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Retevmo: Strength and Precision. Hit RET like never before. Retevmo is the first medicine approved by the FDA specifically for patients with certain RET-driven cancers

The clinical data for Retevmo were from LIBRETTO-001, a phase I/II, open-label, single-arm clinical trial.1,3

See clinical trial design below.

All results reviewed by an independent review committee (IRC).1,4

Retevmo demonstrated a robust and durable response in certain RET-driven cancers1

In treatment-naive patients with metastatic RET fusion-positive NSCLC (n=39)1:

85% objective response rate ORR for treatment-naïve patients with metastatic RET fusion-positive NSCLC

Median DoR not yet reached (95% CI: 12, NE)1

  • Median follow-up: 7.4 months1,4


In previously treated* patients with metastatic RET fusion-positive NSCLC (n=105)1:

64% objective response rate ORR for previously treated* patients with metastatic RET fusion-positive NSCLC

Median DoR 17.5 months (95% CI: 12, NE)1

  • Median follow-up: 12.1 months1,4

In systemic therapy-naive† patients with advanced or metastatic RET fusion-positive thyroid cancer (non-medullary thyroid cancer (non-MTC))‡ (n=8)1:

100% objective response rate ORR for systemic therapy-naïve patients with advanced or metastatic RET fusion-positive thyroid cancer

Median DoR not yet reached (95% CI: NE, NE)1

  • Median follow-up: 8.8 months1,4


In previously treated§ patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC) (n=19)1:

79% objective response rate ORR for previously treated patients with advanced or metastatic RET fusion-positive thyroid cancer

Median DoR 18.4 months (95% CI: 7.6, NE)1

  • Median follow-up: 17.5 months1,4


In cabozantinib/vandetanib treatment-naive patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) (n=88)1:

73% objective response rate ORR for cabozantinib/vandetanib treatment-naïve patients with advanced or metastatic RET-mutant medullary thyroid cancer

Median DoR 22.0 months (95% CI: NE, NE)1

  • Median follow-up: 7.8 months1,4


In patients previously treated‖ with cabozantinib and/or vandetanib with advanced or metastatic RET-mutant MTC (n=55)1:

69% objective response rate ORR for patients previously treated with cabozantiniband or vandetanib with advanced or metastatic RET-mutant medullary thyroid cancer

Median DoR not yet reached (95% CI: 19.1, NE)1

  • Median follow-up: 14.1 months1,4


ORR was defined as CR + PR and was assessed by independent review committee (IRC) according to RECIST v1.1.1


Take action on RET. First, test. Then treat.


Select Important Safety Information

The labeling for Retevmo contains Warnings and Precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity. Monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) prior to initiating Retevmo, every 2 weeks during the first 3 months of treatment, then monthly thereafter and as clinically indicated. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly, and as clinically indicated. 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. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg. See full Prescribing Information for further management instructions and dosage modifications for adverse reactions. 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. Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Advise females and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose. Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequent serious adverse reaction (≥2%) was pneumonia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3). Most common adverse reactions, including laboratory abnormalities, (≥25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

LIBRETTO-001 Trial Design

The phase I/II, open-label, single-arm, multicenter LIBRETTO-001 trial evaluated the efficacy of Retevmo in a population of 702 patients with metastatic RET fusion-positive NSCLC (n=332), advanced or metastatic RET fusion-positive thyroid cancer (non-MTC)¶ (n=38), advanced or metastatic RET-mutant MTC (n=306), and certain other advanced solid tumors with RET alterations (n=26).# Both treatment-naive patients and previously treated patients were evaluated in this trial. Major efficacy outcomes were ORR and DoR. In phase II, the dose for Retevmo was 160 mg PO BID.1,3,5**

*Efficacy was evaluated in 105 adult patients with metastatic RET fusion-positive NSCLC who were previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. All 105 patients received systemic therapy (with a median of 3 prior systemic regimens).1
†Patients received no prior systemic therapy other than radioactive iodine (RAI).1
‡Primary tumor histologies included papillary thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid cancer, and Hurthle cell thyroid cancer.1
§Patients received a prior systemic therapy (including sorafenib, lenvatinib, or both) other than RAI.1
||The efficacy of Retevmo was evaluated in 55 patients with RET-mutant advanced MTC who were previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001.1
¶Non-MTC by histology included papillary (n=31), poorly differentiated (n=4), anaplastic (n=2), and Hurthle cell (n=1).1,5
#Other tumors included pancreatic cancer (n=7), colon cancer (n=5), and adrenal gland carcinoma (n=3).5
**Patients with RET-mutant NSCLC and RET-mutant thyroid cancer (non-MTC) were not enrolled in the trial since RET is not the driver of tumor growth in these cancers.1,6

BID=twice daily; CI=confidence interval; CR=complete response; DoR=duration of response; NE=not estimable; NSCLC=non-small cell lung cancer; ORR=objective response rate; PO=orally; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; RET=rearranged during transfection.

See full trial results

References: 1. Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 2. Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. 3. Phase 1/2 study of LOXO-292 in patients with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). https://clinicaltrials.gov/ct2/show/NCT03157128. Updated March 2, 2020. Accessed March 18, 2020. 4. Data on File, Lilly USA, LLC, DOF-SE-US-0032. 5. Data on File, Lilly USA, LLC, DOF-SE-US-0033. 6. Mulligan LM. GDNF and the RET receptor in cancer: new insights and therapeutic potential. Front Physiol. 2019;9:1873.

Indications

Retevmo is a kinase inhibitor indicated for the treatment of:

  • adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC)
  • adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy
  • adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

These indications are approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR). Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information for Retevmo™ (selpercatinib)

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased aspartate aminotransferase (AST) occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased alanine aminotransferase (ALT) occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 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 dose or permanently discontinue Retevmo based on the severity.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% 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 dose, or permanently discontinue Retevmo based on the severity.

Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. 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 dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo. Grade ≥3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivity occurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg. 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. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect 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.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequently reported serious adverse reaction (in ≥ 2% of patients) was pneumonia.

Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (33%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) ≥20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (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).

Concomitant use of strong and moderate CYP3A inhibitors increases selpercatinib plasma concentrations 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 a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently.

Concomitant use of strong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations 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.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older.

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] ≥30 mL/Min, estimated by Cockcroft-Gault). A recommended dosage has not been established for patients with severe renal impairment or end-stage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

Please see full Prescribing Information for Retevmo.

SE HCP ISI All_25AUG2020

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