LIBRETTO-531

LIBRETTO-531: A Phase III superiority trial evaluating Retevmo versus cabozantinib or vandetanib in RET-mutant advanced or metastatic MTC 1,2^*†‡

^a PD was confirmed by IRC

Trial excluded patients who had presence of other validated oncogenic drivers.
Retevmo was dosed at 160 mg BID. Cabozantinib was dosed at 140 mg QD and vandetanib was dosed at 300 mg QD.

^*All primary and secondary endpoints listed were reviewed by IRC per RECIST v1.1.

^†Stratification factors: investigator’s choice of treatment if randomized to control arm (choice/intent of treatment regimen must be declared prior to randomization), mutation status (M918T versus other).¹

^‡73 patients and 25 patients received cabozantinib and vandetanib, respectively, within the control arm. Numerical imbalance may be due to worldwide supply shortage of vandetanib during the trial.²

BID=twice a day; DoR=duration of response; IRC=independent review committee; MTC=medullary thyroid cancer; ORR=overall response rate; PD=progressive disease; PFS=progression-free survival; QD=every day; RECIST=Response Evaluation Criteria in Solid Tumours; RET=rearranged during transfection

PFS

In patients with RET-mutant advanced or metastatic MTC

Retevmo demonstrated superior PFS compared to cabozantinib or vandetanib^1,2

Kaplan-Meier curve showing progression-free survival for Retevmo-treated patients versus cabozantinb — This image shows median PFS in Retevmo-treated patients (n=193) versus those treated with cabozantinib or vandetanib (n=98). PFS was assessed in all randomized patients and was based on an interim analysis with a data cutoff date of May 22, 2023. For patients treated with Retevmo, median PFS was not yet reached (95% CI not estimable) with median follow-up of 12.5 months. In patients treated with cabozantinib or vandetanib, median PFS was 16.8 months (95% CI: 12.2, 25.1) with median follow-up of 11.0 months. An accompanying Kaplan-Meier curve shows progression-free survival for Retevmo-treated patients of 86% at 12 months. PFS for patients treated with cabozantinib or vandetanib was 66% at 12 months. Hazard ratio was 0.28 (p<0.0001).

PFS was assessed in all randomized patients. Based on an interim analysis with a data cutoff date of May 22, 2023.^1,2

HR=hazard ratio; NE=not estimable

Select 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.

ORR and DoR

Overall response rate and duration of response for Retevmo vs cabozantinib or vandetanib^1,2,§

Image showing Overall Response Rate for Retevmo versus cabozantinib or vandetanib. ORR for Retevmo (n=193) was 69% (95% CI: 62, 76). Within this group, 58% of patients showed Partial Response and 12% showed Complete Response. In patients treated with cabozantinib or vandetanib (n=98), ORR was 39% (95% CI: 29, 49). Within this group, 35% of patients showed Partial Response and 4% showed Complete Response.

Median duration of response for Retevmo versus cabozantinib or vandetanib — Image showing Duration of Response for Retevmo versus cabozantinib or vandetanib. DoR for Retevmo was not yet reached (95% CI: NE, NE). Median follow-up was 11.1 months. In patients treated with cabozantinib or vandetanib DoR was 16.6 months (95% CI: 10.4, NE). Median follow-up was 12.8 months.

ORR, a secondary endpoint, was defined as CR+PR and was assessed by the IRC according to RECIST v1.1.
Based on an interim analysis with a data cutoff date of May 22, 2023.^1,2
At the time of this analysis, overall survival (OS) data were immature with 18 deaths observed.¹

^§Due to rounding, percentages presented may not add up to the indicated totals.

CI=confidence interval; CR=complete response; PR=partial response

Safety

Safety and tolerability were evaluated for Retevmo in LIBRETTO-531¹

Adverse Events (≥10%) in Patients Who Received Retevmo in LIBRETTO-531

Table of adverse events in patients who received Retevmo in LIBRETTO-531 — Adverse Events (≥10%) in Patients Who Received Retevmo in LIBRETTO-531

**Retevmo, Grades 1-4:** In Retevmo-treated patients (n=193), Vascular disorders of Grades 1-4 included hypertension (43%). General disorders and administration-site conditions of Grades 1-4 included edema (33%), fatigue (28%), and pyrexia (12%). Gastrointestinal disorders of Grades 1-4 included dry mouth (32%), diarrhea (26%), abdominal pain (18%), constipation (16%), stomatitis (14%), pyrexia (12%), and nausea (10%). Nervous system disorders of Grades 1-4 included headache (23%). Skin and subcutaneous tissue disorders of Grades 1-4 included rash (19%). Reproductive system and breast disorders of Grades 1-4 included erectile dysfunction (16%). Investigations category included electrocardiogram QT prolonged (14%). Metabolism and nutrition disorders of Grades 1-4 included decreased appetite (12%). Endocrine disorders of Grades 1-4 included hypothyroidism (11%).

**Retevmo, Grades 3-4:** In Retevmo-treated patients (n=193), Vascular disorders of Grades 3-4 included hypertension (19%). General disorders and administration-site conditions of Grades 3-4 included edema (0.0%), fatigue (4.1%), and pyrexia (1.0%). Gastrointestinal disorders of Grades 3-4 included dry mouth (0.5%), diarrhea (3.1%), abdominal pain (0.5%), constipation (0.0%), stomatitis (0.5%), pyrexia (1.0%), and nausea (1.0%). Nervous system disorders of Grades 3-4 included headache (0.5%). Skin and subcutaneous tissue disorders of Grades 3-4 included rash (1.6%). Reproductive system and breast disorders of Grades 3-4 included erectile dysfunction (0.0%). Investigations category included electrocardiogram QT prolonged (4.7%). Metabolism and nutrition disorders of Grades 3-4 included decreased appetite (0.5%). Endocrine disorders of Grades 3-4 included hypothyroidism (0.0%). All non-zero values for Retevmo Grades 3-4 are footnoted to indicate: “Only includes a Grade 3 adverse reaction.”

**Cabozantinib or Vandetanib, Grades 1-4:** In cabozantinib- or vandetanib-treated patients (n=97), Vascular disorders of Grades 1-4 included hypertension (41%). General disorders and administration-site conditions of Grades 1-4 included edema (5%), fatigue (47%), and pyrexia (2.1%). Gastrointestinal disorders of Grades 1-4 included dry mouth (10%), diarrhea (61%), abdominal pain (21%), constipation (12%), stomatitis (42%), pyrexia (2.1%), and nausea (32%). Nervous system disorders of Grades 1-4 included headache (21%). Skin and subcutaneous tissue disorders of Grades 1-4 included rash (27%). Reproductive system and breast disorders of Grades 1-4 included erectile dysfunction (0.0%). Investigations category included electrocardiogram QT prolonged (13%). Metabolism and nutrition disorders of Grades 1-4 included decreased appetite (28%). Endocrine disorders of Grades 1-4 included hypothyroidism (21%).

**Cabozantinib or Vandetanib, Grades 3-4:** In cabozantinib- or vandetanib-treated patients (n=97), Vascular disorders of Grades 3-4 included hypertension (18%). General disorders and administration-site conditions of Grades 3-4 included edema (0.0%), fatigue (9%), and pyrexia (0.0%). Gastrointestinal disorders of Grades 3-4 included dry mouth (1.0%), diarrhea (8%), abdominal pain (2.1%), constipation (0.0%), stomatitis (13%), pyrexia (0.0%), and nausea (5%). Nervous system disorders of Grades 3-4 included headache (0.0%). Skin and subcutaneous tissue disorders of Grades 3-4 included rash (4.1%). Reproductive system and breast disorders of Grades 3-4 included erectile dysfunction (0.0%). Investigations category included electrocardiogram QT prolonged (2.1%). Metabolism and nutrition disorders of Grades 3-4 included decreased appetite (5%). Endocrine disorders of Grades 3-4 included hypothyroidism (0.0%). All non-zero values for Cabozantinib or Vandetanib Grades 3-4 are footnoted to indicate: “Only includes a Grade 3 adverse reaction.”

Footnote: Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.

^*Only includes a Grade 3 adverse reaction

^#Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.

Select Laboratory Abnormalities (≥5%) Worsening from Baseline in Patients Treated with Retevmo in
LIBRETTO-531

Table of laboratory abnormalities — Select Laboratory Abnormalities (≥5%) Worsening from Baseline in Patients Treated with Retevmo in LIBRETTO-531

**Retevmo, Grades 1-4:** In Retevmo-treated patients, Chemistry-related laboratory abnormalities of Grades 1-4 included calcium decreased (55%), ALT increased (53%), AST increased (47%), alkaline phosphatase increased (37%), total bilirubin increased (32%), blood creatinine increased (27%) sodium decreased (20%), albumin decreased (11%), magnesium decreased (9%), and potassium decreased (8%). Hematology-related laboratory abnormalities of Grades 1-4 included lymphocyte count decreased (41%), neutrophil count decreased (33%), platelets decreased (28%), and hemoglobin decreased (18%).

**Retevmo, Grades 3-4:** In Retevmo-treated patients, Chemistry-related laboratory abnormalities of Grades 3-4 included calcium decreased (5%), ALT increased (16%), AST increased (5%), alkaline phosphatase increased (6%), total bilirubin increased (1.1%), blood creatinine increased (6%) sodium decreased (3.2%; Grade 3 AE only), albumin decreased (1.1%), magnesium decreased (3.3%), and potassium decreased (0.0%). Hematology-related laboratory abnormalities of Grades 3-4 included lymphocyte count decreased (18%), neutrophil count decreased (14%), platelets decreased (1.1%), and hemoglobin decreased (2.1%; Grade 3 AE only).

**Cabozantinib or Vandetanib, Grades 1-4:** In cabozantinib- or vandetanib-treated patients, Chemistry-related laboratory abnormalities of Grades 1-4 included calcium decreased (62%), ALT increased (72%), AST increased (68%), alkaline phosphatase increased (28%), total bilirubin increased (30%), blood creatinine increased (16%) sodium decreased (16%), albumin decreased (7%), magnesium decreased (26%), and potassium decreased (22%). Hematology-related laboratory abnormalities of Grades 1-4 included lymphocyte count decreased (36%), neutrophil count decreased (42%), platelets decreased (34%), and hemoglobin decreased (23%).

**Cabozantinib or Vandetanib, Grades 3-4:** In cabozantinib- or vandetanib-treated patients, Chemistry-related laboratory abnormalities of Grades 3-4 included calcium decreased (11%), ALT increased (7%; Grade 3 AE only), AST increased (3.2%), alkaline phosphatase increased (5%), total bilirubin increased (3.2%; Grade 3 AE only), blood creatinine increased (8%) sodium decreased (0.0%), albumin decreased (0.0%), magnesium decreased (9%), and potassium decreased (4.4%; Grade 3 AE only). Hematology-related laboratory abnormalities of Grades 3-4 included lymphocyte count decreased (13%), neutrophil count decreased (19%), platelets decreased (1.1%; Grade 3 AE only), and hemoglobin decreased (2.1%; Grade 3 AE only).

Treatment group footnote: Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: Retevmo (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients).

^a Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: Retevmo (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients).¹

Serious adverse reactions occurred in 22% of patients who received Retevmo. The most frequent serious adverse reactions were pneumonia and pyrexia (n = 3, each) and hypertension and urinary tract infection (n = 2, each).
Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each).
Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received Retevmo. Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, and AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19 and somatic symptom disorder (n = 1, each).
Dosage interruptions due to an adverse reaction occurred in 49% of patients who received Retevmo. Adverse reactions requiring dosage omission in ≥5% of patients included ALT increased (9%) and hypertension (7%).
Dose reductions due to an adverse reaction occurred in 39% of patients who received Retevmo. One adverse reaction, increased ALT (7%), required a dose reduction in ≥5% of patients.
The most common adverse reactions (≥25%) in patients who received Retevmo were hypertension, edema, dry mouth, fatigue, diarrhea.
The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received Retevmo were decreased lymphocyte, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST.
Clinically relevant adverse reactions in ≤10% of patients who received Retevmo include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites and hypersensitivity (all < 2%).

For complete details on adverse reactions and laboratory abnormalities, please see full Prescribing Information.

AE=adverse event; ALT=alanine transaminase; AST=aspartate aminotransferase; COVID-19=coronavirus disease 2019; GGT=gamma-glutamyl transferase; INR=international normalized ratio; LFT=liver function test; WBC=white blood cell

Select Important Safety Information

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.

L-001 Efficacy Summary

In patients with RET-mutant advanced or metastatic MTC

Retevmo was granted initial approval based on LIBRETTO-001, a Phase I/II trial

Efficacy in cabozantinib/vandetanib-naive patients (n=88)^1,3

Overall Response Rate and Median Duration of Response for Retevmo in cabozantinib/vandetanib-naive patients — Graphic showing Objective Response Rate and Median Duration of Response for Retevmo treatment in cabozantinib/vandetanib-naive patients. ORR was 81% (95% CI: 71, 88), with 28% complete response (CR) and 52% PR (partial response). Median DoR not yet reached (95% CI: 51.3, NE). Median follow-up was 44.2 months. Due to rounding, percentages presented may not add up to the indicated totals.

Major efficacy outcome measures for patients previously treated^ǁ with cabozantinib and/or vandetanib (n=55)¹:

ORR = 76% (95% CI: 63, 87)
- 18% CR + 58% PR
Median DoR = 45.3 months (95% CI: 29.9, NE); Median follow-up: 50.7 months³

Time-to-event endpoints are not interpretable in a single-arm study. The clinical significance of this descriptive analysis is not known.

ORR was defined as CR + PR and was assessed by IRC according to RECIST v1.1.¹

All results reviewed by an IRC.¹

Due to rounding, percentages presented may not add up to the indicated totals.

^ǁThe 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

L-001 Trial Design

The phase I/II, multicohort, open-label, single-arm, multicenter LIBRETTO-001 trial included a pooled safety population of 796 patients with locally advanced or metastatic RET fusion-positive NSCLC^¶, advanced or metastatic RET fusion-positive thyroid cancer (non-MTC)^#, advanced or metastatic RET-mutant MTC, and other cancers, including patients with RET alterations in other tumors^**. Major efficacy outcomes were ORR and DoR, and were evaluated in 565 patients. Other efficacy outcomes, evaluated in subsets of patients, included CNS ORR, CNS DoR, PFS, OS, time to response, and best change in tumor size from baseline. In phase II, the dose for Retevmo was 160 mg PO BID.^1,4

^¶Patients with locally 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

^#Non-MTC by histology included papillary (n=54), poorly differentiated (n=6), anaplastic (n=4), and Hurthle cell (n=1).¹

^**Other tumors included pancreatic adenocarcinoma (n=11), colorectal cancer (n=10), and salivary cancer (n=4).¹

CNS=central nervous system; PO=orally.

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.

References: 1. Retevmo (selpercatinib). Prescribing Information. Lilly USA, LLC. 2. Hadoux J, Elisei R, Brose MS, et al. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. 2023;389(20):1851-1861. doi:10.1056/NEJMoa2309719 3. Data on File, Lilly USA, LLC. DOF-SE-US-0089. 4. 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.

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 and 1 adolescent patient (0.5% of 193 patients) receiving Retevmo in LIBRETTO-531. 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%).

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-121 were vomiting (7%), constipation (7%), increased weight (7%), nausea (3.7%), and hemorrhage (3.7%).

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo or chemotherapy with or without pembrolizumab in LIBRETTO-431 were hypertension (20% vs 3.1%), electrocardiogram QT prolonged (9% vs 0%), fatigue (3.2% vs 5%), edema (2.5% vs 0%), rash (1.9% vs 1.0%), diarrhea (1.3% vs 2.0%), abdominal pain (0.6% vs 2.0%), pyrexia (0.6% vs 0%), COVID19 infection (0.6% vs 0%), constipation (0% vs 1.0%), nausea (0% vs 1.0%), vomiting (0% vs 1.0%), and decreased appetite (0% vs 2.0%).

Severe adverse reactions (Grade 3-4) occurring in ≥10% of patients who received Retevmo in LIBRETTO-531 were (Retevmo vs cabozantinib / vandetanib) hypertension (19% vs 18%), electrocardiogram QT prolonged (4.7% vs 2.1%), fatigue (4.1% vs 9%), diarrhea (3.1% vs 8%), rash (1.6% vs 4.1%), pyrexia (1.0% vs 0%), nausea (1.0% vs 5%), dry mouth (0.5% vs 1.0%), abdominal pain (0.5% vs 2.1%), stomatitis (0.5% vs 13%), headache (0.5% vs 0%), and decreased appetite (0.5% vs 5%).

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. 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).

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.

Serious adverse reactions occurred in 35% of patients who received Retevmo in LIBRETTO-431. The most frequently reported serious adverse reactions (≥2% of patients) were pleural effusion and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received Retevmo in LIBRETTO-431; fatal adverse reactions included myocardial infarction (n=2), respiratory failure (n=2), cardiac arrest, malnutrition, and sudden death (n=1 each).

Serious adverse reactions occurred in 22% of patients who received Retevmo in LIBRETTO-531. The most frequent serious adverse reactions were pneumonia and pyrexia (n=3 each), and hypertension and urinary tract infection (n=2 each). Fatal adverse reactions occurred in 2.1% of patients who received Retevmo in LIBRETTO-531; fatal adverse reactions included COVID19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each).

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%).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-121 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%).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo or chemotherapy with or without pembrolizumab in LIBRETTO-431 were hypertension (48% vs 7%), diarrhea (44% vs 24%), edema (41% vs 28%), dry mouth (39% vs 6%), rash (33% vs 30%), fatigue (32% vs 50%), abdominal pain (25% vs 19%), musculoskeletal pain (25% vs 28%), constipation (22% vs 40%), electrocardiogram QT prolonged (20% vs 1.0%), COVID19 infection (19% vs 18%), stomatitis (18% vs 16%), decreased appetite (17% vs 34%), nausea (13% vs 44%), vomiting (13% vs 23%), and pyrexia (13% vs 23%).

Common adverse reactions (all grades) occurring in ≥10% of patients who received Retevmo in LIBRETTO-531 (Retevmo vs cabozantinib / vandetanib) were hypertension (43% vs 41%), edema (33% vs 5%), dry mouth (32% vs 10%), fatigue (28% vs 47%), diarrhea (26% vs 61%), headache (23% vs 21%), rash (19% vs 27%), abdominal pain (18% vs 21%), constipation (16% vs 12%), erectile dysfunction (16% vs 0%), stomatitis (14% vs 42%), electrocardiogram QT prolonged (14% vs 13%), pyrexia (12% vs 2.1%), decreased appetite (12% vs 28%), hypothyroidism (11% vs 21%), and nausea (10% vs 32%).

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%).

Laboratory abnormalities (all grades ≥15%; Grade 3-4) worsening from baseline in patients who received Retevmo in LIBRETTO-121 were decreased calcium (59%; 7%), increased ALT (56%; 3.7%), increased alkaline phosphatase (52%; 0%), increased AST (48%; 3.7%), decreased albumin (44%; 0%), decreased neutrophils (44%; 7%), increased bilirubin (30%; 0%), decreased lymphocytes (24%; 4.8%), increased creatinine (22%, 0%), decreased potassium (22%; 3.7%), decreased platelets (22%; 0%), decreased hemoglobin (19%; 7%), and decreased magnesium (15%; 3.7%).

Laboratory abnormalities (all grades ≥20%; Grade 3-4) worsening from baseline in patients who received Retevmo or chemotherapy with or without pembrolizumab in LIBRETTO-431 were increased ALT (81%; 21% vs 63%; 4.1%), increased AST (77%; 10% vs 46%; 0%), decreased calcium (53%; 1.9% vs 24%; 1.0%), decreased platelets (53%; 3.2% vs 39%; 5%), decreased lymphocytes (53%; 8% vs 64%; 15%), decreased neutrophils (53%; 2.0% vs 58%; 11%), increased bilirubin (52%; 1.3% vs 9%; 0%), increased alkaline phosphatase (35%; 1.3% vs 22%; 0%), decreased sodium (31%; 3.2% vs 41%; 2.1%), decreased albumin (25%; 0% vs 5%; 0%), increased blood creatinine (23%; 0% vs 21%; 0%), decreased hemoglobin (21%; 0% vs 91%; 5%), decreased potassium (17%; 1.3% vs 15%; 1.0%), and decreased magnesium (16%; 0.6% vs 8%; 0%).

Laboratory abnormalities (all grades ≥5%; Grade 3-4) worsening from baseline in patients who received Retevmo in LIBRETTO-531 (Retevmo vs cabozantinib / vandetanib) were decreased calcium (55%; 5% vs 62%; 11%), increased ALT (53%; 16% vs 72%; 7%), increased AST (47%; 5% vs 68%; 3.2%), decreased lymphocytes (41%; 18% vs 36%; 13%), increased alkaline phosphatase (37%; 6% vs 28%, 5%), increased bilirubin (32%; 1.1% vs 30%; 3.2%), decreased neutrophils (33%; 14% vs 42%; 19%), decreased platelets (28%; 1.1% vs 34%; 1.1%),increased creatinine (27%; 6% vs 16%; 8%), decreased sodium (20%; 3.2% vs 16%; 0%), decreased hemoglobin (18%; 2.1% vs 23%; 2.1%), decreased albumin (11%; 1.1% vs 7%; 0), magnesium decreased (9%; 3.3% vs 26%; 9%), and decreased potassium (8%; 0% vs 22%; 4.4%).

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) and BCRP inhibitor. Concomitant use of Retevmo with P-gp or BCRP substrates increases their plasma concentrations, 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.

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.

SE HCP ISI All_18DEC24

Please see full Prescribing Information for Retevmo.

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^*

^*This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

LIBRETTO-531

LIBRETTO-531: A Phase III superiority trial evaluating Retevmo versus cabozantinib or vandetanib in RET-mutant advanced or metastatic MTC 1,2*†‡

PFS

ORR and DoR

Safety

L-001 Efficacy Summary

L-001 Trial Design

IMPORTANT SAFETY INFORMATION

INDICATIONS

LIBRETTO-531: A Phase III superiority trial evaluating Retevmo versus cabozantinib or vandetanib in RET-mutant advanced or metastatic MTC 1,2^*†‡