Metformin Plus Tyrosine Kinase Inhibitors for Treatment of Patients With Non-small Cell Lung Cancer With EGFR Mutations

Official title

Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine Kinase Inhibitors Alone for Patients With Advanced Non-small Cell Lung Cancer and EGFR Mutations: Phase 3 Randomized Clinical Trial

Overview

Lung cancer is the most common neoplastic disease globally, with over 2 million new cases annually, accounting for 11.6% of all cancer diagnoses. It remains the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) makes up 80-85% of lung cancer cases, with most patients diagnosed at an advanced stage. Five-year survival rates are low, ranging from 8-18% worldwide. Advances in molecular biology have led to the identification of therapeutic targets in NSCLC. One of the most studied is the epidermal growth factor receptor (EGFR), a key regulator of tumor cell functions and a focus of targeted therapy development. EGFR mutations occur in about 15% of NSCLC cases globally but reach up to 34% in Mexico. Patients with these mutations are treated with tyrosine kinase inhibitors (TKIs), which improve response rates and progression-free survival (PFS) over chemotherapy. However, resistance to TKIs typically develops, prompting the need for strategies to overcome this challenge and extend PFS. Up to 30% of NSCLC patients have somatic mutations in the liver kinase B1 (LKB1) gene, a tumor suppressor that inhibits mTOR. In one study, 24 patients with LKB1 expression treated with metformin plus TKIs showed significantly improved overall survival. LKB1 activates AMP-activated protein kinase (AMPK), which regulates cell cycle and survival in NSCLC. Loss of LKB1 reduces AMPK activation and increases tumor necrosis following bevacizumab treatment. A study of 99 NSCLC samples linked high AMPK expression to poorer survival, though its role in metformin response is unclear. Metformin, a biguanide used for type 2 diabetes, has shown anticancer properties. Studies suggest metformin reduces cancer incidence and mortality. In vitro, it induces G0/G1 cell cycle arrest and counters TKI resistance due to epithelial-mesenchymal transition (EMT). Retrospective studies support its benefit in NSCLC, and prospective trials of metformin plus TKIs have yielded mixed results. This phase 3 randomized study aims to evaluate PFS in NSCLC patients with EGFR mutations treated with TKIs plus placebo versus TKIs plus metformin.

Interventions

• Drug Metformin Hydrochloride
  Metformin 500 mg twice daily until disease progression.
• Other Placebo
  Placebo 500 mg twice daily until disease progression

Primary outcome measures

• Progression-free survival [Time frame: 48 months]

Secondary outcome measures (2)

• Overall survival [Time frame: 48 months]
• Overall Response Rate [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• Patients with a histologically confirmed diagnosis of non-small cell lung cancer (stage IIIB-IV) according to the American Joint Committee on Cancer (AJCC) eight edition.
• Measurable disease by RECIST 1.1.
• 18 years of age or older.
• Functional status 0-2 as assessed by Eastern Cooperative Oncology Group (ECOG) scale.
• Life expectancy of minimum12 weeks.
• Patients with non-small cell lung cancer and a documented EGFR sensitizing mutation.
• Patients without previous EGFR-TKI treatment. Previous use of chemotherapy is allowed with a washout period of at least 6 months.
• Patients with asymptomatic brain metastases, or if symptoms are present treatment with radiotherapy (whole brain radiotherapy, stereotactic radiosurgery) or surgery must be administered.
• Neutrophil count ≥1.5 x 103/mm3, and platelet count >100 x (103/mm3).
• Serum bilirubin ≤1.5 the superior upper limit.
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2 superior upper limit (or ≤ 5 times the superior upper limit in patients with liver metastases).
• Serum creatinine ≤ 1.5 superior upper limit, or creatinine clearance ≥ 60ml/min.
• Full ability to complete all study procedures and follow up.
• Women with child-bearing potential must have a negative pregnancy test within 72 hours of treatment start.
• Patients with reproductive potential must use effective contraception.
• Signed informed consent for participation in the study.
• Availability of tumor tissue (pre-treatment biopsy) to determine LKB1 and AMPK status.

Exclusion criteria

• Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart disease, hepatic diseases, renal diseases).
• Patients previously treated with an EGFR-TKI.
• Patients diagnosed with any other neoplastic disease in the previous 5 years (except in situ cervical carcinoma or basocellular skin cancer, treated accordingly).
• Patients unable to receive oral medication, who require IV nourishment, or who underwent surgical procedures with affect nutrient absorption, or with an active peptic ulcer.
• Pregnant or lactating women.
• Patients diagnosed with type 2 diabetes or a glycated hemoglobin ≥ 6.5%.
• Patients being currently treated with metformin.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Mexico · 1 center

• Instituto Nacional de Cancerologia — Mexico City

Identifiers

NCT: NCT05445791 · (020/023/ICI) (CEI/1421/19)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗