Summary

This phase II Lung-MAP treatment trial tests whether carboplatin and pemetrexed with or without selpercatinib works to shrink tumors in patients with RET fusion-positive non-small cell lung cancer that is stage IV or has not responded to previous RET directed therapy. Chemotherapy drugs, such as carboplatin and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Selpercatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving selpercatinib in combination with carboplatin and pemetrexed may help lower the chance of the cancer growing and spreading.

Objectives

PRIMARY OBJECTIVE:
I. To compare investigator-assessed progression-free survival (IA-PFS) in participants with RET fusion-positive non-small cell lung cancer (NSCLC) with acquired selective RET inhibitor resistance randomized to carboplatin and pemetrexed with or without selpercatinib.

SECONDARY OBJECTIVES:
I. To evaluate if the combination of selpercatinib combined with carboplatin and pemetrexed during the first cycle of treatment has an acceptable toxicity rate.
II. To evaluate the frequency and severity of toxicities within the arms.
III. To compare the investigator-assessed objective response rate (ORR) (complete or partial confirmed response) between the arms.
IV. To compare overall survival (OS) between the arms.
V. To evaluate duration of investigator-assessed response among responders within each treatment arm.

TRANSLATIONAL MEDICINE OBJECTIVES:
I. To collect, process, and bank cell-free deoxyribonucleic acid (cfDNA) at baseline, progression, and end of treatment for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor deoxyribonucleic acid (ctDNA).
II. To establish a tissue/blood repository from participants with refractory non-small cell lung cancer (NSCLC).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive carboplatin intravenously (IV) over 30 minutes and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also selpercatinib orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients in both arms also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans during screening and on study, and collection of blood samples on study.

After completion of study treatment, patients who had disease progression are followed up every 6 months for 2 years and then at 3 years. Patients who did not have disease progression are followed up every 12 weeks until disease progression.

Eligibility

1. Participants must have stage IV or recurrent disease
2. Participants must have been assigned to S1900F based on biomarker analysis of tissue and/or blood and determined to have RET fusion-positive NSCLC as defined here: * Participants must have RET fusion-positive NSCLC as determined by the Foundation Medicine (FMI) tissue-assay or other tumor-based assays such as next generation sequencing (NGS), polymerase chain reaction (PCR), or fluorescent in situ hybridization (FISH), or by cfDNA blood assay as outlined in the LUNGMAP Screening Protocol. Participants previously tested for and determined to have RET-fusion-positive NSCLC outside of LUNGMAP, must also submit tissue for central FMI testing on the LUNGMAP Screening Protocol. Participants with RET fusions detected by IHC alone are not eligible. The testing must be done within a laboratory with Clinical Laboratory Improvement Act (CLIA), International Organization for Standardization (ISO)/International Electrotechnical Commission (IEC), College of American Pathologists (CAP), or similar certification. Presence of RET fusions detected on tests performed outside of LUNGMAP must have been confirmed by the study biomarker review panel
3. Participants must be negative for all additional validated oncogenic drivers that could cause resistance to selpercatinib treatment. This includes EGFR sensitizing mutations, EGFR T790M mutations, ALK gene fusions, ROS1 gene fusion, KRAS activating mutations, BRAF V600E mutation and MET exon 14 skipping mutations or high-level amplification and expression * NOTE: EGFR, ALK, ROS, KRAS, and BRAF testing is performed as part of the LUNGMAP screening/pre-screening FoundationOne test. If prior data is not available, results from the FMI testing must be obtained prior to sub-study randomization.
4. Participants must have measurable disease documented by CT or MRI. The CT from a combined positron emission tomography (PET)/CT may be used to document only non-measurable disease unless it is of diagnostic quality. Measurable disease must be assessed within 28 days prior to sub-study randomization. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study randomization. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to randomization
5. Participants must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to sub-study randomization
6. Participants must have received and developed disease progression during or after an anti-RET inhibitors treatment. The anti-RET inhibitor therapy must be the most recent therapy
7. Participants must have progressed (in the opinion of the treating physician) following the most recent line of therapy
8. Participants must have recovered (=< grade 1) from any side effects of prior therapy. Participants must not have received any radiation therapy within 14 days prior to sub-study randomization
9. Participants must have an electrocardiogram (ECG) performed within 28 days prior to sub-study randomization to obtain a baseline value. It is suggested that a local cardiologist review the corrected QT by Fridericia's correction formula (QTcF) intervals
10. Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL obtained within 28 days prior to sub-study randomization
11. Platelet count >= 100 x 10^3/uL obtained within 28 days prior to sub-study randomization
12. Hemoglobin >= 9 g/dL obtained within 28 days prior to sub-study randomization
13. Serum bilirubin =< institutional upper limit of normal (IULN) and either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN within 28 days 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 AST must be =< 5 x IULN (if both ALT and AST are done, both must be =< 5 x IULN)
14. Participants must have a serum creatinine =< the IULN OR measured or calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study randomization
15. Participants must have Zubrod performance status 0-1 documented within 28 days prior to sub-study randomization
16. Participants must provide pre-study history and physical exam within 28 days prior to sub-study randomization
17. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to sub-study randomization
18. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to sub-study randomization
19. Participants with known human immunodeficiency virus (HIV) infection are eligible, provided they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to sub-study randomization
20. Participants must be able to swallow capsules
21. Participants must agree to have blood specimens submitted for circulating tumor DNA (ctDNA)
22. Participants must also be offered participation in banking and in the correlative studies for collection and future use of specimens
23. Participants with impaired decision-making capacity are eligible as long as their neurological or psychological condition does not preclude their safe participation in the study (e.g., tracking pill consumption and reporting adverse events to the investigator)
24. Participants must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

Treatment Sites in Georgia