Selpercatinib (Retevmo®): A Comprehensive Monograph on a First-in-Class Selective RET Inhibitor

Executive Summary

Selpercatinib, marketed under the brand names Retevmo® and Retsevmo®, is a first-in-class, orally bioavailable, small-molecule inhibitor of the Rearranged during Transfection (RET) receptor tyrosine kinase. It represents a landmark achievement in precision oncology, having been specifically designed for high potency and selectivity against cancers driven by RET gene alterations, including activating point mutations and oncogenic fusions. The development and approval of selpercatinib have fundamentally transformed the treatment landscape for patient populations with previously limited therapeutic options.

Clinical validation for selpercatinib is anchored in the results of the pivotal, multicenter Phase 1/2 LIBRETTO-001 trial, which demonstrated unprecedented and durable clinical activity across multiple tumor types. In its approved indications, selpercatinib has produced high objective response rates (ORR) and prolonged durations of response (DoR) and progression-free survival (PFS). Key approved indications include RET fusion-positive non-small cell lung cancer (NSCLC), both in treatment-naïve and previously treated settings; advanced RET-mutant medullary thyroid cancer (MTC); advanced RET fusion-positive thyroid cancer; and a tumor-agnostic indication for advanced RET fusion-positive solid tumors that have progressed on prior therapy.

A defining feature of selpercatinib is its robust intracranial efficacy, showing high response rates in patients with central nervous system (CNS) metastases, a common and challenging clinical scenario. Furthermore, its highly selective kinase inhibition profile translates into a manageable safety profile that, while characterized by frequent adverse events, is associated with a low rate of treatment discontinuation. This tolerability is a significant advantage over older, less specific multi-kinase inhibitors. The comprehensive clinical data have established selpercatinib as a global standard of care, underscoring the success of a biomarker-driven, targeted approach to cancer therapy and offering a new paradigm of effective treatment for patients with RET-altered malignancies.

Introduction: The Emergence of RET-Targeted Therapy

The RET Proto-Oncogene as a Therapeutic Target

The Rearranged during Transfection (RET) gene encodes a transmembrane receptor tyrosine kinase that is critical for the normal development and function of the enteric nervous system, the sympathetic and parasympathetic nervous systems, and the kidneys.[1] Under physiological conditions, the RET receptor is activated upon binding of its glial cell line-derived neurotrophic factor (GDNF) family ligands in conjunction with a glycosylphosphatidylinositol-anchored co-receptor. This ligand-induced dimerization triggers autophosphorylation of the intracellular kinase domain, initiating downstream signaling cascades, including the RAS/MAPK and PI3K/AKT pathways, which regulate cell proliferation, survival, differentiation, and migration.[2]

In the context of oncology, aberrant, ligand-independent activation of the RET kinase transforms it into a potent oncogenic driver.[3] This pathological activation occurs primarily through two distinct mechanisms: activating point mutations within the RET gene or chromosomal rearrangements that result in the in-frame fusion of the RET kinase domain with an upstream partner gene.[2] These genetic alterations lead to constitutive dimerization and kinase activity, providing a constant, powerful growth and survival signal to the cancer cell, thereby driving tumorigenesis and metastasis.[3]

The Clinical Landscape of RET-Altered Malignancies

RET alterations are the defining oncogenic drivers in several distinct malignancies. Activating point mutations in RET are found in approximately 60-70% of sporadic medullary thyroid cancers (MTC) and are the germline cause of hereditary MTC syndromes, such as multiple endocrine neoplasia type 2 (MEN2).[2] RET gene fusions, most commonly involving partners like KIF5B or CCDC6, are identified in approximately 1-2% of non-small cell lung cancers (NSCLC) and 10-20% of papillary and other differentiated thyroid cancers.[2] Furthermore, RET fusions have been identified as rare but actionable drivers across a wide spectrum of other solid tumors, including pancreatic adenocarcinoma, colorectal cancer, and salivary gland tumors, establishing RET as a true tumor-agnostic target.[7]

Historical Unmet Need and the Limitations of Multi-Kinase Inhibitors (MKIs)

Prior to the development of selective RET inhibitors, the therapeutic options for patients with advanced RET-driven cancers were limited and largely inadequate. These patients were often treated with multi-kinase inhibitors (MKIs) such as cabozantinib and vandetanib.[9] While these agents possess some inhibitory activity against the RET kinase, they are non-selective and potently inhibit numerous other kinases, notably vascular endothelial growth factor receptors (VEGFRs).[10] This lack of specificity results in significant off-target toxicities, including hypertension, diarrhea, fatigue, and hand-foot syndrome, which frequently necessitate dose reductions or treatment discontinuation, thereby limiting their therapeutic window and overall efficacy.[9] The objective response rates for these MKIs in RET fusion-positive NSCLC were modest, ranging from 16% to 53%, highlighting a profound unmet clinical need for more effective and better-tolerated treatments for this genetically defined patient population.[10]

Selpercatinib: A New Paradigm of Selective Inhibition

Selpercatinib (formerly known as LOXO-292) was rationally designed and developed by Loxo Oncology to address the shortcomings of existing MKIs.[3] It is a next-generation, highly potent, and exquisitely selective inhibitor of the RET kinase.[4] By specifically targeting the oncogenic driver with high precision, selpercatinib was engineered to maximize on-target efficacy while minimizing the off-target toxicities associated with the older, less specific agents. This approach heralded a new paradigm in the treatment of RET-altered cancers, with the potential to offer superior tumor response, durable disease control, and a more favorable safety profile, ultimately changing the standard of care for these patients.

Physicochemical and Pharmaceutical Profile

Selpercatinib is a synthetic, small-molecule compound designed for oral administration as a targeted anticancer agent. Its precise chemical and pharmaceutical properties are essential for its identity, manufacturing, and clinical application.

Nomenclature

The drug is identified by a standardized set of names and codes used across research, clinical, and regulatory domains:

• Generic Name: Selpercatinib [1]
• Brand Names: In the United States and Canada, it is marketed as Retevmo®.[11] In Europe, the brand name is Retsevmo®.[1]
• Developmental and Research Codes: During its development, selpercatinib was known by several codes, including LOXO-292, LY3527723, and ARRY-192.[1]

Chemical Identifiers and Structure

The unique chemical identity of selpercatinib is defined by the following standard identifiers:

• DrugBank ID: DB15685 [User Query]
• CAS Number: 2152628-33-4 [12]
• Type: Small Molecule [1]
• Chemical Formula: C29​H31​N7​O3​ [1]
• Molecular Weight: The average molecular weight is 525.61 g/mol, with a monoisotopic mass of 525.248837886 Da.[1]
• IUPAC Name: 6-(2-hydroxy-2-methylpropoxy)-4-[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.[4]
• Structure Identifiers:
• InChI: 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 [4]
• InChIKey: XIIOFHFUYBLOLW-UHFFFAOYSA-N [4]
• SMILES: CC(C)(COC1=CN2C(=C(C=N2)C#N)C(=C1)C3=CN=C(C=C3)N4CC5CC(C4)N5CC6=CN=C(C=C6)OC)O [4]

Pharmaceutical Formulation

Selpercatinib is formulated for oral use, with multiple dosage strengths available to accommodate weight-based and body surface area-based dosing regimens across adult and pediatric populations.

• Dosage Forms: The medication is available as both hard capsules and tablets.[4]
• Capsules: 40 mg (gray opaque) and 80 mg (blue opaque).[20]
• Tablets: 40 mg, 80 mg, 120 mg, and 160 mg.[20]
• Solubility: Selpercatinib is soluble in dimethyl sulfoxide (DMSO) for laboratory use.[19] Its clinical pharmacokinetics suggest a pH-dependent solubility, as evidenced by the significant drug interaction with acid-reducing agents like proton-pump inhibitors, which necessitates administration with food to ensure adequate absorption.[25]

Table 1: Key Physicochemical and Identification Properties of Selpercatinib

Property	Value	Source(s)
Generic Name	Selpercatinib	1
Brand Names	Retevmo® (US), Retsevmo® (EU)	14
DrugBank ID	DB15685	[User Query]
CAS Number	2152628-33-4	12
Type	Small Molecule	1
Chemical Formula	C29​H31​N7​O3​	1
Molecular Weight	525.61 g/mol (Average)	1
IUPAC Name	6-(2-hydroxy-2-methylpropoxy)-4-[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	4
InChIKey	XIIOFHFUYBLOLW-UHFFFAOYSA-N	4
Developmental Codes	LOXO-292, LY3527723	1
Dosage Forms	Oral Capsules (40 mg, 80 mg), Oral Tablets (40 mg, 80 mg, 120 mg, 160 mg)	20
Administration Route	Oral	4

Clinical Pharmacology

The clinical utility of selpercatinib is a direct result of its carefully engineered pharmacodynamic and pharmacokinetic properties. Its potent and selective mechanism of action drives its efficacy, while its metabolic profile dictates key aspects of clinical management.

Pharmacodynamics: Mechanism of Potent and Selective RET Inhibition

Selpercatinib's therapeutic effect is derived from its function as a highly potent and selective inhibitor of the RET receptor tyrosine kinase.[12] It is an ATP-competitive inhibitor that binds to the kinase domain of the RET protein, blocking its phosphorylation and subsequent activation of downstream signaling pathways.[2] By interrupting this aberrant signaling cascade, selpercatinib effectively halts the uncontrolled proliferation and survival signals that drive the growth of RET-altered cancer cells.[14]

The potency of selpercatinib is demonstrated by its low nanomolar half-maximal inhibitory concentrations (IC50​) against wild-type RET and a wide array of clinically relevant RET alterations. These include activating point mutations common in MTC (e.g., M918T, V804M, V804L) and RET fusion proteins found in NSCLC and thyroid cancer (e.g., KIF5B-RET, CCDC6-RET).[5] Reported

IC50​ values are consistently in the 0.45 nM to 4 nM range, signifying a very high degree of potency.[13]

However, the defining pharmacodynamic characteristic of selpercatinib is its remarkable selectivity. In broad kinase panel screening, it was found to be over 100-fold more selective for RET than for more than 95% of 228 other kinases evaluated.[13] While selpercatinib can inhibit other kinases like VEGFR1/3 and FGFR1/2/3 at higher concentrations, these are still within a clinically achievable range. Critically, cellular assays show that it inhibits RET at concentrations approximately 8-fold lower than for VEGFR3 and 60-fold lower than for FGFR1 and FGFR2.[1]

This high degree of selectivity is not merely a biochemical detail; it is the central pillar of selpercatinib's therapeutic advantage. The older MKIs used for RET-driven cancers, such as cabozantinib and vandetanib, are non-selective and inhibit multiple kinases, leading to a wide array of off-target toxicities that often limit dosing and lead to treatment cessation.[9] Selpercatinib was engineered to avoid this "dirty" kinase profile. The clinical benefit of this precision was directly demonstrated in the LIBRETTO-531 trial, which compared selpercatinib to cabozantinib or vandetanib in patients with RET-mutant MTC. Selpercatinib not only demonstrated superior efficacy but was also associated with a dramatically lower rate of treatment discontinuation due to adverse events (5% vs. 27% in the MKI arm).[9] This provides definitive evidence that the engineered selectivity of selpercatinib translates directly into a superior clinical outcome, characterized by both enhanced efficacy and improved tolerability.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion

The journey of selpercatinib through the body is characterized by properties that support convenient oral dosing but also necessitate careful management of potential drug interactions.

• Absorption: Selpercatinib is orally bioavailable, reaching peak plasma concentrations (Tmax) at a median of approximately 2 hours after administration.[3] Its absorption is influenced by gastric pH. The co-administration of a proton-pump inhibitor (PPI), which raises gastric pH, can reduce selpercatinib exposure. This effect can be mitigated by taking selpercatinib with food, a critical piece of patient counseling derived directly from its pharmacokinetic properties.[25]
• Distribution: The drug distributes widely throughout the body, with an apparent volume of distribution (Vd​) of 191 L, a value that increases with patient body weight.[1] In the bloodstream, selpercatinib is highly bound (97%) to plasma proteins, a binding that is independent of drug concentration.[1]
• Metabolism: Selpercatinib is metabolized predominantly in the liver, primarily by the cytochrome P450 3A4 (CYP3A4) enzyme system.[1] This heavy reliance on a single metabolic pathway makes it highly susceptible to drug-drug interactions with inhibitors or inducers of CYP3A4.
• Excretion: Following a single oral dose, the majority of the drug is eliminated via the feces (69% of the dose, of which 14% is unchanged selpercatinib), with a smaller portion eliminated in the urine (24% of the dose, of which 12% is unchanged).[1]
• Half-Life: The mean elimination half-life (t1/2​) of selpercatinib in healthy individuals is approximately 32 hours.[1] This relatively long half-life supports a convenient twice-daily dosing regimen, which helps maintain steady-state plasma concentrations above the therapeutic threshold required for continuous RET inhibition.

The pharmacokinetic profile of selpercatinib directly informs several critical clinical management strategies. Its metabolism via CYP3A4 means that co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole) will increase selpercatinib exposure and the risk of toxicity, necessitating a dose reduction, while co-administration with strong CYP3A4 inducers (e.g., rifampin) will decrease its exposure and risk sub-therapeutic efficacy, and thus should be avoided.[27] The pH-dependent absorption requires specific instructions for patients taking acid-reducing medications.[26] Therefore, a thorough understanding of its pharmacokinetics is essential for safe and effective use.

Table 2: Summary of Key Pharmacokinetic Parameters of Selpercatinib

Parameter	Value	Clinical Relevance/Comments	Source(s)
Route of Administration	Oral	Allows for at-home, patient-administered therapy.	4
Time to Peak (Tmax)	~2 hours	Rapid absorption after oral dose.	3
Volume of Distribution (Vd)	191 L	Wide distribution throughout the body. Vd increases with body weight.	1
Plasma Protein Binding	97%	Highly bound to plasma proteins.	1
Metabolism	Predominantly hepatic via CYP3A4	High potential for drug-drug interactions with CYP3A4 inhibitors and inducers.	1
Elimination Half-Life (t½)	32 hours	Supports a twice-daily (BID) dosing schedule.	1
Excretion	69% in feces, 24% in urine	Primarily eliminated through the gastrointestinal tract.	1

Clinical Efficacy in RET-Altered Malignancies

The clinical development of selpercatinib has been defined by the landmark LIBRETTO-001 trial, which has provided the foundational evidence for its approvals across a range of RET-driven cancers. The results from this study and subsequent confirmatory trials have established selpercatinib as a new standard of care.

The Pivotal LIBRETTO-001 Trial (NCT03157128): A Pan-Tumor Validation

LIBRETTO-001 is a global, multicenter, open-label, single-arm Phase 1/2 clinical trial that served as the primary registrational study for selpercatinib.[12] The study employed a classic design with an initial dose-escalation phase (Phase 1) to determine the optimal dose, followed by a large dose-expansion phase (Phase 2) in specific cohorts of patients with advanced solid tumors harboring RET alterations.[7] The trial enrolled a large and diverse population of over 700 patients across 16 countries, including cohorts for RET fusion-positive NSCLC, RET-mutant MTC, RET fusion-positive thyroid cancer, and a "basket" cohort for other RET fusion-positive solid tumors.[7] The primary efficacy endpoint was Objective Response Rate (ORR), as determined by a blinded independent review committee (BIRC) using RECIST v1.1 criteria. Key secondary endpoints included Duration of Response (DoR), Progression-Free Survival (PFS), Overall Survival (OS), and a critical assessment of intracranial activity (CNS-ORR and CNS-DoR).[7]

RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)

In patients with RET fusion-positive NSCLC, selpercatinib has demonstrated profound and durable efficacy in both previously treated and treatment-naïve populations.

• Efficacy in Previously Treated Patients: In the cohort of 247 patients who had previously received at least one line of platinum-based chemotherapy, final analysis from LIBRETTO-001 showed an impressive ORR of 61-62%.[8] The responses were exceptionally durable, with a median DoR of 31.6 months and a median PFS of 26.2 months.[31] These data represent a significant improvement over historical outcomes with chemotherapy or MKIs. The median OS in this heavily pretreated population was a remarkable 47.6 months.[31]
• Efficacy in Treatment-Naïve Patients: When used as a first-line therapy in 69 patients, selpercatinib's efficacy was even more striking. The ORR was 83-84%, indicating that the vast majority of patients experienced significant tumor shrinkage.[8] The median DoR was 20.3 months and the median PFS was 22.0 months.[31] At the time of final analysis, the median OS had not been reached, with a 3-year landmark survival rate of 66%, underscoring the long-term benefit of upfront targeted therapy.[31]
• Confirmatory Evidence (LIBRETTO-431, NCT04194944): The robust findings from the single-arm LIBRETTO-001 trial were definitively confirmed by the randomized, Phase 3 LIBRETTO-431 trial. This study compared first-line selpercatinib to the standard of care (platinum-based chemotherapy with or without pembrolizumab). The results showed that selpercatinib more than doubled the median PFS, with 24.8 months for the selpercatinib arm versus 11.2 months for the control arm.[6] This trial has firmly established selpercatinib as the preferred first-line treatment for patients with advanced RET fusion-positive NSCLC.[33]

Table 3: Efficacy of Selpercatinib in RET Fusion-Positive NSCLC (LIBRETTO-001 & LIBRETTO-431)

Patient Cohort	Trial	N	ORR (95% CI)	Median DoR (months, 95% CI)	Median PFS (months, 95% CI)	Median OS (months, 95% CI)	Source(s)
Treatment-Naïve	LIBRETTO-001	69	83% (73-92)	20.3 (13-NE)	22.0	Not Reached	8
Previously Treated	LIBRETTO-001	247	62% (55-67)	31.6 (20-NE)	26.2	47.6	8
Treatment-Naïve	LIBRETTO-431	-	84%	-	24.8 (19.2-NE)	-	6
Control Arm	LIBRETTO-431	-	65%	-	11.2 (8.8-16.8)	-	6
NE = Not Estimable

RET-Altered Thyroid Cancers

Selpercatinib has shown equally transformative results in patients with RET-driven thyroid malignancies.

• RET-Mutant Medullary Thyroid Cancer (MTC): In patients with RET-mutant MTC, selpercatinib demonstrated high efficacy regardless of prior treatment history. In 143 patients who were naïve to prior MKIs (cabozantinib or vandetanib), the ORR was 82.5%.[35] Even in the more challenging population of 152 patients who had previously been treated with these MKIs, selpercatinib achieved a substantial ORR of 77.6%.[35] The randomized Phase 3 LIBRETTO-531 trial (NCT04211337) provided the highest level of evidence, demonstrating that selpercatinib resulted in a statistically significant and clinically meaningful improvement in PFS compared to physician's choice of cabozantinib or vandetanib. The median PFS was not reached in the selpercatinib arm versus 16.8 months in the control arm, with a hazard ratio of 0.280, representing a 72% reduction in the risk of progression or death.[16] These results led to the full, traditional FDA approval for this indication.[16]
• RET Fusion-Positive Thyroid Cancer: For patients with advanced, radioactive iodine (RAI)-refractory thyroid cancer driven by a RET fusion, selpercatinib has been practice-changing. In the treatment-naïve cohort, the ORR was an exceptional 96%.[8] In the previously treated cohort (n=41), the ORR remained very high at 85%, with a median DoR of 26.7 months.[8] This robust and durable activity supported both the initial accelerated approval and the subsequent conversion to traditional FDA approval for this indication.[14]

Tumor-Agnostic Efficacy in RET Fusion-Positive Solid Tumors

Reflecting the principle that a strong oncogenic driver can be targeted regardless of the tissue of origin, selpercatinib received a tumor-agnostic approval for any solid tumor with a RET gene fusion that has progressed on or after prior systemic treatment or for which there are no satisfactory alternative options.[1] This approval was based on the "basket" cohort of the LIBRETTO-001 trial, which included 41 patients with 14 different cancer types.[7] In this diverse group, selpercatinib achieved an overall ORR of 44% with a median DoR of 24.5 months, demonstrating broad activity.[7]

However, a deeper analysis of these data reveals an important nuance in the concept of tumor-agnostic therapy. While the presence of a RET fusion is a prerequisite for response, the magnitude of that response appears to be modulated by the underlying tumor histology. For instance, in the 11 patients with RET fusion-positive pancreatic cancer, the ORR was 55%.[8] In contrast, in the 10 patients with RET fusion-positive colorectal cancer (CRC), the ORR was only 20%.[8] This disparity suggests that co-occurring genetic alterations and the specific tumor microenvironment of different cancers, such as CRC, may influence the ultimate sensitivity to RET inhibition. This observation tempers the "one-size-fits-all" view of targeted therapy and suggests that while broad biomarker testing for RET fusions is critical, clinical expectations and future research into combination strategies may need to be tailored to the specific cancer type.

Intracranial Efficacy: Addressing CNS Metastases

A critical and differentiating feature of selpercatinib is its ability to effectively treat cancer that has spread to the brain. Central nervous system (CNS) metastases are a frequent and devastating complication of advanced cancers, particularly NSCLC, and the blood-brain barrier often prevents systemic therapies from reaching effective concentrations in the brain. Historically, this has necessitated the use of local therapies like brain radiation, which can carry significant long-term neurocognitive side effects.

Selpercatinib was designed for CNS penetration, and this was confirmed with remarkable clinical results in the LIBRETTO-001 trial.[5] In a pre-planned analysis of NSCLC patients with measurable baseline CNS metastases (n=22-26), selpercatinib achieved an intracranial ORR (CNS-ORR) of 82-85%.[12] This means that the vast majority of brain tumors shrank in response to the oral medication. These responses were also durable, with a median CNS duration of response of 9.4 months and a median CNS progression-free survival of 11.0 to 13.7 months.[12] This robust and sustained intracranial activity is a major clinical advantage, as it allows for the simultaneous treatment of both systemic and CNS disease with a single agent. This provides the opportunity to delay or even avoid the need for brain radiation, thereby preserving neurocognitive function and improving the overall quality of life for these patients.

Safety and Tolerability Profile

The safety profile of selpercatinib has been extensively characterized in the pooled population of 796 patients from the LIBRETTO-001 trial. While adverse events are common, the profile is generally predictable and manageable, leading to a low rate of permanent treatment discontinuation.

Overview of Adverse Reactions

• Most Common Adverse Reactions (AEs): The most frequently reported AEs of any grade (occurring in ≥25% of patients) were edema (49%), diarrhea (47%), fatigue (46%), dry mouth (43%), hypertension (41%), abdominal pain (34%), constipation (33%), rash (33%), nausea (31%), and headache (28%).[14]
• Most Common Laboratory Abnormalities: The most common Grade 3 or 4 laboratory abnormalities (occurring in ≥5% of patients) included decreased lymphocytes (20%), increased alanine aminotransferase (ALT) (12%), increased aspartate aminotransferase (AST) (11%), decreased sodium (11%), and decreased calcium (5.7%).[7]
• Serious Adverse Reactions (SAEs): SAEs were reported in 44% of patients. The most frequent SAEs (≥2%) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients and included events such as sepsis, respiratory failure, and hemorrhage.[27]
• Dose Modifications and Discontinuations: The pattern of dose modifications underscores the manageability of the safety profile. While dose interruptions due to AEs were common (64%), as were dose reductions (41%), the rate of permanent discontinuation due to an AE was very low.[27] For instance, key AEs like fatigue and increased ALT each led to discontinuation in less than 1% of patients.[27] This indicates that most toxicities can be effectively managed with temporary dose holds or reductions, allowing patients to continue benefiting from the therapy long-term. This contrasts sharply with the experience with older MKIs, where toxicities were more often treatment-limiting.

Table 6: Summary of Common and Serious Adverse Reactions to Selpercatinib (Pooled Safety Population, N=796)

Adverse Reaction	All Grades (%)	Grade 3-4 (%)	Source(s)
Most Common Adverse Reactions (≥25%)
Edema	49	1.8	14
Diarrhea	47	5	14
Fatigue	46	6	14
Dry Mouth	43	0.1	14
Hypertension	41	20	14
Abdominal Pain	34	4.1	14
Constipation	33	1.1	14
Rash	33	1.9	14
Nausea	31	1.4	14
Headache	28	1.9	14
Most Common Grade 3-4 Laboratory Abnormalities (≥5%)
Decreased Lymphocytes	50	20	14
Increased ALT	45	12	14
Increased AST	43	11	14
Decreased Sodium	27	11	14
Decreased Calcium	47	5.7	14

Warnings, Precautions, and Management of Key Toxicities

The prescribing information for selpercatinib includes several important warnings and precautions, each with specific monitoring and management guidelines to ensure patient safety.

• Hepatotoxicity: Elevations in liver transaminases (ALT and AST) are common. Serious hepatic adverse reactions occurred in 3% of patients.[37] Therefore, monitoring of ALT and AST levels is mandatory prior to starting treatment, every 2 weeks for the first 3 months of therapy, and then monthly thereafter or as clinically indicated. For Grade 3 or 4 elevations, selpercatinib should be withheld, and the dose should be reduced upon resolution, according to a specific re-escalation schedule.[27]
• Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal cases of ILD/pneumonitis have been reported in 1.8% of patients. Clinicians must monitor for any new or worsening pulmonary symptoms, such as dyspnea, cough, or fever. If ILD/pneumonitis is suspected, selpercatinib should be withheld and promptly investigated. The drug should be permanently discontinued for confirmed Grade 3 or 4 ILD/pneumonitis.[27]
• Hypertension: High blood pressure is a very common side effect, occurring in 41% of patients, with 20% experiencing Grade 3 hypertension. Blood pressure must be well-controlled before initiating selpercatinib. It should be monitored after 1 week, at least monthly thereafter, and as clinically indicated. Antihypertensive medications should be initiated or adjusted as needed. For severe or persistent hypertension, selpercatinib may need to be withheld, dose-reduced, or permanently discontinued.[26]
• QT Interval Prolongation: Selpercatinib can cause a concentration-dependent prolongation of the QT interval on an electrocardiogram (ECG), which can increase the risk of serious cardiac arrhythmias. An increase in the QTcF interval to >500 ms was observed in 7% of patients.[8] Baseline and periodic monitoring of ECGs and serum electrolytes (potassium, magnesium, calcium) is required. This is especially important for patients with pre-existing risk factors or those taking concomitant medications known to prolong the QT interval or strong CYP3A4 inhibitors, which increase selpercatinib exposure.[26]
• Hemorrhagic Events: Serious and sometimes fatal bleeding events can occur. Selpercatinib should be permanently discontinued in patients who experience severe or life-threatening hemorrhage.[26]
• Hypersensitivity Reactions: Hypersensitivity reactions occurred in 6% of patients, typically manifesting as fever, rash, and arthralgias/myalgias, sometimes with laboratory changes like thrombocytopenia or transaminitis.[27] Management involves withholding selpercatinib and initiating corticosteroids. Upon resolution, the drug may be resumed at a significantly reduced dose with a slow upward titration under corticosteroid coverage.[26]
• Risk of Impaired Wound Healing: Due to its potential effects on pathways involved in healing, selpercatinib should be withheld for at least 7 days prior to elective surgery. It should not be administered for at least 2 weeks following major surgery and until the wound has adequately healed.[26]
• Tumor Lysis Syndrome (TLS): Cases of TLS have been reported, particularly in patients with MTC who have a high tumor burden. Patients at risk should be monitored closely, hydrated, and receive prophylactic treatment as clinically indicated.[23]
• Hypothyroidism: New or worsening hypothyroidism can occur. Thyroid function should be monitored at baseline and periodically during treatment, with thyroid hormone replacement initiated or adjusted as needed.[27]

Dosage, Administration, and Drug Interactions

The safe and effective use of selpercatinib relies on adherence to specific guidelines for patient selection, dosing, administration, and the management of drug-drug interactions.

Dosing and Administration Guidelines

• Patient Selection: A critical prerequisite for initiating therapy is the confirmation of a qualifying RET gene alteration (a gene fusion for NSCLC, thyroid cancer, and other solid tumors, or an activating point mutation for MTC) in a tumor or plasma specimen, as detected by an FDA-approved test.[14]
• Adult and Adolescent Dosing (age ≥12 years): The recommended dosage is based on body weight:
• Weight < 50 kg: 120 mg taken orally twice daily.
• Weight ≥ 50 kg: 160 mg taken orally twice daily.

[20]

• Pediatric Dosing (age 2 to <12 years): The recommended dosage for younger children is based on body surface area (BSA) to ensure appropriate exposure:
• BSA 0.33 to 0.65 m2: 40 mg taken orally three times daily.
• BSA 0.66 to 1.08 m2: 80 mg taken orally twice daily.
• BSA 1.09 to 1.52 m2: 120 mg taken orally twice daily.
• BSA ≥1.53 m2: 160 mg taken orally twice daily.

[20]

• Administration Instructions: Selpercatinib should be taken approximately every 12 hours (for twice-daily regimens) and continued until disease progression or the development of unacceptable toxicity. The capsules or tablets must be swallowed whole and should not be crushed or chewed. If a dose is missed, it should only be taken if there are more than 6 hours remaining until the next scheduled dose. If vomiting occurs after taking a dose, an additional dose should not be taken; the patient should wait for the next scheduled dose.[22]
• Dose Modifications for Adverse Reactions: To manage toxicities, a structured dose reduction schedule is recommended. Patients who are unable to tolerate the third dose reduction level should have the drug permanently discontinued.

Table 7: Recommended Dose Reductions for Adverse Reactions

Dose Reduction	Patients Weighing < 50 kg	Patients Weighing ≥ 50 kg	Source(s)
First Reduction	80 mg orally twice daily	120 mg orally twice daily	26
Second Reduction	40 mg orally twice daily	80 mg orally twice daily	26
Third Reduction	40 mg orally once daily	40 mg orally twice daily	26

Significant Drug-Drug Interactions

Selpercatinib's pharmacokinetic profile creates several clinically significant drug-drug interactions that require careful management.

• Interaction with Acid-Reducing Agents: The absorption of selpercatinib is pH-dependent. Co-administration with drugs that increase gastric pH can decrease selpercatinib plasma concentrations and potentially reduce its efficacy. Specific management is required:
• Proton-Pump Inhibitors (PPIs): If co-administration is unavoidable, selpercatinib must be taken with food.
• H2 Receptor Antagonists: Selpercatinib should be taken 2 hours before or 10 hours after the H2 antagonist.
• Locally-Acting Antacids: Selpercatinib should be taken 2 hours before or 2 hours after the antacid.

[22]

• Interaction with CYP3A4 Modulators: As selpercatinib is primarily metabolized by CYP3A4, its exposure is significantly affected by CYP3A4 inhibitors and inducers.
• Strong and Moderate CYP3A4 Inhibitors: These drugs (e.g., ketoconazole, clarithromycin) increase selpercatinib concentrations, raising the risk of toxicity, including QT prolongation. Co-administration should be avoided. If necessary, the selpercatinib dose must be reduced, and QT interval monitoring should be increased.[27]
• Strong and Moderate CYP3A4 Inducers: These drugs (e.g., rifampin, carbamazepine, St. John's Wort) decrease selpercatinib concentrations, risking sub-therapeutic levels and reduced antitumor activity. Co-administration should be avoided.[27]
• Interaction as an Inhibitor: Selpercatinib itself is an inhibitor of several key proteins involved in drug metabolism and transport. It is a moderate inhibitor of CYP2C8 and a weak inhibitor of CYP3A and the P-glycoprotein (P-gp) transporter.[4] Therefore, co-administration with sensitive substrates of these pathways (e.g., certain statins, anticoagulants) should be avoided. If co-administration is necessary, the dose of the substrate drug may need to be adjusted according to its own prescribing information.[27]

Table 8: Clinically Significant Drug-Drug Interactions with Selpercatinib

Interacting Drug Class	Mechanism of Interaction	Clinical Effect on Selpercatinib	Recommended Management	Source(s)
Strong/Moderate CYP3A Inhibitors	Inhibition of selpercatinib metabolism	Increased selpercatinib plasma concentration and risk of toxicity (e.g., QT prolongation)	Avoid co-administration. If unavoidable, reduce selpercatinib dose and increase monitoring.	27
Strong/Moderate CYP3A Inducers	Induction of selpercatinib metabolism	Decreased selpercatinib plasma concentration and risk of reduced efficacy	Avoid co-administration.	27
Proton-Pump Inhibitors (PPIs)	Increased gastric pH, decreasing selpercatinib dissolution and absorption	Decreased selpercatinib plasma concentration and risk of reduced efficacy	If co-administration is unavoidable, take selpercatinib with food.	26
H2 Receptor Antagonists	Increased gastric pH, decreasing selpercatinib dissolution and absorption	Decreased selpercatinib plasma concentration and risk of reduced efficacy	Separate dosing: take selpercatinib 2 hours before or 10 hours after the H2 antagonist.	26

Regulatory and Health Economic Landscape

The journey of selpercatinib from clinical trial to standard-of-care therapy has involved a rapid and evolving series of regulatory approvals worldwide, alongside complex discussions regarding its cost and value within healthcare systems.

Global Regulatory Approvals: FDA and EMA

• U.S. Food and Drug Administration (FDA) (Retevmo): Selpercatinib has had a notably rapid and successful regulatory path with the FDA, marked by multiple expedited review designations.
• It first received accelerated approval in May 2020 for three indications: RET fusion-positive NSCLC, RET-mutant MTC, and RET fusion-positive thyroid cancer in patients aged 12 and older.[5]
• In September 2022, it gained a tumor-agnostic accelerated approval for adult patients with RET fusion-positive solid tumors that have progressed on prior therapy.[7]
• Based on confirmatory data from randomized trials and long-term follow-up, these accelerated approvals have been progressively converted to traditional (full) approvals: for NSCLC, for RET fusion-positive thyroid cancer (June 2024), and for RET-mutant MTC (September 2024).[14]
• The pediatric indication has also been expanded, with approvals granted in 2024 for children as young as 2 years old for the MTC and thyroid cancer indications.[14]
• European Medicines Agency (EMA) (Retsevmo): The regulatory process in Europe has mirrored that in the U.S., albeit with some differences in the specifics of the approved indications.
• The EMA's Committee for Medicinal Products for Human Use (CHMP) recommended a conditional marketing authorisation in December 2020, which was granted in February 2021.[17]
• The initial European indications were often more specific about the required lines of prior therapy, for example, specifying use after immunotherapy and/or platinum chemotherapy for NSCLC, or after prior treatment with sorafenib and/or lenvatinib for thyroid cancer.[1]
• In March 2024, the CHMP adopted a positive opinion to expand the indications to include first-line treatment of RET fusion-positive NSCLC and the tumor-agnostic indication for RET fusion-positive solid tumors, aligning more closely with the FDA approvals.[41]

Reimbursement and Cost-Effectiveness Considerations

The remarkable clinical benefit of selpercatinib is accompanied by a high acquisition cost, creating a significant challenge for healthcare systems and payers worldwide. This dynamic exemplifies the broader value-cost dilemma in modern precision oncology. While the drug provides substantial and durable responses in patient populations with a clear unmet need, its high price tag leads to a major budget impact.[11]

Health Technology Assessment (HTA) bodies, such as the Canadian Agency for Drugs and Technologies in Health (CADTH), conduct formal evaluations to determine if a drug's added benefit justifies its added cost. In its review, CADTH acknowledged the clinical efficacy of selpercatinib and the unmet need it addresses.[11] However, based on economic modeling, it concluded that the drug was not cost-effective at its list price when compared to best supportive care. Consequently, CADTH recommended reimbursement only under the condition of a substantial price reduction (of at least 89%) to meet standard willingness-to-pay thresholds.[11] This situation highlights the systemic tension between ensuring patient access to innovative, life-prolonging therapies and maintaining the financial sustainability of healthcare systems, a central issue in the global discourse on drug pricing and value.

Clinical Positioning and Comparative Analysis

Selpercatinib's place in the therapeutic armamentarium is defined by its advantages over both older, non-selective inhibitors and its direct competitor, the selective RET inhibitor pralsetinib.

Comparison with Pralsetinib

Selpercatinib and pralsetinib are the two highly selective, next-generation RET inhibitors that have become the standards of care for RET-driven cancers.[4] As there are no head-to-head randomized clinical trials directly comparing the two agents, clinicians must rely on cross-trial comparisons and more sophisticated statistical methods like matching-adjusted indirect comparisons (MAICs) to discern potential differences.

An MAIC was conducted using patient data from the LIBRETTO-001 (selpercatinib) and ARROW (pralsetinib) trials in RET fusion-positive NSCLC.[44]

• Efficacy Comparison: The analysis found that the ORR and disease control rates were broadly similar between the two drugs. However, the MAIC suggested a clinically meaningful and statistically significant advantage in median PFS for selpercatinib (22.1 months) compared to pralsetinib (13.3 months).[44]
• Safety Comparison: The indirect comparison also suggested a more favorable safety profile for selpercatinib. The incidence of Grade ≥3 treatment-related adverse events was notably lower with selpercatinib (39.3%) than with pralsetinib (62.6%). Similarly, the rate of treatment discontinuation due to adverse events was lower for selpercatinib (3.6%) compared to pralsetinib (10.0%).[44] While these data are not from a randomized trial, they suggest potential differences in both long-term efficacy and tolerability that may influence treatment choice in clinical practice.

Table 9: Matching-Adjusted Indirect Comparison of Selpercatinib vs. Pralsetinib in RET Fusion-Positive NSCLC

Endpoint	Selpercatinib (LIBRETTO-001)	Pralsetinib (ARROW)	Hazard Ratio / Odds Ratio (95% CI)	Source(s)
Median PFS	22.1 months	13.3 months	HR = 0.67 (0.53–0.85)	44
Objective Response Rate (ORR)	64.5%	65.8%	OR = 0.94 (0.71-1.24)	44
Grade ≥3 Treatment-Related AEs	39.3%	62.6%	OR = 0.39 (0.29–0.49)	44
Discontinuation due to AEs	3.6%	10.0%	OR = 0.34 (0.14–0.58)	44

Advantages Over Previous-Generation Multi-Kinase Inhibitors

The superiority of selpercatinib over older MKIs like cabozantinib and vandetanib is unequivocal and has been demonstrated through both cross-trial comparisons and direct randomized evidence.

• Superior Efficacy: The ORRs achieved with selpercatinib across its indications (ranging from 61% to 96%) are dramatically higher than the historical rates reported for MKIs in RET-driven cancers. For example, the ORR for cabozantinib in RET-rearranged NSCLC was only 28%.[8] Definitive proof came from the randomized LIBRETTO-531 trial in MTC, which showed a clear PFS superiority for selpercatinib over the MKI control arm.[16]
• Superior Safety and Tolerability: As previously discussed, the high selectivity of selpercatinib for its target kinase results in a much more manageable side effect profile. The broad-spectrum off-target toxicities common with MKIs are largely absent or significantly attenuated with selpercatinib, leading to far fewer treatment discontinuations and allowing for more sustained therapy, which is essential for achieving durable disease control.[9]

Future Perspectives and Conclusion

The development of selpercatinib is an ongoing story, with active research aimed at expanding its role and optimizing its use in patients with RET-altered cancers.

Ongoing Research and Future Applications

The clinical development program for selpercatinib continues to explore its potential in new clinical settings, aiming to further improve outcomes for patients.

• Adjuvant Setting (LIBRETTO-432, NCT04819100): A critical ongoing Phase 3 trial is evaluating the use of selpercatinib as an adjuvant (post-operative) therapy for patients with early-stage (Stage IB-IIIA) RET fusion-positive NSCLC who have undergone definitive surgery or radiation.[46] The goal of this study is to determine if selpercatinib can eliminate microscopic residual disease and reduce the risk of cancer recurrence, potentially increasing the cure rate in this setting. This investigation represents a strategic shift in the drug's lifecycle, moving its application from the palliative treatment of advanced disease toward a curative-intent therapy in earlier stages. A positive result from this trial would be a monumental advance, establishing a new standard of care and fundamentally changing the management of early-stage RET-positive lung cancer.
• Pediatric Cancers (Pediatric MATCH, NCT04320888): A Phase 2 trial sponsored by the National Cancer Institute is specifically studying the efficacy and safety of selpercatinib in pediatric patients with a range of advanced solid tumors, lymphomas, or histiocytic disorders that harbor activating RET alterations. This trial aims to formally expand the evidence base for its use in younger patient populations across a tumor-agnostic landscape.[47]
• Combination Therapies and Re-sensitization (NCT05668962): Innovative trials are exploring novel applications for selpercatinib. One such Phase 2 study is investigating whether treatment with selpercatinib can restore the uptake of radioactive iodine (I-131) in patients with RET fusion-positive thyroid cancer that has become refractory to RAI therapy. If successful, this could re-sensitize tumors to a long-established and effective treatment modality, offering a new therapeutic sequence for these patients.[48]

Concluding Remarks

Selpercatinib is more than just another targeted therapy; it is a definitive success story and a cornerstone of modern precision oncology. Its development and clinical validation have served to firmly establish the RET proto-oncogene as a critical, druggable, pan-tumor target. The introduction of selpercatinib has created a new, highly effective global standard of care for patients with RET-altered NSCLC, MTC, and other thyroid cancers, displacing older, more toxic, and less effective multi-kinase inhibitors.

The narrative of selpercatinib—from its rational design centered on kinase selectivity, to its robust clinical validation in biomarker-defined patient populations, and its demonstration of impressive CNS activity and a manageable safety profile—serves as an exemplar for contemporary targeted drug development. It has fundamentally altered the prognosis for patients whose cancers are driven by RET alterations, transforming a specific genomic finding into a clear and direct path toward a highly effective, well-tolerated, and durable treatment. As ongoing research continues to explore its utility in earlier stages of disease and in novel combinations, the impact of selpercatinib on the lives of patients with cancer is poised to grow even further.

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