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

A Study Protocol for Evaluating the Efficacy and Safety of Tunlametinib Combination Therapy in KRAS-Mutated Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancer

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

Inclusion Criteria:

1. Informed consent, all participants will provide written informed consent.
2. Participants older than 18 years of age signed their own informed consent form.
3. 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).
4. Eligible patients had failed, were intolerant to first-line standard treatment after diagnosis.
5. Positive for KRAS driver gene mutations (including: KRAS G12C and KRAS non-G12C).
6. 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).
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. 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.
9. The life expectance should be at least 3 months.
10. 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.

Exclusion Criteria:

1. Subjects had received anticancer drugs or investigational drugs within the following time window: 1) Any KRAS G12C mutation inhibitor within 3 years prior to the first dose in this study, including but not limited to Sotorasib (AMG510), Adagrasib (MRTX849), IBI351 (GFH925), Glecirasib (JAB-21822), JDQ443, LY3537982, and GDC-6036; 2) Cituximab or its analogues within 3 years prior to the first dose of this study; 3) Prior MEK inhibitor therapy; 4) Any anticancer therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) or any other investigational drug within 28 days prior to the first dose of this study; 5) Received traditional Chinese patent medicines with explicit antitumor indications in NMPA-approved drug labels within 2 weeks prior to the first dose of this study (including Compound Mylabris Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Yadanzi Oil Injection/ capsules, Xiaoaiping tablets/injection, Huachansu capsules, etc.) within 28 days prior to receiving any anticancer therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) or any other investigational drug therapy in this study; and 6) Received known CYP2D6, CYP3A4, P-gp, and BCRP sensitive substrates with narrow therapeutic windows within 14 days prior to study dosing or within 5 drug half-lives (whichever is longer), unless the participants are approved for inclusion by the researchers and all parties involved..
2. 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.
3. 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.
4. Symptomatic or progressively worsening CNS metastases or carcinomatous meningitis. Subjects with a history of brain metastases may be considered for inclusion if clinically stable, provided they meet all of the following criteria: 1) Absence of neurological symptoms, no requirement for corticosteroid therapy, and no indication for radiotherapy; the largest lesion on the most recent pre-enrollment imaging study must have a maximum diameter ≤1.5 cm. 2) Active CNS metastases (e.g., brain or meningeal metastases) are not eligible for enrollment. For subjects with brain metastases who have undergone radiotherapy or local treatment: - If no corticosteroids or antiepileptic drugs were used, asymptomatic status must be maintained for at least 7 days after radiotherapy completion. - If corticosteroids or antiepileptic drugs were used, symptomatic status must be maintained for at least 7 days after discontinuation, and the investigator must assess brain metastases as stable and controlled. 3) For subjects asymptomatic after CNS radiotherapy, corticosteroids must have been discontinued for at least 2 weeks prior to the first study dose.
5. 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);
6. 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;
7. Patients with a history of seizures were excluded.
8. The superior vena cava.
9. 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).
10. 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;
11. Active or uncontrolled severe infection (≥ CTCAE Grade 2 infection) or unexplained fever >38.5°C.
12. 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.
13. 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;
14. 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;
15. Received a live attenuated vaccine within 4 weeks prior to the first dose;
16. 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.
17. 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;
18. Human Immunodeficiency Virus (HIV) antibody positive, cirrhosis, or active viral hepatitis: 1) Definition of active viral hepatitis: Hepatitis B surface antigen (HBsAg) positive with hepatitis B virus deoxyribonucleic acid (HBV DNA) copy number >2500 copies [cps]/mL or 500 IU/mL; or hepatitis C virus (HCV) antibody positive with hepatitis C virus ribonucleic acid (HCV RNA) copy number >the lower limit of detection at the study site; 2) Regular assessment and receipt of anti-HBV therapy throughout the study treatment period.
19. active syphilis
20. Renal failure requiring haemodialysis or peritoneal dialysis.
21. Poorly controlled diabetes [fasting blood glucose (FBG) > 10 mmol/L];
22. History of organ transplantation or preparation for organ transplantation;
23. This study excluded participants who, within 4 weeks prior to the first dose, had experienced significant uncontrolled diabetes [fasting blood glucose (FBG) >10 mmol/L]; surgical intervention; or major traumatic injury.
24. Palliative radiation therapy to 1-2 sites of disease is initiated within2 weeks of the first dose
25. Toxicities resulting from prior antitumour therapy (excluding alopecia, hyperpigmentation, and Laboratory test abnormalities without clinical significance are excluded) have not resolved to ≤ Grade 1. Peripheral neurotoxicity has not resolved to ≤ Grade 2 (NCI CTCAE v5.0).

26: 26. History or current presence of retinal diseases, such as: retinal vein occlusion (RVO), retinal artery occlusion (RAO), retinal vasculitis, diabetic retinopathy, hypertensive retinopathy, retinal capillaropathy (Costs disease), pigment epithelial detachment (RPED), etc.

27. History or current presence of neuromuscular diseases associated with elevated CPK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, rhabdomyolysis).

28. Subjects who are pregnant or breastfeeding; 29. Severe psychiatric/psychological disorders or history of drug abuse. 30. Subjects with known allergy or sensitivity to any component of the investigational product were excluded from the study.

31. Any other condition or circumstance that, in the investigator's judgment, would preclude safe participation in or compromise the objectives of the study.