patients receiving anticoagulants or antiplatelet agents are at heightened risk for bleeding. Close monitoring for signs of hemorrhage is advised, particularly in those on concomitant therapies that increase bleeding risk. Severe or life-threatening hemorrhagic events necessitate permanent discontinuation of selpercatinib. Hypersensitivity reactions affect 6% of patients, with grade 3 events in 1.9%. These reactions can be severe and require immediate intervention. Upon suspicion of , withhold selpercatinib, administer corticosteroids, and permanently discontinue if grade 3 or 4 reactions occur; for grade 1 or 2, resume at a reduced dose after resolution. Interstitial lung disease (ILD)/ occurs in 1.8% of patients (grade 3-4 in 0.3%, fatal in 0.3%). Symptoms include dyspnea, , and . Withhold for grade 2 events and permanently discontinue for grade 3 or 4 or recurrence. has been reported in 13% of patients, all grade 1 or 2. Monitor prior to initiation and periodically during treatment. Withhold until euthyroid or discontinue based on severity. Impaired may occur; withhold selpercatinib at least 7 days prior to and resume after . Embryo-fetal is a significant concern; based on findings from animal reproduction studies, selpercatinib can cause fetal harm when administered to women. Selpercatinib is contraindicated during due to the potential for fetal harm. Verify pregnancy status prior to initiation in females of reproductive potential, and advise use of effective contraception during treatment and for at least 1 week after the last dose; males should use contraception during treatment and for 1 week post-treatment. Tumor lysis syndrome, observed in 0.6% of patients with , particularly those with high tumor burden, rapidly proliferating disease, or renal impairment. At-risk patients require close monitoring and prophylactic measures such as adequate hydration and antihyperuricemics. develops in 41% of patients (grade 3 in 20%, grade 4 in 0.1%), necessitating assessment approximately 1 week after starting treatment and monthly thereafter, with optimization of antihypertensive prior to initiation. Withhold for grade 3 hypertension until recovery to grade 1 or 2, and permanently discontinue for grade 4. In pediatric patients (aged ≥2 years), additional monitoring is required for (SCFE) or slipped upper femoral epiphysis (SUFE), reported in 0.5%-3.7% across trials, presenting as or or . Treat medically or surgically as appropriate. Long-term treatment data indicate that serious adverse events occur in 51% of patients over extended follow-up, with manageable patterns including late-onset ILD (2.6%) and chylous effusions (3.9%).

Clinical development

Preclinical research

Selpercatinib, known during development as LOXO-292, was discovered by Loxo Oncology using to target the RET kinase domain, aiming to create a highly selective inhibitor effective against diverse RET alterations including fusions, activating mutations, and acquired resistance mutations. Loxo Oncology, the developer, was acquired by in 2019 for $8 billion. In vitro studies showed selpercatinib potently inhibits wild-type RET with an IC50 of 0.92 nM in biochemical assays at 1 mM ATP. It retains activity against common RET mutants, with IC50 values ranging from 4.9 nM for A883F to 67.8 nM for V804L, and effectively blocks RET-driven in engineered Ba/F3 models expressing KIF5B-RET fusions or M918T mutations, achieving sub-nanomolar to low-nanomolar potency. In vivo efficacy was demonstrated in RET-altered xenograft models, such as those derived from NSCLC and MTC tumors, where oral dosing at 10–30 mg/kg twice daily induced 62%–113% tumor regression or growth inhibition over 14–28 days, surpassing the effects of at 40–60 mg/kg daily. Selpercatinib exhibited high selectivity, inhibiting fewer than 2% of 329 tested kinases at clinically relevant concentrations, with minimal off-target activity against EGFR or VEGFR family members compared to multi-kinase inhibitors. Preclinical safety assessments in rodents and minipigs revealed no significant toxicity at therapeutic doses, with no-observed-adverse-effect levels (NOAEL) of 10–20 mg/kg/day in 28-day rat studies and 12 mg/kg/day in minipigs; the maximum tolerated dose was not reached in short-term rodent studies, supporting safe translation to clinical use.

Clinical trials

The pivotal clinical evaluation of selpercatinib was conducted in the phase 1/2 LIBRETTO-001 trial (NCT03157128), an open-label, multicenter, multi-cohort study assessing its safety and efficacy in patients with advanced solid tumors harboring RET alterations, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other thyroid cancers. The trial enrolled 796 patients across various cohorts, with major efficacy endpoints including objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS), all assessed by blinded independent central review. In the RET fusion-positive NSCLC cohort, among 247 previously treated patients, the confirmed ORR was 62% (95% CI, 55-68), with a median DoR of 31.6 months and median PFS of 26.2 months (median follow-up, 41.2 months); in 69 treatment-naïve patients, the ORR was 83% (95% CI, 72-91), with median PFS of 22.0 months (median follow-up, 38.9 months). For RET-mutant MTC, the ORR was 77.6% (95% CI, 70.2-84.0) in 152 previously treated patients and 84.5% (95% CI, 76.6-90.5) in 116 treatment-naïve patients, with median PFS of 41.4 months in pretreated patients (3-year PFS rate 54.6%) and not reached in treatment-naïve patients (3-year PFS rate 75.2%; median follow-up 42.4-44.0 months). In RET fusion-positive thyroid cancer, the ORR was 85.4% (95% CI, 70.8-94.4) in 41 previously treated patients, with a median PFS of 27.4 months (median follow-up, 30.4 months); in 24 treatment-naïve patients, the ORR was 95.8% (95% CI, 78.9-99.9), with median PFS not reached (median follow-up, 24.9 months). The phase 1/2 LIBRETTO-121 trial (NCT03899792) evaluated selpercatinib in pediatric patients aged 2 years and older with RET-altered solid tumors, demonstrating efficacy with durable responses; as of 2024, the ORR was 52.8% among evaluable patients. The phase 3 LIBRETTO-531 trial (NCT04211337) further supported selpercatinib's role in MTC, randomizing 291 multikinase inhibitor-naïve patients with advanced RET-mutant MTC in a 2:1 ratio to selpercatinib (160 mg twice daily) versus physician's choice of or . The primary endpoint of PFS was superior with selpercatinib, with median PFS not reached versus 16.8 months in the control arm ( 0.28, 95% CI 0.16-0.48; P<0.001), and 12-month PFS rates of 86.8% versus 65.7%; the ORR was 69.4% versus 38.8%. These results contributed to regulatory approvals in 2024. Ongoing trials are exploring selpercatinib in earlier treatment lines and combinations, such as neoadjuvant use in RET-altered thyroid cancer (NCT04759911), with the adverse event profile remaining consistent with that observed in LIBRETTO-001.

Society and culture

Selpercatinib received accelerated approval from the U.S. Food and Drug Administration (FDA) on May 8, 2020, for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), as well as adult and pediatric patients 12 years and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) requiring systemic treatment following prior therapy and for which no satisfactory alternative treatments exist. This initial approval was granted under the FDA's accelerated approval pathway based on objective response rates and response duration observed in the LIBRETTO-001 trial. Subsequent expansions included accelerated approval on September 21, 2022, for adults and pediatric patients 12 years and older weighing at least 40 kg with locally advanced or metastatic solid tumors harboring a RET gene fusion who had progressed on prior systemic therapy and for whom no satisfactory alternatives existed. On May 29, 2024, the FDA further extended accelerated approval to pediatric patients 2 years and older with advanced or metastatic RET-mutant MTC requiring systemic treatment with no satisfactory alternatives, advanced or metastatic RET fusion-positive thyroid cancer (radioactive iodine-refractory, if applicable) requiring systemic treatment with no satisfactory alternatives, or locally advanced or metastatic RET fusion-positive solid tumors that had progressed following prior therapies and lacked satisfactory alternatives. The FDA converted several indications to traditional approval in 2024, confirming clinical benefit: on June 12, 2024, for adult and pediatric patients 2 years and older with advanced or metastatic RET fusion-positive thyroid cancer unresponsive to radioactive iodine and requiring systemic therapy without satisfactory alternatives; and on September 27, 2024, for adult and pediatric patients 2 years and older with advanced or metastatic RET-mutant MTC requiring systemic therapy without satisfactory alternatives. These applications received priority review, breakthrough therapy designation, and orphan drug designation, reflecting the drug's potential to address unmet needs in rare cancers. Additionally, selpercatinib was granted pediatric rare disease designation by the FDA for certain indications in children with RET-altered thyroid cancers and solid tumors. In the European Union, the European Medicines Agency (EMA) granted conditional marketing authorization for Retsevmo (selpercatinib) on February 11, 2021, for adults and adolescents 12 years and older with RET fusion-positive advanced NSCLC not previously treated with a RET inhibitor; advanced RET fusion-positive thyroid cancer not previously treated with a RET inhibitor and requiring systemic therapy after prior external radiotherapy and/or surgery; and advanced RET-mutant MTC not previously treated with a RET inhibitor and requiring systemic therapy. This authorization included orphan drug designation for MTC. Selpercatinib also holds orphan drug status in the EU for the treatment of MTC. In March 2024, the EMA extended the indications to include adults with advanced RET fusion-positive solid tumors that progressed following prior systemic therapies or for which no satisfactory alternative treatment options exist. Approvals in other regions followed closely: Health Canada issued a Notice of Compliance with conditions on June 15, 2021, for adults with RET fusion-positive advanced or metastatic NSCLC or RET-mutant advanced, metastatic, or locally advanced MTC unsuitable for surgery. The Therapeutic Goods Administration in Australia approved selpercatinib in July 2021 for RET fusion-positive NSCLC and thyroid cancers, as well as RET-mutant MTC in adults, with orphan drug designation for MTC. In Japan, the Ministry of Health, Labour and Welfare granted approval in March 2022 for RET fusion-positive unresectable advanced or recurrent NSCLC and thyroid cancer, and RET-mutant unresectable advanced or recurrent MTC. Access to selpercatinib requires laboratory confirmation of a RET gene fusion or mutation using an FDA-approved companion diagnostic, such as the FoundationOne CDx or Oncomine Dx Target Test, to identify eligible patients. In the United States, Eli Lilly and Company offers patient assistance through Lilly Oncology Support Services, providing support for insurance navigation, financial aid, and access for eligible uninsured or underinsured patients.

Brand names and marketing

Selpercatinib is marketed under the brand name Retevmo in the United States and as the primary global , while it is sold as Retsevmo in the . The drug was developed by Loxo Oncology, Inc., and following Eli Lilly and Company's acquisition of Loxo in 2019, Lilly has handled its global marketing and distribution. Retevmo launched in the United States in May 2020 immediately after receiving FDA approval, with the European launch of Retsevmo occurring in March 2021 subsequent to EMA authorization; by 2025, the medication is available in over 50 countries worldwide. It is formulated as oral capsules in 40 mg and 80 mg strengths, with no generic versions available as of 2025 owing to orphan drug exclusivity and patent protections extending into the 2030s. Eli Lilly's commercial strategy emphasizes targeting oncologists through promotion of RET gene testing to identify eligible patients, alongside patient support programs such as Lilly Oncology Support Services, which provide assistance with access, financial aid, and treatment adherence. Economically, the U.S. for Retevmo is approximately $24,000 per month as of 2024, though actual patient costs vary based on insurance and assistance programs; it is also recommended in (NCCN) guidelines for managing RET-altered cancers.

References

  1. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions
  2. https://www.ncbi.nlm.nih.gov/books/NBK594575/
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC7716849/
  4. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-ret-fusion-positive-thyroid-cancer
  5. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-solid-tumors
  6. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-medullary-thyroid-cancer-ret-mutation
  7. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selpercatinib-pediatric-patients-two-years-and-older-ret-altered
  8. https://go.drugbank.com/drugs/DB15685
  9. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213246s012lbl.pdf
  10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213246s011s013lbl.pdf
  11. https://www.aacr.org/patients-caregivers/progress-against-cancer/new-pediatric-indications-for-selpercatinib/
  12. https://www.ncbi.nlm.nih.gov/books/NBK603615/
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC10288430/
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC10452615/
  15. https://www.ema.europa.eu/en/documents/assessment-report/retsevmo-epar-public-assessment-report_en.pdf
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC11630769/
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC6096733/
  18. https://www.prnewswire.com/news-releases/lilly-announces-agreement-to-acquire-loxo-oncology-300773673.html
  19. https://www.nejm.org/doi/full/10.1056/NEJMoa2005653
  20. https://www.nejm.org/doi/full/10.1056/NEJMoa2005651
  21. https://retevmo.lilly.com/hcp/efficacy/libretto-001
  22. https://ascopubs.org/doi/10.1200/JCO-24-02076
  23. https://ascopubs.org/doi/full/10.1200/JCO.23.02503
  24. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.10022
  25. https://www.nejm.org/doi/full/10.1056/NEJMoa2309719
  26. https://clinicaltrials.gov/study/NCT04759911
  27. https://www.ema.europa.eu/en/medicines/human/EPAR/retsevmo
  28. https://www.esmo.org/oncology-news/ema-recommends-extension-of-therapeutic-indications-for-selpercatinib3
  29. https://www.ncbi.nlm.nih.gov/books/NBK601729/
  30. https://synapse.patsnap.com/article/in-which-countries-is-selpercatinib-approved
  31. https://www.foundationmedicine.com/press-release/us-food-and-drug-administration-fda-approves-foundationonercdx-companion-diagnostic-0
  32. https://retevmo.lilly.com/
  33. https://www.fiercepharma.com/pharma/lilly-cashes-loxo-buyout-fda-approval-for-first-class-cancer-drug-retevmo
  34. https://www.ema.europa.eu/en/documents/product-information/retsevmo-epar-product-information_en.pdf
  35. https://www.drugs.com/availability/generic-retevmo.html
  36. https://www.drugpatentwatch.com/p/tradename/RETEVMO
  37. https://retevmo.lilly.com/hcp/testing
  38. https://retevmo.lilly.com/savings-support
  39. https://pricinginfo.lilly.com/retevmo
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