Exploiting Metformin Plus/Minus Cyclic Fasting Mimicking Diet (FMD) to Improve the Efficacy of First Line Chemo-immunotherapy in Advanced LKB1-inactive Lung Adenocarcinoma

Lung cancer is one of the most common malignancies and tumor-related causes of death worldwide. In the last years, significant advances have been observed in the treatment of non small cell lung cancer, in particular for the population of patients with a driver genetic mutation like EGFR and ALK. For the remaining cases, the main novelty has been represented by immunotherapy with anti-PD1/PDL1 agents, which have proved a benefit over previous standard of care (platinum-based chemotherapy in first line and docetaxel in second line). , Only patients wih tumors expressing high PD-L1 levels have had access to immunotherapy alone as first line treatment. For all the remaining cases, the standard-of-care treatment in the first-line setting has remained platinum-based chemotherapy for several years. This algorithm has been recently changed by the approval of combined chemotherapy(platinum salt + pemetrexed) and immunotherapy (pembrolizumab) as a first-line therapy for patients with lung adenocarcinoma and low/absent PD-L1 expression. This regimen has entered into clinical practice following the positive results of a clinical trial, showing superior outcome with the combination than with chemotherapy alone. Lung adenocarcinoma with LKB1 mutations or macro/micro deletions has a particularly aggressive behavior and seems to be resistant to the effects of immunotherapy, either alone or in combination with chemotherapy. Indeed, such a population appears to be disadvantaged as regards therapeutic options and requires the development of different approaches. LKB1 enzyme is involved in intracellular pathways that are crucial in the regulation of cancer cell metabolism. Metabolic reprogramming is a key step in tumorigenesis and several metabolic pathways, including glucose uptake and utilization, or lipid biosynthesis and utilization, are deregulated in cancer cells compared to their normal counterpart. Cells with hypo-active or inactive LKB1 are peculiar in that they show an exquisite vulnerability to energetic deprivation. Indeed, they are unable to survive when exposed to nutrient deprivation or drugs that affect cancer cell bioenergetics or specific metabolic processes. In particular, the class of drugs known as biguanides, which include the antidiabetic compound metformin, are able to inhibit mitochondrial metabolism and to reduce the intracellular concentration of ATP, and have shown antitumor activity in mouse xenografts of LKB1-mutated lung adenocarcinomas. Based on the well known effects of metformin on cancer cell metabolism, as well as on preclinical evidence showing synergistic activity of cisplatin and metformin in lung cancer cell lines and animal models with LKB1 deletion, we hypothesize that combining chemoimmunotherapy (platinum salt + pemetrexed + pembrolizumab) with either metformin (MERCY arm), or metformin plus a lowcalorie, low-carbohydrate, low-protein diet also known as Fasting Mimicking Diet (FMD) (FAME arm), may improve the efficacy of standard treatment alone for patients with LKB1-inactive lung adenocarcinoma.

The patients considered eligible and enrolled in the study will be included in FAME, MERCY or BORN arms according to the aforementioned eligibility criteria. Patients in each arm will receive the following treatment:

• FAME -> up to a maximum of 4 cycles of a platinum salt + pemetrexed + pembrolizumab in association to metformin and to tri-weekly, 5 day-long cycles of FMD.
• MERCY -> up to a maximum of 4 cycles of a platinum salt + pemetrexed + pembrolizumab in association to metformin.
• BORN -> standard treatment at investigator's choice or observation only in case of clinical conditions contraindicating any active therapy.

In both arms FAME and MERCY, the patients with stable or responding disease after 4 cycles of chemotherapy will continue with maintenance pemetrexed and pembrolizumab in association to metformin until disease progression and/or inacceptable toxicity.