A Study of Selpercatinib (LY3527723) in Participants With Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer (LIBRETTO-431)

• ClinicalTrials.gov Identifier: NCT04194944
• Recruitment Status: Active, not recruiting
• First Posted: December 11, 2019
• Last Update Posted: February 21, 2023
• Sponsor: Loxo Oncology, Inc.
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company ( Loxo Oncology, Inc. )

Tracking Information

• First Submitted Date: December 9, 2019
• First Posted Date: December 11, 2019
• Last Update Posted Date: February 21, 2023
• Actual Study Start Date: February 17, 2020
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 19, 2020)

• Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) (with Pembrolizumab) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) ]
  PFS by BICR (with Pembrolizumab)
• PFS by BICR (with or without Pembrolizumab) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) ]
  PFS by BICR (with or without Pembrolizumab)

Original Primary Outcome Measures (submitted: December 9, 2019)

Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) (with or without Pembrolizumab) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) ]

PFS by BICR (with or without Pembrolizumab)

Current Secondary Outcome Measures (submitted: February 2, 2021)

• Disease Control Rate (DCR) by BICR (with Pembrolizumab) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) ]
  DCR by BICR (with Pembrolizumab)
• DCR by BICR (with or without Pembrolizumab) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) ]
  DCR by BICR (with or without Pembrolizumab)
• PFS2 (with Pembrolizumab) [ Time Frame: Baseline to Second Disease Progression or Death from Any Cause (Estimated at up to 36 Months) ]
  PFS2 (with Pembrolizumab)
• PFS2 (with or without Pembrolizumab) [ Time Frame: Baseline to Second Disease Progression or Death from Any Cause (Estimated at up to 36 Months) ]
  PFS2 (with or without Pembrolizumab)
• Overall Response Rate (ORR): Percentage of Participants with Complete Response (CR) or Partial Response (PR) by BICR (with Pembrolizumab) [ Time Frame: Baseline through Disease Progression or Death (Estimated at up to 24 Months) ]
  ORR: Percentage of Participants with CR or PR by BICR (with Pembrolizumab)
• ORR: Percentage of Participants with CR or PR by BICR (with or without Pembrolizumab) [ Time Frame: 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)
• Duration of Response (DoR) by BICR (with Pembrolizumab) [ Time Frame: 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 Pembrolizumab)
• DOR by BICR (with or without Pembrolizumab) [ Time Frame: 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)
• Overall Survival (OS) (with Pembrolizumab) [ Time Frame: Baseline to Date of Death from Any Cause (Estimated at up to 48 Months) ]
  OS (with Pembrolizumab)
• OS (with or without Pembrolizumab) [ Time Frame: Baseline to Date of Death from Any Cause (Estimated at up to 48 Months) ]
  OS (with or without Pembrolizumab)
• Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 by BICR (with Pembrolizumab) [ Time Frame: 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 Pembrolizumab)
• Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RECIST 1.1 by BICR (with or without Pembrolizumab) [ Time Frame: Baseline through 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 DOR per RECIST 1.1 by BICR (with Pembrolizumab) [ Time Frame: 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 Pembrolizumab)
• Intracranial DOR per RECIST 1.1 by BICR (with or without Pembrolizumab) [ Time Frame: 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)
• Time to Deterioration of Pulmonary Symptoms (with Pembrolizumab) [ Time Frame: Baseline to Deterioration of Pulmonary Symptoms (Estimated at up to 24 Months) ]
  Time to Deterioration of Pulmonary Symptoms Measured by the NSCLC-Symptom Assessment Questionnaire (SAQ) (with Pembrolizumab)
• Time to Deterioration of Pulmonary Symptoms (with or without Pembrolizumab) [ Time Frame: Baseline to Deterioration of Pulmonary Symptoms (Estimated at up to 24 Months) ]
  Time to Deterioration of Pulmonary Symptoms Measured by the NSCLC-SAQ (with or without Pembrolizumab)
• 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) [ Time Frame: Baseline ]
  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)
• Time to CNS Progression per RECIST 1.1 by BICR (with Pembrolizumab) [ Time Frame: Baseline through CNS Progression or Death (Estimated at up to 24 Months) ]
  Time to CNS Progression per RECIST 1.1 by BICR (with Pembrolizumab)
• Time to CNS Progression per RECIST 1.1 by BICR (with or without Pembrolizumab) [ Time Frame: 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)
• Intracranial ORR: Percentage of Participants with Intracranial CR or PR per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) by BICR (with Pembrolizumab) [ Time Frame: 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 Pembrolizumab)
• Intracranial ORR: Percentage of Participants with Intracranial CR or PR per RANO-BM by BICR (with or without Pembrolizumab) [ Time Frame: 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 DOR per RANO-BM by BICR (with Pembrolizumab) [ Time Frame: 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 Pembrolizumab)
• Intracranial DOR per RANO-BM by BICR (with or without Pembrolizumab) [ Time Frame: 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)

Original Secondary Outcome Measures (submitted: December 9, 2019)

• PFS by BICR (with Pembrolizumab) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 24 Months) ]
  PFS by BICR (with Pembrolizumab)
• PFS2 (with or without Pembrolizumab) [ Time Frame: Baseline to Second Disease Progression or Death from Any Cause (Estimated at up to 36 Months) ]
  PFS2 (with or without Pembrolizumab)
• Overall Response Rate (ORR): Percentage of Participants with Complete Response (CR) or Partial Response (PR) by BICR (with Pembrolizumab) [ Time Frame: Baseline through Disease Progression or Death (Estimated at up to 24 Months) ]
  ORR: Percentage of Participants with CR or PR by BICR (with Pembrolizumab)
• ORR: Percentage of Participants with CR or PR by BICR (with or without Pembrolizumab) [ Time Frame: 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)
• Duration of Response (DoR) by BICR (with Pembrolizumab) [ Time Frame: 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 Pembrolizumab)
• DOR by BICR (with or without Pembrolizumab) [ Time Frame: Baseline through Disease Progression or Death (Estimated at up to 24 Months) ]
  DOR by BICR (with or without Pembrolizumab)
• Overall Survival (OS) (with Pembrolizumab) [ Time Frame: Baseline to Date of Death from Any Cause (Estimated at up to 48 Months) ]
  OS (with Pembrolizumab)
• OS (with or without Pembrolizumab) [ Time Frame: Baseline to Date of Death from Any Cause (Estimated at up to 48 Months) ]
  OS (with or without Pembrolizumab)
• Intracranial ORR: Percentage of Participants with Intracranial CR or PR by BICR (with or without Pembrolizumab) [ Time Frame: Baseline through Disease Progression or Death (Estimated at up to 24 Months) ]
  Intracranial ORR: Percentage of Participants with Intracranial CR or PR by BICR (with or without Pembrolizumab)
• Intracranial DOR by BICR (with or without Pembrolizumab) [ Time Frame: Baseline through Disease Progression or Death (Estimated at up to 24 Months) ]
  Intracranial DOR by BICR (with or without Pembrolizumab)
• Time to Deterioration of Pulmonary Symptoms (with Pembrolizumab) [ Time Frame: Baseline to Deterioration of Pulmonary Symptoms (Estimated at up to 24 Months) ]
  Time to Deterioration of Pulmonary Symptoms Measured by the NSCLC-Symptom Assessment Questionnaire (SAQ) (with Pembrolizumab)
• Time to Deterioration of Pulmonary Symptoms (with or without Pembrolizumab) [ Time Frame: Baseline to Deterioration of Pulmonary Symptoms (Estimated at up to 24 Months) ]
  Time to Deterioration of Pulmonary Symptoms Measured by the NSCLC-SAQ (with or without Pembrolizumab)
• 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) [ Time Frame: Baseline ]
  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)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Selpercatinib (LY3527723) in Participants With Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Small Cell Lung Cancer

Intervention

• Drug: Selpercatinib
  Administered orally
  Other Names:

  • LY3527723
  • LOXO-292
• Drug: Carboplatin
  Administered IV
• Drug: Cisplatin
  Administered IV
• Drug: Pemetrexed
  Administered IV
• Drug: Pembrolizumab
  Administered IV

Study Arms

• Experimental: Selpercatinib
  Selpercatinib administered orally.
  Intervention: Drug: Selpercatinib
• Active Comparator: Pemetrexed with or without Pembrolizumab
  Pemetrexed administered intravenously (IV) plus the investigator's discretion of carboplatin IV or cisplatin IV with or without pembrolizumab IV.
  Interventions:

  • Drug: Carboplatin
  • Drug: Cisplatin
  • Drug: Pemetrexed
  • Drug: Pembrolizumab
• Active Comparator: Pemetrexed with Pembrolizumab
  Pemetrexed administered IV plus the investigator's discretion of carboplatin IV or cisplatin IV with pembrolizumab IV.
  Interventions:

  • Drug: Carboplatin
  • Drug: Cisplatin
  • Drug: Pemetrexed
  • Drug: Pembrolizumab

Publications *

• Claerhout S, Lehnert S, Vander Borght S, Spans L, Dooms C, Wauters E, Vansteenkiste J, Weynand B, Deraedt K, Bourgain C, Vanden Bempt I. Targeted RNA sequencing for upfront analysis of actionable driver alterations in non-small cell lung cancer. Lung Cancer. 2022 Apr;166:242-249. doi: 10.1016/j.lungcan.2022.02.013. Epub 2022 Mar 1.
• Solomon BJ, Zhou CC, Drilon A, Park K, Wolf J, Elamin Y, Davis HM, Soldatenkova V, Sashegyi A, Lin AB, Lin BK, F Loong HH, Novello S, Arriola E, Perol M, Goto K, Santini FC. Phase III study of selpercatinib versus chemotherapy +/- pembrolizumab in untreated RET positive non-small-cell lung cancer. Future Oncol. 2021 Mar;17(7):763-773. doi: 10.2217/fon-2020-0935. Epub 2020 Nov 5.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: August 19, 2020): 250
• Original Estimated Enrollment (submitted: December 9, 2019): 400
• Estimated Study Completion Date: July 2027
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Hong Kong, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Romania, Russian Federation, Singapore, Spain, Taiwan, Turkey, Ukraine, United Kingdom
• Removed Location Countries: United States

Administrative Information

• NCT Number: NCT04194944
• Other Study ID Numbers: 17479; J2G-MC-JZJC ( Other Identifier: Eli Lilly and Company ); 2019-001979-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: http://vivli.org/

• Current Responsible Party: Eli Lilly and Company ( Loxo Oncology, Inc. )
• Original Responsible Party: Eli Lilly and Company
• Current Study Sponsor: Loxo Oncology, Inc.
• Original Study Sponsor: Eli Lilly and Company
• Collaborators: Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: February 2023