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The Annual Meeting of the European Society of Oncology (ESMO) is the most prestigious and influential oncology conference
In an oral presentation, Professor Jordi Remon Masip presented the results of the APPLE study, which evaluated the feasibility of plasma EGFR T790M monitoring and the best strategy
EORTC Lung Cancer Group 1613 APPLE study details
Professor Jordi Remon Masip
background
Prior to 2016, first- and second-generation EGFR TKIs were first-line treatment options for patients with EGFR-sensitive mutations with NSCLC, with limited
method
The APPLE study was a randomized, non-comparative, open-label, 3-arm, phase II study conducted in patients with common EGFR mutations and in the treatment of NSCLC to evaluate the feasibility of plasma EGFR T790M monitoring and the best strategy
Research design
outcome
Between November 2017 and February 2020, groups B and C randomly enrolled 52 and 51 patients
Referral to osimertinib for treatment
The median follow-up was 30 months
.
The primary endpoints were met: PFSR-OSI-18 in groups B and C were 67.
2% (84% CI 56.
4-75.
9%) and 53.
5% (84% CI 42.
3-63.
5%), respectively, and the median PFS in both groups was 22.
0 months (95% CI 18.
6-NR) and 20.
2 months (95% CI14.
6-35.
0), respectively, and the median OS in both groups was not reached and 42.
8 months, respectively.
The 18-month OS rate was 87% and 77%,
respectively.
Main finish line
OS results
Secondary endpoint
The median BPFS in groups B and C were 24.
4 months (95% CI17.
9-28.
6) and 21.
4 months (95% CI 14.
5-42.
8),
respectively.
Adverse events in both groups were consistent with the results of previous studies
.
Exploratory analysis showed a 65% (67/103) incidence of EGFR mutations on ctDNA testing at baseline, and ctDNA clearance was an early predictor
of better gefitinib treatment.
conclusion
The APPLE study supports continuous monitoring of T790M status via ctDNA in patients with advanced EGFR mutation NSCLC to guide treatment decisions
.
This strategy identifies 17% of patients with molecular progression before disease progression (assessed by RECIST criteria) and directs earlier switching to osimatinib therapy
.
This strategy yields clinically significant PFS and OS
.
The 18-month survival rate in group B reached 87%.
i Hope time
Founder of i Hope Medicine
Professor Qin Haifeng
Review experts
Professor Wang Jun
Deputy Director of the Department of Oncology, First Affiliated Hospital of Shandong First Medical University
Chief Physician, Ph.
D.
, Doctoral SupervisorDeputy Director of Shandong Lung Cancer Research Institute
Director of the Chinese Society of Clinical Oncology (CSCO).
Vice Chairman and Secretary General of the CSCO Expert Committee on Immunotherapy
Vice Chair of the CSCO Expert Committee on Patient Education
Member of the CSCO Expert Committee on Non-Small Cell Lung Cancer
Director of Shandong Society of Immunology
Visiting Professor, MD Anderson Cancer Center, University of Texas, USA
Communication review expert of the National Natural Science Foundation of China
Editorial Board Member of Frontiers in Immunology, Journal of Precision Medicine, Journal of Oncology Pharmacy
He has presided over 3 national natural science foundation projects, 2 natural science foundation projects of Shandong Province, "Guidelines for toxicity management related to CSCO immune checkpoint inhibitors", "Clinical Application Guidelines for CSCO Immune Checkpoint Inhibitors", editor-in-chief/chief translator of 3 monographs, and published more than 50 papers in JCI Insight, Ther Adv Med Oncol, Carcinogenesis, and Cancer Letters as the first/corresponding author.
There are 3 provincial scientific and technological progress/achievement second prizes
Professor Wang Jun: We know that the first-line treatment of advanced NSCLC with EGFR mutation can choose gefitinib or osimitinib
.
According to the conclusion of the AURA trial, treatment with the drug-resistant mutation EGFR T790M after progression is standard of care, but this criterion is based on the imaging RECIST assessment
.
The ability to monitor disease progression earlier, i.
e.
, before imaging progression occurs, and timely programming adjustments are key
to clinical decision-making.
In patients with advanced NSCLC mutations in EGFR, liquid biopsy provides an opportunity for this early monitoring as a new criterion for assessing tumor progression, compared with conventional imaging tests
.
Liquid biopsy can detect a variety of molecules in the peripheral blood, but the most stable detection index is ctDNA, that is, circulating tumor DNA, we can detect not only quantitative changes, but also qualitative changes, including mutations, deletions, insertions, rearrangements, copy number abnormalities, or methylation of free DNA fragments
.
These ctDNA are derived from necrotic, apoptotic tumor cells and can reflect changes in tumor burden early in
tumor recurrence.
For patients with advanced EGFR mutations, monitoring EGFR resistance mutations in ctDNA can reflect whether antineoplastic therapy is effective and whether drug resistance information appears, so as to adjust the treatment plan in time, reduce expensive ineffective treatment, and achieve personalized medication and treatment
.
Anti-tumor therapy here includes any treatment, but if the EGFR T790M mutation is monitored, it is aimed at the resistance strategy
of the first-generation EGFR-TKI treatment.
The APPLE study was a Phase II study designed to assess the predictive value of liquid biopsy, i.
e.
, the feasibility of plasma EGFR T790M monitoring and the best strategy
for switching from gefitinib to osimitinib.
The primary study endpoint was progression-free survival at 18 months of follow-up treatment with osimertinib, with groups B and C 67.
2% and 53.
5%, respectively, suggesting that liquid biopsy monitoring was a feasible strategy, and that liquid biopsy-positive post-conversion osiminib treatment was more effective than imaging assessment of post-progression oxytinib therapy
.
The significance of this result for current clinical decision-making is threefold: First, the EGFR T790M liquid biopsy can be used to monitor early tumor recurrence
.
It has been previously confirmed that there is a good consistency between liquid biopsy and tissue biopsy; The detection of EGFR mutations is actually an early signal for tumor recurrence, and the emergence of drug resistance genes indicates that there are already drug-resistant cells proliferating in the body, and there are tiny lesions (MRDs)
that cannot be found by imaging.
Second, switching therapy immediately after a positive EGFR T790M liquid biopsy may improve survival benefit
.
The study showed that progression-free survival at 18 months was improved, while both median PFS and BPFS were prolonged by 1.
8 months and 3.
0 months, respectively, indicating that immediate conversion was more advantageous than conversion osimumitin after imaging was determined, and that earlier use could delay tumor recurrence, including brain recurrence, and that oshitinib should be considered
before imaging progression occurred.
This is basically consistent
with the 2-3 month advantage of early monitoring of liquid biopsies.
Third, from the OS point of view, the median OS of the two groups was not reached and 42.
8 months, respectively, and it can be seen that the conversion immediately after a positive liquid biopsy has a tendency
to prolong in OS.
This result needs to be analyzed in conjunction with the FAURA and AURA3 studies
.
We know that giving osimtinib after the first generation of EGFR TKI imaging progressed was numerically extended OS (26.
8 vs 22.
5 months (95% CI: 20.
2-28.
8), and the oscitinib group was extended by 4 months in OS values, but without statistical significance (HR = 0.
87; P = 0.
277).
However, in the FLAURA study, the median OS of the osimertinib and first-generation EGFR TKI groups was 38.
6 months and 31.
8 months, respectively, and the risk of disease death was reduced by 20.
1%, and the difference was statistically significant (HR=0.
799; P=0.
0462), making osimitinib the first EGFR TKI
to benefit from OS.
Therefore, the APPLE study can be used as a bridge study to show that osimertinib can be used in the first line, after the progress of imaging, or when the liquid biopsy is positive before the progress of imaging is confirmed
.
Clinically, we can choose the first generation of EGFR TKI treatment, but we need to monitor EGFR T790M, and once positive, there is consideration for conversion, rather than waiting until the image is confirmed
.
Of course, we look forward to the final OS results.
Therefore, the APPLE study provides new ideas for the whole treatment strategy of patients with EGFR mutations, especially the conversion timing and conversion method of the first generation of EGFR TKI, and the early conversion of osimerinib can be more beneficial
.
References:
[1] LBA51-Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial.
2022 ESMO.
[2] Soria JC, Ohe Y, Vansteenkiste J, et al.
Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.
N Engl J Med.
2018 Jan 11; 378(2):113-125.
[3] Yang JC, Ahn MJ, Kim DW, et al.
Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component.
J Clin Oncol.
2017 Apr 20; 35(12):1288-1296.
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