Clinical trial NCT04122833: Impact of Concomitant Genetic Alterations in EGFR Mutated Adenocarcinoma by NGS Analysis: A Multicenter Study
Official title: A Next-generation Sequencing Analysis to Investigate the Clinical Impact of Concomitant Genetic Alterations in the Patients With Advanced EGFR-mutated Lung Adenocarcinoma: A Multicenter Study.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Adenocarcinoma of Lung
EGFR Activating Mutation
Keywords: next generation sequencing
Lead sponsor: Konkuk University Medical Center
Sponsor class: OTHER
Collaborators: name: Roche Diagnostics GmbH
name: Foundation Medicine
First posted: 2019-10-10
Enrollment: 80
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: EGFR-mutated stage IV lung adenocarcinoma patients

Brief summary: The concomitant co-mutation with epidermal growth factor receptor (EGFR) mutation might influence the clinical outcomes. The investigators will identify the impact of concommitant mutation on clinical outcome in patients with advanced -EGFR mutated adenocarcinoma.

The investigators will compare the genetic alterations between tumors of pre and post Tyrosin Kinase Inhibitor(TKI) treatments and predict the resistance mechanism for EGFR-TKIs by next-generation sequencing(NGS) analysis.

Detailed description: The current standard therapies in the treatment of advanced EGFR-mutated lung cancer patients are the 1st or 2nd EGFR-TKIs. Although 70-80% of patients treated by EGFR-TKIS show good responses, they have progression after around 12 months. The concomitant co-mutation with EGFR mutation might influence the drug response of EGFR TKI. The investigators will compare the progression-free survival (PFS) of EGFR-TKI according to co-occuring mutations.

The patients experience the change of molecular profiles after using the TKI. Therefore, the investigators will investigate the molecular profiles through NGS panel with foundation medicine in the tissue of pre/post EGFR-TKI, compare the change of the molecular profiles and tumor mutation burden(TMB), and identify novel mechanisms of drug resistance.

The investigators will collect the tumor tissues and blood of around 80 patients in multi-centers prospectively. Then, They will be sent to FoundationOne in the US and perform NGS analysis. The type of EGFR-TKIs would be selected according to physicians' preference. NGS will be performed twice before the EGFR-TKIs treatment and after the progression.

Eligibility criteria: Inclusion Criteria:

1. Signed Informed Consent Form
2. Age ≥19 years
3. EGFR-mutated stage IV lung adenocarcinoma patients
4. Archival biopsy tissues which are from core needle biopsies, endobronchial ultrasound (EBUS) guided- lymph node biopsy or lymph node excisional biopsy at baseline and at radiologic progression
5. Availability of the 10 unstained slides and 1 H\&E slides at pre/ post TKI treatment
6. Samples should contain a minimum of 20% viable tumor cells that preserve

Exclusion Criteria:

Tumor tissue from bone metastases that have been decalcified are not acceptable.

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Primary outcomes:
measure: Change of mutation profiles between pre/post TKI treatment
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: PFS according to the co-occurring mutations with pre-TKI treatment
timeFrame: through study completion, an average of 1 year
measure: The number and the kinds of co-occurring mutations on tumors before and after TKI treatment
timeFrame: through study completion, an average of 1 year
measure: The correlation between the change of variant allele frequency(VAF) and drug response in matched tumors tissues before and after TKI treatment
timeFrame: through study completion, an average of 1 year
measure: Tumor mutation burden in tumors tissues before and after TKI treatment
timeFrame: through study completion, an average of 1 year
measure: The concordance the the mutation profiles in the NGS results of tissue and blood in the same patients
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Asan medical center
city: Seoul
country: Korea, Republic of
facility: Catholic university medical center, Seoul St. Mary's Hospital
Study officials:
affiliation: Kunkuk University Medical Center
name: In Ae Kim, MD. Ph.D
role: STUDY_DIRECTOR
References:
citation: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. doi: 10.1200/JCO.2012.44.2806. Epub 2013 Jul 1.
citation: Kim Y, Lee B, Shim JH, Lee SH, Park WY, Choi YL, Sun JM, Ahn JS, Ahn MJ, Park K. Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC. J Thorac Oncol. 2019 Feb;14(2):193-202. doi: 10.1016/j.jtho.2018.10.150. Epub 2018 Nov 1.
citation: Offin M, Rizvi H, Tenet M, Ni A, Sanchez-Vega F, Li BT, Drilon A, Kris MG, Rudin CM, Schultz N, Arcila ME, Ladanyi M, Riely GJ, Yu H, Hellmann MD. Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers. Clin Cancer Res. 2019 Feb 1;25(3):1063-1069. doi: 10.1158/1078-0432.CCR-18-1102. Epub 2018 Jul 25.
citation: Yu HA, Suzawa K, Jordan E, Zehir A, Ni A, Kim R, Kris MG, Hellmann MD, Li BT, Somwar R, Solit DB, Berger MF, Arcila M, Riely GJ, Ladanyi M. Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance. Clin Cancer Res. 2018 Jul 1;24(13):3108-3118. doi: 10.1158/1078-0432.CCR-17-2961. Epub 2018 Mar 12.
citation: Socinski MA, Villaruz LC, Ross J. Understanding Mechanisms of Resistance in the Epithelial Growth Factor Receptor in Non-Small Cell Lung Cancer and the Role of Biopsy at Progression. Oncologist. 2017 Jan;22(1):3-11. doi: 10.1634/theoncologist.2016-0285. Epub 2016 Nov 7.