A Study of Selpercatinib (LY3527723) in Participants With Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The reason for this study is to see if the study drug selpercatinib compared to a standard treatment is effective and safe in participants with rearranged during transfection (RET) fusion-positive non-squamous non-small cell lung cancer (NSCLC) that has spread to other parts of the body. Participants who are assigned to the standard treatment and discontinue due to progressive disease have the option to potentially crossover to selpercatinib.

Official Title
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LIBRETTO-431: A Multicenter, Randomized, Open-Label, Phase 3 Trial Comparing Selpercatinib to Platinum-Based and Pemetrexed Therapy With or Without Pembrolizumab as Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Selpercatinib
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Pemetrexed
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed, Stage IIIB-IIIC or Stage IV non-squamous NSCLC that is not suitable for radical surgery or radiation therapy. A RET gene fusion in tumor and/or blood from a qualified laboratory. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Adequate hematologic, hepatic and renal function. Willingness of men and women of reproductive potential to observe conventional and highly effective birth control for the duration of treatment and for 6 months after. Ability to swallow capsules. Exclusion Criteria: Additional validated oncogenic drivers in NSCLC if known. Prior systemic therapy for metastatic disease. Treatment (chemotherapy, immunotherapy, or biological therapy) in the adjuvant/neoadjuvant setting is permitted if it was completed at least 6 months prior to randomization. Major surgery within 3 weeks prior to planned start of selpercatinib. Radiotherapy for palliation within 1 week of the first dose of study treatment or any radiotherapy within 6 months prior to the first dose of study treatment if more than 30 Gy to the lung. Symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or untreated spinal cord compression. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of selpercatinib or prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF) > 470 milliseconds. Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing intercurrent illness, such as hypertension or diabetes, despite optimal treatment. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug. Pregnancy or lactation. Other malignancy unless nonmelanoma skin cancer, carcinoma in situ of the cervix or other in situ cancers or a malignancy diagnosed ≥2 years previously and not currently active. Uncontrolled, disease related pericardial effusion or pleural effusion. Requiring chronic treatment with steroids. Exclusion Criteria for Participants Receiving Pembrolizumab: History of interstitial lung disease or interstitial pneumonitis. Active autoimmune disease or any illness or treatment that could compromise the immune system.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selpercatinib<br>Selpercatinib administered orally. | Drug: Selpercatinib<br>* Administered orally<br>* Other names: LOXO-292;|
| Active Comparator: Pemetrexed with or without Pembrolizumab<br>Pemetrexed administered intravenously (IV) plus the investigator's discretion of carboplatin IV or cisplatin IV with or without pembrolizumab IV. | Drug: Carboplatin<br>* Administered IV<br>Drug: Cisplatin<br>* Administered IV<br>Drug: Pemetrexed<br>* Administered IV<br>Drug: Pembrolizumab<br>* Administered IV<br>|
| Active Comparator: Pemetrexed with Pembrolizumab<br>Pemetrexed administered IV plus the investigator's discretion of carboplatin IV or cisplatin IV with pembrolizumab IV. | Drug: Carboplatin<br>* Administered IV<br>Drug: Cisplatin<br>* Administered IV<br>Drug: Pemetrexed<br>* Administered IV<br>Drug: Pembrolizumab<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) (with Pembrolizumab) | PFS by BICR (with Pembrolizumab) | Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) | 
| PFS by BICR (with or without Pembrolizumab) | PFS by BICR (with or without Pembrolizumab) | Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) by BICR (with Pembrolizumab) | DCR by BICR (with Pembrolizumab) | Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) | 
| DCR by BICR (with or without Pembrolizumab) | DCR by BICR (with or without Pembrolizumab) | Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) | 
| PFS2 (with Pembrolizumab) | PFS2 (with Pembrolizumab) | Baseline to Second Disease Progression or Death from Any Cause (Estimated at up to 36 Months) | 
| PFS2 (with or without Pembrolizumab) | PFS2 (with or without Pembrolizumab) | Baseline to Second Disease Progression or Death from Any Cause (Estimated at up to 36 Months) | 
| Overall Response Rate (ORR): Percentage of Participants with Complete Response (CR) or Partial Response (PR) by BICR (with Pembrolizumab) | ORR: Percentage of Participants with CR or PR by BICR (with Pembrolizumab) | Baseline through Disease Progression or Death (Estimated at up to 24 Months) | 
| ORR: Percentage of Participants with CR or PR by BICR (with or without Pembrolizumab) | ORR: Percentage of Participants with CR or PR by BICR (with or without Pembrolizumab) | Baseline through Disease Progression or Death (Estimated at up to 24 Months) | 
| Duration of Response (DoR) by BICR (with Pembrolizumab) | DOR by BICR (with Pembrolizumab) | Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Estimated at up to 24 Months) | 
| DOR by BICR (with or without Pembrolizumab) | DOR by BICR (with or without Pembrolizumab) | Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Estimated at up to 24 Months) | 
| Overall Survival (OS) (with Pembrolizumab) | OS (with Pembrolizumab) | Baseline to Date of Death from Any Cause (Estimated at up to 48 Months) | 
| OS (with or without Pembrolizumab) | OS (with or without Pembrolizumab) | Baseline to Date of Death from Any Cause (Estimated at up to 48 Months) | 
| Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 by BICR (with Pembrolizumab) | Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RECIST 1.1 by BICR (with Pembrolizumab) | Baseline through Central Nervous System (CNS) Progression or Death (Estimated at up to 24 Months) | 
| Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RECIST 1.1 by BICR (with or without Pembrolizumab) | Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RECIST 1.1 by BICR (with or without Pembrolizumab) | Baseline through CNS Progression or Death (Estimated at up to 24 Months) | 
| Intracranial DOR per RECIST 1.1 by BICR (with Pembrolizumab) | Intracranial DOR per RECIST 1.1 by BICR (with Pembrolizumab) | Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause (Estimated at up to 24 Months) | 
| Intracranial DOR per RECIST 1.1 by BICR (with or without Pembrolizumab) | Intracranial DOR per RECIST 1.1 by BICR (with or without Pembrolizumab) | Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause (Estimated at up to 24 Months) | 
| Time to Deterioration of Pulmonary Symptoms (with Pembrolizumab) | Time to Deterioration of Pulmonary Symptoms Measured by the NSCLC-Symptom Assessment Questionnaire (SAQ) (with Pembrolizumab) | Baseline to Deterioration of Pulmonary Symptoms (Estimated at up to 24 Months) | 
| Time to Deterioration of Pulmonary Symptoms (with or without Pembrolizumab) | Time to Deterioration of Pulmonary Symptoms Measured by the NSCLC-SAQ (with or without Pembrolizumab) | Baseline to Deterioration of Pulmonary Symptoms (Estimated at up to 24 Months) | 
| The Concordance of the Local Lab and the Central Lab RET Results: Percentage of Participants with RET-Positive Specimens as Called by the Central Lab, which is also RET-Positive as Called by a Local Lab (Positive Percent Agreement) | The Concordance of the Local Lab and the Central Lab RET Results: Percentage of Participants with RET-Positive Specimens as Called by the Central Lab, which is also RET-Positive as Called by a Local Lab (Positive Percent Agreement) | Baseline | 
| Time to CNS Progression per RECIST 1.1 by BICR (with Pembrolizumab) | Time to CNS Progression per RECIST 1.1 by BICR (with Pembrolizumab) | Baseline through CNS Progression or Death (Estimated at up to 24 Months) | 
| Time to CNS Progression per RECIST 1.1 by BICR (with or without Pembrolizumab) | Time to CNS Progression per RECIST 1.1 by BICR (with or without Pembrolizumab) | Baseline through CNS Progression or Death (Estimated at up to 24 Months) | 
| Intracranial ORR: Percentage of Participants with Intracranial CR or PR per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) by BICR (with Pembrolizumab) | Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RANO-BM by BICR (with Pembrolizumab) | Baseline through CNS Progression or Death (Estimated at up to 24 Months) | 
| Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RANO-BM by BICR (with or without Pembrolizumab) | Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RANO-BM by BICR (with or without Pembrolizumab) | Baseline through CNS Progression or Death (Estimated at up to 24 Months) | 
| Intracranial DOR per RANO-BM by BICR (with Pembrolizumab) | Intracranial DOR per RANO-BM by BICR (with Pembrolizumab) | Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause (Estimated at up to 24 Months) | 
| Intracranial DOR per RANO-BM by BICR (with or without Pembrolizumab) | Intracranial DOR per RANO-BM by BICR (with or without Pembrolizumab) | Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause (Estimated at up to 24 Months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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targeted therapy