Analysis of Fourth-Generation EGFR Inhibitors

by | Apr 20, 2021 | Industry Research


Lung cancer contributes to the highest number of new and fatal cases of malignant tumors in the world with regards to cancer cases. About 85% of lung cancer cases are non-small cell lung cancer (NSCLC). Most patients with NSCLC often have mutations that lead to further proliferation and differentiation of malignant tumor cells.

The discovery of EGFR tyrosine kinase inhibitor (TKI) is considered a landmark event in the treatment of lung cancer. Compared with patients receiving standard chemotherapy, EGFR-TKI first-line treatment of patients with EGFR mutations can prolong progression-free survival (PFS), improve health-related quality of life, and reduce serious side effects related to treatment.

Currently, there are three generations of EGFR inhibitors on the market. Some drugs of the first generation of EGFR-TKIs include gefitinib, erlotinib, and icotinib. Among them, Betta Pharmaceutical’s icotinib (brand name: Conmana®) is the first in-house developed small molecule targeted drug in China. It was launched in 2011. Ten years of clinical practice have verified icotinib’s efficacy and safety.

In the second generation there are afatinib and dacomitinib, the latter of which is also known by the brand name Vizimpro.
A drug of the third generation is osimertinib. Osimertinib has the longest median progression-free survival (mPFS) and median overall survival (mOS) rates in the history of EGFR-TKIs, reaching 18.9 months and 38.6 months.

However, for cancer patients, issues of drug resistance frequently arise. Osimertinib is no exception. Starting from clinical trials during the third-generation EGFR-TKIs, researchers have discovered and gradually clarified the third-generation drug resistance mechanisms: including major mutations in C797S, C-MET amplification, HER2 amplification, and other bypass mutations.

High competition in the fourth-generation

(1) TQB3804
In October 2019, according to the global clinical trials official website (, the fourth-generation EGFR inhibitor TQB3804, which can overcome osimertinib resistance, officially entered the phase I clinical trials. TQB3804 is a fourth-generation, orally bioavailable, mutant-selective, EGFR inhibitor, with potential antineoplastic activity. Upon oral administration, EGFR mutant-selective inhibitor TQB3804 binds to and inhibits the activity of mutant forms of EGFR, including the C797S EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells.
The preliminary experimental results of TQB3804 were published at the 2019 AACR conference. In addition to inhibiting the C797S mutation and solving osimertinib resistance, the drug is also effective for T790M double mutation after 1/2 generation TKI resistance. Studies have shown that the drug’s IC50 (the concentration of the drug required to kill half of the cancer cells) for d746-750(19del)/T790M/C797S, L858R/T790M/C797S, d746-750/T790M and L858R/T790M is 0.46. 0.13, 0.26 and 0.19 nM, suggesting that tumor cells with triple and double mutations of EGFR after generation 1/2/3 TKI resistance have good inhibitory ability. In contrast, osimertinib has a weaker ability to inhibit C797S.
TQB3804 can delay the growth of tumors in different models of 19del/T790M/C797S, but osimertinib cannot prevent the growth of tumors harboring C797S. This suggests that the dilemma of having no back-up treatment option after osimertinib resistance is acquired may be resolved.

(2) U3-1402
U3-1402 is an HER3 antibody conjugate drug developed by Daiichi Sankyo Pharmaceutical Company. The main therapeutic mechanism is to bind the HER3 protein through U3-1402, and then deliver the therapeutic drug carried into the tumor cells to kill the tumor cell.
The preliminary data of U3-1402 was announced at the 2019 ASCO annual meeting. Studies have shown that it can comprehensively combat various types of EGFR-TKI treatment resistance, and even the resistance of osimertinib is hoped to be solved. At the 2019 WCLC meeting, the control rate of this drug was reported to be as high as 100%.
The latest clinical data of U3-1402 was reported again at the ESMO conference in 2020. The patients included in the group were non-small cell lung cancer patients with EGFR gene mutations, who had previously used targeted drugs and encountered drug resistance after chemotherapy and had used an average of 4 treatment options. 90% of the patients had used chemotherapy, and an average of 2 EGFR-targeted drugs were used, of which 86% of the patients used osimertinib. Nearly half of the patients had brain metastases.
The results showed that there was 1 patient whose visible lesions completely disappeared, and 13 patients whose tumor lesions shrank by more than 30%, achieving partial remission. The overall treatment response rate was 25%, and the disease control rate was 70%.
This is very commendable for patients with drug resistance after an average of 4 lines of treatment. In addition to excellent efficacy, safety is also controllable.

(3) BLU-945
BLU-945 is a fourth-generation EGFR-TKI drug developed by Blueprint Medicines that specifically targets the T790M/C797S co-mutation and other T90M resistance mutations secondary to osimertinib resistance.
In cell line tests, for cell lines carrying EGFR sensitive mutations (19 deletion mutation or L858R mutation), T790M mutation and C797S mutation triple mutation, BLU-945 is more lethal to these types of cancer cells than the first-generation drugs on the market.
In animal experiments, for mice with lung cancer carrying triple mutations, the third-generation targeted drugs alone are no longer effective, and the tumor growth rate and progression in the mice are basically the same as those in mice that have not received drug treatment. If treated with BLU-945, the tumors in the mice can remain relatively stable or shrink. Furthermore, if they receive BLU-945 combined with osimertinib, the tumors in the mice shrink rapidly until they disappear completely.

(4) CH7233163
Chugai Pharmaceutical, a subsidiary of Roche, reported preclinical data of its fourth-generation EGFR inhibitor CH7233163 at the 2020 AACR annual meeting.
CH7233163 is a non-covalent inhibitor of ATP competition and binds to the αC-helix-in conformation of EGFR. In vitro tumor cell line experiments show that CH7233163 is sensitive to EGFR G719S, L861Q, Del 19, L858R, Del 19/T790M, L858R/T790M, Del 19/T790M/C797S, and L858R/T790M/C797S, and is relatively sensitive to wild EGFR cells.
In Del19/L858R/T790M, L858R/T790M mutation and Del 19 mice, after CH7233163 is applied the tumor volume could be significantly reduced. Although it is a pre-clinical study, such results show the hope for improved treatment present in EGFR-TKIs.

(5) JNJ-61186372(JNJ-372)
JNJ-372 is a humanized bispecific antibody targeting EGFR and cMet developed based on the DuoBody platform in cooperation with Johnson & Johnson and Genmab in Denmark. JNJ-372 can simultaneously inhibit the phosphorylation of EGFR and cMet, as well as the activation of downstream signals, and has strong ADCC (antibody-dependent cell-mediated cytotoxicity).
Through dual-target inhibition, JNJ-372 has shown curative effects on multiple types of mutations (including C797S, MET and 20ins) secondary to EGFR-TKI resistance, and is well tolerated (rate of adverse reactions of grade 3 and above is only 9%). It is expected to become a new treatment option to overcome EGFR resistance in the future.


Drug resistance has always been the main obstacle to the successful treatment of EGFR-mutated NSCLC patients. The fourth-generation EGFR-TKIs introduced above bring new hope for improved treatment of EGFR-mutant lung cancer patients, and also demonstrate the determination and enthusiasm of the global oncology industry.


1. “Betta Pharmaceuticals’ fourth-generation EGFR inhibitors are approved for clinical use”, Insight database
2. Preclinical evaluation of TQB3804, a potent EGFR C797S inhibitor
3. Daiichi Sankyo announces clinical trial collaboration with AstraZeneca toevaluate patritumab deruxtecan (U3-1402) in combination with Tagrisso inEGFR-mutated non-small cell lung cancer.
4. 2020ESMO Abstract1296P
5. CH7233163, a mutant-selective EGFR inhibitor, overcomes osimertinib resistant EGFR-T790M/C797S, 2020AACR.