LIBRETTO-431

LIBRETTO-431: A Phase III superiority trial of Retevmo versus chemotherapy with or without pembrolizumab for patients with RET fusion-positive advanced or metastatic NSCLC^1-3

^aPatients with brain metastases were eligible to be enrolled if asymptomatic and neurologically stable for 2 weeks.
^bThe crossover rate to Retevmo on study was 61.8% (n=42/68). Off-study crossover to a selective RET inhibitor occurred in an additional 15% of patients.
^cAll primary and secondary endpoints listed were assessed by IRC per RECIST v1.1. CNS ORR and CNS DoR were also assessed per RANO-BM.

Efficacy presentation focuses on the cohort of patients that investigators intended to treat with pembrolizumab (ITT-pembro), which included 129 patients who were randomized to Retevmo and 83 patients who were randomized to pembrolizumab plus chemotherapy.

Retevmo was dosed at 160 mg BID. Pembrolizumab was dosed at 200 mg Q3W. Chemotherapy included pemetrexed (500 mg/m² Q3W) and carboplatin (AUC 5 Q3W) or cisplatin (75 mg/m² Q3W).

Patients were stratified per investigator's choice of treatment with or without pembrolizumab if randomized to the control arm. Choice was declared prior to randomization. The subset of patients randomized with the intent not to receive pembrolizumab was less than 20% of total randomized patients, and is analyzed only as part of the intent-to-treat population.

Additional stratification factors: geography, brain metastases at baseline per investigator assessment.

AUC=area under the curve; BID=twice a day; CNS=central nervous system; DoR=duration of response; IRC=independent review committee; ITT=intent to treat; NSCLC=non-small cell lung cancer; ORR=overall response rate; PFS=progression-free survival; PD=progressive disease; Q3W=every three weeks; RANO-BM=Response Assessment in Neuro-Oncology Brain Metastases; RECIST=Response Evaluation Criteria in Solid Tumours; RET=rearranged during transfection; SOC=standard of care

PFS

In patients with advanced or metastatic RET fusion-positive NSCLC

Retevmo demonstrated superior PFS compared to pembrolizumab plus chemotherapy^1,3

Kaplan-Meier curve showing progression-free survival — This image shows median progression-free survival (PFS) in Retevmo-treated patients versus those treated with pembrolizumab plus chemotherapy. PFS was assessed in all randomized patients and was based on an interim analysis with a data cutoff date of May 1, 2023. For patients treated with Retevmo (n=129), median PFS was 24.8 months (95% CI: 16.9, NE) with median follow-up of 19.4 months. In patients treated with pembrolizumab plus chemotherapy (n=83), median PFS was 11.2 months (95% CI: 8.8, 16.8), with median follow-up of 18.9 months. An accompanying Kaplan-Meier curve shows progression-free survival for Retevmo-treated patients of 71.2% at 12 months and 58.6% at 18 months. PFS for patients treated with pembrolizumab plus chemotherapy was 47.8% at 12 months and 34.0% at 18 months. Hazard ratio was 0.47 (p=0.0002).

PFS was assessed in all randomized patients.

Based on an interim analysis with a data cutoff date of May 1, 2023.^1,3

HR=hazard ratio; mPFS=median progression-free survival

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

Objective response rate and duration of response for Retevmo vs pembrolizumab plus chemotherapy^1,3

Image of ORR — Graphic showing Objective Response Rate of 84% (95% CI: 76, 90) for Retevmo (n=129) versus 65% (95% CI: 54, 75) for pembrolizumab plus chemotherapy (n=83).^7,9 Partial response (PR) for Retevmo was 77%; Complete Response (CR) for Retevmo was 7%. PR for pembrolizumab plus chemotherapy was 59%; CR for pembrolizumab plus chemotherapy was 6%.

Image of median DoR — Graphic showing median Duration of Response of 24.2 months (95% CI: 17.9, NE) for Retevmo (n=129) versus 11.5 months (95% CI: 9.7, 23.3) with pembrolizumab plus chemotherapy (n=83)^7,9

ORR, a secondary endpoint, was defined as CR+PR and was assessed by the IRC according to RECIST v1.1.¹
Based on an interim analysis with a data cutoff date of May 1, 2023.^1,2

Overall survival (OS) is immature. At a May 2024 interim analysis of OS, a total of 31% and 25% of patients died in the Retevmo and the control arm, respectively, with an OS HR of 1.26 (95% CI: 0.78, 2.04). Overall survival results may be affected by the imbalance in post-progression therapies. At disease progression, nearly three-quarters (50 of 68 patients) in the control arm received Retevmo, while fewer than one-quarter (16 of 71 patients) in the Retevmo arm received chemotherapy, immune check point inhibitor, or both.

CI=confidence interval; CR=complete response; DoR=duration of response; NE=not estimable; PR=partial response

431 CNS ORR and DoR

Retevmo had CNS activity^¶ in patients with RET fusion-positive advanced or metastatic NSCLC^1,3

Responses in patients with measurable CNS metastases at baseline

Libretto 431 CNS ORR 82% Retevmo, 58% pembrolizumab + chemotherapy — Image showing central nervous system Objective Response Rate for Retevmo versus pembrolizumab plus chemotherapy. CNS ORR for Retevmo (n=17) was 82% (95% CI: 57, 96). Within this group, 47% of patients showed partial response and 35% showed complete response. In patients treated with pembrolizumab plus chemotherapy (n=12), CNS ORR was 58% (95% CI: 28, 85). Within this group, 42% of patients showed partial response and 17% showed complete response.

Libretto 431 CNS median DoR, Not Yet Reached Retevmo, 13.4 months pembrolizumab + chemotherapy — Image showing central nervous system median duration of response for Retevmo versus pembrolizumab plus chemotherapy. CNS median DoR for Retevmo (n=14) was not yet reached (95% CI: 7.6, NE). Median follow-up for this group was 9.9 months. In patients treated with pembrolizumab plus chemotherapy (n=7), CNS median DoR was 13.4 months (95% CI: 3.5, NE). Median follow-up for this group was 12.7 months.

CNS ORR (defined as CR+PR) and CNS DoR were prespecified secondary endpoints in the LIBRETTO-431 trial and were evaluated and assessed by IRC according to RECIST v1.1.^1,3

Based on an interim analysis with a data cutoff date of May 1, 2023.^1,3

ITT=intent to treat

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

^¶CNS activity is defined as shrinking current lesions and preventing the occurrence of new CNS lesions.

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.

431 Risk of CNS Progression

Risk of CNS as the first site of progression was reduced with Retevmo compared to pembrolizumab plus chemotherapy^1,3

12-Month CIR for Patients with or without Baseline CNS Metastases (N=192)

Libretto 431 5.5% Retevmo, 20.3% pembrolizumab + chemotherapy — The 12-month CIR for patients with and without baseline CNS metastases was 5.5% with Retevmo compared to 20.3% with pembrolizumab plus chemotherapy. The 95% confidence intervals were 2.2% to 10.8% and 11.3% to 31.1%, respectively. The cause-specific hazard ratio was 0.28 with a 95% confidence interval of 0.12 to 0.68. Cause-specific HR for CNS progression accounts for competing risks of non-CNS PD and death.

^a Cause-specific HR for CNS progression accounts for competing risks of non-CNS PD and death.

Libretto 431 patients with CNS matastases at baseline and patients without cns metastases at baseline comparison chart — The 12-month CIR for patients with baseline CNS metastases was 25.7% with Retevmo compared to 33.3% with pembrolizumab plus chemotherapy. The 95% confidence intervals were 8.8% to 46.7% and 14.3% to 53.8%, respectively. The cause-specific hazard ratio was 0.61 with a 95% confidence interval of 0.19 to 1.92. The 12-month CIR for patients without baseline CNS metastases was 1.1% with Retevmo compared to 14.7% with pembrolizumab plus chemotherapy. The 95% confidence intervals were 0.1% to 5.2% and 5.7% to 27.6%, respectively. The cause-specific hazard ratio was 0.17 with a 95% confidence interval of 0.04 to 0.69. Cause-specific HR for CNS progression accounts for competing risks of non-CNS PD and death.

^a Cause-specific HR for CNS progression accounts for competing risks of non-CNS PD and death.

Intracranial evaluation with CT or MRI was required for all patients at baseline and subsequently at the same frequency as other radiologic imaging and as clinically indicated. All results reviewed by IRC.^1,3

CIR=cumulative incidence rate; CT=computerized tomography

Safety

Safety and tolerability were evaluated in LIBRETTO-431¹

Adverse Events (≥15%) in Patients Who Received Retevmo in LIBRETTO-431¹

Table of adverse events in patients who received Retevmo in LIBRETTO-431 — Adverse Event table

**Retevmo, Adverse Reactions Grades 1-4:** In Retevmo-treated patients (n=158), patients experienced Grades 1-4 Vascular Disorders including hypertension (48%). Patients experienced Grade 1-4 Gastrointestinal Disorders including diarrhea (44%), dry mouth (39%), abdominal pain (25%), constipation (22%), stomatitis (18%), nausea (13%), and vomiting (13%). Grades 1-4 General disorders and administrative site conditions included edema (41%), fatigue (32%), and pyrexia (13%). Grades 1-4 Skin and subcutaneous tissue disorders included rash (33%). Grades 1-4 Musculoskeletal and connective tissue disorders included musculoskeletal pain (25%). Grades 1-4 Investigations included Electrocardiogram QT prolonged (20%). Grades 1-4 Metabolism and nutrition disorders included decreased appetite (17%). Infections and infestations included COVID19 infection (19%).

**Retevmo, Adverse Reactions Grades 3-4:** In Retevmo-treated patients (n=158), Grade 3-4 Vascular Disorders included hypertension (20%). Grade 3-4 Gastrointestinal Disorders included diarrhea (1.3%), dry mouth (0%), abdominal pain (0.6%), constipation (0%), stomatitis (0%), nausea (0%), and vomiting (0%). Grade 3-4 General disorders and administrative site conditions included edema (2.5%), fatigue (3.2%), and pyrexia (0.6%). Grade 3-4 Skin and subcutaneous tissue disorders included rash (1.9%). Grade 3-4 Musculoskeletal and connective tissue disorders included musculoskeletal pain (0%). Grade 3-4 Investigations included Electrocardiogram QT prolonged (9.0%). Grade 3-4 Metabolism and nutrition disorders included decreased appetite (0%). Infections and infestations included COVID-19 infection (0.6%).

**Chemotherapy with or without pembrolizumab, Grades 1-4:** In patients treated with chemotherapy with or without pembrolizumab (n=98), Grades 1-4 Vascular Disorders included hypertension (7%). Patients experienced Grades 1-4 Gastrointestinal Disorders including diarrhea (24%), dry mouth (6%), abdominal pain (19%), constipation (40%), stomatitis (16%), nausea (44%), and vomiting (23%). Grades 1-4 General disorders and administrative site conditions included edema (28%), fatigue (50%), and pyrexia (23%). Grades 1-4 Skin and subcutaneous tissue disorders included rash (30%). Grades 1- 4 Musculoskeletal and connective tissue disorders included musculoskeletal pain (28%). Grades 1-4 Investigations included Electrocardiogram QT prolonged (1.0%). Grades 1-4 Metabolism and nutrition disorders included decreased appetite (34%). Infections and infestations included COVID-19 infection (18%).

**Chemotherapy with or without pembrolizumab, Grades 3-4:** For those undergoing chemotherapy with or without pembrolizumab (n=98), Grade 3-4 Vascular Disorders included hypertension (3.1%). Grade 3-4 Gastrointestinal Disorders included diarrhea (2.0%), dry mouth (0%), abdominal pain (2.0%), constipation (1.0%), stomatitis (0%), nausea (1.0%), and vomiting (1.0%). Grade 3-4 General disorders and administrative site conditions included edema (0%), fatigue (5.0%), and pyrexia (0%). Grade 3-4 Skin and subcutaneous tissue disorders included rash (1.0%). Grade 3-4 Musculoskeletal and connective tissue disorders included musculoskeletal pain (0%). Grade 3-4 Investigations included Electrocardiogram QT prolonged (0%). Grade 3-4 Metabolism and nutrition disorders included decreased appetite (2.0%). Infections and infestations included COVID-19 infection (0%).

Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^*No Grade 4 abnormalities were reported.

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

Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received Retevmo in LIBRETTO-431¹

Table of laboratory abnormalities in patients who received Retevmo in LIBRETTO-431 — Lab abnormality table

Retevmo, Laboratory Abnormalities Grades 1-4: In Retevmo-treated patients (n=158), Grades 1-4 Chemistry abnormalities included ALT increased (81%), AST increased (77%), alkaline phosphatase increased (35%), total bilirubin increased (52%), blood creatinine increased (23%), magnesium decreased (16%), albumin decreased (25%), calcium decreased (53%), sodium decreased (31%), and potassium decreased (17%). Grades 1-4 Hematology abnormalities included platelets decreased (53%), lymphocyte count decreased (53%), hemoglobin decreased (21%), and neutrophil count decreased (53%).

Retevmo, Laboratory Abnormalities Grades 3-4: In Retevmo-treated patients (n=158), Grades 3-4 Chemistry abnormalities included ALT increased (21%), AST increased (10%), alkaline phosphatase increased (1.3%), total bilirubin increased (1.3%), blood creatinine increased (0%), magnesium decreased (0.6%), albumin decreased (0%), calcium decreased (1.9%), sodium decreased (3.2%), and potassium decreased (1.3%). Grades 3-4 Hematology abnormalities included platelets decreased (3.2%), lymphocyte count decreased (8%), hemoglobin decreased (0%), and neutrophil count decreased (2.0%).

Chemotherapy with or without pembrolizumab, Laboratory Abnormalities Grades 1-4: In patients treated with chemotherapy with or without pembrolizumab (n=98), Grades 1-4 Chemistry abnormalities included ALT increased (63%), AST increased (46%), alkaline phosphatase increased (22%), total bilirubin increased (9%), blood creatinine increased (21%), magnesium decreased (8%), albumin decreased (5%), calcium decreased (24%), sodium decreased (41%), and potassium decreased (15%). Grades 1-4 Hematology abnormalities included platelets decreased (39%), lymphocyte count decreased (64%), hemoglobin decreased (91%), and neutrophil count decreased (58%).

Chemotherapy with or without pembrolizumab, Laboratory Abnormalities Grades 3-4: For those undergoing chemotherapy with or without pembrolizumab (n=98), Grades 3-4 Chemistry abnormalities included ALT increased (4.1%), AST increased (0%), alkaline phosphatase increased (0%), total bilirubin increased (0%), blood creatinine increased (0%), magnesium decreased (0%), albumin decreased (0%), calcium decreased (1.0%), sodium decreased (2.1%), and potassium decreased (1.0%). Grades 3-4 Hematology abnormalities included platelets decreased (5%), lymphocyte count decreased (15%), hemoglobin decreased (5%), and neutrophil count decreased (11%).

Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

^a Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 154 to 157 patients) and chemotherapy with or without pembrolizumab (range: 96 to 97 patients)

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

Based on an interim analysis with a data cutoff date of May 1, 2023.^1,3
Serious adverse reactions occurred in 35% of patients who received Retevmo. The most frequent serious adverse reactions (≥2% of patients) were pleural effusion, and abnormal hepatic function.¹
Fatal adverse reactions occurred in 4.4% of patients who received Retevmo; fatal adverse reactions included myocardial infarction (n=2), respiratory failure (n=2), cardiac arrest, malnutrition, and sudden death (n=1, each).¹
Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received Retevmo. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%).¹
Dosage interruptions due to an adverse reaction occurred in 72% of patients who received Retevmo. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection.¹
Dose reductions due to an adverse reaction occurred in 51% of patients who received Retevmo. Adverse reactions requiring dose reductions in ≥5% of patients included increased ALT, increased AST, QT prolongation.¹
Clinically relevant adverse reactions in <15% of patients who received Retevmo include headache (14%); hemorrhage (13%); urinary tract infections (12%); hypothyroidism (9%); pneumonia (9%); dizziness (8%); interstitial lung disease/pneumonitis (4.4%); hypersensitivity, chylous ascites, and chylothorax (all < 2%).¹

See full Prescribing Information for more information on adverse reactions, laboratory abnormalities, and dose modifications.

AE=adverse event; ALT=alanine transaminase; AST=aspartate transferase; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; WBC=white blood cell

Summary

In the 1L treatment of advanced or metastatic RET-fusion positive NSCLC

Retevmo is the first and only targeted agent to have demonstrated superior PFS in a Phase III head-to-head trial against pembrolizumab plus chemotherapy¹

LIBRETTO-431 (N=261) was a randomized, global, multicenter, open-label, Phase III trial that evaluated Retevmo versus chemotherapy with or without pembrolizumab in treatment-naive adult patients with advanced or metastatic RET fusion-positive NSCLC, including those with brain metastases.
The primary endpoint was PFS for Retevmo versus chemotherapy with pembrolizumab.
10% of patients permanently discontinued treatment due to AEs with Retevmo (n=16/158)

Retevmo may affect both healthy cells and tumor cells, which can result in side effects, some of which can be serious.¹

Based on an interim analysis with a data cutoff date of May 1, 2023.^1,4

Graphic of LIBRETTO-431 summary — Median PFS for Retevmo (n=129) with oral administration was 24.8 months (95% CI: 16.9, NE). Median PFS for pembrolizumab plus chemotherapy (n=83) with IV administration was 11.2 months (95% CI: 8.8, 16.8). ORR for Retevmo was 84% (95% CI: 76, 90). ORR for pembrolizumab plus chemotherapy was 65% (95% CI: 54, 75). Median DoR for Retevmo was 24.2 months (95% CI: 17.9, NE). Median DoR for pembrolizumab plus chemotherapy was 11.5 months (95% CI: 9.7, 23.3).

1L=first line; INV=investigator

NSCLC Summary

For patients with locally advanced or metastatic NSCLC

Retevmo was granted approval based on LIBRETTO-001, a Phase I/II trial^1,5

LIBRETTO-001 Trial Design

The phase I/II, multicohort, open-label, single-arm, multicenter LIBRETTO-001 trial enrolled a pooled safety population of 796 patients, including patients with locally advanced or metastatic RET fusion-positive NSCLC.* Major efficacy outcomes were ORR and DoR. 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.^1,5-7

The pooled safety population also included patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC),^† patients with advanced or metastatic RET-mutant MTC, patients with RET fusion-positive solid tumors (other than NSCLC or thyroid),^‡ and patients with other cancers, including cancers without a RET alteration.⁵

*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 RET fusion-positive solid tumors included pancreatic cancer (n=11), colon cancer (n=10), and salivary cancer (n=4).¹

PO=orally

Chart of efficacy outcomes — Graphic showing Major Efficacy Outcomes and Secondary Endpoints for treatment-naive patients (n=69) and patients previously treated with platinum chemotherapy (n=247; image footnote: 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). Among treatment-naive patients (n=69), Objective Response Rate was 84% (95% confidence interval: 73, 92). Median Duration of Response (DoR) was 20.2 months (95% confidence interval: 13, NE). Median follow-up was 20.3 months. Among patients previously treated with platinum chemotherapy (n=247), Objective Response Rate was 61% (95% confidence interval: 55, 67). Median Duration of Response (DoR) was 28.6 months (95% confidence interval: 20, NE). Median follow-up was 21.2 months.

Secondary endpoints were CNS ORR and CNS DoR. Of the 21 patients with measurable disease, 3 patients received radiation therapy to the brain within 2 months prior to study entry. Among treatment-naive patients (n=69), 4 of 5 patients had CNS ORR response. On CNS DoR, 38% had intracranial DoR of greater than 12 months. Among patients previously treated with platinum chemotherapy (n=247), 14 of 16 had CNS ORR response. On CNS DoR, 39% had intracranial DoR of greater than 12 months.

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
ORR, DoR, CNS ORR, CNS DoR results reviewed by an IRC.¹
CNS ORR was a prespecified secondary endpoint that was evaluated and confirmed by an IRC.¹

^a 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

RT=radiation therapy

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. Solomon BJ, Zhou CC, Drilon A, et al. Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated RET positive non-small-cell lung cancer. Future Oncol. 2021;17(7):763-773. 3. Zhou C, Solomon B, Loong HH, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. doi:10.1056/NEJMoa2309457 4. Data on File. Lilly USA, LLC. DOF-SE-US-0077. 5. Drilon A, Subbiah V, Gautschi O, et al. Selpercatinib in patients with RET fusion-positive non-small-cell lung cancer: updated safety and efficacy from the registrational LIBRETTO-001 phase I/II trial. J Clin Oncol. 2023;41(2):385-394. 6. 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. 7. Data on File, Lilly USA, LLC, DOF-SE-US-0063.

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.