Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine Kinase Inhibitors Alone for Patients With Advanced Non-small Cell Lung Cancer and EGFR Mutations: Phase 3 Randomized Clinical Trial

Plain English Summary

Metformin Plus Tyrosine Kinase Inhibitors for Treatment of Patients With Non-small Cell Lung Cancer With EGFR Mutations is a Phase 3 clinical trial sponsored by Instituto Nacional de Cancerologia de Mexico studying Non Small Cell Lung Cancer. This trial tests if adding Metformin to standard targeted therapy (Tyrosine Kinase Inhibitors) improves outcomes for advanced non-small cell lung cancer patients with specific gene mutations. It is for patients with advanced non-small cell lung cancer who have a specific EGFR gene mutation and have not previously received EGFR targeted therapy. Participants will receive either standard targeted therapy alone or targeted therapy plus Metformin. This involves regular clinic visits, blood tests, and scans. Standard treatment for this condition involves targeted therapy alone. Other options may include chemotherapy or immunotherapy depending on the specific mutation and patient's health. The trial aims to enroll 312 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults (18+) with advanced non-small cell lung cancer and a confirmed EGFR gene mutation. Patients must not have received prior treatment with EGFR targeted therapy, but prior chemotherapy is allowed if there's been a sufficient break. Good general health is required, with specific limits on blood counts, liver, and kidney function. Patients with brain metastases must have received treatment for them. Individuals with type 2 diabetes or high blood sugar (HbA1c >= 6.5%), those currently taking Metformin, or with other active cancers in the last 5 years cannot participate. This trial is studying Non Small Cell Lung Cancer, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

Progression-free survival means the length of time patients live without their cancer getting worse, which is a key measure of how well the treatment is working. The specific primary outcome measures are: Progression-free survival (48 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses the challenge of resistance to current targeted therapies in lung cancer by investigating if Metformin, a common diabetes drug with anti-cancer properties, can enhance treatment e As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Non Small Cell Lung Cancer, where improved treatment options are needed.

Investor Insight

This trial targets a significant unmet need in advanced NSCLC, a large market. Success could position Metformin as an adjunct therapy, potentially improving the competitive landscape for TKI treatment Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about the specific type of EGFR mutation you have and if Metformin is appropriate for you. Understand the potential benefits and risks of adding Metformin to your treatment plan. Be prepared for regular study visits, which will include taking medication, undergoing tests, and providing updates on your health. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 312 participants

Interventions

• DRUG: Metformin Hydrochloride — Metformin 500 mg twice daily until disease progression.
• OTHER: Placebo — Placebo 500 mg twice daily until disease progression

Primary Outcomes

• Progression-free survival (48 months)

Secondary Outcomes

• Overall survival (48 months)
• Overall Response Rate (3 months)

Full Eligibility Criteria

Inclusion Criteria:

1. 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.
2. Measurable disease by RECIST 1.1.
3. 18 years of age or older.
4. Functional status 0-2 as assessed by Eastern Cooperative Oncology Group (ECOG) scale.
5. Life expectancy of minimum12 weeks.
6. Patients with non-small cell lung cancer and a documented EGFR sensitizing mutation.
7. Patients without previous EGFR-TKI treatment. Previous use of chemotherapy is allowed with a washout period of at least 6 months.
8. Patients with asymptomatic brain metastases, or if symptoms are present treatment with radiotherapy (whole brain radiotherapy, stereotactic radiosurgery) or surgery must be administered.
9. Neutrophil count ≥1.5 x 103/mm3, and platelet count \>100 x (103/mm3).
10. Serum bilirubin ≤1.5 the superior upper limit.
11. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2 superior upper limit (or ≤ 5 times the superior upper limit in patients with liver metastases).
12. Serum creatinine ≤ 1.5 superior upper limit, or creatinine clearance ≥ 60ml/min.
13. Full ability to complete all study procedures and follow up.
14. Women with child-bearing potential must have a negative pregnancy test within 72 hours of treatment start.
15. Patients with reproductive potential must use effective contraception.
16. Signed informed consent for participation in the study.
17. Availability of tumor tissue (pre-treatment biopsy) to determine LKB1 and AMPK status.

Exclusion Criteria:

1. Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart disease, hepatic diseases, renal diseases).
2. Patients previously treated with an EGFR-TKI.
3. Patients diagnosed with any other neoplastic disease in the previous 5 years (except in situ cervical carcinoma or basocellular skin cancer, treated accordingly).
4. 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.
5. Pregnant or lactating women.
6. Patients diagnosed with type 2 diabetes or a glycated hemoglobin ≥ 6.5%.
7. Patients being currently treated with metformin.

Trial Locations

• Instituto Nacional de Cancerologia, Mexico City, Mexico

Frequently Asked Questions

Related Conditions

• Non-Small Cell Lung Cancer
• Lung Cancer
• EGFR Mutations
• Tyrosine Kinase Inhibitors
• Metformin
• Oncology
• Targeted Therapy
• Cancer Treatment
• Advanced Cancer
• Metabolic Syndrome

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