Non-small-cell Lung CarcinomaOSIRISNCT04737382
Osimertinib Resistance in Patients With Non-small-cell Lung Carcinoma That Have Progressed.
A study testing biopsy and ctDAN analysis in people with Non-small-cell Lung Carcinoma, run by The Netherlands Cancer Institute at 6 sites in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-small-cell Lung Carcinoma
- What is being tested?
- biopsy and ctDAN analysis
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 6 sitesNetherlands
- Study dates
- 22 Aug 2019to 22 Aug 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Netherlands6 sites, 6 recruiting
- Recruiting
The Netherlands Cancer Institute-Antoni van Leeuwenhoek
Amsterdam, North Holland, 1066 CX
J de Langen, MD, PhD, 00315129111, j.d.langen@nki.nl
M Jebbink, 00315129111, j.jebbink@nki.nl
- Not yet recruiting
Vrije Universiteit Medisch Centrum
Amsterdam
S Hashemi, MD
- Not yet recruiting
Universitair Medisch Centrum Groningen
Groningen
A vd Wekken, MD,PhD
- Not yet recruiting
Academisch Ziekenhuis Maastricht
Maastricht
L Hendriks, MD, PhD
- Not yet recruiting
Radboud Universitair Medisch Centrum
Nijmegen
M vd Heuvel, MD, PhD
- Not yet recruiting
Erasmus MC, Universitair Medisch Centrum Rotterdam
Rotterdam
M Paats, Md, PhD
About this study
Official title: 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.
Read the 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.
- Conditions
- Non-small-cell Lung Carcinoma
- Being tested
- biopsy, ctDAN analysis
- Keywords
- Osimertinib, EGFR positive NSCLC, Resistance
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
biopsyDiagnostic test
The formalin fixed material will be processed for molecular analysis in a clinically validated diagnostic pipeline according to ISO 15189 or other acceptable standard
ctDAN analysisDiagnostic test
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.
| Study group | Role | What they receive |
|---|---|---|
| Biopsy and blood | Other | A histological core biopsy of a tumor lesion and a blood sample for ctDNA analysis will be collected Receives: Diagnostic Test: biopsy; Diagnostic Test: ctDAN analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
EGFR TKI resistance analysis on tumor biopsies and ctDNA
Complete osimertinib resistance analysis in tissue and plasma for all patients in the Netherlands that progress on osimertinib treatment
Measured: Trough study completion, an average of 2 years
Recommendation for subsequent treatment
Evaluation of these results in an MTB meeting and recommendations for subsequent treatment.
Measured: Trough study completion, an average of 2 years
Secondary outcomes (3)
Evaluate recommended and actually treatment
Number of patients with concordant recommended and actually provided subsequent treatment.
Measured: Trough study completion, an average of 2 years
Evaluate plasma and tumor tissue
Number of patients with concordance in osimertinib resistance in plasma using ctDNA and in tumor tissue.
Measured: Trough study completion, an average of 2 years
Evaluate success rate
To evaluate the success rate of molecular profiling on tumor tissue and ctDNA (test successfully performed or not).
Measured: Trough study completion, an average of 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Feb 2021
- Study start22 Aug 2019
- Primary completion22 Aug 2024 (estimated)
- Study completion22 Aug 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Non-small-cell Lung CarcinomaStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
- Investigators
- J de Langen, MD, PhD, Principal investigator, The Netherlands Cancer Institute-Antoni van Leeuwenhoek
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04737382
- Sponsor's protocol ID
- M18OSI
- Acronym
- OSIRIS
- Status last verified
- Oct 2023
- First submitted
- 24 Oct 2019
- Last updated
- 10 Oct 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
van der Wel JWT, Ernst SM, Jebbink M, van den Broek D, Badrising SK, Steinbusch LC, Ruiter G, Theelen WSME, van Veggel BAMH, Smit J, Dingemans AM, Paats MS, Dubbink HJ, Hashemi SMS, Radonic T, Cohen D, van der Wekken AJ, Ter Elst A, Timens W, Hendriks LE, Speel EJM, Disselhorst MMJ, Welling A, van der Meer F, Bosch LJW, Monkhorst K, Boelens MC, Smit EF, de Langen AJ. Determining the optimal approach to identify osimertinib resistance; the first line osimertinib cohort of the OSIRIS study. Lung Cancer. 2025 Nov;209:108783. doi: 10.1016/j.lungcan.2025.108783. Epub 2025 Sep 28.
PubMed 41039677
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Osimertinib Resistance Analysis in Patients With EGFR Mutation Positive Non-small-cell Lung Carcinoma That Have Progressed on Osimertinib Treatment'
- ClinicalTrials.gov ID
- NCT04737382
- Acronym / sponsor ID
- OSIRIS / M18OSI
- Conditions
- Non-small-cell Lung Carcinoma
- Keywords
- Osimertinib, EGFR positive NSCLC, Resistance
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 22 Aug 2019 (actual)
- Primary completion
- 22 Aug 2024 (estimated)
- Study completion
- 22 Aug 2024 (estimated)
- First posted
- 3 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Biopsy and blood | Other | Diagnostic Test: biopsy, Diagnostic Test: ctDAN analysisA histological core biopsy of a tumor lesion and a blood sample for ctDNA analysis will be collected |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| biopsyThe 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 | Biopsy and blood |
| ctDAN analysisctDNA 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. | Diagnostic test | Biopsy and blood |
Primary outcome
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
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.
3 secondary outcomes
Evaluate recommended and actually treatment
Time frame: Trough study completion, an average of 2 years
Evaluate plasma and tumor tissue
Time frame: Trough study completion, an average of 2 years
Evaluate success rate
Time frame: Trough study completion, an average of 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2023.
- Derived from this study: PubMed 41039677van der Wel JWT, Ernst SM, Jebbink M, van den Broek D, Badrising SK, Steinbusch LC, Ruiter G, Theelen WSME, van Veggel BAMH, Smit J, Dingemans AM, Paats MS, Dubbink HJ, Hashemi SMS, Radonic T, Cohen D, van der Wekken AJ, Ter Elst A, Timens W, Hendriks LE, Speel EJM, Disselhorst MMJ, Welling A, van der Meer F, Bosch LJW, Monkhorst K, Boelens MC, Smit EF, de Langen AJ. Determining the optimal approach to identify osimertinib resistance; the first line osimertinib cohort of the OSIRIS study. Lung Cancer. 2025 Nov;209:108783. doi: 10.1016/j.lungcan.2025.108783. Epub 2025 Sep 28.
- Individual participant dataSharing planned: Undecided
Related trials for Non-small-cell Lung Carcinoma
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingObservational study
A Prospective ,Multicenter ,Non-interventional ,Real-world Study Observing Changes in Molecular Markers Osimertinib Targeted Therapy in EGFRm NSCLC
Non Small Cell Lung Cancer
RecruitingPhase 3
A Study Evaluating Sotorasib Platinum Doublet Combination Versus Pembrolizumab Platinum Doublet Combination as a Front-Line Therapy in Participants With Stage IV or Advanced Stage IIIB/C Nonsquamous Non-Small Cell Lung Cancers (CodeBreaK 202)
Non-Small Cell Lung Cancer (NSCLC)
Active, not recruitingPhase 2
Datopotamab Deruxtecan (Dato-DXd, DS-1062a) in Advanced and/or Unresectable Non-Small Cell Lung Cancer
Metastatic Lung Cancer, Advanced Non Small Cell Lung Cancer
Not yet recruitingPhase 1/2
STAR0602 With Nivolumab in Non Small Cell Lung Cancer and in Metastatic Castrate-Resistant Prostate Cancer, and STAR0602 Alone in Thymic Carcinoma
NSCLC, Non-Small Cell Lung Cancer
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
J de Langen, MD, PhD principal investigator
The Netherlands Cancer Institute-Antoni van Leeuwenhoek
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing biopsy and ctDAN analysis in people with Non-small-cell Lung Carcinoma, run by The Netherlands Cancer Institute at 6 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact J de Langen, MD, PhD (0031205129111, j.d.langen@nki.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
EGFR TKI resistance analysis on tumor biopsies and ctDNA (time frame: Trough study completion, an average of 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04737382, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2023.