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

  • End date
    Sep 10, 2023
  • participants needed
  • sponsor
    Marina Garassino
Updated on 26 January 2021


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 chemoimmunotherapy with metformin plus/minus FMD in patients with LKB1-inactive, advanced 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.

Condition Advanced LKB1-inactive Lung Adenocarcinoma, Advanced LKB1-inactive Lung Adenocarcinoma, Advanced LKB1-inactive Lung Adenocarcinoma
Treatment cisplatin, carboplatin, Pembrolizumab, Pemetrexed, Metformin Hydrochloride, Fasting-mimicking diet
Clinical Study IdentifierNCT03709147
SponsorMarina Garassino
Last Modified on26 January 2021


Yes No Not Sure

Inclusion Criteria

Age 18 years
Histologically confirmed diagnosis of LKB1-inactive lung adenocarcinoma, as defined on the basis of absence of LKB1 expression at immunoistochemistry, and/or presence of pathogenic LKB1 mutation at next-generation sequencing analysis
Absence of EGFR mutations, ALK and ROS-1 rearrangements, and absence of high expression of PD-L1 ( 50% in immunohistochemistry)
Advanced disease, defined as unresectable, locally advanced (stage IIIB) or metastatic (stage IV) lung adenocarcinoma, which is not candidate to be treated with concomitant or sequential definitive chemo-radiation
Signed and dated informed consent, indicating that the patient has been informed on all the aspects of the study prior to the enrollment
At least one exclusion criteria of FAME and MERCY arm

Exclusion Criteria

Patients who are eligible for the FAME arm will be preferentially proposed to
be enrolled in the FAME. If they refuse, then they will be proposed to be
enrolled in the MERCY arm. If they also refuse to be enrolled in the MERCY
arm, they will be proposed to be enrolled in the BORN arm
Patients who are eligible for the MERCY arm will be preferentially proposed to
be enrolled in the MERCY arm; if they refuse, the will be proposed to be
enrolled in the BORN arm
Finally, patients who are ineligible for both the FAME and MERCY arms will be
proposed to be enrolled in the BORN arm
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