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

Sponsor
Instituto Nacional de Cancerologia de Mexico
Study ID
NCT05445791
Phase
PHASE3
Status
Recruiting
Apply to this trial

Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Metformin Hydrochloride — DRUG
    Metformin 500 mg twice daily until disease progression.
  • Placebo — OTHER
    Placebo 500 mg twice daily until disease progression

Study Details

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.

Key Dates

Start date
Jul 15, 2021
Status verified
Apr 2026
Primary completion
Jul 14, 2026
Completion
Jul 14, 2027

Study Design

Enrollment
312 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Placebo Comparator: Placebo
    Patients randomized to this study arm will be treated with tyrosine kinase inhibitors (Gefitinib 250 mg/day; afatinib 30-40 mg/day; erlotinib 150 mg/day) plus placebo 500 mg twice daily until disease progression.
  • Experimental: Metformin
    Patients randomized to this study arm will be treated with tyrosine kinase inhibitors (Gefitinib 250 mg/day; afatinib 30-40 mg/day; erlotinib 150 mg/day) plus metformin 500 mg twice daily until disease progression.

Primary Outcome Measure

Progression-free survival [ Time Frame: 48 months ]

Central Contacts

Related Studies