Metformin With a Carbohydrate Restricted Diet In Combination With Platinum Based Chemotherapy In Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NS-NSCLC) - METRO Study

Lung cancer is the leading cause of cancer related mortality in both men and women. In the U.S. alone, an estimated 160,340 lung cancer related deaths occurred in 2012, accounting for about 28% of all cancer related deaths. Approximately 85% of lung cancer is classified as non-small-cell lung cancer (NSCLC) with roughly two-thirds of these patients presenting with advanced disease. Histologically, NSCLC can be subdivided into adenocarcinoma, squamous cell, large cell, and non-small cell lung cancer that cannot be further classified. Those tumors that are not squamous (adenocarcinoma, large cell, not classified) are collectively termed as non-squamous, non-small cell lung cancer (NS-NSCLC) and account for roughly 75% of all non small cell cancer cases.

The most accepted upfront treatment for patients with advanced stage NSCLC has been platinum based chemotherapy. Current standard practice for treatment of stage IV non-squamous NSCLC patients with cytotoxic chemotherapy has evolved over the past decade. In a sentinel study in 2005, Sandler and colleagues demonstrated that the addition of bevacizumab to platinum doublet chemotherapy (carboplatin/paclitaxel) followed by maintenance bevacizumab conferred a survival advantage when compared to platinum doublet chemotherapy alone (12.1 mos vs. 10. mos) in patients with stage IV non squamous, non-small cell lung cancer. Following this, the largest phase III study ever conducted in stage IV NSCLC randomized more than 1700 patients with stage IV lung cancer to either cisplatin/pemetrexed or cisplatin/gemcitabine. This study was the first to reveal an interaction between chemotherapy and histology,demonstrating a survival advantage for the subset of patients with non-squamous cell treated with cisplatin/pemetrexed when compared to those treated with cisplatin/gemcitabine (11.0 vs 10 mos, p<0.05. Building upon this, a recent study evaluating maintenance pemetrexed (continuing treatment after the four cycles of platinum doublet therapy) in non-squamous cell lung cancer demonstrated a significant survival advantage for patients receiving maintenance pemetrexed vs. placebo after four cycles of cisplatin/pemetrexed (13.9 mos vs. 11.0 mos, p<0.05). Based on these studies, a regimen of cisplatin or carboplatin with pemetrexed followed by maintenance single agent pemetrexed has become one of the most accepted frontline treatments for patients with stage IV non-squamous, non small cell carcinoma.

Recently, there has been a firmer understanding of the relevant signaling pathways critical for lung cancer growth, leading to the development of novel, targeted therapies. The discovery of the EGFR and ALK pathways in lung cancer and the subsequent development of drugs that target these pathways, erlotinib and crizotinib respectively, has yielded unprecedented survival times in stage IV non-squamous, non small cell lung cancer. Unfortunately, only 25 to 30% of patients harbor these mutations, and platinum based chemotherapy remains the cornerstone of treatment for the 60-70% of patients with stage IV disease without identifiable targets. In attempts to improve outcome, a large need remains to develop novel, effective agents to combine with platinum therapy that possess a favorable toxicity profile at a reasonable cost.

Metformin:

Metformin, an oral biguanide agent used for the treatment of non-insulin-dependent diabetes mellitus, is now prescribed to more than 120 million people worldwide. Its glucose lowering effects result from both inhibition of liver gluconeogenesis and increased insulin sensitivity in peripheral tissue. Metformin has limited adverse effects with little or no risk of hypoglycemia in healthy, nondiabetic controls. In addition to its anti-diabetic properties, metformin has demonstrated both chemopreventative and therapeutic effects in both prostate and breast cancer. Jiralersprong et al reported that diabetic patients with breast cancer receiving metformin had a 24% complete pathological response rate to neoadjuvant chemotherapy compared to only 8% of those in the non-metformin group. More recently Joshua et al reported reduced tumor Ki-67 rate as well as significant reductions in fasting glucose, insulin growth factor 1 and BMI (body mass index) in prostate cancer patients receiving neoadjuvant metformin prior to radical prostatectomy. Large epidemiological studies consistently have shown substantially lower incidence of cancer occurrence and death in diabetic patients taking metformin compared to those receiving other therapies. Most recently, a retrospective study of patients with ovarian cancer found that 5-year disease-specific survival was significantly better for diabetic patients who took metformin than for those who did not (67% vs 47%; P = .007). Based on these important observational studies, there are currently several, ongoing prospective studies evaluating metformin in nondiabetic patients with both early stage and late stage breast cancer and prostate cancer, respectively.