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.

Inclusion Criteria:

1. 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.
2. Measurable disease by RECIST 1.1.
3. 18 years of age or older.
4. Functional status 0-2 as assessed by Eastern Cooperative Oncology Group (ECOG) scale.
5. Life expectancy of minimum12 weeks.
6. Patients with non-small cell lung cancer and a documented EGFR sensitizing mutation.
7. Patients without previous EGFR-TKI treatment. Previous use of chemotherapy is allowed with a washout period of at least 6 months.
8. Patients with asymptomatic brain metastases, or if symptoms are present treatment with radiotherapy (whole brain radiotherapy, stereotactic radiosurgery) or surgery must be administered.
9. Neutrophil count ≥1.5 x 103/mm3, and platelet count >100 x (103/mm3).
10. Serum bilirubin ≤1.5 the superior upper limit.
11. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2 superior upper limit (or ≤ 5 times the superior upper limit in patients with liver metastases).
12. Serum creatinine ≤ 1.5 superior upper limit, or creatinine clearance ≥ 60ml/min.
13. Full ability to complete all study procedures and follow up.
14. Women with child-bearing potential must have a negative pregnancy test within 72 hours of treatment start.
15. Patients with reproductive potential must use effective contraception.
16. Signed informed consent for participation in the study.
17. Availability of tumor tissue (pre-treatment biopsy) to determine LKB1 and AMPK status.

Exclusion Criteria:

1. Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart disease, hepatic diseases, renal diseases).
2. Patients previously treated with an EGFR-TKI.
3. Patients diagnosed with any other neoplastic disease in the previous 5 years (except in situ cervical carcinoma or basocellular skin cancer, treated accordingly).
4. 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.
5. Pregnant or lactating women.
6. Patients diagnosed with type 2 diabetes or a glycated hemoglobin ≥ 6.5%.
7. Patients being currently treated with metformin.