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The fourth dual antibody: Johnson & Johnson EGFR/cMET was approved
The fourth dual antibody: Johnson & Johnson EGFR/cMET was approved. On May 21, FDA accelerated the approval of Johnson & Johnson’s EGFR/c-Met dual anti-Rybrevant (amivantamab-vmjw) listing.
It is used to treat patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations that have progressed after platinum-based chemotherapy. This is the first drug approved by the FDA for this type of mutation. It is also the fourth dual-antibody drug approved by the FDA so far. The three previous double antibody products were Removab, Blincyto and Hemlibra.
It is commonplace to accelerate the approval of the listing based on the excellent results of the phase 2 clinical trial, but it is quite unexpected that Johnson & Johnson’s Rybrevant double antibody was approved by the FDA quickly based on the results of the phase 1 trial. Let us find out.
01. Target selection
These two targets selected by Johnson & Johnson are both proven drug targets in the field of lung cancer. Needless to say, EGFR, and c-Met research and development has become increasingly hot in recent years.
Key signaling pathways of oncogenic driver genes in NSCLC
It has been reported in multiple literatures that c-Met is closely related to EGFR resistance.
c-Met is a hepatocyte growth factor receptor with tyrosine kinase activity. The c-MET proto-oncogene can bypass the inhibited EGFR phosphorylation kinase pathway through the ERBB3-PI3K-AKT and MAPK-ERK1/2T pathways to produce expansion. Increased, amplified c-Met promotes downstream signal transduction through bypass activation, avoids the killing of EGFR-TKIs, promotes the proliferation of cancer cells, and ultimately leads to patients’ resistance to EGFR-TKIs. c-MET is low or not expressed in general tissues, but the expression of c-MET can be seen in lung cancer, liver cancer, pancreatic cancer and thyroid cancer tissues.
Studies have shown that cancer cells can secrete and produce multiple types of cytokines to encourage peripheral fibroblasts to continuously secrete HGF. Some cancer tissues can even express c-MET and HGF at the same time, forming a positive feedback loop, leading to unlimited growth of cancer cells. In clinical practice, it has been found that the efficacy of gefitinib or erlotinib in the treatment of patients with c-MET-amplified drug-resistant tumor cells is not satisfactory, while the efficacy of c-MET kinase inhibitors is not satisfactory. Improved quickly.
INJ-372 Brief Introduction
Therefore, Johnson & Johnson chose the EGFR/c-Met dual target as the dual antibody, which can theoretically target EGFR resistance mutations, MET mutations and amplified NSCLC, and has a broad application prospect.
02. Specific test data
According to the data released by the ASCO2020 conference, all 39 patients with assessable EGFR exon 20 insertion mutation NSCLC had an ORR of 36%, a median duration of response (DOR) of 10 months, and a median PFS of 8.3 months; previous acceptance The ORR of patients who had undergone platinum-containing chemotherapy was 41% (12/29), the median DOR was 7 months, and the median PFS was 8.6 months.
ASCO2020 data disclosure
The FDA approval is also based on data from the amivantamab monotherapy cohort in the Phase I CHRYSALIS study.
This phase 1 data was approved for listing, and it is still a major indication for NSCLC, which shows how urgently the market for EGFR-resistant NSCLC is breaking new drugs.
03. Chinese Pharm. Companies
For EGFR/c-MET double antibodies, China has Anmai, Betta, Jiahe and others at the forefront.
Among them, the EGFR/c-MET dual antibody EMB-01 developed by Anmai is in the phase 2 clinical research phase, and is constructed using the FTI-Ig dual antibody technology of Anmai tandem Fab. Betta introduced Merus’s EGFR/c-MET double antibody MCLA-129. Jiahe is researching EGFR/cMET double antibody GB263, and its double antibody technology is imported from Ab studio.
According to the EMB-01 preclinical research data published on AACR in June 2020, the double antibody molecule can simultaneously bind to EGFR and cMet, and induce the co-degradation of the two target receptors in various tumor cells.
Compared with monoclonal antibodies, EMB-01 shows a broader inhibition of EGFR and cMet pathway downstream signals, as well as a more effective and longer-lasting in vivo anti-tumor efficacy in various PDX tumor models.
In the advancement of the clinical stage, Anmai conducted a climbing test of 5 dose groups in the first year, which was very close to the clinically effective dose. The safety of EMB-01 has been well verified, and some relatively good therapeutic effects have also been seen in terms of effectiveness.
EMB-01 has significant efficacy in multiple tumor PDX models
The reforms of CDE in recent years have greatly improved in terms of rapid approval. In September 2020, amivantamab obtained the breakthrough therapy qualification granted by CDE. The success of amivantamab has shown us that the development of dual-antibody drugs based on two drug targets of the same cancer species is a relatively low-risk option.
(source:internet, reference only)