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
4 other identifiers
interventional
37
1 country
9
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Aug 2026
9 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 29, 2025
CompletedFirst Posted
Study publicly available on registry
June 10, 2025
CompletedStudy Start
First participant enrolled
August 7, 2026
ExpectedPrimary Completion
Last participant's last visit for primary outcome
June 14, 2027
Study Completion
Last participant's last visit for all outcomes
June 14, 2027
April 13, 2026
April 1, 2026
10 months
May 29, 2025
April 10, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
Dose-limiting toxicities of combined trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) treatment (Phase I)
Will be defined as an adverse event (AE) that is at least possibly related to the study treatment. Severity will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Within the first 21 days of treatment initiation
Overall response rate (ORR) (Phase II)
Will be defined as the proportion of patients with a confirmed response as per investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Will be plotted using Kaplan-Meier method.
Up to 5 years
Secondary Outcomes (8)
Maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) combination (Phase I)
Up to 5 years
ORR (Phase I)
Up to 5 years
Progression-free survival (PFS) (Phase II)
From start of treatment to disease progression or death due to any cause, assessed up to 5 years
Duration of response (Phase II)
From the time measurement criteria are first met for complete response or partial response until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years
Overall survival (OS) (Phase II)
From first treatment to time of death due to any cause, assessed up to 5 years
- +3 more secondary outcomes
Other Outcomes (8)
Correlation between HER2 immunohistochemistry (IHC) archival and pre-treatment (study biopsy) results and ORR, PFS, and OS (Phase II)
Up to 5 years
Correlation between ERBB2 gene expression and ORR, PFS, and OS (Phase II)
Up to 5 years
Correlation between circulating tumor deoxyribonucleic acid (ctDNA) clearance and ORR, PFS, and OS (Phase II)
Up to 5 years
- +5 more other outcomes
Study Arms (1)
Treatment (trastuzumab deruxtecan, sotorasib)
EXPERIMENTALPatients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 and sotorasib PO 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 MRI at screening and ECHO or MUGA, CT, MRI and blood sample collection throughout the study. Additionally, patients with brain metastasis undergo brain MRI throughout the study.
Interventions
Given PO
Undergo tumor biopsy
Undergo blood sample collection
Undergo CT
Undergo MUGA
Given IV
Undergo MRI
Undergo ECHO
Eligibility Criteria
You may qualify if:
- Patients must have histologically or cytologically documented locally advanced or metastatic KRAS\^G12C-mutant NSCLC that has previously been treated with a KRAS\^G12C inhibitor AND an immune checkpoint inhibitor (ICI) AND chemotherapy, either given concurrently or sequentially, UNLESS they have any contra-indications to any drug class described above
- Patients must have KRAS\^G12C mutation identified by tumor tissue or plasma circulating tumor deoxyribonucleic acid (ctDNA) profiling using a Clinical Laboratory Improvement Act (CLIA) certified College of American Pathologists (CAP) accredited platform; local molecular testing will be allowed. Testing must have been done within the last 5 years before enrollment in this study
- Data must be available for which prior KRAS\^G12C inhibitor treatment the patient has received and the dates that they received it (type of KRAS\^G12C inhibitor used and start and end dates must be collected prior to enrollment)
- Data must be available on the date patients received the last dose of KRAS\^G12C inhibitor and the date of disease progression on their last treatment prior to screening for this trial. Data must be available on the last treatment they received and if it was not or did not include a KRAS\^G12C inhibitor. The time between last KRAS\^G12C inhibitor and treatment on this trial will be collected prior to enrollment
- Data must be available on historical HER2 immunohistochemistry (IHC) status (date of test, type of antibody used for the IHC test, scoring system \[i.e., breast versus (vs.) gastric\], and results must be collected prior to enrollment). Patients must also have ERBB2 (HER2) mutations status identified by tumor tissue or plasma ctDNA profiling; local (i.e., commercial or institutional next generation sequencing \[NGS\]) molecular testing will be allowed. Patients who do not have this information available for collection will not be enrolled on this study
- Patients must have measurable disease, as defined by RECIST v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI). Previously irradiated lesions cannot be counted as target lesions unless there has been demonstrated progression in the lesions since radiotherapy and no other lesions are available for selection as target lesions
- Age ≥ 18 years at date of informed consent form signature
- Because no dosing or adverse event data are currently available on the use of sotorasib (AMG-510) in combination with trastuzumab deruxtecan (DS-8201a) in patients \< 18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- Hemoglobin ≥ 9 g/dL (within 14 days of enrollment)
- Leukocytes ≥ 3,000/mcL (within 14 days of enrollment)
- Absolute neutrophil count ≥ 1,500/mcL (within 14 days of enrollment)
- No administration of granulocyte colony stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment
- Platelets ≥ 100,000/mcL (within 14 days of enrollment)
- No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
- +20 more criteria
You may not qualify if:
- Patients with a history of (non-infectious) interstitial lung disease (ILD) that required steroids, has current ILD, or where suspected ILD cannot be ruled out by imaging at screening. These patients will be excluded because trastuzumab deruxtecan (DS-8201a) is known to increase the risk of developing ILD and pneumonitis
- Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, prior complete pneumonectomy), and any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis, etc.) where there is documented or a suspicion of pulmonary involvement or pneumonectomy at the time of screening. These patients will be excluded because trastuzumab deruxtecan (DS-8201a) is known to increase the risk of developing ILD and pneumonitis
- Patients who have had chest radiation therapy within 4 weeks (2 weeks for palliative stereotactic body radiation therapy). These patients will be excluded because trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) are known to increase the risk of developing pneumonitis
- Patients who have had a major surgery and are not yet fully healed from surgical incisions
- Patients who have had prior treatment with an antibody drug conjugate with a topoisomerase 1 inhibitor payload (i.e., sacituzumab govitecan, datopotomab deruxtecan, or trastuzumab deruxtecan) or with a topoisomerase inhibitor
- Patients with a history of significant lung disease requiring systemic corticosteroids treatment (\> 10 mg of prednisone daily) within the last six months of registration
- Based on pre-clinical data, trastuzumab deruxtecan (DS-8201a) is associated with corneal disease. Patients with clinically significant corneal disease, in the opinion of the investigator, will be excluded from this study
- Patients with spinal cord compression, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
- Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia. Subjects with chronic grade 2 toxicities (i.e., defined as no worsening to \> grade 2 for at least 3 months prior to first exposure to study intervention and managed with standard of care treatment) may be eligible per the discretion of the investigator after consultation with the sponsor medical monitor or designee (e.g., grade 2 chemotherapy-induced neuropathy). Subjects should no longer be symptomatic nor require treatment with corticosteroids (prednisone \> 10 mg or equivalent) or anticonvulsants and must have recovered from the acute toxic effect of radiotherapy
- Patients who are receiving any other investigational agents
- Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to sotorasib (AMG-510), such as adagrasib, or trastuzumab deruxtecan (DS-8201a)
- Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies
- Patients who are taking strong CYP3A4 inducers should be switched to an alternative drug
- Avoid coadministration with P-glycoprotein (P-gp) substrates for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, dose adjustment of the substrate may be required. Please refer to the prescribing information for the substrate
- +8 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (9)
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817, United States
Moffitt Cancer Center-International Plaza
Tampa, Florida, 33607, United States
Moffitt Cancer Center - McKinley Campus
Tampa, Florida, 33612, United States
Moffitt Cancer Center
Tampa, Florida, 33612, United States
Moffitt Cancer Center at Wesley Chapel
Wesley Chapel, Florida, 33544, United States
Case Western Reserve University
Cleveland, Ohio, 44106, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
University of Virginia Cancer Center
Charlottesville, Virginia, 22908, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Andreas N Saltos
University Health Network Princess Margaret Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 29, 2025
First Posted
June 10, 2025
Study Start (Estimated)
August 7, 2026
Primary Completion (Estimated)
June 14, 2027
Study Completion (Estimated)
June 14, 2027
Last Updated
April 13, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.