Metformin Plus Tyrosine Kinase Inhibitors for Treatment of Patients With Non-small Cell Lung Cancer With EGFR Mutations
Status:
Recruiting
Trial end date:
2025-07-14
Target enrollment:
Participant gender:
Summary
Lung cancer represents the most frequent neoplastic disease worldwide, with an annual
incidence of over 2 million cases, which represents 11.6% of all cancer diagnoses. Further,
it constitutes the main cause of cancer-related deaths. Among the lung cancer types,
non-small cell lung cancer represents 80-85% of cases, and the majority of patients are
diagnosed with locally advanced or metastatic disease, and 5-year survival rates remain
discouraging in most world regions, ranging from 8-18%.
Advances in molecular biology have led to the discovery of several molecular targets and
development of targeted therapy for patients with specific molecular subtypes of NSCLC. One
of the most widely studied is the epidermic growth factor receptor (EGFR), which has been
long recognized as a key modulator for specific tumor cell functions, and thus it has been
used in drug development strategies.
Mutations in the EGFR gene are reported in 15% of all NSCLC cases, though incidence varies
widely and in Mexico up to 34% of patients present with tumors with EGFR mutations. Treatment
of patients with tumors with these characteristics is based on specific tyrosine kinase
inhibitors (TKIs), achieving higher objective response rates and improved progression-free
survival (PFS) compared with chemotherapy-based schemes. Nonetheless, despite the initial
response, most patients treated with TKIs will eventually develop resistance mechanisms and
present progressive disease. Consequently, the development of novel strategies to overcome
TKI resistance and improve PFS of patients with NSCLC with EGFRm is priority.
Up to 30% of patients with NSCLC present with somatic mutations in the LKB1 gene, which acts
as a tumor suppresor through inhibition of mTOR. In a study which included 24 patients with
LKB1 expression who received treatment with metformin + TKIs, overall survival was improved
significantly, and therefore it is important to evaluate LKB1 expression in addition to
mutations which could be related with treatment response in patients given metformin plus
antineoplastic agents. LKB1 can activate AMPK signaling through specific phosphorilations at
aminoacid residues. AMPK can regulate cell cycle, cell proliferation and cell survival in
NSCLC. Recently, the loss of expression of LKB1 has been associated with a reduced activation
in AMPK using in vivo models, and increase in tumor necrosis after treatment with
bevacizumab. The expression of AMPK has also been evaluated in NSCLC, a study which included
99 samples concluded that increased AMPK expression was associated with worse overall
survival. Nonetheless, the association between AMPK expression and metformin treatment has
not been ascertained.
Metformin is a biguanide used as treatment for type 2 diabetes. Additionally, several studies
have identified a reduced incidence and mortality from diverse neoplasms in patients treated
with metformin. In vitro studies have shown that metformin is cytotoxic in lung
adenocarcinoma cells, producing a cell cycle arrest at G0 and G1, and it inhibits resistance
to TKIs induced by Epithelial-Mesenchimal transition (EMT). Retrospective trials have also
provided evidence as to the benefit of metformin in patients undergoing treatment for NSCLC.
Several prospective trials have evaluated the concurrent use of metformin plus TKIs for
patients with lung adenocarcinoma, though results have been controversial.
This randomized, phase 3 study will evaluate the PFS in patients with NSCLC with EGFR
mutations undergoing treatment with TKIs plus placebo vs. TKIs plus metformin.