Treatment for Advanced Non-small Cell Lung Cancer With Actionable Genomic Alterations After Targeted Treatment and Chemotherapy (An Expanded Lung-MAP Treatment Trial)

This phase II Expanded Lung-MAP treatment trial compares how well sacituzumab govitecan alone, ivonescimab alone, or sacituzumab govitecan in combination with ivonescimab works in treating patients with non-small cell lung cancer (NSCLC) that has come back after a period of improvement (recurrent) or is stage IV and has a change in at least 1 of these genes: ALK, EGFR, HER2 (ERBB2), MET, NTRK, RET, and ROS1. This type of gene change is called an actionable genomic alteration (AGA), which means certain treatments can target the change to fight the cancer. Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a toxic drug called SN-38. Sacituzumab govitecan is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of tumor cells, known as TROP2 receptors, and delivers SN-38 to kill them. Ivonescimab is a bispecific antibody that can bind to two different antigens at the same time. It binds to programmed cell death protein 1 (PD1), a protein found on the surface of T cells (a type of white blood cell) and vascular endothelial growth factor (VEGF), a protein found on the surface of tumor cells. Ivonescimab may strengthen the immune system and interfere with the ability of tumor cells to grow and spread. Giving a combination of sacituzumab govitecan and ivonescimab work better than either drug alone, and sacituzumab govitecan alone, ivonescimab alone, or sacituzumab govitecan and ivonescimab together may work better than standard treatments at shrinking NSCLC with an AGA.

PRIMARY OBJECTIVES: I. To compare progression-free survival (PFS) between participants randomized to the combination of sacituzumab govitecan plus ivonescimab (SG-I) and sacituzumab govitecan (SG) alone. (Comparison between arms) II. To compare progression-free survival (PFS) between participants randomized to SG-I and ivonescimab (I) alone. (Comparison between arms) III. To evaluate the response (confirmed and unconfirmed, complete and partial) rate of SG against historical response rates. (Single Arm evaluation) IV. To evaluate the response (confirmed and unconfirmed, complete and partial) rate of I against historical response rates. (Single Arm evaluation) V. To evaluate the response (confirmed and unconfirmed, complete and partial) rate of SG-I against historical response rates. (Single Arm evaluation) SECONDARY OBJECTIVES: I. To evaluate the rate of dose-limiting toxicities among participants treated with SG-I in the safety run-in analysis population. II. To compare response rates between ivonescimab with or without sacituzumab govitecan. III. To compare response rates of sacituzumab govitecan with or without ivonescimab. IV. To compare overall survival between the SG-I and SG arms. V. To compare overall survival between the SG-I and I arms. VI. To summarize disease control rates within each treatment arm. VII. To summarize the duration of response (DoR) among responders within each treatment arm. VIII. To evaluate the central nervous system (CNS) progression-free survival per local investigator assessment in participants with baseline CNS metastasis within each treatment arm. VIII. To evaluate the frequency and severity of toxicities within each treatment arm. IX. To evaluate if clinical outcomes (response, progression-free survival \[PFS\], overall survival \[OS\]) within each treatment arm differs between the subgroup of participants with EGFR mutations to those without EGFR mutations. X. To evaluate if clinical outcomes (response, PFS, OS) within each treatment arm differs between the subgroup of participants by the presence or absence of PD-L1 expression (\< 1% vs 1% or greater). TRANSLATIONAL MEDICINE OBJECTIVES: I. To perform comprehensive next-generation sequencing of circulating tumor deoxyribonucleic acid (DNA) (ctDNA) at baseline in all participants to assess its clinical utility in comparison to tumor tissue biomarker profiles. II. To process and bank cell free DNA (cfDNA) at cycle 3 day 1 and progression for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor DNA (ctDNA). III. To establish a tissue/blood repository to pursue future studies. OUTLINE: Patients are randomized to 1 of 3 arms. ARM 1: Patients receive ivonescimab intravenously (IV) over 1-2 hours on day 1 of each cycle and sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the study. ARM 2: Patients receive sacituzumab govitecan IV over 1-3 hours on day 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study. ARM 3: Patients receive ivonescimab IV over 1-2 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the study. After completion of study treatment, patients without disease progression are followed every 12 weeks or more often as clinically indicated until progression, then every 6 months for 2 years and then at end of 3 years from date of randomization. Patients with disease progression are followed every 6 months for 2 years and then at end of 3 years from date of randomization.