Effect of Metformin in Combination With Tyrosine Kinase Inhibitors (TKI) on Clinical, Biochemical and Nutritional in Patients With Non-Small Cell Lung Carcinoma (NSCLC): Randomized Clinical Trial

Lung cancer is the first cause of death in men and women, representing 28% and 26% of registered deaths worldwide, respectively. Among patients with this disease, at least 80% has non-small cell lung cancer (NSCLC), and 60% of patients are diagnosed when they already have a locally advanced or metastatic disease. NSCLC therapy regimens depend on the stage of disease and may require surgery, chemotherapy, radiotherapy, or a combination of these. Survival rate at 5 years is low for patients with stage II and III of the disease, with variation from 30% to 5%, this means that an improvement in therapy are required.

Advances in molecular biology of cancer have led to discovering several molecular targets and developing new target therapies. Epidermal growth factor receptor (EGFR) is involved in the development and progression of several types of cancer, including NSCLC. However, despite clinical success with different tyrosine kinase specific domain inhibitors (TKIs), most of the patients respond to these drugs initially, but eventually develop resistance to these drugs after and average period of time of 10 months. Thus, innovative treatment strategies are required urgently to overcome therapeutic resistance to EGFR-TKIs and to improve survival of patients with NSCLC.

Recently, metformin has been associated with reduction in the global risk of incidence and mortality of different types of cancer, due to its anti-tumor properties. In specific types of cancer, retrospective studies have demonstrated a clinical benefit from the use of metformin combined with the treatment of cancer.

Patients with NSCLC with positive EGFR mutations are highly sensible to specific anti-EGFR tyrosine kinase inhibitors, however, most of the patients who initially respond to these target therapies, will present progression of the disease posteriorly during the treatment, this is known as acquired resistance. Acquired resistance to target therapies was first studied in patients with chronic myeloid leukemia with BCR-ABL translocation treated with Imitanib, an inhibitor of aberrant kinase BCR-ABL. Thanks to research, mutations associated with resistance to treatment with TKIs in NSCLC with positive EGFR mutations were discovered. By several studies, additional mutations were found in the kinase domain and in KRAS in those patients with acquired resistance to Gefitinib or Erlotinib. By PCR it was found that 50% of patients with resistance to TKI develop a specific mutation in exon 20 (T790M). However, the mechanism by which the other 50% of patients develop resistance to anti-EGFR TKI is yet unknown. Some studies have found focal amplification of MET proto-oncogen in 22% of the patients with acquired resistance to Gefitinib. The proposed mechanism is that MET amplification promotes resistance by activation of HER3 depending PI3K pathway. Nonetheless, there are few studies with few patients about MET amplification as a resistance mechanism.

On the other hand, there are patients who have this resistance mutation since the first presentation, or de novo. T790M mutation may be present before exposition to TKI and it's generally found with other activating mutations in EGFR (exon 19 deletion and punctual L858R mutation). A response rate of 8% has been reported in those patients treated with gefitinib or erlotinib whose T790M mutation was positive at the time of the diagnosis, with progression-free survival of 2 months and global survival median of 16 months.