Sotorasib in Combination With Trastuzumab Deruxtecan for the Treatment of Locally Advanced and Metastatic Non-small Cell Lung Cancer With a KRAS G12C Mutation

PRIMARY OBJECTIVES: I. To determine the safety and tolerability of sotorasib (AMG-510) combined with trastuzumab deruxtecan (DS-8201a) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS\^G12C mutation who progress on a KRAS\^G12C inhibitor and platinum-based chemotherapy with or without programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) inhibitors or PD1/L1 inhibitors alone. (Phase I) II. To determine overall response rate (ORR) defined as the proportion of patients with a confirmed response as per investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. (Phase II) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. (Phase I) II. To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) when combined. (Phase I) III. To estimate overall response rate (ORR) defined as the proportion of patients with a confirmed response as per investigator assessment according to RECIST version 1.1. (Phase I) IV. To estimate progression free survival (PFS). (Phase II) V. To estimate duration of response (DOR). (Phase II) VI. To estimate overall survival (OS). (Phase II) VII. To estimate adverse events (AEs) associated with the combination treatment. (Phase II) EXPLORATORY OBJECTIVES: I. To assess the rate of overexpression of ERBB2/ERBB3 gene expression by ribonucleic acid (RNA) sequencing (RNAseq) on NSCLC biopsy specimens collected at the pre-treatment timepoint in patients receiving sotorasib (AMG-510) + trastuzumab deruxtecan (DS-8201a). (Phase II) II. To estimate the correlation of ERBB2 gene expression measured by RNAseq on pre-treatment biopsies with response to the combination therapy and duration of response. (Phase II) III. To evaluate the pharmacokinetics (PK) of trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) and the immunogenicity of trastuzumab deruxtecan (DS-8201a). (Phase II) OUTLINE: This is a phase I dose-escalation study of sotorasib in combination with trastuzumab deruxtecan (DS-8201a) followed by a phase II dose-expansion study. Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 and sotorasib orally (PO) once daily (QD) on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsy and brain magnetic resonance imaging (MRI) at screening and echocardiography (ECHO) or multigated acquisition scan (MUGA), computed tomography (CT), MRI and blood sample collection throughout the study. Additionally, patients with brain metastasis undergo brain MRI throughout the study. After completion of study treatment, patients are followed every 3 months for up to 5 years.