This phase II trial compares the effect of sotorasib to durvalumab in treating patients with minimal residual disease (MRD) and non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced) who also have a KRAS G12C gene mutation. Sotorasib is a is type of targeted therapy. It works by blocking a protein made by the mutated KRAS gene, and this blocking action may help keep tumor cells from growing and may kill them. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. For patients with MRD after standard treatment, switching to sotorasib may be a better treatment option compared to the standard treatment approach of staying on durvalumab.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT06333678.
PRIMARY OBJECTIVE:
I. To determine whether switch sotorasib therapy can improve progression-free survival (PFS) compared to continuation of consolidation of durvalumab in patients with LA-NSCLC who have a KRAS G12C mutation and MRD after chemoradiation and during consolidative durvalumab therapy.
SECONDARY OBJECTIVES:
I. To determine whether switch sotorasib therapy has acceptable high-grade toxicity in patients with LA-NSCLC who have a KRAS G12 C mutation and MRD after chemoradiation and during consolidative durvalumab therapy.
II. To determine whether switch sotorasib therapy improves overall survival (OS) compared to continuation durvalumab in patients with LA-NSCLC who have a KRAS G12 C mutation and MRD after chemoradiation and during consolidative durvalumab therapy.
III. To determine whether circulating tumor DNA (ctDNA) clearance at 6 months is associated with PFS and OS, in order to determine whether ctCNA clearance using liquid biopsies can be used as a surrogate for future survival events.
EXPLORATORY OBJECTIVES:
I. To evaluate the correlation between changes/kinetics in circulating tumor DNA during treatment with durvalumab and: a) response rate to sotorasib (if applicable), b) PFS, and c) OS.
II. To evaluate the concordance and tumor heterogeneity between plasma and tissue mutational profiles in patients who have undergone sequencing using both methods up to 12 weeks apart.
III. To assess the correlation between PFS on durvalumab and additional biomarkers, specifically: a) PD-L1 expression and b) co-mutational status.
OUTLINE:
PRE-MONITORING PHASE: Patients continue to receive standard of care (SOC) chemoradiation. Patients with detectable MRD and without progression of disease on imaging post chemoradiation continue onto the Monitoring Phase of the study.
MONITORING PHASE: Patients receive SOC durvalumab intravenously (IV) every 2 or 4 weeks. Patients with detectable MRD and without progression of disease on imaging after durvalumab continue onto the Treatment Phase of the study.
TREATMENT PHASE: Patients are randomized to 1 of 2 groups.
GROUP 1: Patients receive SOC durvalumab IV every 2 or 4 weeks up to 12 months in the absence of disease progression or unacceptable toxicity.
GROUP 2: Patients receive sotorasib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity.
All patients also undergo computed tomography (CT) and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months during year 2, then every 6 months during years 3-5, then once a year or every 2 weeks during month 1, then every 4 weeks during months 2-24, then every 3 months during years 3-5, then twice yearly.
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorNarek Shaverdian
