Osimertinib Resistance in Patients With Non-small-cell Lung Carcinoma That Have Progressed. (OSIRIS)

October 6, 2023 updated by: The Netherlands Cancer Institute

Osimertinib Resistance Analysis in Patients With EGFR Mutation Positive Non-small-cell Lung Carcinoma That Have Progressed on Osimertinib Treatment'

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

200

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
        • Not yet recruiting
        • Vrije Universiteit Medisch Centrum
        • Contact:
          • S Hashemi, MD
      • Groningen, Netherlands
        • Not yet recruiting
        • Universitair Medisch Centrum Groningen
        • Contact:
          • A vd Wekken, MD,PhD
      • Maastricht, Netherlands
        • Not yet recruiting
        • Academisch Ziekenhuis Maastricht
        • Contact:
          • L Hendriks, MD, PhD
      • Nijmegen, Netherlands
        • Not yet recruiting
        • Radboud Universitair Medisch Centrum
        • Contact:
          • M vd Heuvel, MD, PhD
      • Rotterdam, Netherlands
        • Not yet recruiting
        • Erasmus MC, Universitair Medisch Centrum Rotterdam
        • Contact:
          • M Paats, Md, PhD
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1066 CX
        • Recruiting
        • The Netherlands Cancer Institute-Antoni van Leeuwenhoek
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Biopsy and blood
A histological core biopsy of a tumor lesion and a blood sample for ctDNA analysis will be collected
Diagnostic test: biopsy
The formalin fixed material will be processed for molecular analysis in a clinically validated diagnostic pipeline according to ISO 15189 or other acceptable standard
Diagnostic test: ctDAN analysis
ctDNA analysis will be performed using the AVENIO ctDNA targeted kit according to the guidelines from the manufacturer with respect to isolation, library preparation and bioinformatics analysis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
EGFR TKI resistance analysis on tumor biopsies and ctDNA
Time Frame: Trough study completion, an average of 2 years
Complete osimertinib resistance analysis in tissue and plasma for all patients in the Netherlands that progress on osimertinib treatment
Trough study completion, an average of 2 years
Recommendation for subsequent treatment
Time Frame: Trough study completion, an average of 2 years
Evaluation of these results in an MTB meeting and recommendations for subsequent treatment.
Trough study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate recommended and actually treatment
Time Frame: Trough study completion, an average of 2 years
Number of patients with concordant recommended and actually provided subsequent treatment.
Trough study completion, an average of 2 years
Evaluate plasma and tumor tissue
Time Frame: Trough study completion, an average of 2 years
Number of patients with concordance in osimertinib resistance in plasma using ctDNA and in tumor tissue.
Trough study completion, an average of 2 years
Evaluate success rate
Time Frame: Trough study completion, an average of 2 years
To evaluate the success rate of molecular profiling on tumor tissue and ctDNA (test successfully performed or not).
Trough study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Netherlands Cancer Institute

Collaborators

AstraZeneca

Investigators

  • Principal Investigator: J de Langen, MD, PhD, The Netherlands Cancer Institute-Antoni van Leeuwenhoek

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 22, 2019

Primary Completion (Estimated)

August 22, 2024

Study Completion (Estimated)

August 22, 2024

Study Registration Dates

First Submitted

October 24, 2019

First Submitted That Met QC Criteria

February 2, 2021

First Posted (Actual)

February 3, 2021

Study Record Updates

Last Update Posted (Estimated)

October 9, 2023

Last Update Submitted That Met QC Criteria

October 6, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • M18OSI

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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