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

Plain English Summary

Sotorasib in Combination With Trastuzumab Deruxtecan for the Treatment of Locally Advanced and Metastatic Non-small Cell Lung Cancer With a KRAS G12C Mutation is a Phase 2 clinical trial sponsored by National Cancer Institute (NCI) studying 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. Tests the safety and effectiveness of combining sotorasib and trastuzumab deruxtecan for locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation. For patients with KRAS G12C mutated non-small cell lung cancer that has spread to nearby tissues or lymph nodes or to other parts of the body. Participation involves regular check-ups, blood tests, and imaging scans. Patients will receive sotorasib and trastuzumab deruxtecan. Alternative treatments include other targeted therapies and chemotherapy. The trial aims to enroll 37 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible if over 18, with a KRAS G12C mutation, previously treated with a KRAS G12C inhibitor, an immune checkpoint inhibitor, and chemotherapy. Not eligible if under 18, with active brain metastases, or with certain liver or kidney issues. Must have measurable disease, and be in good overall health with no major organ problems. Must have a performance status of ≤ 2, and no active infections. This trial is studying 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, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures will show if the combination of sotorasib and trastuzumab deruxtecan is safe and effective in treating patients with locally advanced or metastatic non-small cell lung can The specific primary outcome measures are: Dose-limiting toxicities of combined trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) treatment (Phase I) (Within the first 21 days of treatment initiation); Overall response rate (ORR) (Phase II) (Up to 5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial aims to fill a treatment gap for patients with KRAS G12C mutated non-small cell lung cancer who have not responded to previous treatments. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets 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, where improved treatment options are needed.

Investor Insight

The market for targeted therapies for KRAS G12C mutated non-small cell lung cancer is growing, with this trial potentially leading to new treatment options. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor if you have a KRAS G12C mutation and if you are a candidate for this trial. Participation involves regular check-ups, blood tests, and imaging scans. This trial is currently recruiting participants. The trial is being conducted at 4 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 37 participants

Interventions

• 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

Primary Outcomes

• Dose-limiting toxicities of combined trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) treatment (Phase I) (Within the first 21 days of treatment initiation)
• Overall response rate (ORR) (Phase II) (Up to 5 years)

Secondary Outcomes

• 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)

Full Eligibility Criteria

Inclusion Criteria:

* 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
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 14 days of enrollment), (\< 3 x ULN in the presence of documented Gilbert's syndrome or liver metastases at baseline)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN (within 14 days of enrollment) (\< 5 x ULN in participants with liver metastases)
* Serum albumin ≥ 2.5 g/dL (within 14 days of enrollment)
* International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (within 14 days of enrollment)
* Creatinine ≤ 1.5 x institutional ULN OR creatinine clearance (CrCL) ≥ 30 mL/min/ as determined by (using actual body weight) (within 14 days of enrollment)
* Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with treated brain metastases are eligible with 1 day washout for stereotactic radiosurgery (SRS) and 2 weeks washout for whole brain radiation (WBRT)
* Patients with new or progressive brain metastases (active brain metastases) are eligible if the treating physician determines 

Trial Locations

• Moffitt Cancer Center-International Plaza, Tampa, Florida, United States
• Moffitt Cancer Center - McKinley Campus, Tampa, Florida, United States
• Moffitt Cancer Center, Tampa, Florida, United States
• Moffitt Cancer Center at Wesley Chapel, Wesley Chapel, Florida, United States

Frequently Asked Questions

Related Conditions

• KRAS G12C mutated non-small cell lung cancer
• Lung cancer
• Cancer
• Lung
• Non-small cell lung cancer
• Cancer treatment
• Targeted therapy
• Lung cancer treatment
• KRAS G12C inhibitors
• Immune checkpoint inhibitors

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