Neoadjuvant Lazertinib Therapy in EGFR-Mutation Positive Lung Adenocarcinoma Detected by BALF Liquid Biopsy

Complete surgical resection is the standard treatment in early-stage lung cancer. However, the patients with early resected Epidermal Growth Factor Receptor(EGFR)-mutated lung cancers have high recurrence rate. The efficacy of neoadjuvant treatment by first-generation EGFR-Tyrosine Kinase Inhibitor(TKI) has been demonstrated, however, that of the third-generation EGFR-TKI(lazertinib) has not yet been fully investigated. The aim of this study is to evaluate the efficacy of neoadjuvant Lazertinib in resectable EGFR mutation-positive NSCLC and clinical application of extracellular vesicles(EVs) based BALF liquid biopsy to identify EGFR mutation without invasive tissue biopsy.

Sex

All

Minimum age

19 Years

Inclusion Criteria:

1. Age ≥ 19 years
2. Patients with suspected lung cancer on chest CT findings
3. Patients with the following EGFR gene mutations in the test on bronchoalveolar lavage fluid: E19Del, L858R alone or concurrent rare EGFR gene mutations (T790M, G719X, exon 20 insertion, S768I)
4. Patients whose tumor can be completely resected by surgery: patients with stage I-IIIB, or stage IVA who has single metastasis
5. Patients not previously treated with EGFR-TKIs such as gefitinib, erlotinib, afatinib, dacomitinib
6. Patients with the measurable lesion of 1 cm or more according to RECIST v1.1
7. Eastern Cooperative Oncology Group (ECOG) 0-1
8. EGFR-TKIs (gefitinib, erlotinib, afatinib,dacomitinib) naive patients
9. Patients with adequate pulmonary and heart function for surgery
10. Adequate organ function defined as Hemoglobin ≥ 9.0g/dL Absolute neutrophil count ≥ 1500/mm3 Platelet ≥ 100,000 /mm3 Serum creatinine≤ normal range\*1.5x Aminotransferase/Alkaline phosphatase ≤normal range\*2.5x Total bilirubin ≤1.5 mg/dL Liver metastasis: Aminotransferase/Alkaline phosphatase ≤ normal range\* 5x Bone metastasis Alkaline phosphatase ≤ normal range\* 5x
11. Female patients with childbearing potential should be using adequate contraceptive measures. Female patients must have evidence of non-child-bearing potential(Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments)
12. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception for at least 14 days prior to administration of the first dose of study treatment, during the study, and for 3 months following the last dose of Lazertinib.

Exclusion Criteria:

1. Uncontrolled active interstitial lung disease
2. Pathologically confirmed N3 disease
3. Uncontrolled stage III-IV other malignancy
4. Uncontrolled Hypertension, Congestive Heart failure with New York Heart Association(NYHA) ≥ 3, acute myocardial infarct history within 6 months before screening. 2nd- 3rd Atrio-Ventricular(AV) block or complete AV block
5. Gastrointestinal diseases (e.g. Chron's disease, ulcerative colitis) or malabsorption syndrome that would impact on drug absorption
6. Active infection requiring ongoing treatment(e.g. active Hepatitis B virus, Hepatitis C virus or Human immunodeficiency virus)
7. History of hypersensitivity to active or inactive excipients of Lazertinib or drugs with a similar chemical structure.
8. No ability to comply with protocol requirements.

• BACKGROUNDZhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Shen Y, Liu YY, Chen C, Cheng Y, Xu L, Wang J, Fei K, Li XF, Li J, Huang C, Liu ZD, Xu S, Chen KN, Xu SD, Liu LX, Yu P, Wang BH, Ma HT, Yan HH, Yang XN, Zhou Q, Wu YL; ADJUVANT investigators. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148. doi: 10.1016/S1470-2045(17)30729-5. Epub 2017 Nov 21. PMID 29174310
• BACKGROUNDXie H, Wang H, Xu L, Li M, Peng Y, Cai X, Feng Z, Ren W, Peng Z. Gefitinib Versus Adjuvant Chemotherapy in Patients With Stage II-IIIA Non-Small-Cell Lung Cancer Harboring Positive EGFR Mutations: A Single-Center Retrospective Study. Clin Lung Cancer. 2018 Nov;19(6):484-492. doi: 10.1016/j.cllc.2018.05.007. Epub 2018 May 26. PMID 30369426
• BACKGROUNDYue D, Xu S, Wang Q, Li X, Shen Y, Zhao H, Chen C, Mao W, Liu W, Liu J, Zhang L, Ma H, Li Q, Yang Y, Liu Y, Chen H, Wang C. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med. 2018 Nov;6(11):863-873. doi: 10.1016/S2213-2600(18)30277-7. Epub 2018 Aug 24. PMID 30150014
• BACKGROUNDLiu SY, Zhang JT, Zeng KH, Wu YL. Perioperative targeted therapy for oncogene-driven NSCLC. Lung Cancer. 2022 Oct;172:160-169. doi: 10.1016/j.lungcan.2022.05.007. Epub 2022 May 21. PMID 35644704
• BACKGROUNDPennell NA, Neal JW, Chaft JE, Azzoli CG, Janne PA, Govindan R, Evans TL, Costa DB, Wakelee HA, Heist RS, Shapiro MA, Muzikansky A, Murthy S, Lanuti M, Rusch VW, Kris MG, Sequist LV. SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. J Clin Oncol. 2019 Jan 10;37(2):97-104. doi: 10.1200/JCO.18.00131. Epub 2018 Nov 16. PMID 30444685
• BACKGROUNDZhang Y, Fu F, Hu H, Wang S, Li Y, Hu H, Chen H. Gefitinib as neoadjuvant therapy for resectable stage II-IIIA non-small cell lung cancer: A phase II study. J Thorac Cardiovasc Surg. 2021 Feb;161(2):434-442.e2. doi: 10.1016/j.jtcvs.2020.02.131. Epub 2020 Mar 19.