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

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.

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.