Qingli Xinsheng breaks advanced gastrointestinal stromal tumors——Congratulations on Qingle® (Repetinib tablets) approved in China

March 31, 2021-Zai Lab announced that the National Medical Products Administration (NMPA) of China has approved the marketing application of Qingle® (Repetinib tablets) for the treatment of those who have received imatinib Adult patients with advanced gastrointestinal stromal tumor (GIST) with 3 or more kinase inhibitors.

This approval marks that Qingle® will become the first GIST fourth-line treatment approved to be marketed in China, filling the gap in the treatment of this disease in my country, and bringing more choices and hopes to the majority of patients with advanced GIST.

What is the current status of advanced GIST treatment? ——Secondary drug resistance is not optimistic.
GIST is the most common mesenchymal tumor of the digestive tract, with an incidence of about 1 in 100,000.

Traditional tyrosine kinase inhibitors (TKI) such as imatinib, sunitinib and regorafenib are all designed to compete with the ATP binding region of kinases to prevent kinase phosphorylation and activation.
The inhibitory effect of drugs is affected by ATP.
Concentration; and secondary mutations mainly lead to changes in the structure of the ATP binding region or activation loop of the kinase, so that TKI cannot bind to the ATP binding region of the kinase, that is, drug resistance occurs.

For advanced patients, patients with advanced first-line imatinib treatment have multiple drug-resistant mutation sites, and patients with advanced second- and third-line therapy have more complicated gene mutations.
It is difficult for drugs with a single target to effectively inhibit tumor cell growth.
Proliferation and genetic mutations in GIST patients with advanced multi-line therapy are highly heterogeneous, which are important reasons for rapid tumor resistance.

Based on this, the treatment situation of patients with advanced GIST is severe, and new treatment drugs are urgently needed.

The sensitivity of different TKIs to different exons.
Who can break the GIST resistance dilemma? ——Repetinib turned out to be the world’s only tyrosine kinase "switch control" inhibitor.
Unlike other TKIs that act on the ATP binding region, repetinib’s unique role is in the switch pocket and The activation loop, on the one hand, it occupies the switch pocket and prevents the activation loop from entering the switch pocket.
On the other hand, it forms a variety of stable chemical structures with the activation loop.
The inhibitory effect of the drug is not affected by the ATP concentration or secondary mutations (ATP binding region or activation).
Ring), and accurately inhibit a variety of mutations of KIT and PDGFRA.

Repetinib is suitable for adult patients with advanced GIST who have been treated with 3 or more TKIs (including imatinib) (applicable to patients with any mutation, including: KIT, PDGFRA, wild-type), breaking the advanced GIST The predicament of drug resistance.

The new mechanism of action of repetinib is a randomized, double-blind, placebo-controlled international multi-center phase III registered clinical study INVICTUS.
The results have confirmed the clinical benefit of repetinib in patients with advanced GIST ≥ 4 lines.

INVICTUS enrolled 129 advanced adult GIST patients from 29 hospitals in 12 countries who had received at least imatinib, sunitinib, and regorafenib treatment for disease progression or intolerance, and they were randomly divided into 2:1 Repetinib 150mg/day (n=85) and placebo (n=44) were treated.

The primary research endpoint is progression-free survival (PFS), and the secondary research endpoints are overall survival (OS), objective response rate (ORR) and safety.

The results of the INVICTUS study showed that repetinib has strong PFS benefits and broad safety: the median PFS in the repetinib group (n=85) was 6.
3 months, and the placebo group was 1.
0 months (n=44) (P＜0.
0001), significantly reduced the risk of disease progression by 84%; ORR in the repetinib group was 11.
8%, and placebo was 0.
0%; the OS in the repetinib group was not reached, and it was 6.
3 months in the placebo group, which was a significant decrease of 58 % Risk of death.

Repetinib significantly reduces the risk of disease progression in patients with various types of gene mutations.

The median PFS in the repetinib group was 6.
3 months vs.
1.
0 month in the placebo group (p<0.
0001).
The HR* of PFS benefit in different secondary gene mutation types subgroups.
In terms of safety, there were many adverse events related to treatment with repetinib Grade 1-2, the total incidence of grade 3/4 adverse reactions in the repetinib group and the placebo group is similar; the dose adjustment rate due to adverse reactions is similar between the repetinib group and the placebo group .

In terms of taking, repetinib is convenient to take, once a day, not affected by meals, and does not require mutation testing before use.

Repetinib treatment-related adverse events are mostly grade 1-2.
What is the status of repetinib? ——The standard treatment plan of authoritative guidelines at home and abroad is based on the excellent clinical benefits of repetinib 4-line treatment.
Repetinib is recommended by the latest NCCN (2021 v1) as the fourth-line standard treatment recommended by the latest NCCN (2021 v1) guidelines.
my country, August 2020 The first edition of the "CSCO Gastrointestinal Stromal Tumor Diagnosis and Treatment Guidelines" also recommended repetinib as the only grade I recommended drug for GIST with Class 1A evidence after the failure of third-line imatinib and sunitinib.

Currently, Repetinib has also been approved by the U.
S.
Food and Drug Administration, Health Canada and the Australian Medicines Agency for fourth-line treatment of patients with advanced GIST.

In general, repetinib targets the dual mechanism of action of the KIT switch pocket and activation ring, breaking the severe situation and drug resistance predicament of advanced GIST treatment.

The approval of Qingle® provides clinicians with new treatment options, and it is possible for patients with gastrointestinal stromal tumors to obtain a longer survival time and better quality of life.

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