Lazertinib & Tepotinib for EGFR Mutant NSCLC in MET Overexpressed or Amplified Who Progressed After Lazertinib Treatment

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

As the 3rd generation, EGFR TKI has become a standard treatment option for the 1st line therapy in EGFR mutated patients, the necessity for evaluating resistant mechanism to determine the matched subsequent therapeutic option has been highlighted. From the 1st line Osimertinib treatment, the heterogenous resistance mechanism has been observed showing most commonly by MET amplification (7-15%) followed by additional on-target EGFR mutation (6-10%), BRAF, PI3KCA, KRAS, HER2 mutation (13-14%) and still 40 to 50% remain unknown for the mechanism. (A. Leonetti et al.British Journal of Cancer(2019))

Based on the observation showing the MET amplification as the most common resistance mechanism to the 3rd generation EGFR TKI treatment, the "TATTON" study, a multi-arm, phase IB trial, demonstrated early clinical data of Osimertinib in combined with savolitinib. Among the patients, c-MET amplified patients who were previously treated with 3rd generation EGFR TKI, a combination of Osimertinib and savolitinib, showed an objective response rate of 33% and median PFS of 5.5 months. (G. Oxnard et al. Annals of Oncology(2020))

The clinical efficacy of Osimertinib with savolitinib in MET overexpressed or amplification patients are reported from the global phase II, "SAVANNAH" study. The preliminary results from the SAVANNAH trial showed that Osimertinib plus savolitinib demonstrated an objective response rate of 49% in patients with a high level of MET overexpression and/or amplification, defined as IHC90+ and/or FISH 10+, whose disease progressed on treatment with Osimertinib. The highest ORR was observed in patients with a high level of MET who were not treated with prior chemotherapy (52%). In patients whose tumors did not show a high level of MET, the ORR was 9% (MJ Ahn, WCLC, 2022). There are ongoing global Phase III SAFFRON study to validate the outcome from SAVANNAH study.

It has been reported that around 62% of tumor in Osimertinib progressed sample has MET overexpression and/or amplification, and more than one-third (34%) met the defined high MET level cut-off.

As Lazertinib is about to be approved as the treatment option for the treatment naïve EGFR mutated NSCLC, it is also becoming important to develop a further treatment plan based on the MET amplification status. In this study, the investigators designed a phase II study based on the MET amplification status to evaluate the clinical efficacy of Lazertinib + tepotinib.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer Metastatic
• Intervention / Treatment: Drug: Lazertinib; Drug: Tepotinib

• Study Type: Interventional
• Enrollment (Estimated): 47
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Myung-Ju Ahn; Phone Number: 82-10-3410-3438; Email: silkahn@skku.edu

Study Locations

• Korea, Republic of
  • Gangnam-gu
    • Seoul, Gangnam-gu, Korea, Republic of, 06351
      • Samsung Medical Center
      • Contact: Myung-Ju Ahn; Phone Number: +821034103438; Email: silkahn@skku.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: single arm; Patients will be treated with Lazertinib + tepotinib based on the MET FISH results. Lazertinib 240mg daily Tepotinib 500mg daily	Drug: Lazertinib; Lazertinib 240mg/day; Drug: Tepotinib; Tepotinib 500mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
objective response rate (ORR)	9 months after completion of enrollment

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression free survival (PFS)	up to 60 months
Duration of Response (DoR)	up to 60 months
Disease control rate (DCR)	up to 60 months
Overall survival (OS)	up to 60 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resistance mechanism analysis -tumor tissue	Using cf DNA acquired from baseline and at the time point of drug resistance, resistance mechanism will be evaluated. Using clinical outcome and confirmed mutation profile, resistance mechanism will be evaluated. Correlation between tissue and cfDNA based mutation profile will be analzed.	up to 60 months

Collaborators and Investigators

• Sponsor: Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): February 2, 2024
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): September 30, 2029

Study Registration Dates

• First Submitted: October 12, 2023
• First Submitted That Met QC Criteria: October 27, 2023
• First Posted (Actual): October 30, 2023

Study Record Updates

• Last Update Posted (Actual): October 30, 2023
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tepotinib; Lazertinib
• Other Study ID Numbers: 2023-10-053

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No