Ignite Creation Date:
2024-06-16 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 3:30 PM
Study NCT ID:
NCT06436144
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-30
First Post:
2024-05-21
Brief Title:
Osimertinib and Etoposide as First-Line Treatment in Osimertinib-Resistant Advanced EGFR-Mutant NSCLC
Sponsor:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Organization:
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Study Overview
Official Title:
A Single-Center Prospective Single-Arm Observational Study Evaluating the Efficacy and Safety of Osimertinib Combined With Etoposide as First-Line Treatment in Patients With Osimertinib-Resistant or -Insensitive Advanced EGFR-Mutant Non-Small Cell Lung Cancer
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Osimertinib though a standard first-line treatment for EGFR-mutant advanced NSCLC shows primary resistance in 10-30 of patients leading to disease progression within 3-4 months This resistance is linked to co-mutations in genes like TP53 RB1 and PIK3CA among others Studies indicate that Topo II inhibitor Etoposide VP-16 can reduce cell survival enhance DNA damage and delay resistance in Osimertinib-resistant cells suggesting a potential combination therapy to manage resistanceThis study is a single-center prospective single-arm study evaluating the efficacy and safety of osimertinib combined with etoposide as a first-line treatment in patients with osimertinib-resistant or -insensitive advanced non-small cell lung cancer NSCLC The study focuses on patients with advanced NSCLC stage IIIB or IV with EGFR-sensitive mutations who developed slow resistance to osimertinib and for whom secondary biopsy after resistance did not identify any therapeutic targets
Detailed Description:
Although Osimertinib has become the standard first-line treatment choice for EGFRm advanced NSCLC a subset of patients still do not benefit from first-line Osimertinib treatment Some patients even experience disease progression at the initial stages of Osimertinib treatment As early as 2010 and 2016 studies published in J Clin Oncol and Onco Targets Ther noted that approximately 10-30 of patients either do not respond to initial EGFR TKI treatment or experience disease control for less than 3 months despite carrying EGFR mutations PMID 19949011 27382309 Furthermore the FLAURA study on first-line Osimertinib treatment for EGFRm advanced NSCLC patients found that 3 of patients did not respond to Osimertinib indicating potential primary resistance to Osimertinib PMID 29151359 This primary resistance is characterized by disease progression or stabilization within 3-4 months of EGFR TKI treatment with no evidence of objective response during treatment PMID 27382309 Thus primary resistance to third-generation EGFR-TKI Osimertinib significantly limits its clinical efficacy and presents a critical clinical challenge
The mechanisms underlying primary resistance to Osimertinib are complex and not well understood and research data are limited Current evidence suggests that primary resistance to first-line Osimertinib in EGFRm advanced NSCLC patients may be related to concomitant co-mutations such as atypical EGFR mutations and downstreambypass pathway gene abnormalities see Figure 1 Approximately 20-30 of EGFR mutation patients present with co-mutations at initial diagnosis with common co-mutated genes including TP53 546-646 RB1 96-1033 ERBB2 8-11 CTNNB1 96 PIK3CA 9-124 and cell cycle-related genes like CDK4CDK6CCNE1 MET KEAP1NFE2L2CUL3 axis etc These gene abnormalities can mediate primary resistance to EGFR-TKI therapy by activating EGFR bypass or downstream signaling pathways PMID 38382773 37093192 A 2023 article in Targeted Oncology noted that TP53mutations high AXL mRNA expression and low BIM mRNA expression might be associated with poor response to Osimertinib PMID 37017806 Additionally a case study published in Lung Cancer in 2023 reported that a patient with primary resistance to Osimertinib had simultaneous EGFR L858R and EGFR S645C mutations After one month of Osimertinib treatment there was no reduction in the right upper lobe nodule size and CEA levels continued to rise The patient continued with Osimertinib combined with anlotinib for four months with no reduction in the primary tumor and persistently elevated CEA levels indicating primary resistance to Osimertinib PMID 37842288 Other studies suggest that primary EGFR 20ins and BIM polymorphism deletion may mediate primary resistance to Osimertinib PMID 34669648 EGFR TKI primarily works by competitively binding to the ATP binding site blocking EGFR phosphorylation and downstream signaling pathway activation thus inducing tumor cell apoptosis However the crystal structure of EGFR 20ins does not affect the ATP binding pocket preventing increased affinity between EGFR TKI and EGFR protein leading to insensitivity and resistance to EGFR TKI therapy PMID 34301786 In patients with BIM gene abnormalities compared to wild-type BIM EGFR mutation patients with concurrent BIM deletion had lower ORR 28 vs 525 P0026 and shorter PFS 83m vs 105m P0031 following Osimertinib treatment PMID 34669648 Additionally NSCLC patients with concurrent SCLC components or SCLC transformation may also exhibit primary resistance to Osimertinib PMID 29290257Recent research has found that the DNA topoisomerase II Topo II inhibitor Etoposide VP-16 synergistically reduces cell survival enhances DNA damage and apoptosis induction in Osimertinib-resistant cells inhibits the growth of Osimertinib-resistant tumors and delays the emergence of acquired resistance to Osimertinib Mechanistically Osimertinib promotes proteasomal degradation mediated by fbxw7 leading to DNA damage and reduced Topo IIα levels in NSCLC cells these effects are absent in Osimertinib-resistant cell lines with high Topo IIα levels Elevated Topo IIα levels have also been detected in most EGFRm NSCLC tissues that recur after EGFR-TKI treatment In sensitive EGFRm NSCLC cells forced expression of ectopic TOP2A confers resistance to Osimertinib whereas knocking down TOP2A in Osimertinib-resistant cell lines restores their response to Osimertinib-induced DNA damage and apoptosis Overall these findings reveal the important role of Topo IIα inhibition in mediating the therapeutic effects of Osimertinib on EGFRm NSCLC and provide a scientific rationale for targeting Topo II with Etoposide VP-16 to manage Osimertinib-insensitive or primary-resistant cases PMID 38451729
The mechanisms underlying primary resistance to Osimertinib are complex and not well understood and research data are limited Current evidence suggests that primary resistance to first-line Osimertinib in EGFRm advanced NSCLC patients may be related to concomitant co-mutations such as atypical EGFR mutations and downstreambypass pathway gene abnormalities see Figure 1 Approximately 20-30 of EGFR mutation patients present with co-mutations at initial diagnosis with common co-mutated genes including TP53 546-646 RB1 96-1033 ERBB2 8-11 CTNNB1 96 PIK3CA 9-124 and cell cycle-related genes like CDK4CDK6CCNE1 MET KEAP1NFE2L2CUL3 axis etc These gene abnormalities can mediate primary resistance to EGFR-TKI therapy by activating EGFR bypass or downstream signaling pathways PMID 38382773 37093192 A 2023 article in Targeted Oncology noted that TP53mutations high AXL mRNA expression and low BIM mRNA expression might be associated with poor response to Osimertinib PMID 37017806 Additionally a case study published in Lung Cancer in 2023 reported that a patient with primary resistance to Osimertinib had simultaneous EGFR L858R and EGFR S645C mutations After one month of Osimertinib treatment there was no reduction in the right upper lobe nodule size and CEA levels continued to rise The patient continued with Osimertinib combined with anlotinib for four months with no reduction in the primary tumor and persistently elevated CEA levels indicating primary resistance to Osimertinib PMID 37842288 Other studies suggest that primary EGFR 20ins and BIM polymorphism deletion may mediate primary resistance to Osimertinib PMID 34669648 EGFR TKI primarily works by competitively binding to the ATP binding site blocking EGFR phosphorylation and downstream signaling pathway activation thus inducing tumor cell apoptosis However the crystal structure of EGFR 20ins does not affect the ATP binding pocket preventing increased affinity between EGFR TKI and EGFR protein leading to insensitivity and resistance to EGFR TKI therapy PMID 34301786 In patients with BIM gene abnormalities compared to wild-type BIM EGFR mutation patients with concurrent BIM deletion had lower ORR 28 vs 525 P0026 and shorter PFS 83m vs 105m P0031 following Osimertinib treatment PMID 34669648 Additionally NSCLC patients with concurrent SCLC components or SCLC transformation may also exhibit primary resistance to Osimertinib PMID 29290257Recent research has found that the DNA topoisomerase II Topo II inhibitor Etoposide VP-16 synergistically reduces cell survival enhances DNA damage and apoptosis induction in Osimertinib-resistant cells inhibits the growth of Osimertinib-resistant tumors and delays the emergence of acquired resistance to Osimertinib Mechanistically Osimertinib promotes proteasomal degradation mediated by fbxw7 leading to DNA damage and reduced Topo IIα levels in NSCLC cells these effects are absent in Osimertinib-resistant cell lines with high Topo IIα levels Elevated Topo IIα levels have also been detected in most EGFRm NSCLC tissues that recur after EGFR-TKI treatment In sensitive EGFRm NSCLC cells forced expression of ectopic TOP2A confers resistance to Osimertinib whereas knocking down TOP2A in Osimertinib-resistant cell lines restores their response to Osimertinib-induced DNA damage and apoptosis Overall these findings reveal the important role of Topo IIα inhibition in mediating the therapeutic effects of Osimertinib on EGFRm NSCLC and provide a scientific rationale for targeting Topo II with Etoposide VP-16 to manage Osimertinib-insensitive or primary-resistant cases PMID 38451729
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None