Metformin Plus Tyrosine Kinase Inhibitors for Treatment of Patients With Non-small Cell Lung Cancer With EGFR Mutations

NCT05445791 | Recruiting Phase 3

• 1 other identifier: (020/023/ICI) (CEI/1421/19)
• Study Type: interventional
• Target: 312
• Locations: 1 country
• Sites: 1

Brief Summary

Lung cancer is the most common neoplastic disease globally, with over 2 million new cases annually, accounting for 11.6% of all cancer diagnoses. It remains the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) makes up 80-85% of lung cancer cases, with most patients diagnosed at an advanced stage. Five-year survival rates are low, ranging from 8-18% worldwide. Advances in molecular biology have led to the identification of therapeutic targets in NSCLC. One of the most studied is the epidermal growth factor receptor (EGFR), a key regulator of tumor cell functions and a focus of targeted therapy development. EGFR mutations occur in about 15% of NSCLC cases globally but reach up to 34% in Mexico. Patients with these mutations are treated with tyrosine kinase inhibitors (TKIs), which improve response rates and progression-free survival (PFS) over chemotherapy. However, resistance to TKIs typically develops, prompting the need for strategies to overcome this challenge and extend PFS. Up to 30% of NSCLC patients have somatic mutations in the liver kinase B1 (LKB1) gene, a tumor suppressor that inhibits mTOR. In one study, 24 patients with LKB1 expression treated with metformin plus TKIs showed significantly improved overall survival. LKB1 activates AMP-activated protein kinase (AMPK), which regulates cell cycle and survival in NSCLC. Loss of LKB1 reduces AMPK activation and increases tumor necrosis following bevacizumab treatment. A study of 99 NSCLC samples linked high AMPK expression to poorer survival, though its role in metformin response is unclear. Metformin, a biguanide used for type 2 diabetes, has shown anticancer properties. Studies suggest metformin reduces cancer incidence and mortality. In vitro, it induces G0/G1 cell cycle arrest and counters TKI resistance due to epithelial-mesenchymal transition (EMT). Retrospective studies support its benefit in NSCLC, and prospective trials of metformin plus TKIs have yielded mixed results. This phase 3 randomized study aims to evaluate PFS in NSCLC patients with EGFR mutations treated with TKIs plus placebo versus TKIs plus metformin.

Conditions

Non Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• Progression-free survival

  Time from treatment start until documented disease progression (according to RECIST criteria) or death by any cause.

  48 months

Secondary Outcomes (2)

• Overall survival

  48 months

• Overall Response Rate

  3 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Patients randomized to this study arm will be treated with tyrosine kinase inhibitors (Gefitinib 250 mg/day; afatinib 30-40 mg/day; erlotinib 150 mg/day) plus placebo 500 mg twice daily until disease progression.

Other: Placebo

Metformin

EXPERIMENTAL

Patients randomized to this study arm will be treated with tyrosine kinase inhibitors (Gefitinib 250 mg/day; afatinib 30-40 mg/day; erlotinib 150 mg/day) plus metformin 500 mg twice daily until disease progression.

Drug: Metformin Hydrochloride

Interventions

Metformin Hydrochloride DRUG

Metformin 500 mg twice daily until disease progression.

Also known as: FICONAX

Metformin

Placebo OTHER

Placebo 500 mg twice daily until disease progression

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a histologically confirmed diagnosis of non-small cell lung cancer (stage IIIB-IV) according to the American Joint Committee on Cancer (AJCC) eight edition.
• Measurable disease by RECIST 1.1.
• years of age or older.
• Functional status 0-2 as assessed by Eastern Cooperative Oncology Group (ECOG) scale.
• Life expectancy of minimum12 weeks.
• Patients with non-small cell lung cancer and a documented EGFR sensitizing mutation.
• Patients without previous EGFR-TKI treatment. Previous use of chemotherapy is allowed with a washout period of at least 6 months.
• Patients with asymptomatic brain metastases, or if symptoms are present treatment with radiotherapy (whole brain radiotherapy, stereotactic radiosurgery) or surgery must be administered.
• Neutrophil count ≥1.5 x 103/mm3, and platelet count \>100 x (103/mm3).
• Serum bilirubin ≤1.5 the superior upper limit.
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2 superior upper limit (or ≤ 5 times the superior upper limit in patients with liver metastases).
• Serum creatinine ≤ 1.5 superior upper limit, or creatinine clearance ≥ 60ml/min.
• Full ability to complete all study procedures and follow up.
• Women with child-bearing potential must have a negative pregnancy test within 72 hours of treatment start.
• Patients with reproductive potential must use effective contraception.

You may not qualify if:

• Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart disease, hepatic diseases, renal diseases).
• Patients previously treated with an EGFR-TKI.
• Patients diagnosed with any other neoplastic disease in the previous 5 years (except in situ cervical carcinoma or basocellular skin cancer, treated accordingly).
• Patients unable to receive oral medication, who require IV nourishment, or who underwent surgical procedures with affect nutrient absorption, or with an active peptic ulcer.
• Pregnant or lactating women.
• Patients diagnosed with type 2 diabetes or a glycated hemoglobin ≥ 6.5%.
• Patients being currently treated with metformin.

Sponsors & Collaborators

• Instituto Nacional de Cancerologia de Mexico: lead

Study Sites (1)

Instituto Nacional de Cancerologia

Mexico City, 14080, Mexico

RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Metformin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Oscar Gerardo Arrieta Rodríguez

  Instituto Nacional de Cancerologia de Mexico

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Oscar Arrieta, M.Sc.

CONTACT

5556280400; oscararrietaincan@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Coordinator of the Thoracic Oncology Unit

Study Record Dates

• First Submitted: June 30, 2022
• First Posted: July 6, 2022
• Study Start: July 15, 2021
• Primary Completion (Estimated): July 14, 2026
• Study Completion (Estimated): July 14, 2027
• Last Updated: April 9, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)