Clinical trial NCT04737382: Osimertinib Resistance in Patients With Non-small-cell Lung Carcinoma That Have Progressed.
Official title: Osimertinib Resistance Analysis in Patients With EGFR Mutation Positive Non-small-cell Lung Carcinoma That Have Progressed on Osimertinib Treatment'
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Non-small-cell Lung Carcinoma
Keywords: Osimertinib
EGFR positive NSCLC
Resistance
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2021-02-03
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: Initially, patients with EGFR mutation positive NSCLC respond well to osimertinib, a third generation EGFR tyrosine kinase inhibitor (TKI), but eventually progress. Upon progression multiple resistance mechanisms have been described and new therapeutic strategies are being developed to target these resistance mechanisms. Thorough and complete osimertinib resistance analysis enables optimal treatment decision making and might identify new targets for molecular treatment, thereby potentially improving patient outcome.

Detailed description: Initially, patients with EGFR mutation positive NSCLC respond well to osimertinib, a third generation EGFR tyrosine kinase inhibitor (TKI), but eventually progress. Upon progression, three main resistance mechanisms can be found (1, 2): 1) alteration of the drug target by secondary or tertiary EGFR mutations (e.g. C797S mutation in the EGFR kinase domain), 2) alteration of downstream signal transduction proteins (e.g. KRAS mutation / amplification) and 3) bypass track resistance like MET or HER2 amplification. A fourth, less frequent, mechanism involves morphological alterations: dedifferentiation by epidermal-mesenchymal transition (EMT) or change to small-cell-lung carcinoma (SCLC), including RB1 loss.

New therapeutic strategies are being developed to target these resistance mechanisms and reports have been published about successful treatment of HER2 and MET amplification. Drugs targeting the C797S mutation are entering the clinic.

Next Generation Sequence (NGS) technology rapidly evolves and it is now feasible to analyse broad panels of genetic alterations in tumor tissue as well as in circulating tumor DNA (ctDNA).

ctDNA based T790M detection is a valid method to test for resistance to first or second generation EGFR TKI's and the ctDNA based technique is increasingly being used for patients with progression on the third generation EGFR TKI osimertinib. Actually, the distribution of osimertinib resistance mechanisms, as known to date, largely comes from ctDNA based datasets, because biopsy based analyses are scarce. Due to impaired sensitivity of ctDNA based analyses when compared to tissue based analysis, especially for copy number variations, these reports might be misleading and lead to suboptimal treatment. Early reports of tumor samples obtained after progression on first / second generation EGFR TKI's have shown that ctDNA and tumor based drug resistance analyses can be concordant or disconcordant and that the tests should be regarded as complimentary \[Oxnard et al\].

Sensitivity and specificity of ctDNA and biopsy based drug resistance analysis after osimertinib treatment and how these tests behave within individual patients are unknown.

Thorough and complete osimertinib resistance analysis enables optimal treatment decision making and might identify new targets for molecular treatment, thereby potentially improving patient outcome.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed metastatic NSCLC, characterized by a sensitizing EGFR mutation.

  2. Progressive disease, as assessed by the treating physician during osimertinib monotherapy.

  3. Eligible for subsequent treatment. 4. Willing to undergo a histological biopsy and withdrawal of a blood sample for ctDNA analysis.

  5. Technically possible to take a histological biopsy.

Exclusion Criteria:

- 1. Osimertinib discontinuation before blood draw and / or histological tumor biopsy.

2. Initiation of a new line of anticancer therapy before blood draw and / or histological tumor biopsy.

Primary outcomes:
measure: EGFR TKI resistance analysis on tumor biopsies and ctDNA
timeFrame: Trough study completion, an average of 2 years
measure: Recommendation for subsequent treatment
timeFrame: Trough study completion, an average of 2 years
Secondary outcomes:
measure: Evaluate recommended and actually treatment
timeFrame: Trough study completion, an average of 2 years
measure: Evaluate plasma and tumor tissue
timeFrame: Trough study completion, an average of 2 years
measure: Evaluate success rate
timeFrame: Trough study completion, an average of 2 years
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute-Antoni van Leeuwenhoek
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus MC, Universitair Medisch Centrum Rotterdam
Study officials:
affiliation: The Netherlands Cancer Institute-Antoni van Leeuwenhoek
name: J de Langen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: