New data released on pozytinib, revealing insertion site analysis and secondary resistance mechanisms

Recently, "Cancer Cell" published the results of a phase II clinical study of Poziotinib (Chinese temporary translation of poziotinib, R&D number HM781-36B, online nickname 781, hereinafter referred to as poziotinib) including 50 patients with EGFR 20ins , this study has reached the end point, but the article is attractive not only for the data of drug efficacy and patient survival, but for the first time I have seen a systematic analysis of the sensitivity of a certain EGFR 20ins exclusive investigational drug at different sites in EGFR 20ins In addition, I will briefly introduce the potential applications of pan-ERBB drugs with you toda.

Pozitinib "returns a city" in the treatment of EGFR 20ins

In the previous clinical trials of pozidetinib, there were clinical research results with an objective response rate of less than 20%, which also greatly reduced the expectations of the majority of patients with EGFR 20ins on pozytini.

The following are other data of this study, friends who are concerned about such content can take a loo.

The primary endpoint of the study was RECIST version 1, with ORR defined as at least a 30% reduction in evaluable lesions, and patients received 16 mg of pozytinib orally daily until objective disease progression (greater than 20%.

EGFR 20ins mutation, what is the difference between specific sites?

In previous studies of EGFR 20ins, a distinction needs to be made between front-end insertions (on the C-helix of EGFR20 exon, codons D761-M766) and back-end insertions (after the C-helix of EGFR20 exon, codons A767-C775.

In silico modeling and molecular dynamics simulations prior to this clinical study of pozidetinib, it was found that poxitinib sensitivity was highly dependent on insertion position, with near-loop insertions (codons A767 to P772) being more sensitive than far-loop insertions (H773-C775) was more sensitive, and the results of clinical studies confirmed that the ORR of pozidetinib was 46% and 0% in the proximal and distal loops (p = 0015), further identifying patients with insertions at the rear end of EGFR 20 Among them, the dominant population for pozytinib is codons A767 to P772, and patients with insertions after P772 are given priority to other drugs as far as the current information is concerne.

What is the cause of secondary resistance in patients with EGFR 20ins under pozytinib treatment?

T790M and MET amplification account for the vast majority of the mechanisms of secondary resistance to EGFR-sensitive mutations (19Del/L858), respectively (49%-61% and 10%-20%.

To identify the underlying mechanisms of acquired resistance to pozytinib, we developed multiple models of acquired resistance preclinically using cell lines expressing different EGFR exon 20 mutations, T790M, C797S and epithelial-mesenchymal transitio.

Taken together, these data suggest that EMT may be a mechanism of resistance to pozytinib, and that patients with EGFR 20ins also share at least some resistance mechanisms with patients with classical EGFR-sensitizing mutations (eg, EGFR T790M, MET expansion.

Are there other potential applications for pan-ERBB drugs?

I don’t know if you have noticed that in the previous article, I wrote “special drugs for EGFR 20ins” with quotation marks (you can guess the reason), and when comparing pozytinib, mopotinib, and evantuzumab, I gave The target description of pozytinib is "pan-ERBB drug", so what is "pan-ERBB drug"?

The ERBB family of genes includes ERBB1, ERBB2, ERBB3, and ERBB ERBB1 is EGFR, and it can also be called HER- Everyone is used to the name of EGFR, while ERBB2 has a more familiar name - HER-2 , The high-frequency mechanism of EGFR-sensitive mutations in the secondary drug resistance of third-generation drugs is the overexpression of ERBB3 (that is, HER3), and there is no major breakthrough in the current treatment-related research of ERBB4.

At present, the first-, second- and third-generation drugs of EGFR mainly target one gene of EGF.

Reveal the answer:

The reason for the quotation marks for "specific drugs for EGFR 20ins" should be said to be that pan-ERBB drugs such as bozitinib and mopotinib were selected for the treatment of EGFR 20ins mutations that lacked high-efficiency drugs before, rather than pan-ERBB drugs specifically for EGFR 20in.

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