NCT07012031

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

A Phase I/II Study Evaluating the Safety, Tolerability, and Efficacy of Sotorasib Plus Trastuzumab Deruxtecan in Patients With Advanced Non-Small Cell Lung Cancer With a KRASG12C Mutation

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 37 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This phase I/II trial tests the safety, side effects and best dose of sotorasib with trastuzumab deruxtecan and how well the combination works in treating patients with KRAS G12C mutated non-small cell lung cancer that has spread to nearby tissues or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Sotorasib blocks a protein made by the mutated KRAS gene (KRAS p.G12C), which may help keep tumor cells from growing and may kill them. It is a type of targeted therapy. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Giving sotorasib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or effective in treating patients with locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation.

Detailed description

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.

Conditions

• Locally Advanced Lung Non-Small Cell Carcinoma
• Metastatic Lung Non-Small Cell Carcinoma
• Stage III Lung Cancer AJCC v8
• Stage IV Lung Cancer AJCC v8

Interventions

Type	Name	Description
PROCEDURE	Biopsy Procedure	Undergo tumor biopsy
PROCEDURE	Biospecimen Collection	Undergo blood sample collection
PROCEDURE	Computed Tomography	Undergo CT
PROCEDURE	Echocardiography Test	Undergo ECHO
PROCEDURE	Magnetic Resonance Imaging	Undergo MRI
PROCEDURE	Multigated Acquisition Scan	Undergo MUGA
DRUG	Sotorasib	Given PO
BIOLOGICAL	Trastuzumab Deruxtecan	Given IV

Timeline

• Start date: 2026-08-07
• Primary completion: 2027-06-14
• Completion: 2027-06-14
• First posted: 2025-06-10
• Last updated: 2026-04-13

Locations

9 sites across 1 country: United States

Regulatory

• FDA-regulated drug study