RETEVMO ® is a kinase inhibitor indicated for the treatment of: Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test ( 1.1 ) Adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy ( 1.2 ) Adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) ( 1.3 ) Adult and pediatric patients 2 years of age and older 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 ( 1.4 ) 1 This indication is approved under accelerated approval based on overall response rate and duration of response.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
1.1RET Fusion-Positive Non-Small Cell Lung Cancer
RETEVMO ® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.
1.2 RET -Mutant Medullary Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.
1.3RET Fusion-Positive Thyroid Cancer
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older 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. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.4 )] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Contraindications
None. None. ( 4 )
Warnings and precautions
Hepatotoxicity : Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms. Withhold, reduce the dose or permanently discontinue RETEVMO based on severity.
( 2.5 , 5.2 ) Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.3 ) QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation.
Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.4 ) Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage.
( 2.5 , 5.5 ) Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at a reduced dose and increase dose by 1 dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. ( 2.5 , 5.6 ) Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. ( 5.7 ) Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days prior to elective surgery.
Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. ( 5.8 ) Hypothyroidism: Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Withhold until clinically stable or permanently discontinue based on severity. ( 5.9 ) Embryo-Fetal Toxicity: Can cause fetal harm.
Advise females of reproductive potential of the possible risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis (SCFE/SUFE) in Pediatric Patients: Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate ( 5.11 , 6.1 )
5.1Hepatotoxicity
Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12% [see Adverse Reactions ( 6.1 )] . The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 years).
Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration ( 2.5 )] .
5.2Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever).
Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD [ see Dosage and Administration ( 2.5 ) ].
5.3Hypertension
Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions ( 6.1 )] . Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO.
Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity [see Dosage and Administration ( 2.5 )] .
5.4QT Interval Prolongation
RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology ( 12.2 )] . An increase in QTcF interval to >500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients [see Adverse Reactions ( 6.1 )] . RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction.
Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating RETEVMO and during treatment.
Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration ( 2.5 )] .
5.5Hemorrhagic Events
Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1). Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Dosage and Administration ( 2.5 )] .
5.6Hypersensitivity
RETEVMO can cause hypersensitivity, including severe skin reactions such as Stevens Johnson Syndrome. All grade hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 in 1.9%. The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. Stevens Johnsons Syndrome has been observed in the post-marketing setting [see Adverse Reactions ( 6.2 )] .
Discontinue RETEVMO in patients with Stevens Johnson Syndrome. If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration ( 2.5 )] .
Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.
5.7Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions ( 6.1 )] . Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as cl
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Interactions
Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). ( 2.4 , 7.1 ) Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. ( 2.6 , 7.1 ) Strong and Moderate CYP3A Inducers: Avoid coadministration.
( 7.1 ) CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 ) Certain P-gp and BCRP Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 )
7.1Effects of Other Drugs on
RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) [see Dosage and Administration ( 2.4 )] .
Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently [see Dosage and Administration ( 2.6 ), Warning and Precautions ( 5.4 )] .
Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce RETEVMO anti-tumor activity. Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.
7.2Effects of
RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions.
If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates.
Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.
7.3 Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.2 )] . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on findings from animal studies, and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily.
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss.
At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax).
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions ( 5.1 )] Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] QT Interval Prolongation [see Warnings and Precautions ( 5.4 )] Hemorrhagic Events [see Warnings and Precautions ( 5.5 )] Hypersensitivity [see Warnings and Precautions ( 5.6 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.7 )] Risk of Impaired Wound Healing [see Warnings and Precautions ( 5.8 )] Hypothyroidism [see Warnings and Precautions ( 5.9 )] Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients [see Warnings and Precautions ( 5.11 )] The most common adverse reactions (≥25%) include: Adult patients with solid tumors: edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.
( 6 ) Pediatric patients with solid tumors: musculoskeletal pain, diarrhea, nausea, hemorrhage, pyrexia, abdominal pain, headache, vomiting, fatigue, cough, rash, coronavirus infection, upper respiratory tract infection, and edema. ( 6 ) The most common Grade 3 or 4 laboratory abnormalities (≥5%) include: Adult patients with solid tumors: decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium.
( 6 ) Pediatric patients with solid tumors: decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased alanine aminotransferase, decreased magnesium, and decreased potassium. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 796 patients with advanced solid tumors in LIBRETTO-001 [see Clinical Studies ( 14 )] .
RET Gene Fusion or Gene Mutation Positive Solid Tumors LIBRETTO-001 Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily. The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 51% were male; and 69% were White, 23% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino.
The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%). Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1).
Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0.6%), fatigue (0.6%), sepsis (0.5%), and increased AST (0.5%). Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, diarrhea, and hypertension.
Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema. The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.
The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. Table 6 summarizes the adverse reactions in LIBRETTO-001. Table 6: Adverse Reactions (≥20%) in Patients Who Received RETEVMO in LIBRETTO-001 1 Edema includes edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema. 2 Fatigue includes asthenia and malaise. 3 Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence. 4 Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain. 5 Rash includes rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular. 6 Headache includes sinus headache, tension headache. 7 Cough includes productive cough, upper airway cough syndrome. 8 Dyspnea includes dyspnea exertional, dyspnea at rest. 9 Hemorrhage includes, epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemorrhoidal hemorrhage, hepatic hemorrhage, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, post procedural hemorrhage, postmenopausal hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma. * Only includes a grade 3 adverse reaction. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version
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