Selpercatinib, an inhibitor of multiple receptor tyrosine kinases, including wild-type and mutated rearranged during transfection ( RET ) isoforms, is an antineoplastic agent.1, 3, 6
Selpercatinib is used for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.1 The drug has been designated an orphan drug by FDA for the treatment of this cancer.2
This indication for selpercatinib is based on results for a cohort of 247 adults with advanced or metastatic RET fusion-positive NSCLC previously treated with platinum-based chemotherapy and 69 adults with treatment-naïve locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic RET fusion-positive NSCLC (without prior systemic therapy) in a multicenter, single-arm, open-label, phase 1/2 study (LIBRETTO-001).1, 6, 9 Presence of RET fusion was determined by next generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), or fluorescence in situ hybridization (FISH) or other local testing methods.1, 9 In this study, patients received selpercatinib 160 mg twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase of the study were permitted to adjust their dose to 160 mg twice daily.1, 9 The primary efficacy end points were objective response rate (as evaluated by a blinded independent review committee) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response; a secondary end point was progression-free survival.1, 3, 9 In the previously treated and treatment-naive cohorts, the most common RET fusion was KIF5B-RET and CCDC6 .9
In the previously treated cohort, the median age was 61 years; 90% had adenocarcinoma histology, 57% were female, 44% were white, 48% were Asian, 4.9% were Black, 2.8% were Hispanic/Latino, and 97% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1 Patients had received a median of 2 prior systemic therapies; 58% of patients previously received an anti-programmed-death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) either sequentially or concurrently with platinum-based chemotherapy.1 Most patients (97%) had metastatic disease and 31.2% of patients had CNS metastases at baseline (as assessed by an independent review committee).1, 9 One of the patients with baseline measurable CNS metastases had received prior radiation therapy to the brain within 2 months of study entry.1 The overall response rate in the previously treated cohort was 61%; complete response was achieved in 7.3% of patients.1, 9 At the time of analysis, the median duration of response was 28.6 months and 63% of patients had durable responses of at least 12 months.1, 9 In the subgroup of patients with baseline measurable CNS metastases, intracranial response was achieved in 14 of 16 patients; 39% of responders had an intracranial duration of response of at least 12 months.1, 9
In the treatment-naïve cohort, the median age was 63 years; 62% were female, 70% were white, 19% were Asian, and 6% were Black.1, 9 Ninety-nine percent of patients had metastatic disease and 94% had an ECOG performance status of 0 or 1; 5 patients had measurable CNS metastases at baseline as assessed by a blinded independent review committee and 2 patients received radiation therapy to the brain within 2 months prior to study entry.1 At the time of evaluation, the overall response rate in the treatment-naïve cohort was 84%; complete response was achieved in 5.8% of these patients and a partial response in 78% of patients.1, 9 At the time of analysis, the median duration of response was 20.2 months and 50% of patients had durable responses of at least 12 months.1, 9 Responses for intracranial lesions were observed in 4 of the 5 patients; 38% of responders had an intracranial duration of response of at least 12 months.1
In an open-label, randomized, active-controlled trial, the efficacy of selpercatinib was compared to platinum-based chemotherapy with or without pembrolizumab as first-line therapy for patients with RET fusion-positive NSCLC (LIBRETTO-431).1, 11 The study enrolled adults with pathologically confirmed unresectable stage IIIB, IIIC, or IV nonsquamous NSCLC who had not received prior systemic treatment for metastatic disease, had an ECOG performance status score of 0 to 2, adequate organ function, and the presence of a RET gene fusion.11 A total of 261 patients were randomly assigned to selpercatinib 160 mg orally twice daily in continuous 21-day cycles or pemetrexed 500 mg/m2 of body surface area IV with vitamin supplementation in addition to an investigator's choice of platinum therapy (carboplatin or cisplatin) with or without pembrolizumab 200 mg IV every 21 days.1, 11 Treatment continued until disease progression or unacceptable toxicity and patients were allowed to crossover to the selpercatinib treatment arm from the control if disease progression occurred.1, 11 The primary study end point was progression-free survival; other outcomes included overall survival and overall response rate.1, 11
Of the 261 randomized patients, 212 were included in the intention-to-treat population; the median age of enrolled patients was 61.5 years (range, 31-84 years), 47% were male, 41% white, 55% Asian, and 0.9% Black or African American.1, 11 Detectable RET fusions were apparent in 60% of patients using NGS and 40% using PCR.1 Results from the pre-planned interim efficacy analysis revealed a median progression-free survival of 24.8 months with selpercatinib versus 11.2 months with control therapy.1, 11 The overall response rate was improved with selpercatinib (84% versus 65%).1, 11 Complete responses were seen in 7% and 6% of patients in the selpercatinib and control groups, respectively; partial responses occurred in 77% and 59% of patients in each group.1 The median duration of response was 24.2 months in the selpercatinib group as compared to 11.5 months in the control group.1, 11 Overall survival data were immature at the time of the interim analysis.1, 11
The American Society of Clinical Oncology (ASCO) living guideline for stage IV NSCLC with driver alterations states that for patients with a RET rearrangement, clinicians should offer selpercatinib as a first-line treatment option.10 If selpercatinib is unavailable, then clinicians may offer pralsetinib.10 If neither of these agents are available, clinicians may offer standard therapy following non-driver alteration guidelines.10 In the second-line and subsequent treatment option arena, clinicians should offer selpercatinib or pralsetinib to patients who have not received a RET inhibitor.10 If neither agent is available, clinicians may offer treatment following non-driver alteration guidelines.10
Selpercatinib is used for the treatment of advanced or metastatic medullary thyroid cancer with a RET mutation, as detected by an FDA-approved test, in adults and pediatric patients ≥2 years of age who require systemic therapy.1 The drug also is used for the treatment of advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, in adults and pediatric patients ≥2 years of age who require systemic therapy and are refractory to radioactive iodine (iodine-131) (for those who were candidates for such therapy).1 The drug has been designated an orphan drug by FDA for the treatment of this cancer.2
These indications for selpercatinib are based principally on the results of several cohorts with advanced or metastatic RET mutation-positive medullary thyroid cancer and RET fusion-positive thyroid cancer in a multicenter, single-arm, open-label, phase 1/2, clinical study (LIBRETTO-001).1, 4, 6 Presence of RET aberrations (e.g., mutation, gene fusion) were determined by NGS, RT-PCR, or FISH.1, 4 In this study, patients received selpercatinib 160 mg twice daily; patients in the dose escalation phase of the study received dosages ranging from 20 mg once daily to 240 mg twice daily.4 Therapy was continued until disease progression or unacceptable toxicity occurred.1 The primary efficacy end point was objective response rate (as evaluated by a blinded independent review committee) according to RECIST 1.1; additional efficacy end points were duration of response and progression-free survival.1, 4
The cohort of patients with advanced or metastatic RET mutation-positive medullary thyroid cancer included 55 patients previously treated with cabozantinib or vandetanib and 88 cabozantinib- or vandetanib-naïve patients.1, 4, 6 The most common RET mutation in the cohorts combined was M918T .1, 4 Patients with synonymous, frameshift, or nonsense RET mutations were excluded from the study.1 In the previously treated cohort, the median age of patients was 57 years (range: 17-84 years); 66% were male, 89% were White, 7% were Hispanic/Latino, 1.8% were Black, 98% had metastatic disease, 95% had an ECOG performance status of 0 or 1, and the median number of prior systemic therapies was 2.1, 4 The objective response rate in the previously treated cohort was 76%; complete response was achieved in 18% of patients.1 At the time of analysis, median duration of response was 45.3 months with 76% experiencing a durable response for ≥12 months.1 In the cabozantinib- or vandetanib-naïve cohort, the median age of patients was 58 years (range: 15-82 years); 66% were male, 86% were White, 4.5% were Asian, 2.3% were Hispanic/Latino, 100% had metastatic disease, 97% had an ECOG performance status of 0 or 1, and 18% had received 1 or 2 prior systemic therapies (i.e., tyrosine kinase inhibitors, chemotherapy, anti-PD-1/anti-PD-L1 therapy, radioactive iodine).1, 4 The objective response rate for selpercatinib-treated patients naïve to cabozantinib or vandetanib therapy was 81%; complete response was achieved in 28% of patients.1 At the time of analysis, the median duration of response was not reached and 90% of patients experienced a durable response for ≥12 months.1
The cohort of patients with RET fusion-positive thyroid cancer included 65 adults who were refractory to radioactive iodine therapy (for those who were candidates for such therapy) but naïve to systemic therapy and patients who were previously treated, in separate cohorts.1, 4, 6 In the combined cohorts, the median age of patients was 59 years; 49% were male, 65% were White, 20% were Asian, 11% were Hispanic/Latino, 4.6% were Black, and 94% had an ECOG performance status of 0 or 1.1 All patients had metastatic disease.1 Primary tumor histologies included papillary thyroid cancer (83%), poorly differentiated thyroid cancer (9%), anaplastic thyroid cancer (6%), and Hurthle cell thyroid cancer (1.5%).1 Previously treated patients had received a median of 1 prior therapy (range: 1-4).1 The objective response rate in the previously treated cohort was 85%; complete response was achieved in 12% of patients and partial response was achieved in 73% of patients.1 At the time of analysis, the median duration of response was 26.7 months in the previously treated cohort, 54% experienced a durable response for ≥12 months.1 In the cohort of patients naïve to systemic therapy, the objective response rate was 96%; complete response was achieved in 21% of patients and partial response was achieved in 75% of patients.1 At the time of analysis, the median duration of response was not estimable in this cohort; however, 65% of patients had durable responses of ≥12 months.1
In an open-label, randomized, active-controlled trial, the efficacy of selpercatinib was compared to cabozantinib or vandetanib (physician's choice) in advanced or metastatic RET -mutant medullary thyroid carcinoma (LIBRETTO-531).1, 12 The study enrolled adults and adolescents (≥12 years of age) with pathologically confirmed unresectable locally advanced or metastatic medullary thyroid cancer without a history of kinase inhibitor therapy, radiologic progressive disease at screening, and a confirmed pathogenic RET alteration.12 A total of 291 patients were randomly assigned in a 2:1 ratio to selpercatinib 160 mg orally twice daily or the physician's choice of cabozantinib 140 mg orally once daily or vandetanib 300 mg orally once daily.1, 12 Treatment continued until disease progression or unacceptable toxicity.1, 12 The primary study end point was progression-free survival.1, 12
The median age of enrolled patients was 55 years (range, 12-84 years), 63% were male, 58% white, 23% Asian, and 2.4% Black or African American.1 Detectable RET fusions were apparent in 90% of patients using NGS and 10% using PCR.1 Results from the pre-planned interim efficacy analysis revealed that the median progression-free survival was not reached in the selpercatinib group and was 16.8 months in the control group.1, 12 The overall response rate was improved with selpercatinib (69% versus 39%).1, 12 Complete responses were seen in 12% and 4% of patients in the selpercatinib and control groups, respectively; partial responses occurred in 58% and 35% of patients in each group.1, 12 The median duration of response was not reached in the selpercatinib group and was 16.6 months in the control group.1 The median follow-up time was 11.1 months in the selpercatinib group versus 12.8 months in the control group.1
Selpercatinib is indicated for the treatment of adults and pediatric patients ≥2 years of age with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.1 The accelerated approval of selpercatinib for this indication is based on overall response rate and duration of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of selpercatinib in confirmatory studies.1 The drug has been designated an orphan drug by FDA for the treatment of this type of cancer.2
The current indication for selpercatinib in patients with locally advanced or metastatic RET fusion-positive solid tumors was evaluated in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001).1 Efficacy was evaluated in 41 patients with RET fusion-positive tumors, other than NSCLC and thyroid cancer, with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options.1 In the combined cohorts, the median age was 50 years (range 21 to 85), 54% were female, 68% were white, 24% were Asian, 7% were Hispanic/Latino, and 4.9% were Black.1 In this clinical trial, 95% of patients had metastatic disease and 90% of patients received prior systemic therapy (median 2 [range 0 - 9]; 32% received 3 or more).1 The most common primary tumors included were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%), and unknown primary (7%).1
At the time of analysis, the overall response rate was 44%; 4.9% of patients were determined to have a complete response and 39% were determined to have a partial response.1 The median duration of response was 24.5 months; 67% of patients had durable responses of at lest 6 months.1 Specific overall response rates by tumor type were pancreatic adenocarcinoma (55%), colorectal (20%), salivary (50%) and unknown primary (33%).1
Selpercatinib is administered as capsules or tablets without regard to meals unless taken with an acid-reducing agent (i.e., proton pump inhibitor, histamine H2-receptor antagonist, antacid).1 If concomitant use of a proton-pump inhibitor cannot be avoided, selpercatinib should be taken with food.1 If concomitant use of a histamine H2-receptor antagonist cannot be avoided, selpercatinib should be administered 2 hours before or 10 hours after administration of the histamine H2-receptor antagonist.1 If concomitant use of an antacid cannot be avoided, selpercatinib should be administered 2 hours before or 2 hours after administration of the antacid.1
The capsules and tablets should be swallowed whole and should not be crushed or chewed.1 The capsules should not be administered to pediatric patients who are unable to swallow a capsule.1
If a dose of selpercatinib is missed, the missed dose should be taken as soon as it is remembered unless the next dose is due within 6 hours.1 If a dose is vomited following administration, an additional dose should not be administered to make up for the vomited dose and the next dose should be taken at the regularly scheduled time.1
Selpercatinib capsules and tablets should be stored at 20-25°C, with excursions permitted between 15-30ºC.1
The recommended dosage of selpercatinib for the treatment of metastatic RET gene fusion-positive non-small cell lung cancer (NSCLC) in adults weighing at least 50 kg is 160 mg twice daily.1 In adults weighing less than 50 kg , the recommended dosage is 120 mg twice daily.1
Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of advanced or metastatic RET mutation-positive medullary thyroid cancer, the recommended dosage of selpercatinib is 160 mg twice daily in adults and adolescents ≥12 years of age or older weighing at least 50 kg .1 In adults and adolescents ≥12 years of age weighing less than 50 kg , the recommended dosage is 120 mg twice daily.1
The recommended dosage of selpercatinib for the treatment of metastatic RET mutation-positive medullary thyroid cancer in pediatric patients 2 to <12 years of age is based on body surface area (BSA).1 For patients with a BSA of 0.33 to 0.65 m2, the recommended dosage is 40 mg three times daily.1 For those with a BSA of 0.66 to 1.08 m2, the recommended dosage is 80 mg twice daily.1 For those with a BSA of 1.09 to 1.52 m2, the recommended dosage is 120 mg twice daily and for those with a BSA ≥1.53 m2, the recommended dosage is 160 mg twice daily.1 Dosing pediatric patients with a BSA <0.33 m2 is not recommended.1
Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of advanced or metastatic RET gene fusion-positive thyroid cancer in patients who require systemic therapy and are refractory to radioactive iodine (iodine-131) therapy (for those who were candidates for such therapy), the recommended dosage of selpercatinib is 160 mg twice daily in adults and adolescents ≥12 years of age weighing at least 50 kg .1 In adults and adolescents ≥12 years of age weighing less than 50 kg , the recommended dosage is 120 mg twice daily.1
The recommended dosage of selpercatinib for the treatment of advanced or metastatic RET gene fusion-positive thyroid cancer in pediatric patients 2 to <12 years of age is based on body surface area (BSA).1 For patients with a BSA of 0.33 to 0.65 m2, the recommended dosage is 40 mg three times daily.1 For those with a BSA of 0.66 to 1.08 m2, the recommended dosage is 80 mg twice daily.1 For those with a BSA of 1.09 to 1.52 m2, the recommended dosage is 120 mg twice daily and for those with a BSA ≥1.53 m2, the recommended dosage is 160 mg twice daily.1 Dosing pediatric patients with a BSA <0.33 m2 is not recommended.1
Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of locally advanced or metastatic solid tumors with a RET gene fusion, the recommended dosage of selpercatinib is 160 mg twice daily in adults and adolescents ≥12 years of age weighing at least 50 kg .1 In adults and adolescents ≥12 years of age weighing less than 50 kg , the recommended dosage is 120 mg twice daily.1
The recommended dosage of selpercatinib for the treatment of locally advanced or metastatic solid tumors with a RET gene fusion in pediatric patients 2 to <12 years of age is based on body surface area (BSA).1 For patients with a BSA of 0.33 to 0.65 m2, the recommended dosage is 40 mg three times daily.1 For those with a BSA of 0.66 to 1.08 m2, the recommended dosage is 80 mg twice daily.1 For those with a BSA of 1.09 to 1.52 m2, the recommended dosage is 120 mg twice daily and for those with a BSA ≥1.53 m2, the recommended dosage is 160 mg twice daily.1 Dosing pediatric patients with a BSA <0.33 m2 is not recommended.1
Therapy should be continued until disease progression or unacceptable toxicity occurs.1
If adverse reactions occur during selpercatinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of selpercatinib should be reduced as described in Table 1.1 Selpercatinib should be permanently discontinued in patients who cannot tolerate three dose reductions.1
Current Dosage | First Dose Reduction | Second Dose Reduction | Third Dose Reduction |
|---|---|---|---|
40 mg three times daily | 40 mg twice daily | 40 mg once daily | Permanently discontinue |
80 mg twice daily | 40 mg twice daily | 40 mg once daily | Permanently discontinue |
120 mg twice daily | 80 mg twice daily | 40 mg twice daily | 40 mg once daily |
160 mg twice daily | 120 mg twice daily | 80 mg twice daily | 40 mg twice daily |
The following table (Table 2) indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.1
Adverse Reaction and Severity | Modification |
|---|---|
Hepatotoxicity (Grade 3 or 4) | Withhold therapy and monitor AST and ALT concentrations once weekly When the toxicity resolves to baseline or grade 1, resume at a dosage reduced by 2 dose levels (see Table 1) and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of grade 3 or 4 increased AST or ALT Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence |
Interstitial Lung Disease (ILD)/Pneumonitis (Grade 2) | Withhold therapy until resolution, then resume at a reduced dose.1 Discontinue therapy for recurrent ILD/pneumonitis.1 |
Interstitial Lung Disease (ILD)/Pneumonitis (Grade 3 or 4) | Discontinue therapy for confirmed ILD/pneumonitis.1 |
Hypertension (Grade 3) | Withhold therapy if grade 3 hypertension occurs despite optimal antihypertensive therapy When hypertension is controlled, resume at reduced dosage (see Table 1) |
Hypertension (Grade 4) | Discontinue therapy |
Prolongation of QT Interval (Grade 3) | Withhold therapy; when toxicity improves to baseline or grade 1 or less, resume at reduced dosage (see Table 1) or discontinue therapy |
Prolongation of QT Interval (Grade 4) | Discontinue therapy |
Hemorrhagic Events (Grade 3 or 4) | Withhold therapy until toxicity improves to baseline or grade 1 or less If severe or life-threatening hemorrhagic events occur, permanently discontinue therapy |
Hypersensitivity Reactions (All grades) | Withhold therapy and initiate corticosteroid therapy When the reaction has resolved, resume at a dosage reduced by 3 dose levels (see Table 1) and then increase dosage by 1 dose level in 1-week intervals until the dosage used prior to onset of the reaction is reached Taper corticosteroid therapy when dosage returns to dosage used prior to onset of the reaction If hypersensitivity reactions recur, permanently discontinue therapy |
Hypothyroidism (Grade 3 or 4) | Withold therapy until toxicity improves to baseline or grade 1.1 Discontinue therapy based on severity.1 |
Other Toxicity (Grade 3 or 4) | Withhold therapy until toxicity improves to baseline or grade 1 or less; resume at reduced dosage (see Table 1) |
Concomitant Use with CYP3A Inhibitors
Concomitant use of selpercatinib with moderate and strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided; if concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of selpercatinib as described in Table 3.1 When concomitant use of the moderate or strong CYP3A inhibitor is discontinued, the selpercatinib dosage should be returned (after 3-5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the moderate or strong CYP3A inhibitor.1
Current Dosage | Recommended Dosage when Used with a Moderate CYP3A Inhibitor | Recommended when Used with a Strong CYP3A Inhibitor |
|---|---|---|
40 mg three times daily | 40 mg once daily | 40 mg once daily |
80 mg twice daily | 40 mg twice daily | 40 mg twice daily |
120 mg twice daily | 80 mg twice daily | 40 mg twice daily |
160 mg twice daily | 120 mg twice daily | 80 mg twice daily |
For patients with severe hepatic impairment (total bilirubin concentration exceeding 3-10 times the upper limit of normal [ULN] with any AST concentration), the manufacturer recommends a selpercatinib dosage of 80 mg twice daily for those patients currently receiving 120 mg or 160 mg twice daily and a selpercatinib dosage of 40 mg twice daily for those patients currently receiving 40 mg three times daily or 80 mg twice daily.1
No dosage adjustment is necessary in patients with mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN with any AST concentration) or moderate (total bilirubin concentration exceeding 1.5-3 times the ULN with any AST concentration) hepatic impairment.1
Because of the possibility of an increased risk of adverse reactions, monitor patients with hepatic impairment for signs of selpercatinib toxicity.1
No dosage adjustment is necessary in patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] of 15-89 mL/minute).1
The manufacturer makes no specific dosage recommendations for patients with end-stage renal disease.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious hepatic adverse reactions have been reported in 3% of patients receiving selpercatinib.1 In a pooled safety population, elevations in AST or ALT concentrations occurred in 59 or 55% of patients, respectively, and were grade 3-4 in 11 or 12% of patients, respectively.1 The median time to initial onset of elevated AST or ALT concentrations was 6 or 5.8 weeks, respectively.1
Liver function tests (i.e., ALT and AST concentrations) should be evaluated prior to initiation of therapy and monitored every 2 weeks for the first 3 months of therapy, monthly thereafter, and as clinically indicated.1 Temporary interruption of selpercatinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary if hepatotoxicity occurs during therapy with the drug.1
Interstitial Lung Disease/Pneumonitis
Serious, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis has been reported in patients receiving selpercatinib.1 ILD/pneumonitis occurred in 1.8% of patients who received selpercatinib, including 0.3% with grade 3 or 4 events, and 0.3% with fatal reactions.1
Monitor for pulmonary symptoms indicative of ILD/pneumonitis.1 Withhold selpercatinib and promptly evaluate for ILD in any patient who presents with acute or worsening of respiratory symptoms (e.g., dyspnea, cough, and fever).1 Withhold, reduce dose, or permanently discontinue selpercatinib based on severity of confirmed ILD.1
Hypertension has been reported in patients receiving selpercatinib.1 In a pooled safety population, hypertension occurred in 41% of patients receiving selpercatinib and was grade 3 in 20% and grade 4 in 0.1% of patients.1 Temporary interruption or dosage reduction was necessary because of hypertension in 6.3 or 1.3%, respectively, of patients receiving the drug.1 Treatment-emergent hypertension was most commonly managed with antihypertensive therapy.1
Blood pressure should be assessed and controlled prior to initiating selpercatinib therapy; the drug should not be initiated in patients with uncontrolled hypertension.1 Blood pressure should be monitored after 1 week of selpercatinib therapy, at least monthly thereafter, and as clinically indicated.1 If hypertension occurs, antihypertensive therapy should be initiated or adjusted as needed to control blood pressure during therapy.1 Temporary interruption of selpercatinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary if hypertension occurs during therapy with the drug.1
Selpercatinib prolongs the QT interval in a concentration-dependent manner.1 At the mean steady-state peak plasma concentration attained with a selpercatinib dosage of 160 mg twice daily in healthy subjects, the largest mean increase in QTc interval is expected to be 10.6 msec.1 In clinical trials, an increase in QT intervals (corrected for heart rate using Fridericia's formula [QTcF]) exceeding 500 msec occurred in 7% of selpercatinib-treated patients, and an increase in the QTcF interval of 60 msec or more from baseline occurred in 20% of patients.1, 6 Selpercatinib has not been studied in patients with clinically important active cardiovascular disease or recent myocardial infarction.1
Patients with risk factors for developing QTc interval prolongation (e.g., long QT syndromes, clinically important bradyarrhythmia, and severe or uncontrolled heart failure) should be monitored.1 QT interval, electrolyte concentrations, and thyroid stimulating hormone (TSH) concentrations should be assessed at baseline and monitored periodically during therapy; frequency of monitoring should be adjusted based upon risk factors (including diarrhea).1 Monitoring of the QT interval should occur more frequently in patients receiving concomitant drugs known to prolong the QTc interval or potent or moderate CYP3A inhibitors.1 Electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia) should be corrected prior to initiation of and during selpercatinib therapy.1 Temporary interruption of selpercatinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary if QTc interval prolongation occurs during therapy with the drug.1
Serious, sometimes fatal, hemorrhagic events have been reported in patients receiving selpercatinib.1 Grade 3 or greater hemorrhagic events have been reported in 3.1% of patients receiving selpercatinib, including 4 fatal events (i.e., cerebral hemorrhage, tracheostomy site hemorrhage, hemoptysis).1
If a grade 3 or 4 hemorrhagic event occurs, temporarily interrupt selpercatinib therapy until the hemorrhagic event improves to baseline or grade 1.1 If a severe or life-threatening hemorrhagic event occurs, selpercatinib therapy should be permanently discontinued.1
Hypersensitivity reactions have been reported in 6% of patients receiving selpercatinib and was grade 3 in 1.9% of patients.1 The median time to onset of hypersensitivity was 1.9 weeks (range: 5 days to 2 years).1 Signs and symptoms of hypersensitivity reactions included fever, rash, and arthralgia or myalgia with concurrent decreased platelet counts or elevated aminotransferase concentrations.1
If a hypersensitivity reaction occurs, selpercatinib therapy should be withheld until the reaction resolves, and corticosteroid therapy should be initiated (1 mg/kg of prednisone [or equivalent]).1 Once the hypersensitivity reaction has resolved, selpercatinib therapy should be resumed at a reduced dosage followed by a gradual increase (by 1 dose level each week) to the dosage used prior to onset of the hypersensitivity reaction; the corticosteroid dosage should be tapered once the target selpercatinib dosage has been reached.1 If recurrent hypersensitivity reactions occur, selpercatinib therapy should be permanently discontinued.1
Tumor lysis syndrome has been reported in 0.6% of patients with medullary thyroid carcinoma receiving selpercatinib.1 The risk of tumor lysis syndrome is increased in patients with rapidly growing tumors, high tumor burden, renal dysfunction, or dehydration.1 Patients at risk for tumor lysis syndrome (e.g., high tumor burden, rapidly growing tumors, renal dysfunction, dehydration) should be monitored closely and appropriate prophylaxis (e.g., adequate hydration) should be considered.1 If tumor lysis syndrome occurs, appropriate treatment should be initiated as clinically indicated.1
Inhibitors of vascular endothelial growth factor (VEGF) signaling pathway, such as selpercatinib, may impair wound healing.1
The manufacturer recommends temporary interruption of selpercatinib therapy for at least 7 days prior to elective surgery.1 The drug should not be administered for at least 2 weeks following major surgery; selpercatinib therapy should not be resumed postoperative until adequate wound healing has occurred.1 Safety of resuming selpercatinib therapy following resolution of wound healing complications has not been established.1
Hypothyroidism has been reported in 13% of patients receiving selpercatinib; all reported reactions were Grade 1 or 2.1 Hypothyroidism occurred in 13% of patients with thyroid cancer and 13% of patients with other solid tumors including NSCLC.1
Monitor thyroid function before treatment with selpercatinib and periodically during treatment.1 Treat with thyroid hormone replacement as clinically indicated.1 Withhold selpercatinib until clinically stable or permanently discontinue selpercatinib based on severity.1
Fetal/Neonatal Morbidity and Mortality
Selpercatinib may cause fetal harm if administered to pregnant women; embryotoxicity and malformations have been demonstrated in animals.1 There are no available data regarding use of selpercatinib in pregnant women to inform a drug-associated risk.1 In animal reproduction studies, embryotoxicity (i.e., postimplantation loss, early resorption, decreased fetal body weight) and teratogenicity (i.e., short tail, small snout, localized edema of the neck and thorax) were observed in pregnant rats receiving selpercatinib at exposure levels approximately less than or equal to the human exposure at the 160 mg twice daily dosage.1
Pregnancy should be avoided during selpercatinib therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of selpercatinib therapy in females of reproductive potential and states that such females should be advised to use effective contraceptive methods while receiving selpercatinib and for at least 1 week after the final dose.1 Males who are partners of such females should use effective methods of contraception while receiving selpercatinib and for at least 1 week after the final dose.1 Patients should be apprised of the potential hazard to the fetus if selpercatinib is used during pregnancy.1
Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients
Slipped capital femoral epiphysis/slipped upper femoral epiphysis occurred in 2 adolescents in clinical trials involving selpercatinib.1 Patients should be monitored for symptoms indicative of slipped capital femoral epiphysis/slipped upper femoral epiphysis and treated appropriately.1
Selpercatinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
Pregnancy should be avoided during selpercatinib therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of selpercatinib therapy in females of reproductive potential and states that such females should be advised to use effective contraceptive methods while receiving selpercatinib and for at least 1 week after the final dose.1 Males who are partners of such females should use effective methods of contraception while receiving selpercatinib and for at least 1 week after the final dose.1 Patients should be apprised of the potential hazard to the fetus if selpercatinib is used during pregnancy.1
It is not known whether selpercatinib or its metabolites are distributed into human milk.1 The effects of the drug on nursing infants or on the production of milk are unknown.1 Because of the potential for adverse reactions to selpercatinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 1 week after the final dose.1
Females and Males of Reproductive Potential
A pregnancy test should be performed prior to initiation of selpercatinib therapy in females of reproductive potential and such females should be advised to use effective contraceptive methods while receiving selpercatinib and for at least 1 week after the final dose.1 Males who are partners of such females should use effective methods of contraception while receiving selpercatinib and for at least 1 week after the final dose.1
Results of animal studies suggest that selpercatinib may impair male and female fertility.1
Safety and efficacy of selpercatinib for advanced or metastatic medullary thyroid cancer with a RET mutation, advanced or metastatic thyroid cancer with a RET gene fusion (requiring systemic therapy and radioactive iodine-refractory), and locally advanced or metastatic solid tumors with a RET gene fusion that have progressed or who have no satisfactory alternative treatment options are supported by evidence from adequate and well-controlled studies in adults and pediatric patients with additional pharmacokinetic and safety data in pediatric patients ≥2 years of age.1 The LIBRETTO-121 trial specifically evaluated the efficacy of selpercatinib in a limited number of pediatric and young adult patients with advanced RET -activated solid tumors.1 Safety and efficacy have not been established in pediatric patients <2 years of age.
Skeletal (i.e., physeal hypertrophy) abnormalities that were not reversible have been observed in immature animals (equivalent to a human child to late adolescent) receiving selpercatinib at exposure levels equivalent to or greater than the human exposure at the 160 mg twice daily dosage.1, 6 Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density.1 Other abnormalities noted in animal studies include reversible hypocellularity of bone marrow in males at ≥30 mg/kg (approximately equivalent to or greater than the adult human exposure at the 160 mg twice daily dosage), and reversible alterations of dentin composition at ≥50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily).1
The manufacturer recommends monitoring growth plates in pediatric patients with open growth plates.1 If growth plate abnormalities occur, interruption or discontinuance of therapy should be considered based on the severity of the abnormality and individual risk-benefit assessment.1
In pediatric patients 6 months to 21 years of age enrolled in a clinical trial evaluating selpercatinib in advanced solid or primary CNS tumors† harboring an activating RET aberration (LOXO-RET-18036; NCT03899792), growth plate monitoring, dental examinations, and physical development (i.e., Tanner staging) were assessed.6, 7
In clinical studies, 34% of 796 selpercatinib-treated patients were 65 years of age or older, while 9% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric patients and younger adults.1
In patients with mild, moderate, or severe hepatic impairment, AUC of selpercatinib increased by 1.1-, 1.3-, or 1.8-fold, respectively, compared with individuals with normal hepatic function.1
For patients with severe hepatic impairment (total bilirubin concentration exceeding 3-10 times the upper limit of normal [ULN] with any AST concentration), the manufacturer recommends to reduce the selpercatinib dosage.1
Because of the possibility of an increased risk of adverse reactions, monitor patients with hepatic impairment for signs of selpercatinib toxicity.1
In a population pharmacokinetic analysis, mild, moderate, or severe renal impairment did not have clinically important effects on the pharmacokinetics of selpercatinib.1 No dosage adjustment is necessary in patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] of 15-89 mL/minute).1
The pharmacokinetic profile of selpercatinib has not been established in patients with end-stage renal disease.1
Selpercatinib has been shown to increase serum creatinine concentrations.1 Selpercatinib decreases tubular secretion of creatinine by inhibiting multidrug and toxin extrusion transporter (MATE) 1.1 Serum creatinine concentrations increased by 18% after 10 days in healthy individuals who received selpercatinib 160 mg twice daily.1 The manufacturer states that parameters other than serum creatinine should be considered to evaluate renal function if elevated concentrations of serum creatinine persist.1
The most common adverse reactions (≥25%) of adult patients with solid tumors receiving selpercatinib include edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.1 For pediatric patients with solid tumors receiving selpercatinib, the most common adverse reactions include musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage.1
Selpercatinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1 Selpercatinib is a moderate inhibitor of CYP2C8 and a weak inhibitor of CYP3A.1 In vitro, selpercatinib does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 2D6 at clinically important concentrations.1
In vitro studies indicate that selpercatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, and MATE2K.1 In vitro, selpercatinib inhibits MATE1, P-gp, and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, bile salt export pump (BSEP), and MATE2K.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of selpercatinib with moderate or strong inhibitors of CYP3A may result in increased systemic exposure of selpercatinib and increased incidence of adverse effects (e.g., QTc-interval prolongation).1 When the strong CYP3A inhibitor itraconazole (200 mg once daily for 7 days) was administered concomitantly with selpercatinib in healthy individuals, the area under the concentration-time curve (AUC) or peak plasma concentration of selpercatinib (160 mg twice daily for 24 days) increased by 2.3-fold or 1.3-fold, respectively.1, 6 Simulations using physiologically based pharmacokinetic models suggest that the moderate CYP3A inhibitors diltiazem, fluconazole, and verapamil may increase AUC or peak plasma concentration of selpercatinib by 1.6 to 2-fold or 1.5 to 1.8-fold, respectively.1, 6
Concomitant use of selpercatinib with moderate and strong inhibitors of CYP3A should be avoided.1 If concomitant use of a moderate or strong CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of selpercatinib .1 When concomitant use of the moderate or strong CYP3A inhibitor is discontinued, the selpercatinib dosage should be returned (after 3-5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the moderate or potent CYP3A inhibitor.1
Concomitant use of selpercatinib with moderate or strong inducers of CYP3A may result in decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy.1 When the strong CYP3A inducer rifampin (600 mg once daily) was administered concomitantly with selpercatinib in healthy individuals, AUC or peak plasma concentration of selpercatinib (160 mg twice daily for 24 days) decreased by 87 or 70%, respectively.1, 6 Simulations using physiologically based pharmacokinetic models suggest that the moderate CYP3A inducers bosentan and efavirenz may decrease AUC or peak plasma concentration of selpercatinib by 40-70 or 34-57%, respectively.1, 6 Simulations using physiologically based pharmacokinetic models also suggest that the weak CYP3A inducer modafinil may decrease AUC or peak plasma concentration of selpercatinib by 33 or 26%, respectively.1, 6
Concomitant use of selpercatinib with moderate and strong inducers of CYP3A should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of selpercatinib with CYP2C8 and 3A substrates may result in increased systemic exposure to the CYP2C8 or 3A substrate and increased incidence of adverse effects of the substrate drug.1 When the sensitive CYP2C8 substrate repaglinide (single 0.5-mg dose) was administered concomitantly with selpercatinib (160 mg twice daily for 10 days) in healthy individuals, AUC or peak plasma concentration of repaglinide increased by 2.9-fold and 1.9-fold, respectively.1, 6 When the sensitive CYP3A substrate midazolam (single 2-mg dose) was administered concomitantly with selpercatinib (160 mg twice daily for 10 days), AUC or peak plasma concentration of midazolam increased by 1.5-fold and 1.4-fold, respectively.1, 6
Concomitant use of selpercatinib with CYP2C8 or CYP3A substrates that have a narrow therapeutic index should be avoided.1 If concomitant use of CYP2C8 or CYP3A substrates that have a narrow therapeutic index cannot be avoided, the dosage of the CYP2C8 or 3A substrate should be adjusted as appropriate.1
Concomitant use of selpercatinib with P-gp or BCRP substrates may increase plasma concentrations of the substrate drug, increasing the risk of adverse effects.1 Coadministration of selpercatinib with dabigatran (P-gp substrate) increased the dabigatran AUC by 1.4-fold and peak plasma concentration by 1.4-fold.1 Coadministration of selpercatinib with rosuvastatin (BCRP substrate) increased the rosuvastatin AUC by 1.9-fold and peak plasma concentration by 1.7-fold.1 Avoid concomitant use of selpercatinib with P-gp or BCRP substrates with a narrow therapeutic index.1 If concomitant use cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.1
Drugs Affecting Gastric Acidity
Concomitant use of selpercatinib with drugs that reduce gastric acidity may result in decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy.1 When the proton-pump inhibitor omeprazole was administered concomitantly with selpercatinib (single-160 mg dose) in a fasted state, AUC and peak plasma concentrations of selpercatinib decreased by 69 and 88%, respectively.1, 6 Concomitant administration of selpercatinib (single-160 mg dose) and omeprazole with food (high- or low-fat meal) does not significantly change systemic exposure of selpercatinib.1, 6
Avoid concomitant use of selpercatinib with proton-pump inhibitors.1 If concomitant use of a proton-pump inhibitor cannot be avoided, selpercatinib should be taken with food.1
Histamine H2-receptor Antagonist
Concomitant use of selpercatinib with drugs that reduce gastric acidity may result in decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy.1 Concomitant administration of the histamine H2-receptor antagonist ranitidine (not commercially available in the US) 10 hours before or 2 hours after selpercatinib (single-160 mg dose) in a fasted state did not result in clinically important changes in pharmacokinetics of selpercatinib.1, 6
Avoid concomitant use of selpercatinib with histamine H2-receptor antagonists.1 If concomitant use of a histamine H2-receptor antagonist cannot be avoided, selpercatinib should be administered 2 hours before or 10 hours after administration of the histamine H2-receptor antagonist.1
Concomitant use of selpercatinib with drugs that reduce gastric acidity may result in decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy.1 Avoid concomitant use of selpercatinib with antacids.1 If concomitant use of an antacid cannot be avoided, selpercatinib should be administered 2 hours before or 2 hours after administration of the antacid.1
Drugs that Prolong the QT Interval
Selpercatinib is associated with concentration-dependent QT interval prolongation.1
If a drug known to prolong the QT interval must be used concomitantly with selpercatinib, more frequent ECG monitoring is recommended.1
When selpercatinib was coadministered with metformin (a MATE1 substrate), no clinically important changes on blood glucose concentrations were observed.1
Concomitant administration of repeated doses of rifampin (a potent CYP3A inducer) with selpercatinib decreased AUC and peak plasma concentration of selpercatinib by 87 and 70%, respectively.1
Concomitant administration of a single dose of rifampin (a P-gp inhibitor) with selpercatinib did not result in clinically important changes in pharmacokinetics of selpercatinib.1
Concomitant use of selpercatinib and rifampin should be avoided.1
Selpercatinib, an inhibitor of multiple receptor tyrosine kinases, including wild-type and mutated rearranged during transfection ( RET ) isoforms, is an antineoplastic agent.1, 3, 6 RET is a receptor tyrosine kinase (RTK) involved in the initiation of various cascades of intracellular signaling events (i.e., MAPK, PI3K, JAK-STAT, Pka, Pkc signal transduction pathways) which leads to cell proliferation critical to development of the enteric nervous system and kidney.1 Postnatally, RET contributes to the maintenance of neural, neuroendocrine, hematopoietic, and male germ cell tissues.6 Genomic aberrations in RET have been implicated in the pathogenesis of several human cancers.6 Chromosomal rearrangements involving in-frame fusions of RET with various partners or point or insertion-deletion (indel) mutations can result in constitutively activated chimeric RET fusion proteins that act as oncogenic drivers by promoting cell proliferation of tumor cell lines.1, 3, 6 In enzyme assays, selpercatinib has demonstrated inhibition of wild-type RET and several mutated RET isoforms (e.g., RET-V804L , RET-V804M , RET-A883F , RET-S904F , RET-M918T ).1, 6 In cellular assays, selpercatinib demonstrated inhibition of vascular endothelial growth factor receptor (VEGFR) 3 or fibroblast growth factor receptor (FGFR) 1 and FGFR2 at concentrations approximately 60- or 8-fold, respectively, higher than the inhibitory concentration for RET.1
The capsule and tablet dosage forms of selpercatinib are bioequivalent.1 Following administration of selpercatinib capsules, peak plasma concentrations and systemic exposure to selpercatinib increase in a slightly greater than dose-proportional manner over a dosage range of 20 mg once daily to 240 mg twice daily.1 The mean absolute bioavailability of selpercatinib capsules following oral administration is 73%.1, 6 Following administration of selpercatinib 160 mg twice daily, peak plasma concentrations of the drug are achieved in a median of 2 hours.1 Following repeated administration of twice-daily dosing, steady-state concentrations of selpercatinib are attained in approximately 7 days, with a median accumulation ratio of 3.4-fold.1 Administration of selpercatinib capsules or tablets with a high-fat meal resulted in no clinically significant differences in AUC or maximum serum concentration.1, 6 In vitro, selpercatinib is 96% bound to plasma proteins, and binding is independent of selpercatinib concentration.1 Selpercatinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1 Following oral administration of a single radiolabeled 160-mg dose of selpercatinib, 69% of the dose is recovered in feces (14% as unchanged drug) and 24% of the dose is recovered in urine (12% as unchanged drug).1 The mean elimination half-life of selpercatinib is 32 hours.1 Apparent volume of distribution and clearance of selpercatinib increases with increasing body weight (27-177 kg).1
The pharmacokinetics of selpercatinib are not affected by age (15-90 years of age) and sex.1 Selpercatinib exposure in pediatric patients is predicted to be comparable to adults administered recommended dosages.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Selpercatinib can be obtained only through designated specialty pharmacies and distributors.5 Contact manufacturer for additional information.1
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 40 mg | Retevmo® | Eli Lilly and Company |
80 mg | Retevmo® | Eli Lilly and Company | ||
Tablets | 40 mg | Retevmo® | ||
80 mg | Retevmo® | |||
120 mg | Retevmo® | |||
160 mg | Retevmo® |
1. Lilly USA, LLC. Retevmo® (selpercatinib) capsules prescribing information. Indianapolis, IN; 2024 Dec.
2. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Nov. [Web]
3. Drilon A, Oxnard GR, Tan DSW et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med . 2020; 383:813-824. [PubMed 32846060]
4. Wirth LJ, Sherman E, Robinson B et al. Efficacy of Selpercatinib in RET -Altered Thyroid Cancers. N Engl J Med . 2020; 383:825-835. [PubMed 32846061]
5. Lilly USA, LLC. Retevmo® (selpercatinib) specialty pharmacy network. From Lilly for US Healthcare Providers website. Accessed 2024 Nov 19. [Web]
6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 213246Orig1s000: Multi-discipline review. From FDA website. [Web]
7. A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors (LIBRETTO-121). From ClinicalTrials.gov registry.
9. Drilon A, Subbiah V, Gautschi O, et al. Selpercatinib in Patients With RETFusion-Positive Non-Small-Cell Lung Cancer:Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial. J Clin Oncol. 2022; 41:385-94.
10. Jaiyesimi I, Leighl NB, Ismaila N, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3. J Clin Oncol 2024; 42:e1-e22.
11. Zhou C, Solomon B, Loong HH, et al. for the LIBRETTO-431 trial investigators. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med . 2023;389:1839-1850.
12. Hadoux J, Elisei R, Brose MS, et al. for the LIBRETTO-531 trial investigators. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med . 2023;389:1851-61.