Retevmo was evaluated in a phase I/II trial: the largest trial ever reported in patients with RET-driven cancer^1-2

796 patients with RET-altered advanced or metastatic solid tumors were included in LIBRETTO-001, an open-label, single-arm, multicenter, phase I/II, multicohort trial.^1-5*

Libretto-001 trial design chart with major efficacy outcomes and other efficacy outcomes — LIBRETTO-001 included 796 patients, and the major efficacy outcomes were ORR and DoR; other efficacy outcomes included CNS ORR, CNS DoR, PFS, OS, time to response, and best change in tumor size from baseline.^1,3,5

The overall safety analysis included 24 patients with other cancers, including cancers without a RET alteration.⁴

Phase 1 dose escalation: Retevmo dosed at 20 mg QD–240 mg BID. Intra-patient dose escalation was allowed by protocol.³
Phase 2 dose: Retevmo dosed at 160 mg BID.³

See full Prescribing Information for dosing instructions.

Objective response rate (ORR) was defined as complete response (CR) + partial response (PR) and was assessed by independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.¹

The intent-to-treat (ITT) population was analyzed in the LIBRETTO-001 trial because this type of analysis avoids the selective exclusion of patients, which can lead to a biased assessment of an intervention's effectiveness.^6-9

^aPatients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and those without prior systemic therapy were enrolled in separate cohorts.¹
^bEfficacy was evaluated in 41 patients, including those with the following tumor types: pancreatic adenocarcinoma (n=11); colorectal (n=10); salivary (n=4); unknown primary (n=3); breast (n=2); sarcoma (soft tissue) (n=2); xanthogranuloma (n=2); carcinoid (bronchial) (n=1); carcinoma of the skin (n=1); cholangiocarcinoma (n=1); ovarian (n=1); pulmonary carcinosarcoma (n=1); rectal neuroendocrine (n=1); small intestine (n=1).¹
^cEfficacy was evaluated in 247 adult patients with advanced or metastatic RET fusion-positive NSCLC who were previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. All 247 patients received systemic therapy (with a median of 2 prior systemic regimens). 144 of the 247 patients received prior anti-PD-1/PD-L1 therapy, and 85 of the 247 patients received a prior MKI.³
^dNon-MTC by histology included papillary (n=54), poorly differentiated (n=6), anaplastic (n=4), and Hurthle cell (n=1).¹
^eNumber of patients included in the initial efficacy analysis. Efficacy was based on patients who had at least 6 months of follow-up.⁴
^fPatients in this cohort received no prior systemic therapy other than RAI.¹
^gPatients in this cohort received a prior systemic therapy other than RAI.¹
^hThe 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
ⁱPatients in this cohort could have received prior systemic therapies with a median of 2 prior systemic therapies (range 0-9).¹

^*Pooled safety analysis: data as of June 15, 2021

BID=twice daily; CNS=central nervous system; CRC=colorectal cancer; DoR=duration of response; MKI=multikinase inhibitor; MTC=medullary thyroid cancer; NSCLC=non-small cell lung cancer; OS=overall survival; PD-1=programmed cell death 1; PD-L1=programmed death-ligand 1; PFS=progression-free survival; QD=once daily; RET=rearranged during transfection.

See efficacy results in patients with certain RET-driven cancers

Response in patients with locally advanced or metastatic RET fusion-positive NSCLC¹

Treatment-naive patients (n=69)¹

84% ORR - 78% PR, 6% CR in circular pie graph format — Objective response rate in treatment-naive patients in LIBRETTO-001 was 84% (95% CI: 73, 92; 6% CR + 78% PR).¹

Median DoR was 20.2 months in treatment-naive patients in LIBRETTO-001 (95% CI: 13, NE). The median follow-up was 20.3 months.^1,2

Median DoR
20.2 months

(95% CI: 13, NE)
Median follow-up: 20.3 months^1,3

For treatment-naive patients who responded (n=58) to treatment, the median time to objective response was 1.8 months (range: 0.7, 10.8)^10†

The major efficacy outcome measures in LIBRETTO-001 were objective response rate (ORR) and duration of response (DoR)¹.

Time to any and best response was a prespecified secondary endpoint.¹¹

Time-to-event endpoints are not interpretable in a single-arm study.

Previously treated^‡ patients (n=247)¹

61% ORR - 54% PR, 7% CR in circular pie graph format

Median DoR
28.6 months

(95% CI: 20, NE)
Median follow-up: 21.2 months^1,3

For previously treated^‡ patients who responded (n=151) to treatment, the median time to objective response was 1.9 months (range: 0.7, 21.9)^10†

The major efficacy outcome measures in LIBRETTO-001 were objective response rate (ORR) and duration of response (DoR).¹

Time to any and best response was a prespecified secondary endpoint.¹¹

Time-to-event endpoints are not interpretable in a single-arm study.

All results reviewed by an IRC.^1,9,10,11

^†According to the protocol, scans were to be performed every 8 weeks (±7 days). The protocol allowed investigators to conduct an initial scan at 4 weeks (±7 days).¹²
^‡Efficacy was evaluated in 247 adult patients with locally advanced or metastatic RET fusion-positive NSCLC who were previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. All 247 patients received systemic therapy (with a median of 2 prior systemic regimens).¹

Retevmo had CNS activity in patients with measurable brain metastases. CNS ORR was observed in the LIBRETTO-001 trial¹

Of the 21 patients with measurable disease, 3 patients received RT to the brain within 2 months prior to study entry.¹

Efficacy of LIBRETTO-001 Trial: Image of tumor reduction, baseline and Week 8 shown

CNS ORR and CNS DoR were prespecified secondary endpoints that were evaluated and confirmed by an IRC.^1,13

Select Important Safety Information

Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient. 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 dose, or permanently discontinue Retevmo based on the severity.

Response in patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC)^1§

Systemic therapy-naive^‖ patients (n=24)^1,14

96% ORR - 75% PR, 21% CR in circular pie graph format

Median DoR not yet reached

(95% CI: NE, NE)

The major efficacy outcome measures in LIBRETTO-001 were ORR and DoR.

Objective response rate (ORR) was defined as complete response (CR) + partial response (PR) and was assessed by independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.¹

Previously treated^¶ patients (n=41)^1,14

85% ORR - 73% PR, 12% CR in circular pie graph format

Median DoR

18.4

months

(95% CI: 7.6, NE)

All results reviewed by an IRC.^1,14,15

Due to rounding, numbers presented may not add up to the totals indicated and percentages may not reflect the absolute figures for the same reason.

^§Primary tumor histologies included papillary thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid cancer, and Hurthle cell thyroid cancer.¹
^‖Patients received no prior systemic therapy other than RAI.¹
^¶Patients received a prior systemic therapy other than RAI.¹

Response in patients with advanced or metastatic RET-mutant MTC¹

Cabozantinib/vandetanib-naive patients (n=88)^1,16

73% ORR - 61% PR, 11% CR in circular pie graph format

Median DoR

22.0

months

(95% CI: NE, NE)
Median follow-up: 7.8 months^1,15

The major efficacy outcome measures in LIBRETTO-001 were ORR and DoR.

Patients previously treated^# with cabozantinib and/or vandetanib (n=55)^1,16

69% ORR - 60% PR, 9% CR in circular pie graph format

Median DoR not yet reached

(95% CI: 19.1, NE)
Median follow-up: 14.1 months^1,15

All results reviewed by an IRC.^1,15,16

^#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

Response in the tumor agnostic cohort in patients with locally advanced or metastatic RET fusion-positive solid tumors¹

In the tumor agnostic^** cohort (n=41)^1,5:

44% ORR - 39% PR, 4.9% CR in circular pie graph format

Median DoR

24.5

months

(95% CI: 9.2, NE)
Median follow-up: 14.9 months

All results reviewed by an IRC.¹

Due to rounding, numbers presented may not add up to the totals indicated and percentages may not reflect the absolute figures for the same reason.

At the time of analysis (September 24, 2021), 50% of responses (n=9/18) were ongoing.⁵

^**Efficacy was evaluated in 41 adult patients with advanced or metastatic RET fusion-positive solid tumors. Thirty-seven patients received prior systemic therapy (with a median of 2 prior systemic regimens).¹

In RET fusion-positive pancreatic adenocarcinoma, more than half of patients responded to Retevmo (n/N=6/11)^1,17

55% ORR - 55% PR, 0% CR in circular pie graph format

DoR Range

2.5, 38.3+ months
(Based on 6 responders)

+Denotes ongoing response.
Median prior systemic therapies: 2.¹⁸

In RET fusion-positive colorectal cancer (n=10)^1,19

20% ORR - 20% PR, 0% CR in circular pie graph format

DoR Range

5.6, 13.3 months
(Based on 2 responders)
Median prior systemic therapies: 3.5.¹⁸

The major efficacy outcome measures in LIBRETTO-001 were ORR and DoR.

All results reviewed by an IRC.^1,17

Because Retevmo is approved across all lines of therapy, including first line in certain RET-driven cancers, consider waiting for genomic test results, including RET alteration results, before making therapeutic decisions¹

Select Important Safety Information

Retevmo can cause concentration-dependent QT interval prolongation. 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. 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 thyroid-stimulating hormone (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.

Selpercatinib (Retevmo) is NCCN preferred

Selpercatinib (Retevmo) is a National Comprehensive Cancer Network^® (NCCN^®)-preferred (category 2A^††) treatment option for first-line or subsequent^‡‡ therapy in patients with RET-positive metastatic non-small cell lung cancer (NSCLC)^19§§

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) recommendations for NSCLC¹⁹:

Specific targeted therapies are the preferred systemic treatment options for eligible patients with metastatic NSCLC with certain driver alterations.^‖‖

For patients with metastatic NSCLC who are RET rearrangement positive, NCCN NSCLC Panel recommends selpercatinib (Retevmo) as a first-line or subsequent^‡‡ therapy option (category 2A^††) (preferred) for patients with metastatic NSCLC who are positive for RET rearrangements.

NCCN Guidelines^® recommendations for RET alteration-positive thyroid cancer²⁰:

Selpercatinib is a recommended systemic therapy option (category 2A^††) in RET fusion-positive:

Structurally persistent/recurrent locoregional or distant metastatic (including bone or CNS metastases) papillary carcinoma, follicular carcinoma, or Hurthle carcinoma, that is not amenable to RAI therapy

Selpercatinib is a preferred systemic therapy option (category 2A^††) in RET fusion-positive:

Metastatic anaplastic carcinoma^¶¶

Selpercatinib is a preferred systemic therapy option (category 2A^††) in RET mutation-positive medullary carcinoma^##:

Locoregional, unresectable carcinoma that is symptomatic or progressing by RECIST criteria
Distant metastatic, asymptomatic carcinoma that is unresectable and progressing by RECIST criteria
Distant metastatic, symptomatic or progressive carcinoma

^††Category 2A: Based upon lower-level evidence, and there is uniform NCCN consensus that the intervention is appropriate.
^‡‡If RET inhibitors have not been previously used.
^§§See the NCCN Guidelines for NSCLC for detailed recommendations, including other preferred treatment options.
^‖‖The NCCN Guidelines for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.
^¶¶Molecular testing should include BRAF, NTRK, ALK, RET, MSI, dMMR, and tumor mutational burden.
^##RET somatic genotyping in patients who are germline wild-type or germline unknown.

See NCCN Guidelines for recommendations for RET testing

See safety results for Retevmo

ALK=anaplastic lymphoma kinase; BRAF=v-raf murine sarcoma viral oncogene homolog B; CI=confidence interval; dMMR=DNA mismatch repair; MSI=microsatellite instability; NE=not estimable; NTRK=neurotrophic receptor tyrosine kinase.

References: 1. Retevmo (selpercatinib). Prescribing Information. Lilly USA, LLC. 2. 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 June 9, 2022. Accessed June 14, 2022. 3. Drilon A, Subbiah V, Gautschi O, et al. Durability of efficacy and safety with selpercatinib in patients with RET fusion+ non-small-cell lung cancer: LIBRETTO-001. Poster presented at: European Lung Cancer Congress; March 30–April 2, 2022. Poster 27P. 4. Data on File, Lilly USA, LLC, DOF-SE-US-0063. 5. Subbiah V, Wolf J, Konda B, et al. Tumor agnostic efficacy of selpercatinib in patients with RET fusion-positive solid tumors: a global, multicenter trial updated (LIBRETTO-001). Presented at: 2022 ASCO Annual Meeting; June 3-7, 2022; Chicago. Abstract 3094. 6. 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(9):813-824. 7. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. 8. McCoy CE. Understanding the intention-to-treat principle in randomized controlled trials. West J Emerg Med. 2017;18(6):1075-1078. 9. Gupta SK. Intention-to-treat concept: a review. Perspect Clin Res. 2011;2(3):109-112. 10. Data on File, Lilly USA, LLC, DOF-SE-US-0058. 11. Data on File, Lilly USA, LLC, DOF-SE-US-0028. 12. Data on File, Lilly USA, LLC, DOF-SE-US-0013. 13. Data on File, Lilly USA, LLC, DOF-SE-US-0033. 14. Data on File, Lilly USA, LLC, DOF-SE-US-0031. 15. Data on File, Lilly USA, LLC, DOF-SE-US-0032. 16. Data on File, Lilly USA, LLC, DOF-SE-US-0024. 17. Data on File, Lilly USA, LLC, DOF-SE-US-0069. 18. Data on File, Lilly USA, LLC, DOF-SE-US-0067. 19. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Non-Small Cell Lung Cancer V5.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed December 1, 2022. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 20. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Thyroid Carcinoma V3.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed December 1, 2022. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org.

IMPORTANT SAFETY INFORMATION

Hepatotoxicity: Serious hepatic adverse reactions occurred in 3% of patients treated with Retevmo. Increased aspartate aminotransferase (AST) occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased alanine aminotransferase (ALT) occurred in 55% of patients, including Grade 3 or 4 events in 12%. 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.

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 dose, or permanently discontinue Retevmo based on severity of confirmed ILD.

Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient. 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 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 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% 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 thyroid-stimulating hormone (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 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.

Hypersensitivity occurred in 6% of patients receiving Retevmo, including Grade 3 hypersensitivity 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. 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. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving Retevmo. 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 clinically indicated.

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.

Retevmo can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with Retevmo; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC. Monitor thyroid function before treatment with Retevmo and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold Retevmo until clinically stable or permanently discontinue Retevmo based on severity.

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 and females of reproductive potential 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 1 week after the last 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 last dose.

Slipped capital femoral epiphysis/slipped upper femoral epiphysis in pediatric patients (SCFE/SUFE) occurred in 1 adolescent (3.7% of 27 patients) receiving RETEVMO in LIBRETTO-121. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate.

Severe adverse reactions (Grade 3-4) occurring in ≥20% of patients who received Retevmo in LIBRETTO-001 were hypertension (20%), diarrhea (5%), prolonged QT interval (4.8%), dyspnea (3.1%), fatigue (3.1%), hemorrhage (2.6%), abdominal pain (2.5%), vomiting (1.8%), headache (1.4%), nausea (1.1%), constipation (0.8%), edema (0.8%), rash (0.6%), and arthralgia (0.3%). Serious adverse reactions occurred in 44% of patients who received Retevmo in LIBRETTO-001. The most frequently reported serious adverse reactions (in ≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who receive Retevmo in LIBRETTO-121 were vomiting (7%), constipation (7%), increased weight (7%), nausea (3.7%), and hemorrhage (3.7%). Serious adverse reactions occurred in 22% of patients who received Retevmo in LIBRETTO-121. The serious adverse reactions (in 1 patient each) were abdominal infection, abdominal pain, aspiration, constipation, diarrhea, epiphysiolysis, nausea, pneumonia, pneumatosis intestinalis, rhinovirus infection, sepsis, and vomiting.

Fatal adverse reactions occurred in 3% of patients in LIBRETTO-001; 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).

Common adverse reactions (all grades) occurring in ≥20% of patients who received Retevmo in LIBRETTO-001, were edema (49%), diarrhea (47%), fatigue (46%), dry mouth (43%), hypertension (41%), abdominal pain (34%), rash (33%), constipation (33%), nausea (31%), headache (28%), cough (24%), vomiting (22%), dyspnea (22%), hemorrhage (22%), arthralgia (21%), and prolonged QT interval (21%). In LIBRETTO-121, common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo were musculoskeletal pain (56%), diarrhea (41%), headache (33%), nausea (30%), vomiting (30%), coronavirus infection (30%), abdominal pain (26%), fatigue (26%), pyrexia (26%), hemorrhage (26%), upper respiratory tract infection (22%), oropharyngeal pain (22%), cough (22%), hypothyroidism (19%), constipation (19%), edema (19%), increased weight (19%), rash (19%), stomatitis (15%), and proteinuria (15%).

Laboratory abnormalities (all grades ≥20%; Grade 3-4) worsening from baseline in patients who received Retevmo in LIBRETTO-001, were increased AST (59%; 11%), decreased calcium (59%; 5.7%), increased ALT (56%; 12%), decreased albumin (56%; 2.3%), increased glucose (53%; 2.8%), decreased lymphocytes (52%; 20%), increased creatinine (47%; 2.4%), decreased sodium (42%; 11%), increased alkaline phosphatase (40%; 3.4%), decreased platelets (37%; 3.2%), increased total cholesterol (35%; 1.7%), increased potassium (34%; 2.7%), decreased glucose (34%; 1.0%), decreased magnesium (33%; 0.6%), increased bilirubin (30%; 2.8%), decreased hemoglobin (28%; 3.5%), and decreased neutrophils (25%; 3.2%). In LIBRETTO-121, the most common Grade 3 or 4 laboratory abnormalities (all grades ≥15%; Grade 3-4) worsening from baseline in patients who received Retevmo were decreased calcium (59%, 7%), increased ALT (56%, 3.7%), increased alkaline phosphatase (52%, 0%), increased AST (48%, 3.7%), decreased albumin (44%, 0%), increased bilirubin (30%, 0%), increased creatinine (22%, 0%), decreased potassium (22%, 3.7%), decreased magnesium (15%, 3.7%), decreased neutrophils (44%, 7%), decreased lymphocytes (24%, 4.8%), decreased platelets (22%, 0%), and decreased hemoglobin (19%, 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.

Retevmo is a P-glycoprotein (P-gp) inhibitor. Concomitant use of Retevmo with P-gp substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with P-gp substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 2 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients 2 years of age and older for the treatment of advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy, advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate), and locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

Monitor open growth plates in pediatric patients. Consider interrupting or discontinuing Retevmo if abnormalities occur.

No dosage modification is recommended for patients with mild to severe renal impairment (estimated Glomerular Filtration Rate [eGFR] ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease [MDRD] equation). A recommended dosage has not been established for patients with 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.

Retevmo (selpercatinib) is available as 40 mg and 80 mg capsules, and 40 mg, 80 mg, 120 mg, and 160 mg tablets.

Please see full Prescribing Information for Retevmo.

SE HCP ISI All_29MAY24

INDICATIONS

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
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^*
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)
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^*

^*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.

Retevmo was evaluated in a phase I/II trial: the largest trial ever reported in patients with RET-driven cancer1-2

See efficacy results in patients with certain RET-driven cancers

Retevmo had CNS activity in patients with measurable brain metastases. CNS ORR was observed in the LIBRETTO-001 trial1

Response in patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC)1§

Response in patients with advanced or metastatic RET-mutant MTC1

Response in the tumor agnostic cohort in patients with locally advanced or metastatic RET fusion-positive solid tumors1

In RET fusion-positive pancreatic adenocarcinoma, more than half of patients responded to Retevmo (n/N=6/11)1,17

In RET fusion-positive colorectal cancer (n=10)1,19

IMPORTANT SAFETY INFORMATION

INDICATIONS

Retevmo was evaluated in a phase I/II trial: the largest trial ever reported in patients with RET-driven cancer^1-2

Retevmo had CNS activity in patients with measurable brain metastases. CNS ORR was observed in the LIBRETTO-001 trial¹

Response in patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC)^1§

Response in patients with advanced or metastatic RET-mutant MTC¹

Response in the tumor agnostic cohort in patients with locally advanced or metastatic RET fusion-positive solid tumors¹

In RET fusion-positive pancreatic adenocarcinoma, more than half of patients responded to Retevmo (n/N=6/11)^1,17

In RET fusion-positive colorectal cancer (n=10)^1,19