Clinical trial NCT06081270: Prospective Study on Resistance-associated Mutations in Metastatic Lung Cancer
Official title: Prospective Study on Resistance-associated Mutations in Metastatic Lung Neoplasm Patients With Alterations in Driver Oncogenes, Except EGFR, Undergoing Treatment With Specific Inhibitors
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Lung Cancer
Keywords: ALK (anaplastic lymphoma kinase)
ROS (ROS proto-oncogene 1)
RET (Rearranged during transfection)
B-RAF
lung cancer
tyrosine kinase inhibitor
Lead sponsor: University of Milano Bicocca
Sponsor class: OTHER
First posted: 2023-10-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Twenty patients will be enrolled in the study

Brief summary: This single-centre prospective study is aimed at analysing, by means of liquid biopsy with next generation sequencing analysis on circulating tumor DNA, resistance mutations arising during therapy with selective inhibitors in patients with RTK-positive NSCLC or with mutations in the Ras/MAPK (mitogen-activated protein kinase) pathway, treated at the San Gerardo Hospital, Monza.

Detailed description: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease that may have several genetic alterations in oncogenes responsible for progression. 30-40% of NSCLC patients carry mutations affecting the Ras/MAPK pathway, while alterations in receptor tyrosine kinases (RTKs) are found in approximately 25-35% of cases. More than half of the latter are in the Epithelial Growth Factor Receptor (EGFR) gene and have been extensively studied. In the remaining cases, several genes are involved, each with lower frequencies, ranging from around 1% to 5%, depending on the studies. Despite the wide availability of inhibitors, progression remains inevitable due to the emergence of drug resistance mechanisms. The mechanisms by which resistance can be established are essentially of three types: amplification of the target gene, activation of other signal translation pathways (by-pass track) and the occurrence of mutations in the tyrosine kinase domain of the target protein. Liquid biopsy with circulating tumour DNA (ctDNA) analysis provides a non-invasive surrogate method to identify somatic mutations by means of a simple blood sample, without risk to the patient. Moreover, liquid biopsy, by collecting ctDNA from different metastatic sites, could better reflect tumour heterogeneity, both spatial and temporal, and could, therefore, constitute a simple method of longitudinal monitoring during treatment, possibly making it possible to identify relapse early before clinical manifestation. This single-centre prospective study is aimed at analysing, by means of liquid biopsy with next generation sequencing analysis on ctDNA, resistance mutations arising during therapy with selective inhibitors in patients with RTK-positive NSCLC or with mutations in the Ras/MAPK pathway, treated at the San Gerardo Hospital, Monza.

Eligibility criteria: Inclusion Criteria:

1. Over 18 years of age.
2. Histological diagnosis of inoperable metastatic or locally advanced lung cancer.
3. Positivity for ALK, ROS1, MET, RET (Rearranged during transfection), NTRK (NEUROTROPHIC TYROSINE RECEPTOR KINASE) rearrangements, or KRAS (Kirsten rat sarcoma)-G12C (glycine 12 cysteine) or BRAF-V600E (valine 600 glutamate) mutations, detected by validated method (IHC Immunohistochemistry 3+, FISH (fluorescence in situ hybridization) or Next Generation Sequencing).
4. Patients undergoing radiological progression according to RECIST 1.1 criteria to treatment with generation I, II or III inhibitors in any line of treatment. Patients may also have been pre-treated with chemotherapy in earlier lines.
5. Presence of measurable disease on radiological investigations. Patients with brain metastases, even as a single site of disease, are eligible for the study.
6. Informed consent freely given and obtained before the start of the study.

Exclusion Criteria:

1. Under 18 years of age
2. Unconfirmed histological diagnosis
3. Absence of rearrangement or mutation of ALK, ROS1, MET, RET, NTRK, KRAS-G12C or BRAF-V600E
4. Progression to chemotherapy in the absence of treatment with TKI or RAS or BRAF inhibitor
5. Unmeasurable disease

Primary outcomes:
measure: Identification of mutation during therapy with selective inhibitors
timeFrame: At treatment initiation (baseline), up to 12 weeks from treatment initiation, at the date of first documented progression, assessed up to 24 months from treatment initiation
Secondary outcomes:
Other outcomes:
Locations:
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
state: MB
Study officials:
affiliation: Fondazione IRCCS San Gerardo dei Tintori, Monza
name: Diego Cortinovis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Milano Bicocca
name: Luca Mologni, PhD
role: STUDY_CHAIR
References: