Prof. Shu Yongqian: For the treatment of the EGFR-sensitive mutation NSCLC, I am more likely to choose vometinib

At present, three third-generation EGFR targeted therapy drugs have been approved for the first-line treatment of advanced non-small cell lung cancer (NSCLC) with classical mutations in EGFR, including the recently approved Chinese original research drugs for this indication, vometinib and ametinib, and the imported third-generation EGFR-TKI osimitinib approved for first-line treatment indications in 2019

The first-line treatment indications for osimitinib were included in the National Medical Insurance Reimbursement Directory in 2020, while vometinib, which was approved as a first-line treatment indication on June 28, 2022, and ametinib, which was approved as an indication in December 2021, are eligible to participate in this year's updated medical insurance reimbursement directory

Both vometinib and ametinib are innovative drugs

Molecular structure of three-generation EGFR-TKI drugs

China's original research has excellent efficacy

If we compare the results of the phase III clinical study of the first-line treatment of EGFR-sensitive mutations with advanced NSCLC of three drugs, in terms of efficacy data, the progression-free survival (PFS) and risk ratio (HR) of the two Chinese original drug treatment Chinese groups are not inferior at all, and even exceed osetinib ^1-4

Efficacy data in FURLONG (vomitinib), AENEAS (ametinib) and FLAURA (osimertinib) studies ^1-4

Notably, the fumetinib group in the FURLONG study included a larger population with CNS metastases and L858R mutations (35% and 49%, respectively), and both groups were observed to benefit from PFS from the treatment of vometinib1

The FURLONG study enrolled a higher proportion of people with CNS metastases and L858R mutations ^1-4

CNS metastases are the most common type of distal lung cancer metastasis and are one of the important causes of treatment failure, and its prevention and control is a crucial indicator

This year's ASCO conference published data analysis of baseline populations associated with CNS transfer in the FURLONG ^study5

Whether it is CNS PFS data, or CNS objective response rate (CNS ORR), CNS disease control rate (CNS DCR) or CNS response duration (CNS DOR) data, the CNS efficacy data of the first-line treatment Chinese group of vometinib are very similar to the data of the osimerinib treatment group in the FLAURA ^{study6 and 7}
.

CNS PFS：FURLONG vs FLAURA^6、7

Professor Shu Yongqian, director of the Oncology Center, director of the Department of Oncology and director of the Department of Geriatric Oncology of Jiangsu Provincial People's Hospital, believes that although the clinical application of the three-generation EGFR-TKI drugs of the two Chinese original research institutes into the first-line treatment seems to be only the "icing on the cake" in terms of efficacy data, their phase III clinical studies are enrolled in the Chinese group, so compared with the FLAURA study on the treatment of global populations with osimtinib, its research results are more instructive for the clinical practice of treating lung cancer patients in China; In addition, China's original research drugs also give doctors more choices, and will also promote the price reduction of imported drugs, so that more Chinese patients can benefit
from the third-generation EGFR-TKI drug treatment.

Structural optimization Security advantages

If the efficacy data of the first-line treatment of the two original Chinese drugs have not yet shown the advantages of their optimized molecular structure, then in terms of safety data, the advantages of optimized structure are clearly visible
.

Structural modifications of volteminib and ametinib increased the selectivity
of these two drugs to mutant EGFR.
And another result of the introduction of phometinib into trifluoroethoxypyridine is that AST5902, the main metabolite of vometinib, also has antitumor activity and is highly selective for various mutations
in EGFR.

For example, vometinib and AST5902 inhibit wild-type EGFR (EGFR WT) IC50 110-140 times more inhibit EGFR classical mutations
.

Vometinib and its metabolites inhibit various mutations EGFR with high selectivity

This high degree of selectivity lays the safety basis for the clinical application of voltmetinib, which is characterized by a relatively low incidence of rash and diarrhea in clinical studies
.

The adverse reaction profiles of the three generations of EGFR-TKI vary ^{from 1 to 4}

According to Professor Shu Yongqian, osimtinib was approved earlier, so there are more patients in clinical application; In the process of treatment, we did find that its toxic side effects, including abnormal liver function, cardiotoxicity, interstitial pneumonia, etc.
, affected the treatment efficacy and the quality of life of
patients.

"Clinically, there is no shortage of patients with cardiotoxicity or severe mouth ulcers after treatment with osimertinib, and the efficacy is maintained after switching to the third-generation EGFR-TKI treatment of China's original research institute, and the toxic side effects are reduced or even disappeared
.
" Professor Shu Yongqian concluded, "This is the benefit of having multiple similar drugs for clinical practice; At the same time, this also shows that China's original research drugs have their own unique safety advantages compared with imported three generations
of EGFR-TKI.
”

"Some doctors may feel that the quality of imported drugs is more stable and the quality is more reliable; However, according to my experience of using Chinese original research drugs, I think that the anti-tumor efficacy of the original research drugs is not inferior, and because the toxic side effects are lower, it can be doubled to overcome CNS resistance," professor Shu Yongqian shared
.

"So I think that vomitinib has its application prospects, and if the first-line treatment indication can enter Medicare, I am more likely to choose vomitinib than osimitinib
.
"

References:

[1] Shi Y, Chen G, Wang X, et al.
Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multi- centre, double- blind, randomised phase 3 study.
Lancet Respir Med.
Published on Jun 2, 2022.
DOI: https:// doi.
org/10.
1016/S2213- 2600(22)00168-0

[2] Lu S et al.
, AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations, J Clin Oncol.
2022 May 17; doi: 10.
1200/JCO.
21.
02641

[3] J.
-C.
Soria et al.
, Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer; N Engl J Med 2018; 378:113-25.
DOI: 10.
1056/NEJMoa1713137

[4] Cheng Y, He Y, Li W, et al.
Osimertinib Versus Comparator EGFR TKIEGFR-TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study.
Target Oncol.
2021 Mar; 16(2):165-176

[5] Chen GY et al.
, Central nervous system efficacy of furmonertinib versus gefitinib in non-small cell lung cancer patients with epidermal growth factor receptor mutations: results from FURLONG study, ASCO 2022, Abstract #9101

[6] Shi YK et al.
, Central nervous system efficacy of furmonertinib (AST2818) versus gefitinib as first-line treatment for EGFR mutated non-small cell lung cancer: results from the FURLONG study , J Thorac Oncol.
2022 Aug 3:S1556-0864 (22)01496-4.
doi: 10.
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2022.
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[7] Reungwetwattana T et al.
, CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer, J Clin Oncol.
2018 Aug 28; JCO2018783118.
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