Adding tepotinib to lazertinib for EGFR‑mutant metastatic lung cancer with MET overexpression or amplification after progression on lazertinib

Lazertinib and Tepotinib for EGFR Mutant NSCLC in MET Overexpressed or Amplified Who Progressed After Lazertinib Treatment: A Phase II Multi-center Trial

This trial tests whether adding the MET blocker tepotinib to lazertinib helps people with EGFR‑mutant metastatic non‑small cell lung cancer whose tumors show MET overexpression or amplification and who have progressed on lazertinib.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 47 (estimated)
• Ages: 19 Years and up
• Sex: All
• Sponsor: Samsung Medical Center (Academic / other)
• Drugs / interventions: lazertinib, chemotherapy, radiation, Osimertinib, savolitinib, tepotinib
• Locations: 1 site (Seoul, Gangnam-gu)
• Trial ID: NCT06106802 on ClinicalTrials.gov

What this trial studies

This phase 2 interventional trial enrolls patients with metastatic EGFR‑mutant NSCLC who progressed after first‑line lazertinib and whose tumors meet predefined MET amplification/overexpression criteria by FISH. Enrolled participants receive a combination of lazertinib plus tepotinib and are followed for tumor response, safety, and progression‑related outcomes. Patients are molecularly selected using MET GCN ≥5 and/or MET/CEP7 ≥2 to target MET‑driven resistance. The study is conducted at Samsung Medical Center in Seoul with serial clinical and radiographic assessments.

Who should consider this trial

Good fit: Ideal candidates are adults with metastatic EGFR‑mutant (exon 19 deletion or L858R) NSCLC who previously benefited from first‑line lazertinib for at least six months and have MET amplification or overexpression by FISH.

Not a fit: Patients whose tumors lack MET amplification/overexpression or whose disease is driven primarily by other resistance mechanisms are unlikely to benefit from this combination.

Why it matters

Potential benefit: If successful, this combination could control cancers driven by MET‑mediated resistance and delay the need for systemic chemotherapy.

How similar studies have performed: Early‑phase studies combining third‑generation EGFR inhibitors with MET inhibitors (for example osimertinib plus savolitinib) have shown promising activity in MET‑amplified resistance settings.

Eligibility criteria

Inclusion Criteria:

1. Histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer which is not amenable to treatment with a curative aim (e.g., surgery or radiation)
2. Confirmed EGFR mutations (exon 19 deletion, L858R) with acquired resistance after first-line lazertinib treatment (either partial response, complete response or stable disease last more than 6 months after initiation of Lazertinib) - patient can maintain the treatment with prior EGFR treatment as beyond progression until the patient start the treatment per this protocol
3. First-line cytotoxic chemotherapy received as palliative treatment is acceptable after the failure of Lazertinib (Patients with disease progression after adjuvant or neoadjuvant chemotherapy within 6 months are eligible to participate)
4. Patient with MET amplification FISH GCN ≥5 and/or MET/CEP7 ≥ 2 (If additional resistance mechanism to lazertinib, such as C797S, is observed with MET amplification, the recruitment needs to be discussed in advance with the principal investigator)
5. Available tissue for MET FISH
6. Age of 19 or more
7. Performance status of Eastern Cooperative Oncology Group 0 to 2
8. Expected minimum life expectancy of 12 weeks
9. Adequate organ function

   1. Absolute neutrophil count (ANC) ≥1500cells/mm3
   2. Platelet count ≥100,000cells/mm3
   3. Total bilirubin ≤1.5 x upper limit of normal(ULN)
   4. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN (or ≤5.0 x ULN, if liver metastasis is present)
   5. Creatinine level ≤1.5 x upper limit of normal (ULN) or creatinine clearance ≥ 45mL/min (Calculated with Cockcroft- Gault equation)
10. Available to provide the adequate tissue and blood for the genomic tests

    \- At least 20 unstained slide and 20 cc of blood at baseline and disease progression (If not, participant must be confirmed by the principal investigator
11. Agreed to perform re-biopsy at the timepoint of disease progression
12. Female subjects must either be of non-reproductive potential
13. Subject willing and able to comply with the protocol
14. Signed written informed consent

Exclusion Criteria:

1. Previously treatment with any kind of EGFR TKI other than lazertinib
2. All concurrent and/or other active malignant tumors requiring systemic therapy within 2 years prior to the initial administration of the investigational drug (However, the patient may participate if previous malignant tumor has been cured, and no further treatment is required)
3. Uncontrolled central nervous system metastases
4. Spinal cord compression, leptomeningeal carcinomatosis
5. Uncontrolled systemic illness, including uncontrolled hypertension, active bleeding, or active infection
6. Radiotherapy with a wide field of radiation within 2 weeks or radiotherapy with a limited field of radiation (localized radiotherapy or gamma knife surgery) for palliation within 1 week
7. Any unresolved toxicities from prior therapy, greater than CTCAE grade 1
8. Prior history of interstitial lung disease (ILD) or ILD like symptoms
9. Mean QT interval corrected for heart rate (QTc) ≥ 470 ms
10. No measurable lesion
11. Unable to swallow the product due to refractory nausea, vomiting or chronic gastrointestinal disease

Where this trial is running

Seoul, Gangnam-gu

• Samsung Medical Center — Seoul, Gangnam-gu, South Korea (Recruiting)

Study contacts

• Principal investigator: Myung-Ju Ahn — Samsung Medical Center
• Study coordinator: Myung-Ju Ahn

Conditions Non-Small Cell Lung Cancer Metastatic