Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04737382 |
| Other study ID # |
M18OSI |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 22, 2019 |
| Est. completion date |
August 22, 2024 |
Study information
| Verified date |
October 2023 |
| Source |
The Netherlands Cancer Institute |
| Contact |
J de Langen, MD, PhD |
| Phone |
0031205129111 |
| Email |
j.d.langen[@]nki.nl |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical 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 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.
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.
