LIBRETTO 431

NSCLC Summary

For patients with locally advanced or metastatic NSCLC

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

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 356 patients with locally advanced or metastatic RET fusion-positive NSCLC.* Major efficacy outcomes were ORR and DoR, and were evaluated in 316 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

The pooled safety population also included 54 patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC),^† 319 patients with advanced or metastatic RET-mutant MTC, 43 patients with RET fusion-positive solid tumors (other than NSCLC or thyroid),^‡ and 24 patients with other cancers, including cancers without a RET alteration.³

*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=21), poorly differentiated (n=3), anaplastic (n=2), 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.

BID=twice daily; CNS=central nervous system; DoR=duration of response; NSCLC=non-small cell lung cancer; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PO=orally; RET=rearranged during transfection.

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.^1,5
CNS ORR was a prespecified secondary endpoint that was evaluated and confirmed by an IRC.¹

^* 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

CI=confidence interval; CNS=central nervous system; CR=complete response; DoR=duration of response; IRC=independent review committee; NE=not estimable; NSCLC=non-small cell lung cancer; ORR=objective response rate; OS=overall survival; PFS=progression free survival; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; RET=rearranged during transfection; RT=radiation therapy

Select Important Safety Information from LIBRETTO-001

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.

Trial Design

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^6-8

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.

^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.

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^7,9

Kaplan-Meier curve showing progression-free survival — This image shows median 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).

Median PFS: 24.8 months (95% CI: 17.3, NE) with Retevmo (n=159) vs 11.2 months (95% CI: 8.8, 16.8) for the entire control arm (n=102).^7,9,§

PFS was assessed in all randomized patients.
Based on an interim analysis with a data cutoff date of May 1, 2023.^7,9

^§Median follow-up time for patients treated with Retevmo was 19.4 months. Median follow-up time for patients in the entire control arm was 16.5 months.

HR=hazard ratio; NSCLC=non-small cell lung cancer; mPFS=median progression-free survival; PFS=progression-free survival

Select Important Safety Information from LIBRETTO-001

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.

ORR and DoR

Objective response rate and duration of response for Retevmo vs pembrolizumab plus chemotherapy^7,9

ORR:

84% (95% CI: 77, 89; 7.5% CR + 76% PR) with Retevmo (n=159) vs 63% (95% CI: 53, 72; 4.9% CR + 58% PR) for the entire control arm (n=102)

Median DoR:

24.2 months (95% CI: 17.9, NE) Retevmo (n=159) vs 12.0 months (95% CI: 9.7, 23.3) for the entire control arm (n=102)*

ORR, a secondary endpoint, was defined as CR+PR and was assessed by the IRC according to RECIST v1.1.⁹ Based on an interim analysis with a data cutoff date of May 1, 2023.^7,9

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

^‖Median follow-up for patients treated with Retevmo was 18.0 months. Median follow-up time for patients in the entire control arm was 12.7 months.

CI=confidence interval; CR=complete response; DoR=duration of response; IRC=independent review committee; NE=not estimable; NSCLC=non-small cell lung cancer; ORR=objective response rate; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumours; RET=rearranged during transfection

Safety

Safety and tolerability were evaluated in LIBRETTO-431^7,10

Select Adverse Events (≥20%) in Patients Who Received Retevmo in LIBRETTO-431^7,10

Table of adverse events — **Retevmo (n=158)** **Control Arm (n=98)**

**Adverse Event** **Retevmo (n=158)** **Any Grade** **Retevmo (n=158)** **Grade 3/4/5** **Control Arm (n=98)** **Any Grade** **Control Arm (n=98)** **Grade 3/4/5**

**Adverse Event** **Gastrointestinal**

**Gastrointestinal**
Diarrhea^a **Retevmo (n=158) Any Grade** 44.3% **Retevmo (n=158) Grade 3/4/5** 1.3% **Control Arm (n=98) Any Grade** 24.5% **Control Arm (n=98) Grade 3/4/5** 2.0%

**Gastrointestinal**
Dry Mouth^b **Retevmo (n=158) Any Grade** 39.2% **Retevmo (n=158) Grade 3/4/5** 0% **Control Arm (n=98) Any Grade** 6.1% **Control Arm (n=98) Grade 3/4/5** 0%

**Gastrointestinal**
Abdominal Pain^c **Retevmo (n=158) Any Grade** 25.3% **Retevmo (n=158) Grade 3/4/5** 0.6% **Control Arm (n=98) Any Grade** 19.4% **Control Arm (n=98) Grade 3/4/5** 2.0%

**Gastrointestinal**
Constipation **Retevmo (n=158) Any Grade** 21.5% **Retevmo (n=158) Grade 3/4/5** 0% **Control Arm (n=98) Any Grade** 39.8% **Control Arm (n=98) Grade 3/4/5** 1.0%

**Adverse Event** **Vascular**

**Vascular**
Hypertension **Retevmo (n=158) Any Grade** 48.1% **Retevmo (n=158) Grade 3/4/5** 20.3% **Control Arm (n=98) Any Grade** 7.1% **Control Arm (n=98) Grade 3/4/5** 3.1%

**Adverse Event** **General**

**General**
Edema^d **Retevmo (n=158) Any Grade** 41.1% **Retevmo (n=158) Grade 3/4/5** 2.5% **Control Arm (n=98) Any Grade** 27.6% **Control Arm (n=98) Grade 3/4/5** 0%

**General**
Fatigue^e **Retevmo (n=158) Any Grade** 32.3% **Retevmo (n=158) Grade 3/4/5** 3.2% **Control Arm (n=98) Any Grade** 50.0% **Control Arm (n=98) Grade 3/4/5** 5.1%

**Adverse Event** **Skin**

**Skin**
Rash^f **Retevmo (n=158) Any Grade** 32.9% **Retevmo (n=158) Grade 3/4/5** 1.9% **Control Arm (n=98) Any Grade** 29.6% **Control Arm (n=98) Grade 3/4/5** 1.0%

**Adverse Event** **Investigations**

**Investigations**
Prolonged QT Interval **Retevmo (n=158) Any Grade** 20.3% **Retevmo (n=158) Grade 3/4/5** 8.9% **Control Arm (n=98) Any Grade** 1.0% **Control Arm (n=98) Grade 3/4/5** 0%

	Retevmo (n=158)		Control Arm (n=98)
Adverse Event	Retevmo (n=158) Any Grade	Retevmo (n=158) Grade 3/4/5	Control Arm (n=98) Any Grade	Control Arm (n=98) Grade 3/4/5
Adverse Event Gastrointestinal
Gastrointestinal Diarrhea^a	Retevmo (n=158) Any Grade 44.3%	Retevmo (n=158) Grade 3/4/5 1.3%	Control Arm (n=98) Any Grade 24.5%	Control Arm (n=98) Grade 3/4/5 2.0%
Gastrointestinal Dry Mouth^b	Retevmo (n=158) Any Grade 39.2%	Retevmo (n=158) Grade 3/4/5 0%	Control Arm (n=98) Any Grade 6.1%	Control Arm (n=98) Grade 3/4/5 0%
Gastrointestinal Abdominal Pain^c	Retevmo (n=158) Any Grade 25.3%	Retevmo (n=158) Grade 3/4/5 0.6%	Control Arm (n=98) Any Grade 19.4%	Control Arm (n=98) Grade 3/4/5 2.0%
Gastrointestinal Constipation	Retevmo (n=158) Any Grade 21.5%	Retevmo (n=158) Grade 3/4/5 0%	Control Arm (n=98) Any Grade 39.8%	Control Arm (n=98) Grade 3/4/5 1.0%
Adverse Event Vascular
Vascular Hypertension	Retevmo (n=158) Any Grade 48.1%	Retevmo (n=158) Grade 3/4/5 20.3%	Control Arm (n=98) Any Grade 7.1%	Control Arm (n=98) Grade 3/4/5 3.1%
Adverse Event General
General Edema^d	Retevmo (n=158) Any Grade 41.1%	Retevmo (n=158) Grade 3/4/5 2.5%	Control Arm (n=98) Any Grade 27.6%	Control Arm (n=98) Grade 3/4/5 0%
General Fatigue^e	Retevmo (n=158) Any Grade 32.3%	Retevmo (n=158) Grade 3/4/5 3.2%	Control Arm (n=98) Any Grade 50.0%	Control Arm (n=98) Grade 3/4/5 5.1%
Adverse Event Skin
Skin Rash^f	Retevmo (n=158) Any Grade 32.9%	Retevmo (n=158) Grade 3/4/5 1.9%	Control Arm (n=98) Any Grade 29.6%	Control Arm (n=98) Grade 3/4/5 1.0%
Adverse Event Investigations
Investigations Prolonged QT Interval	Retevmo (n=158) Any Grade 20.3%	Retevmo (n=158) Grade 3/4/5 8.9%	Control Arm (n=98) Any Grade 1.0%	Control Arm (n=98) Grade 3/4/5 0%

^aDiarrhea includes diarrhea, anal incontinence

^bDry mouth includes dry mouth, mucosal dryness

^cAbdominal pain includes abdominal pain upper, abdominal pain, abdominal discomfort, abdominal pain lower, gastrointestinal pain

^dEdema includes peripheral edema, face edema, edema, periorbital edema, swelling face, peripheral swelling, penile edema, scrotal edema, eye edema, eyelid edema, localized edema, orbital edema, orbital swelling, periorbital swelling

^eFatigue includes fatigue, asthenia, malaise

^fRash includes rash, dermatitis, rash maculo-papular, skin exfoliation, dermatitis allergic, rash macular, rash papular, rash pustular, rash erythematous, rash vesicular, urticaria

Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received Retevmo in LIBRETTO-431^7,10,a

Table of laboratory abnormalities — **Retevmo (n=158)** **Control Arm (n=98)**

**Laboratory Abnormality** **Retevmo (n=158)** **Any Grade** **Retevmo (n=158)** **Grade 3/4** **Control Arm (n=98)** **Any Grade** **Control Arm (n=98)** **Grade 3/4**

**Laboratory Abnormality** **Chemistry**

**Chemistry**
Increased ALT **Retevmo (n=158) Any Grade** 80.9% **Retevmo (n=158) Grade 3/4** 21.0% **Control Arm (n=98) Any Grade** 62.9% **Control Arm (n=98) Grade 3/4** 4.1%

**Chemistry**
Increased AST **Retevmo (n=158) Any Grade** 76.9% **Retevmo (n=158) Grade 3/4** 9.6% **Control Arm (n=98) Any Grade** 46.4% **Control Arm (n=98) Grade 3/4** 0%

**Chemistry**
Decreased calcium **Retevmo (n=158) Any Grade** 52.6% **Retevmo (n=158) Grade 3/4** 1.9% **Control Arm (n=98) Any Grade** 23.7% **Control Arm (n=98) Grade 3/4** 1.0%

**Chemistry**
Increased bilirubin **Retevmo (n=158) Any Grade** 51.6% **Retevmo (n=158) Grade 3/4** 1.3% **Control Arm (n=98) Any Grade** 9.4% **Control Arm (n=98) Grade 3/4** 0%

**Chemistry**
Decreased sodium **Retevmo (n=158) Any Grade** 30.8% **Retevmo (n=158) Grade 3/4** 3.2% **Control Arm (n=98) Any Grade** 41.2% **Control Arm (n=98) Grade 3/4** 2.1%

**Chemistry**
Increased alkaline phosphatase **Retevmo (n=158) Any Grade** 35.0% **Retevmo (n=158) Grade 3/4** 1.3% **Control Arm (n=98) Any Grade** 21.7% **Control Arm (n=98) Grade 3/4** 0%

**Chemistry**
Increased magnesium **Retevmo (n=158) Any Grade** 26.9% **Retevmo (n=158) Grade 3/4** 1.9% **Control Arm (n=98) Any Grade** 15.5% **Control Arm (n=98) Grade 3/4** 0%

**Chemistry**
Increased potassium **Retevmo (n=158) Any Grade** 25.8% **Retevmo (n=158) Grade 3/4** 2.6% **Control Arm (n=98) Any Grade** 15.5% **Control Arm (n=98) Grade 3/4** 1.0%

**Chemistry**
Decreased albumin **Retevmo (n=158) Any Grade** 24.8% **Retevmo (n=158) Grade 3/4** 0% **Control Arm (n=98) Any Grade** 5.2% **Control Arm (n=98) Grade 3/4** 0%

**Chemistry**
Increased creatinine **Retevmo (n=158) Any Grade** 22.9% **Retevmo (n=158) Grade 3/4** 0% **Control Arm (n=98) Any Grade** 20.6% **Control Arm (n=98) Grade 3/4** 0%

**Chemistry**
Increased sodium **Retevmo (n=158) Any Grade** 21.8% **Retevmo (n=158) Grade 3/4** 0% **Control Arm (n=98) Any Grade** 13.4% **Control Arm (n=98) Grade 3/4** 0%

**Laboratory Abnormality** **Hematology**

**Hematology**
Decreased WBC **Retevmo (n=158) Any Grade** 56.5% **Retevmo (n=158) Grade 3/4** 1.3% **Control Arm (n=98) Any Grade** 61.9% **Control Arm (n=98) Grade 3/4** 9.3%

**Hematology**
Decreased neutrophils **Retevmo (n=158) Any Grade** 53.3% **Retevmo (n=158) Grade 3/4** 2.0% **Control Arm (n=98) Any Grade** 57.7% **Control Arm (n=98) Grade 3/4** 11.3%

**Hematology**
Decreased lymphocyte **Retevmo (n=158) Any Grade** 52.6% **Retevmo (n=158) Grade 3/4** 8.4% **Control Arm (n=98) Any Grade** 62.9% **Control Arm (n=98) Grade 3/4** 15.5%

**Hematology**
Decreased platelets **Retevmo (n=158) Any Grade** 52.6% **Retevmo (n=158) Grade 3/4** 3.3% **Control Arm (n=98) Any Grade** 39.2% **Control Arm (n=98) Grade 3/4** 5.2%

**Hematology**
Decreased hemoglobin **Retevmo (n=158) Any Grade** 21.4% **Retevmo (n=158) Grade 3/4** 0% **Control Arm (n=98) Any Grade** 90.7% **Control Arm (n=98) Grade 3/4** 5.2%

**Hematology**
Increased hemoglobin **Retevmo (n=158) Any Grade** 20.1% **Retevmo (n=158) Grade 3/4** 0% **Control Arm (n=98) Any Grade** 1.0% **Control Arm (n=98) Grade 3/4** 0%

	Retevmo (n=158)		Control Arm (n=98)
Laboratory Abnormality	Retevmo (n=158) Any Grade	Retevmo (n=158) Grade 3/4	Control Arm (n=98) Any Grade	Control Arm (n=98) Grade 3/4
Laboratory Abnormality Chemistry
Chemistry Increased ALT	Retevmo (n=158) Any Grade 80.9%	Retevmo (n=158) Grade 3/4 21.0%	Control Arm (n=98) Any Grade 62.9%	Control Arm (n=98) Grade 3/4 4.1%
Chemistry Increased AST	Retevmo (n=158) Any Grade 76.9%	Retevmo (n=158) Grade 3/4 9.6%	Control Arm (n=98) Any Grade 46.4%	Control Arm (n=98) Grade 3/4 0%
Chemistry Decreased calcium	Retevmo (n=158) Any Grade 52.6%	Retevmo (n=158) Grade 3/4 1.9%	Control Arm (n=98) Any Grade 23.7%	Control Arm (n=98) Grade 3/4 1.0%
Chemistry Increased bilirubin	Retevmo (n=158) Any Grade 51.6%	Retevmo (n=158) Grade 3/4 1.3%	Control Arm (n=98) Any Grade 9.4%	Control Arm (n=98) Grade 3/4 0%
Chemistry Decreased sodium	Retevmo (n=158) Any Grade 30.8%	Retevmo (n=158) Grade 3/4 3.2%	Control Arm (n=98) Any Grade 41.2%	Control Arm (n=98) Grade 3/4 2.1%
Chemistry Increased alkaline phosphatase	Retevmo (n=158) Any Grade 35.0%	Retevmo (n=158) Grade 3/4 1.3%	Control Arm (n=98) Any Grade 21.7%	Control Arm (n=98) Grade 3/4 0%
Chemistry Increased magnesium	Retevmo (n=158) Any Grade 26.9%	Retevmo (n=158) Grade 3/4 1.9%	Control Arm (n=98) Any Grade 15.5%	Control Arm (n=98) Grade 3/4 0%
Chemistry Increased potassium	Retevmo (n=158) Any Grade 25.8%	Retevmo (n=158) Grade 3/4 2.6%	Control Arm (n=98) Any Grade 15.5%	Control Arm (n=98) Grade 3/4 1.0%
Chemistry Decreased albumin	Retevmo (n=158) Any Grade 24.8%	Retevmo (n=158) Grade 3/4 0%	Control Arm (n=98) Any Grade 5.2%	Control Arm (n=98) Grade 3/4 0%
Chemistry Increased creatinine	Retevmo (n=158) Any Grade 22.9%	Retevmo (n=158) Grade 3/4 0%	Control Arm (n=98) Any Grade 20.6%	Control Arm (n=98) Grade 3/4 0%
Chemistry Increased sodium	Retevmo (n=158) Any Grade 21.8%	Retevmo (n=158) Grade 3/4 0%	Control Arm (n=98) Any Grade 13.4%	Control Arm (n=98) Grade 3/4 0%
Laboratory Abnormality Hematology
Hematology Decreased WBC	Retevmo (n=158) Any Grade 56.5%	Retevmo (n=158) Grade 3/4 1.3%	Control Arm (n=98) Any Grade 61.9%	Control Arm (n=98) Grade 3/4 9.3%
Hematology Decreased neutrophils	Retevmo (n=158) Any Grade 53.3%	Retevmo (n=158) Grade 3/4 2.0%	Control Arm (n=98) Any Grade 57.7%	Control Arm (n=98) Grade 3/4 11.3%
Hematology Decreased lymphocyte	Retevmo (n=158) Any Grade 52.6%	Retevmo (n=158) Grade 3/4 8.4%	Control Arm (n=98) Any Grade 62.9%	Control Arm (n=98) Grade 3/4 15.5%
Hematology Decreased platelets	Retevmo (n=158) Any Grade 52.6%	Retevmo (n=158) Grade 3/4 3.3%	Control Arm (n=98) Any Grade 39.2%	Control Arm (n=98) Grade 3/4 5.2%
Hematology Decreased hemoglobin	Retevmo (n=158) Any Grade 21.4%	Retevmo (n=158) Grade 3/4 0%	Control Arm (n=98) Any Grade 90.7%	Control Arm (n=98) Grade 3/4 5.2%
Hematology Increased hemoglobin	Retevmo (n=158) Any Grade 20.1%	Retevmo (n=158) Grade 3/4 0%	Control Arm (n=98) Any Grade 1.0%	Control Arm (n=98) Grade 3/4 0%

Based on an interim analysis with a data cutoff date of May 1, 2023.^7,10
10.1% (n=16) of patients permanently discontinued Retevmo (N=158) due to adverse events. 7.1% (n=11) were considered treatment-related, as assessed by trial investigator. Adverse events resulting in permanent discontinuation in ≥ 2 patients included increased ALT (n=2) and myocardial infarction (n=2)
Serious adverse events occurred in 34.8% of patients who received Retevmo. The most frequently reported serious adverse events (in ≥2% of patients) were pleural effusion, hepatic function abnormal, ascites, cholecystitis, and pneumonia.
More deaths were observed among those receiving Retevmo versus the entire control arm while on treatment or within 30 days of the last dose (n=7/158 vs n=0/98).
- Fatal adverse events occurred in 4.4% of patients; fatal adverse events included myocardial infarction (n=2), acute respiratory failure (n=1), cardiac arrest (n=1), malnutrition (n=1), respiratory failure (n=1), and sudden death (n=1). One additional patient randomized to the control arm had a fatal event (respiratory failure) during crossover treatment with Retevmo.
Dose interruptions and dose reductions due to adverse events occurred in 75.9% and 51.3% of patients who received Retevmo, respectively. See full Prescribing Information for dose modifications.
Adverse events requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, COVID-19, diarrhea, QT prolongation, and hypertension.
Adverse events requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, hypertension, hepatic function abnormal, and platelet count decreased.
Clinically relevant toxicities included decreased appetite (17.1%), hemorrhage (16.5%), interstitial lung disease/pneumonitis (4.4%), hypothyroidism (3.2%), hypersensitivity (2.5%), chylothorax (< 1%)
Five randomized patients never received study drug and were excluded from the safety analysis.
Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

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

Select Important Safety Information from LIBRETTO-001

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.

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 chemotherapy^7,9

LIBRETTO-431 (N=261) is 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 against chemotherapy with pembrolizumab and against the entire control arm.
10% of patients permanently discontinued treatment due to AEs with Retevmo (n=16/158)¹⁰

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.^7,9

Efficacy outcomes for patients treated with Retevmo (n=159) versus the entire control arm (n=102):

Median PFS = 24.8 months (95% CI: 17.3, NE) vs 11.2 months (95% CI: 8.8, 16.8)
ORR = 84% (95% CI: 77, 89) vs 63% (95% CI: 53, 72)
Median DoR = 24.2 months (95% CI: 17.9, NE) vs 12.0 months (95% CI: 9.7, 23.3)

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; CI=confidence interval; CNS=central nervous system; mDoR=median duration of response; INV=investigator; IRC=independent review committee; NE=not estimable; NSCLC=non-small cell lung cancer; ORR=objective response rate; RANO-BM=Response Assessment in Neuro-Oncology Brain Metastases; RECIST=Response Evaluation Criteria in Solid Tumours; RET=rearranged during transfection

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. Data on File, Lilly USA, LLC, DOF-SE-US-0063. 4. 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. 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. 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. 7. Zhou C, Solomon B, Loong HH, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med. In press. 8. Data on File. Lilly USA, LLC. DOF-SE-US-0076. 9. Data on File. Lilly USA, LLC. DOF-SE-US-0077. 10. Data on File. Lilly USA, LLC. DOF-SE-US-0078.

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.

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. 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; 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%).

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%).

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 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. Monitor open growth plates in adolescent 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.

Please see full Prescribing Information for Retevmo.

SE HCP ISI All_21SEP22

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 12 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 12 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 patients with 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^*

^*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.