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.~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.
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.