Patient case: 72-year-old male with lung adenocarcinoma; genetic feature: EZR-ROS1 fusion

Clinical trial: Metformin Plus/Minus Fasting Mimicking Diet to Target the Metabolic Vulnerabilities of LKB1-inactive Lung Adenocarcinoma

Summary: Lung adenocarcinoma with inactive LKB1 has emerged as a particularly aggressive form of lung cancer, with poor response to immune checkpoint inhibitors. Recent preclinical evidences have demonstrated that LKB1-inactive lung adenocarcinoma is characterized by specific metabolic vulnerabilities, which make it hypersensitive to energetic crisis. For instance, by inhibiting mitochondrial metabolism and reducing ATP availability to cancer cells, the antidiabetic compound metformin has anticancer activity and prevents acquired resistance to cisplatin in lung adenocarcinoma with inactive LKB1. Similarly to metformin, glucose starvation, which can be recapitulated in vivo by cyclic fasting or fasting-mimicking diet (FMD), can cause metabolic crisis in these neoplasms. In this trial, the investigators will assess for the first time the efficacy of combining standard-of-care platinum-based chemotherapy with metformin plus/minus FMD in patients with LKB1-inactive, advanced lung adenocarcinoma.

Detailed description: Lung cancer is one of the most common malignancies and tumor-related causes of death worldwide. In the last years, significant advances have occurred in the treatment of non small cell lung cancer, in particular for the population of patients with a driver genetic mutation like EGFR, ALK or ROS1. For the remaining cases, the main novelty has been represented by immunotherapy, with anti-PD1/PDL1 agents having demonstrated a benefit over previous standard of care treatments, consisting platinum-based chemotherapy in first line and docetaxel in second line. Nonetheless, not all these patients are amenable to first-line immunotherapy, as only tumors expressing high PD-L1 levels seem to respond to these treatments. Lung adenocarcinoma with LKB1 mutations or macro/micro deletions has a particularly aggressive behavior and seems to be resistant to the effects of immunotherapy. Indeed, such a population appears to be disadvantaged as regards therapeutic options and requires the development of different approaches. LKB1 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. Based on the well known effects of metformin on cancer cell metabolism, as well as of preclinical evidence that demonstrate a synergism between cisplatin and metformin in lung cancer cell lines and animal models with LKB1 inactivation, the investigators hypothesize that combining standard platinum-based chemotherapy with metformin, with or without a low-calorie, low-carbohydrate, low-protein diet, also known as Fasting Mimicking Diet (FMD), may improve the efficacy of chemotherapy alone for the treatment of patients with LKB1-inactive lung adenocarcinoma.
  To test this hypothesis, the investigators will perform an open label, randomized, phase II trial in which patients with advanced LKB1-inactive NSCLC will be randomized in a 1:1 way to receive standard-of-care platinum-pemetrexed chemotherapy plus metformin without (arm A) or with (Arm B) cyclic FMD, The primary study objective is to demonstrate that the experimental treatment (armA plus arm B) improves median PFS from 7.6 months (historical control) to 12 months. Secondary study objectives will be to investigate the impact of the experimental treatment on overall survival, objective response rate, adverse events, systemic metabolic parameters (plasma glucose, amino acids, lipid profile).

Eligibility: Inclusion Criteria:
  -  Age ≥ 18 and ≤ 75 years.
  -  confirmed diagnosis of LKB1-inactive lung adenocarcinoma
  -  Absence of EGFR mutations, ALK/ROS1 gene rearrangements and PD-L1 expression < 50% at IHC
  -  Presence of advanced disease, as defined as unresectable, locally advanced (stage IIIB) or metastatic disease (stage IV) not candidate to concomitant or sequential definitive radiotherapy on the primary tumor. Palliative radiotherapy on specific disease sites is allowed.
  -  Personally signed and dated informed consent document (ICD) indicating that the patient has been informed of all pertinent aspects of the study before enrollment and FMD prescription.
  -  Willingness and ability to comply with the FMD protocol, the scheduled visits, treatment plans, laboratory tests and other procedures.
  -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  -  Patients with brain metastases can be included if they do not cause neurologic symptoms and do not require radiotherapy and corticosteroid dosage higher than 25 mg prednisone equivalent.
  -  Presence of adequate bone marrow and organ function as defined by the following laboratory values:
  -  ANC ≥ 1.5 x 109/l
  -  platelets ≥ 100 x 109/l
  -  hemoglobin ≥ 9.0 g/dl
  -  calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according to NCI-CTCAE version 4.03 if not clinically significant
  -  potassium within the normal limits, or corrected with supplements
  -  glomerular filtration rate (GFR) > 60 ml/min as estimated on the basis of 24 h urine collection and analysis, The GFR will be also calculated with the Cockroft-Gault formula on the basis of blood creatinine levels
  -  blood uric acid < 10 mg/dl
  -  ALT and AST ≤ 2.5 x ULN (Upper Limit of Normal). In the case of documented liver metastases, a threshold of ALT and AST ≤ 5 x ULN will be considered acceptable
  -  total bilirubin < 1.5 ULN except for patients with Gilbert syndrome who may only be included in the total bilirubin is < 3.0 x ULN or direct bilirubin < 1.5 x ULN
  -  Albumin > 3 g/dL
  -  Fasting glucose ≤ 200 mg/dl.
  -  Female patients of childbearing potential must agree to sexual abstinence or to use two highly effective method of contraception throughout the study and for at least 30 days after the end of the FMD. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide. A patient is of childbearing potential if, in the opinion of the Investigator, she is biologically capable of having children and is sexually active. Female patients are not of childbearing potential if they meet at least one of the following criteria:
  -  Have undergone a documented hysterectomy and/or bilateral oophorectomy
  -  Have medically confirmed ovarian failure
  -  Achieved post-menopausal status, defined as: (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries) and have a serum FSH level within the laboratory's reference range for postmenopausal females.
  Exclusion Criteria:
  -  Prior systemic treatment for advanced lung cancer
  -  Having completed (neo)adjuvant platinum-based chemotherapy less than 6 months before disease relapse
  -  Diagnosis of a concurrent malignancy in the last 5 years, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. Malignancies diagnosed more than 5 years before the diagnosis of advanced lung adenocarcinomas must have been definitively treated and must have never recurred.
  -  Body Mass Index (BMI) < 20 Kg/m2.
  -  Anamnesis of alcohol abuse.
  -  Unintentional weight loss ≥ 5% in the last three months, unless the patient has a BMI > 25 Kg/m2 at study enrollment. Intentional weight loss is permitted if < 10% in the last three months only if patient BMI is > 22 kg/m2 and weight loss has completely stabilized in the last month.
  -  Current status of pregnancy or lactation, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
  -  Active HBV or HCV infection.
  -  Severe infections within 4 weeks prior to FMD initiation, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
  -  Active autoimmune diseases that require systemic treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
  -  History of recent diagnosis of hypothyroidism for which replacement therapy (e.g., thyroxine) and blood endocrine profile (fT3, fT4 and TSH within the normal range) are not stabilized yet.
  -  Established diagnosis of diabetes mellitus type I or diabetes mellitus type II that requires pharmacological treatment (including, but not limited to, insulin, insulin secretagogues and metformin).
  -  Severe impairment of the gastrointestinal (GI) function or GI disease that may alter the digestion and absorption of nutrients during the re-feeding phase (e.g. active ulcerative diseases of the stomach or intestine, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  -  Known history of Human Immunodeficiency Virus (HIV) infection.
  -  Clinically significant heart disease and/or recent cardiac events including:
  -  history of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 12 months prior to the start of study treatment;
  -  history of documented congestive heart failure (NYHA III-IV);
  -  history of cardiac arythmias, (e.g. ventricular tachycardia, chronic atrial fibrillation), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block), supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
  -  known reduction of left-ventricular ejection fraction (LVEF) to less than 50%, as assessed by multigated radionuclide scintigraphic scan (MUGA) or echocardiography.
  -  Previous episodes of symptomatic hypotension causing unconsciousness.
  -  Baseline fasting plasma glucose ≤ 65 mg/dl.
  -  Ongoing therapy with systemic corticosteroids at a daily dosage equal or superior to 25 mg of prednisone
  -  Serious medical or psychiatric illness that in the assessment of the investigator renders the patient not suitable for participation in this clinical study.
  -  pO2 < 70 mmHg, lactates above the normal limit and pH values below the normal limit at arterial gas analysis.
  -  Requirement of chronic O2 therapy.
  -  Other severe heart, liver, pulmonary, kidney comorbidities that are not specified in the inclusion and exclusion criteria, but which could expose the patient to high risk of lactic acidosis.

Relevance to patient case: not relevant