Advances in clinical studies of EGFR target drugs and accompanying diagnostic solutions

Targeted drugs for EGFR have profoundly changed the way tumors are treated, bringing great benefits to patients.
two decades of development, the drug system of EGFR targets is getting more and more in-depth, and the drug research around EGFR and its drug-resistant targets is increasing.
this paper, this classic target-related drug clinical research and accompanying diagnostic solutions are summarized and discussed.
EGFR Target Overview 01 What is the EGFR gene? EGFR is an important signal conduction molecule for the normal proliferation of human cells, located in chromosome 7, 7p12 region, the expression of the gene can be detected in different endotment source tissues, expression protein activity activation process as shown in Figure 1: the body regulates the secretion of growth factors (EGF, TGF alpha, etc.) combined with extracellular lipolymers, the EGFR is activated to form a cross-membrane dipolymer, which drives the conversion of protein 3D structure, the intracellular TK domain and ATP produce bio-chemical reactions, ATP becomes ADP, and TK phosphorylation activates EGFR enzyme activity.
-active EGFR can transmit proliferation and anti-apoptosis signals to the nucleus through multiple downstream signaling channels, such as PI3K-AKT-mTOR, Ras-Raf-MEK-ERK1/2, and control cell growth and division, as shown in Figure 2.
02EGFR signal overexploitation led to tumor occurrence since the 1980s, found a variety of epitheline sources of solid tumor tissue such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, kidney cancer, bladder cancer, the presence of high expression of EGFR phenomenon, and this part of the patients poor prognosis, suggesting that EGFR over-transmission of growth signal may be one of the reasons for the development of tumors.
years of research, it has been found that the following forms of EGFR lead to overexpression of growth signals and insensitive to anti-growth signals secreted by the body.
1) Signal source over-expression: high expression of growth factors such as EGF, HGF, etc.
2) EGFR itself is over-expressed, such as an increase in the number of copies.
3) The EGFR mutation causes the growth signal to be active.
4) Downstream signal path active mutations, such as KRAS, BRAF mutations, etc.
the above-mentioned EGFR target anomalies, there are large differences in frequency between different populations.
compared with the NCCN and CSCO guidelines for non-small cell lung cancer, the EGFR mutation rate was 40-60% in Chinese lung adenocarcinoma patients and about 10% in U.S. patients, but in pure lung squamous cancer, the mutation rate was <4% in U.S. and Chinese patients.
Since EGFR is not only the driving gene for lung cancer, but also present in other tumors, TKI small molecule drugs may also bind to TK regions of members of the tyrosine kinase family outside EGFR, and TKI drugs have been used in clinical studies of other cancerous species and lysine kinase targets.
November 2005, the FDA approved the use of erlotinib in the treatment of topical advanced or metastatic pancreatic cancer in the same area.
03 Approved Target Drug Overview EGFR (epiderptor growth factor receptor) as a popular drug target, China and the United States have listed targeted drugs as follows.
the 1990s, different researchers have developed different drug development strategies for EGFR, an anti-tumor target.
from the listed products, there are mainly inhibit the extracellular ligate-subject binding EGFR monoantigen drugs, and inhibit intracellular ATP-TK binding TKI (tyrosine kinase inhibitor) small molecular chemical drugs.
the development strategies, applicable populations, testing methods, and accompanying diagnostic solutions for mono-anti-drugs and TKI-type drugs, the following is mainly focused on TKI-type drugs.
EGFR target drug clinical research progress 01 third-generation EGFR-TKI introduction gefitinib is the first TKI drug, in the first phase of clinical trials in 1998 found that some of the progression after chemotherapy NSCLC patients responded very quickly to the drug, the tumor significantly shrunk.
was originally designed for high expression of EGFR, but clinical trials have not found a correlation between high expression and efficacy of EGFR.
it was not until 2004 that the drug be found to be highly efficient when genetic fragments encoded in the EGFR-TK domain showed mutations in exon 19del and L858R.
two types of mutations can lead to the activation of TK structure, is the driving force behind the development of tumors, drugs combined with TK domain, by inhibiting tyrosine kinase activation, play an anti-tumor role.
then, in 2005, it was discovered that the emergence of the T790M mutation could lead to progression in patients with remission of the original disease, as the T790M mutation would form spatial resistance, preventing the drug from binding to TK, and the tumor continued to progress.
, Erotinib and Ektinistinib, which were first listed earlier, will all produce T790M resistance, known as the first generation of TKI.
follow-up research and development of the listing of afatinib, dactinib as a second-generation TKI, the strategy is to combine small molecule drug co-price in EGFR, Her2 TK domain, enhance TK inhibition, but still can not overcome the T790M caused by drug resistance.
Aoxitinist and amedinist to overcome T790M resistance, known as third-generation TKI drugs.
the characteristics of the 1-3 generation drugs are as follows: when specifically related to the treatment of patients, the clinical will be combined with their adaptive disorders (disease stages, treatment stages), EGFR gene mutation status and other factors to make a comprehensive choice.
02EGFR-TKI drug clinical trial progress review EGFR-TKI drug application history, the FDA on May 5, 2003 accelerated the approval of the first EGFR-TKI drug gefitinib, suitable for three-line treatment: for local late-stage or metastasis non-small cell lung cancer patients, in platinum and polysequool chemotherapy after the failure of single drug therapy.
The clinical action of the drug was not clear at the time, and objective remission rates (ORRs) ranged from 8.8% to 19.0% in clinical trials IDEAL1 and IDEAL2 conducted in patient groups of patients with third-line treatment without screening for EGFR mutations.
since 2004, when it was reported that patients with EGFR mutation NSCLC were more drug-sensitive, a series of multi-center clinical studies have been conducted, and the clinical benefits of EGFR mutation patients have been expanding, and some of the results are summarized in the following table.
IPASS study first proved that in patients with advanced NSCLC adenocarcinoma, first-line treatment options preferred TKI drugs when EGFR mutations were positive.
IPASS showed EGFR mutation rates of 59.7% in patients with advanced non-small cell lung adenocarcinoma, with exon 19del mutations and L858R mutations accounting for 90% of all patients with detected mutations.
PFS was 9.8 months and ORR was 71.2% in EGFR patients in the treatment group, significantly better than that in the chemotherapy group (6.4 months in the medium PFS and 32.2% in ORR).
PFS was less than 2 months in the mutant-negative patients in the gyfantinib treatment group, with ANR of 1.1%, significantly lower than in the chemotherapy group.
because 50% of patients treated with first- and second-generation TKI develop T790M resistance, the third-generation TKI drug oxytini is first used in second-line treatment in patients with T790M resistance.
flaURA clinical study compared the effects of oxytinib and a generation of TKI drugs for first-line therapy: medium PFS18.9 months VS10.2 months.
Since only 50% of patients can use oxytinib sequentia after first-line TKI resistance, benefiting less from direct use of oxytinib than first-line therapy, oghithinib has risen to the first-line treatment pathway for late NSCLC.
2020 study, published by Wu Yilong and others, showed that in patients with surgical NSCLC from I.B to III.A, EGFR-positive patients opted for ositeni in postoperative complementary therapy compared to placebo It can significantly extend disease-free survival (DFS, 88% vs 71% of IB patients; 91% vs 56% of Phase II patients; and 88% vs 32% of Phase IIIA patients.
FDA approved oxytinib for complementary therapy in December 2020 and incorporated it into NCCN guidelines.
these TKI drugs are clinical studies based on single-drug therapy.
in combination therapy, a generation of TKI drugs, erotinib/gyfeitinib combination chemotherapy or antiangiogenic therapy, has been carried out in a number of studies and will not be repeated here.
Iii.RCT study for applicable populations in China shows that Erlotini combined beva monoanti, compared to erotinib single drug PFS for 18.0 vs. 11.3 months, so erotinib combined beva monoanti has been written into the CSCO guidelines, as a first-line treatment of the secondary recommendations.
EGFR mutation detection currently common clinical EGFR mutation detection methods include fluorescent PCR method (ARMS, Super ARMS), digital PCR (ddPCR) and NGS method, the main characteristics of each method are as follows: different methods have a certain degree of complementarity, "second generation sequencing" Technology in the clinical application of NSCLC China Expert Consensus (2020 edition)2: For patients with high rates of sensitive mutations, when the conventional genetic test results are negative, it is recommended to use China NMPA or FDA approved NGS products for retesting.
now has a number of fluorescent PCR, NGS kits approved, as far as possible to select approved kits for testing.
Pansheng has been committed to NGS technology research and development, tumor drug target detection.
February this year, Pansheng's human 8 gene mutation joint test kit (semiconductor sequencing method) (National Armour Note 202034000072, hereinafter referred to as Pansheng's lung cancer 8 gene kit) was approved by the State Drug Administration for listing (click Link to learn more), this kit is the first approved pan-birth "one-step" patented technology (Chinese invention patent ZL 201710218529.4) of lung cancer clinical diagnostic kit, can be tested with non-small cells at once 8 gene mutations and fusions closely related to targeted treatment in lung cancer patients - EGFR / ALK / ROS1 / BRAF / KRAS / HER2 / MET / PIK3CA, where 19 exons are missing (19del), L 858R point mutation can be used for the accompanying diagnostic test of giffeitinib tablets, hydrochloric acid ecstasy tablets, T790M point mutation can be used for accompanying diagnostic testing of methicillin oghithini tablets, and the total compliance rate of comparative reagent studies is 95%, The kit fits the NCCN guidelines and has the advantages of accurate detection, low sample dosage and short detection cycle, providing accurate targeted treatment guidance for NSCLC patients.
EGFR and Accompanying Diagnostics as early as August 2014, the FDA issued the first edition of the Introphy Companion Diagnostic Reagent Guidelines.
China's NMPA in July and August 2020, respectively, issued "similar therapeutic drugs based on tumor accompanying diagnostic reagents update and technical review guidelines (draft for comments)" and "listed anti-tumor drugs accompanying diagnostic reagents clinical trial guidelines (draft for comments)"
In accordance with NMPA guidelines, tumor companion diagnostic reagents test samples taken from tumor patients, and the results can provide important information about the safety and effectiveness of patients using anti-tumor drugs, including: identifying patients most likely to benefit from the drug; identifying patients at higher risk of serious adverse reactions associated with the drug; and identifying population subgroups that have been adequately studied for safety and importance.
clinical trials of EGFR-accompanying diagnostic reagents are divided into two parts: one for clinical test accuracy studies and one for clinical validation of accompanying diagnostic uses.
the two drug regulatory departments in China and the United States have very similar regulatory models for accompanying diagnostics.
verification section can choose between listed kits, or next-generation sequencing, technologically proven second-generation sequencing, or clinically recognized genetic testing techniques.
clinical verification part, the original research accompanying diagnostic reagents may submit drug clinical trial data as clinical trial data accompanying diagnostic use verification, note that it should be consistent with the final clinical trial data submitted to the drug review department during the anti-tumor drug market.
New development accompanied by diagnostic reagents, the verification of expected use can be taken with the original research accompanying diagnostic reagents for consistency ratio, briditation test, listed anti-tumor drug efficacy observational research, including adaptive and sample selection, expected use and position selection, consistency evaluation, drug efficacy and other studies.
Since EGFR drugs are still in the development and clinical validation phase, this process requires continuous collection of drug efficacy correlation data to demonstrate and adjust, especially for mutations other than 19del, L858R, and T790M.
NMPA has published guidelines for real-world evidence-backed drug development and review (trial) and technical guidelines for clinical evaluation of real-world data for medical devices (draft for comments), with the hope that subsequent adaptations to EGFR target drugs and accompanying diagnostic reagents will be accelerated.
Pansheng Lung Cancer 8 gene kit is a approved NGS product based on DNA level detection of EGFR mutation, which can be simultaneously equipped with the approved sequencer GENETRON S5 (National Equipment Note: 20193220820) and the fully automatic augmentation system GENETRON Chef (Chef) Yu's note 20192220364) with automated reporting system, can be achieved in the clinical hospital 2-3 days of rapid testing, for the vast number of patients to fight for valuable time for treatment, this clinical terminal testing just needed solutions, while will be very helpful to promote the future commercialization of drugs based on this kit with diagnosis.
welcome to work with relevant pharmaceutical companies to complete more accompanying diagnoses of EGFR targeted drugs