Tunlametinib Combination Therapy in KRAS-Mutated Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancer

NCT07463677 | Not Yet Recruiting Phase 2

• 1 other identifier: B2025-534-01
• Study Type: interventional
• Target: 55
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study investigated the efficacy and safety of Tunlametinib Combination Therapy in KRAS-Mutated Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancer.

Conditions

Lung Cancer (NSCLC)

Keywords

KRAS; Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancer; MEK

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  Defined as the percentage of subjects achieving complete response (CR) or partial response (PR) as assessed by RECIST 1.1.

  up to 180 days

Secondary Outcomes (6)

• Progression Free Survival (PFS)

  up to 180 days

• Disease Control Rate (DCR)

  up to 180 days

• Duration of Response (DoR)

  up to 180 days

• Incidence and severity of adverse events (AEs)

  30 Days, an average of 3 months

• Overall Survival (OS)

  up to 360 days

Study Arms (2)

Arm 1

EXPERIMENTAL

Tunlametinib: 6 mg / 9 mg / 12 mg orally twice daily (BID). Cetuximab β: Administered intravenously at a dose of 500 mg/m² (based on body surface area) once every two weeks. Each treatment cycle is defined as 4 weeks.

Drug: Tunlametinib + Cetuximab β

Arm 2

EXPERIMENTAL

Arm 2: Tunlametinib: 6 mg / 9 mg / 12 mg orally twice daily (BID). Fluorescein: 600 mg orally twice daily (BID). Each treatment cycle is defined as 4 weeks.

Drug: Tunlametinib + Fulzerasib

Interventions

Tunlametinib + Fulzerasib DRUG

Study Population: Previously treated subjects with KRAS G12C mutation-positive, unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) (n=6). Treatment Regimen: Tunlametinib + Fluorescein Starting Dose Cohort: Tunlametinib: 9 mg per dose, administered orally twice daily (BID). Fluorescein: 600 mg per dose, administered orally twice daily (BID). Cycle Definition: Every 4 weeks constitutes one treatment cycle. Second Dose Cohort: Tunlametinib: 12 mg or 6 mg per dose, administered orally twice daily (BID). Fluorescein: 600 mg per dose, administered orally twice daily (BID). Cycle Definition: Every 4 weeks constitutes one treatment cycle.

Also known as: Arm 2

Arm 2

Tunlametinib + Cetuximab β DRUG

Study Population: Previously treated subjects with KRAS (non-G12C) mutation-positive, unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) (n=6). Treatment Regimen: Tunlametinib + Cetuximab β Injection Starting Dose Cohort: Tunlametinib: 9 mg per dose, administered orally twice daily (BID). Cetuximab β Injection: 500 mg/m² per dose (calculated based on body surface area), administered intravenously once every two weeks. Cycle Definition: Every 4 weeks constitutes one treatment cycle. Second Dose Cohort: Tunlametinib: 12 mg or 6 mg per dose, administered orally twice daily (BID). Rationale: This cohort aims to identify the optimal dose. From the perspective of maximizing subject benefit, the dose may be either reduced or increased. Therefore, the dose is subject to dynamic adjustment based on ongoing clinical trial observations, rather than following a traditional dose-escalation design. Investigators will continuously review safety data from subjects a

Also known as: Arm1

Arm 1

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Femal and male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent, all participants will provide written informed consent.
• Participants older than 18 years of age signed their own informed consent form.
• The TNM staging was classified according to the 8th edition of the AJCC Cancer Staging Manual of the American Joint Committee on Cancer (AJCC). Eligible patients had histologically or cytologically confirmed unresectable, locally advanced, or metastatic NSCLC9(IIIB、IIIC、IV).
• Eligible patients had failed, were intolerant to first-line standard treatment after diagnosis.
• Positive for KRAS driver gene mutations (including: KRAS G12C and KRAS non-G12C).
• Patients were required to have at least 1 site of disease that qualified as a measurable (target) lesion by RECIST v1.1 (If the lesion at the previous radiotherapy site is selected as the target lesion, there is a clear evidence of progression of this lesion).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• The functions of the major organs meet the following requirements, and no blood transfusion or use of hematopoietic stimulating factor drugs has been conducted within 14 days prior to the relevant examination: 1) Thrombocytopenia（PLT）≥100×109/L； 2) Blood hemoglobin（HGB）≥90g/L； 3) neutrophil count（NEUT）≥1.5×109/L； 4) creatinine ≤1.5×ULN or Creatinine clearance（CrCl）≥50 mL/min（was calculated using the Modification of CockroftGaul）； 5) alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤2.5×ULN（If the patient has liver metastasis ≤5×ULN）； 6) total bilirubin level（TBIL）≤1.5×ULN（Patients with Gilbert's syndrome may receive ≤3×ULN.）；If direct bilirubin (DBIL) indicates extrahepatic obstruction, then TBIL \< 3.0 × ULN is permissible； 7) International normalized ratio（INR）or prothrombin time（PT）≤1.5×ULN，activated partial thromboplastin time（APTT）≤1.5×ULN，Patients whose bleeding tendency is assessed by the researchers as controllable 8) The urine protein creatinine ratio had to be 2+ or less, or the 24-hour urine protein had to be less than 1,000 mg, for patient enrollment.
• The life expectance should be at least 3 months.
• Eligible patients of child-bearing age (men and women) agreed to take effective contraceptive measures (including hormonal contraception, barrier methods, or abstinence) during the study period and for at least 6 months after the last study drug administration.

You may not qualify if:

• NSCLC with other driver gene mutations that have standard treatment drugs (such as EGFR, ALK, BRAF(V600E), HER-2, MET(exon14), ROS1, RET or NTRK1/2/3, etc.) in the past.
• Concurrent primary malignancies are permitted, except in the following circumstances: Other malignancies treated with a single surgical procedure, with complete remission for at least 3 years prior to enrollment; or Untreated basal cell carcinoma or carcinoma in situ (e.g., carcinoma in situ of the skin, breast carcinoma in situ, cervical carcinoma in situ); Prostate cancer requiring only clinical monitoring without treatment.
• Cardiovascular system meeting any of the following criteria: 1) Congestive heart failure at New York Heart Association (NYHA) functional class II or higher; 2) Severe arrhythmia requiring medication; 3) Acute myocardial infarction, severe or unstable angina, coronary artery bypass grafting (CABG), or peripheral artery bypass grafting within 6 months prior to enrollment; 4) Left ventricular ejection fraction (LVEF) \<50%; 5) Resting QT interval prolongation (QTcF) as measured by the Fridericia formula, ECG-measured QTcF \> 470 ms in females or \> 450 ms in males, or presence of risk factors for torsades de pointes, such as investigator-assessed clinically significant hypokalemia, family history of long QT syndrome, or familial arrhythmia history (e.g., Wolff-Parkinson-White syndrome); 6) Uncontrolled hypertension (defined as systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg despite standardized antihypertensive therapy);
• Patients who have experienced arterial or venous thrombotic events within the past 6 months, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis, pulmonary embolism, hypertensive crisis, or hypertensive encephalopathy;
• Patients with a history of seizures were excluded.
• The superior vena cava.
• Active non-infectious pneumonia with interstitial changes such as interstitial lung disease, radiation pneumonitis, or immune-related pneumonia during the screening period; active pulmonary tuberculosis; pneumoconiosis; or other types of pneumonia classified as Grade ≥2; or severe impairment of pulmonary function confirmed by pulmonary function tests (FEV1 or DLCO or DLCO/VA \<40% of predicted value).
• Severe bone damage caused by tumor bone metastases present at baseline or likely to occur after enrollment, such as weight-bearing pathological fractures, extensive bone metastases, or spinal cord compression occurring within 6 months prior to enrollment or likely to occur after enrollment; or uncontrollable pain related to tumor bone metastases;
• Active or uncontrolled severe infection (≥ CTCAE Grade 2 infection) or unexplained fever \>38.5°C.
• Third-space effusions (including pleural effusion, ascites, or pericardial effusion) that are poorly controlled clinically or require local symptomatic management such as paracentesis. Subjects may be enrolled if clinically stable after symptomatic treatment (e.g., paracentesis and pleurodesis) with no significant increase in effusion volume for at least 3 days after cessation of drainage.
• Within 2 months prior to the first dose, subjects with evidence or history of bleeding tendency, regardless of severity; within 2 weeks prior to the first dose, subjects with a history of hemoptysis (\>2.5 ml/day) or presence of unhealed wounds, ulcers, or fractures;
• Known impaired gastrointestinal (GI) function or GI diseases that may significantly affect the absorption or metabolism of oral medications, such as: nausea, vomiting, severe peptic ulcer disease, liver cirrhosis, active gastrointestinal bleeding, intestinal obstruction, intestinal perforation, inflammatory bowel disease causing chronic diarrhea (e.g., colitis or Crohn's disease), or other conditions affecting tablet swallowing or significantly impairing oral drug absorption. History of major gastrointestinal (esophageal, gastrointestinal) surgery that may alter absorption of the study treatment or prevent swallowing of tablets;
• Received a live attenuated vaccine within 4 weeks prior to the first dose;
• Active autoimmune diseases requiring systemic treatment (e.g., disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressants) within 2 years prior to first dosing, including but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis; subjects with asthma requiring medical intervention with bronchodilators are ineligible. . Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) is not considered systemic treatment.
• Diagnosed with immunodeficiency or currently receiving systemic glucocorticoid therapy or any other form of immunosuppressive therapy (dose \>10 mg/day of prednisone or other equivalent corticosteroids), and continuing such therapy within 2 weeks prior to the first dose;

Sponsors & Collaborators

• Sun Yat-sen University: lead

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

26S proteasome non-ATPase regulatory subunit 13; DMAC2L protein, human

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms

Central Study Contacts

Li Zhang

CONTACT

+8613902282893; zhangli@sysucc.org.cn

Wenfeng Fang

CONTACT

+8615322302066;Ext. +860208734; fangwf@sysucc.org.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Sun Yat-sen University

Study Record Dates

• First Submitted: March 1, 2026
• First Posted: March 11, 2026
• Study Start: March 15, 2026
• Primary Completion (Estimated): May 31, 2028
• Study Completion (Estimated): March 31, 2029
• Last Updated: March 11, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share