Testing the Use of Targeted Treatment for RET Positive Advanced Non-small Cell Lung Cancer

Inclusion Criteria:

• Participants must have stage IV or recurrent disease

• Participants must have been assigned to S1900F based on biomarker analysis of tissueand/or blood and determined to have RET fusion-positive NSCLC as defined here:

• Participants must have RET fusion-positive NSCLC as determined by theFoundation Medicine (FMI) tissue-assay or other tumor-based assays such as nextgeneration sequencing (NGS), polymerase chain reaction (PCR), or fluorescent insitu hybridization (FISH), or by cfDNA blood assay as outlined in the LUNGMAPScreening Protocol. Participants previously tested for and determined to haveRET-fusion-positive NSCLC outside of LUNGMAP, must also submit tissue forcentral FMI testing on the LUNGMAP Screening Protocol. Participants with RETfusions detected by IHC alone are not eligible. The testing must be done withina laboratory with Clinical Laboratory Improvement Act (CLIA), InternationalOrganization for Standardization (ISO)/International ElectrotechnicalCommission (IEC), College of American Pathologists (CAP), or similarcertification. Presence of RET fusions detected on tests performed outside ofLUNGMAP must have been confirmed by the study biomarker review panel

• Participants must be negative for all additional validated oncogenic drivers thatcould cause resistance to selpercatinib treatment. This includes EGFR sensitizingmutations, EGFR T790M mutations, ALK gene fusions, ROS1 gene fusion, KRAS activatingmutations, BRAF V600E mutation and MET exon 14 skipping mutations or high-levelamplification and expression

• NOTE: EGFR, ALK, ROS, KRAS, and BRAF testing is performed as part of theLUNGMAP screening/pre-screening FoundationOne test. If prior data is notavailable, results from the FMI testing must be obtained prior to sub-studyrandomization.

• Participants must have measurable disease documented by computed tomography (CT) ormagnetic resonance imaging (MRI). The CT from a combined positron emissiontomography (PET)/CT may be used to document only non-measurable disease unless it isof diagnostic quality. Measurable disease must be assessed within 28 days prior tosub-study randomization. Pleural effusions, ascites and laboratory parameters arenot acceptable as the only evidence of disease. Non-measurable disease must beassessed within 42 days prior to sub-study randomization. All disease must beassessed and documented on the Baseline Tumor Assessment Form. Participants whoseonly measurable disease is within a previous radiation therapy port must demonstrateclearly progressive disease (in the opinion of the treating investigator) prior torandomization

• Participants must have a CT or MRI scan of the brain to evaluate for central nervoussystem (CNS) disease within 42 days prior to sub-study randomization

• Participants must have received and developed disease progression during or after ananti-RET inhibitors treatment. The anti-RET inhibitor therapy must be the mostrecent therapy

• Participants must have progressed (in the opinion of the treating physician)following the most recent line of therapy

• Participants must have recovered (=< grade 1) from any side effects of priortherapy. Participants must not have received any radiation therapy within 14 daysprior to sub-study randomization

• For participants with stage IV or recurrent disease, the participant must not havereceived a platinum-based chemotherapy regimen. For participants whose priorsystemic therapy was for stage I-III disease only (i.e., participant has notreceived any treatment for stage IV or recurrent disease), disease progression onplatinum-based chemotherapy must not have occurred within one year (365 days) fromthe last date that the participant received that therapy. Prior anti-PD-1/PD-L1therapy, alone or in combination (e.g., nivolumab, pembrolizumab, or durvalumab) isallowed

• Participants must have an electrocardiogram (ECG) performed within 28 days prior tosub-study randomization. It is suggested that a local cardiologist review thecorrected QT by Fridericia's correction formula (QTcF) intervals

• Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL obtained within 28 days prior tosub-study randomization

• Platelet count >= 100 x 10^3/uL obtained within 28 days prior to sub-studyrandomization

• Hemoglobin >= 9 g/dL obtained within 28 days prior to sub-study randomization

• Serum bilirubin =< institutional upper limit of normal (IULN) and either alanineaminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN within 28days prior to sub-study randomization (if both ALT and AST are done, both must be < 2 x IULN). For participants with liver metastases, bilirubin and either ALT or ASTmust be =< 5 x IULN (if both ALT and AST are done, both must be =< 5 x IULN)

• Participants must have a serum creatinine =< the IULN OR measured or calculatedcreatinine clearance >= 50 mL/min using the following Cockcroft-Gault Formula. Thisspecimen must have been drawn and processed within 28 days prior to sub-studyrandomization

• Participants must have Zubrod performance status 0-1 documented within 28 days priorto sub-study randomization

• Participants must provide pre-study history and physical exam within 28 days priorto sub-study randomization

• Participants with evidence of chronic hepatitis B virus (HBV) infection must haveundetectable HBV viral load on suppressive therapy within 28 days prior to sub-studyrandomization

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. Participants with HCV infection who are currently on treatmentmust have an undetectable HCV viral load within 28 days prior to sub-studyrandomization

• Participants with known human immunodeficiency virus (HIV) infection are eligible,provided they are on effective anti-retroviral therapy and have undetectable viralload at their most recent viral load test and within 6 months prior to sub-studyrandomization

• Participants must be able to swallow capsules

• Participants must agree to have blood specimens submitted for circulating tumor DNA (ctDNA)

• Participants must also be offered participation in banking and in the correlativestudies for collection and future use of specimens

• Participants with impaired decision-making capacity are eligible as long as theirneurological or psychological condition does not preclude their safe participationin the study (e.g., tracking pill consumption and reporting adverse events to theinvestigator)

• Participants must be informed of the investigational nature of this study and mustsign and give written informed consent in accordance with institutional and federalguidelines

Exclusion Criteria:

• Participants must not have leptomeningeal disease, spinal cord compression or brainmetastases unless: (1) metastases have been locally treated and have remainedclinically controlled and asymptomatic for at least 14 days following treatment, andprior to sub-study randomization, AND (2) participant has no residual neurologicaldysfunction and has been off corticosteroids for at least 24 hours prior tosub-study randomization

• Participants must not have received any prior systemic therapy (systemicchemotherapy, tyrosine kinase inhibitor [TKI], immunotherapy or investigationaldrug) within 14 days prior to sub-study randomization

• Participants must not be planning to receive any concurrent chemotherapy,immunotherapy, biologic or hormonal therapy for cancer treatment while receivingtreatment on this study. Concurrent use of hormones for non-cancer-relatedconditions (e.g., insulin for diabetes and hormone replacement therapy) isacceptable

• Participants must not have a prior or concurrent malignancy whose natural history ortreatment (in the opinion of the treating physician) has the potential to interferewith the safety or efficacy assessment of the investigational regimen

• Participants must not have had a major surgery within 14 days prior to sub-studyrandomization. Participants must have fully recovered from the effects of priorsurgery in the opinion of the treating investigator

• Participants must not have any grade III/IV cardiac disease as defined by the NewYork Heart Association Criteria (i.e., participants with cardiac disease resultingin marked limitation of physical activity or resulting in inability to carry on anyphysical activity without discomfort), unstable angina pectoris, and myocardialinfarction within 6 months, or serious uncontrolled cardiac arrhythmia

• Participants must not be pregnant or nursing. Individuals who are of reproductivepotential must have agreed to use an effective contraceptive method with detailsprovided as a part of the consent process. A person who has had menses at any timein the preceding 12 consecutive months or who has semen likely to contain sperm isconsidered to be of "reproductive potential." In addition to routine contraceptivemethods, "effective contraception" also includes refraining from sexual activitythat might result in pregnancy and surgery intended to prevent pregnancy (or with aside-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy,bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm inthe semen