Gastrointestinal stromal tumor targeting drug Avapritinib

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Gastrointestinal stromal tumor targeting drug Avapritinib (Avapriny, Ayvakit, BLU-285) is approved by USFDA on 9th January, 2020. The drug covers two indications: for the treatment of adult patients with inoperable resection or metastatic GIST carrying platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation (including PDGFRA D842V mutation) , And four-line non-surgical or metastatic GIST adult patients. 


ORR is as high as 86%, Avapritinib brings new hope to patients with gastrointestinal stromal tumors

In November 2019, the annual meeting of the Connective Tissue Oncology Society (CTOS) announced the results of the NAVIGATOR Phase I clinical trial on avapritinib in PDGFRA exon 18 mutations and patients receiving fourth-line GIST.

1. Research background

As of November 16, 2018, a total of 121 fourth-line and above patients (mainly KIT mutations) and 43 GIST patients with PDGFRA exon 18 mutations were enrolled. The trial explored the initial dose of the trial as “400 mg oral once daily”, and later reduced the recommended dose to “300 mg oral once daily” due to toxicity. The patient received Avapritinib until disease progression or unacceptable toxicity.

2. Efficacy data

For patients with PDGFRA exon 18 mutation, there were 3 cases of complete remission (OR) and 34 cases of partial remission (PR), and the objective response rate (ORR) was 86%. The median duration of response (DOR) and median progression-free survival (PFS) were not reached. As of the data cut-off date (median follow-up time was 10.9 months), 78% of patients still responded.



Of 111 GIST patients with fourth-line or above, 1 had complete remission, 23 had partial remission, ORR was 22%, median response duration was 10.2 months, median PFS was 3.7 months, and median follow-up time was 10.8. month.


In terms of safety, most adverse events (AEs) are mostly grade 1, 2 and the most common are nausea, fatigue, anemia, diarrhea, vomiting, etc .; grade 3-4 related AE ≥ 2%, anemia, fatigue, low Phosphaemia, hyperbilirubinemia, neutropenia and diarrhea. 10% of patients discontinued treatment due to treatment-related AEs.

3. Clinical value

Avapritinib is the first precision therapy approved for GIST patients with PDGFRA exon 18 mutation. It is an oral, potent and selective KIT and PDGFRα inhibitor. Avapritinib has shown extensive inhibition in gastrointestinal stromal tumors (GIST) with KIT and PDGFRα mutations, including the D842V mutation of the PDGFRα gene and other primary or secondary resistance mutations.

Keyless lock-PDGFRA exon 18 mutant GIST

Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tissue tumor, accounting for 0.1% to 3% of all gastrointestinal malignant tumors, with an incidence of 1 to 1.5 / 10 million. In people with gastrointestinal stromal tumors, the most common sites are the stomach and small intestine, but they may also be found anywhere in or near the gastrointestinal tract. If the tumor cannot be completely removed by surgery or the tumor has metastasized, targeted therapy is a standard treatment.

Currently, up to 85% of GIST tumors have one of the two gene mutations PDGFRA and KIT. These mutations lead to the production of abnormal KIT and PDGFRA proteins, which drive cancer. These two proteins can usually be turned off by imatinib and similar drugs that block the protein’s activity. But the mutation of PDGFRA exon 18 is very special, it changes the shape of PDGFRA protein, thus preventing the drug from binding to it. For the PDGFR [exon 18] mutation, the previous “key” is not suitable for this “lock”.

Avapritinib selectively binds PDGFRA and KIT proteins. In laboratory studies, the drug can bind to all tested mutant PDGFRA proteins and inhibit their activity in cancer cells.


Four drugs currently approved for gastrointestinal stromal tumors: Avapritinib, imatinib, sunitinib, and rifaginib. Avapritinib only binds to specific mutant enzymes called kinases (red circles) in cells, while similar drugs bind to more kinases. Image: Cell Signaling Technology.

 Targeted drug approved for gastrointestinal stromal tumor (GIST)  Other cancer indications  Domestic listing
 Gleevec | Imatinib  Acute lymphocytic leukemia (Philadelphia chromosome positive), chronic eosinophilic leukemia, Philadelphia chromosome positive chronic myeloid leukemia, dermatofibrosarcoma protuberans, myeloproliferative tumor  Listed and included in medical insurance
 Regorafenib | Stivarga  Liver cancer, colorectal cancer  Listed and included in medical insurance
 Sutent | Sunitinib  Xixianai, kidney cancer  Listed and included in medical insurance
 Avapritinib (Ayvakit)  no  Unlisted

Other research progress of gastrointestinal stromal tumors


Ripretinib is a type II kinase inhibitor that can widely inhibit the activation loop mutations in KIT and PDGFRA. It is a kinase inhibitor with a “switch control” function, which can activate the activation loop (or activate the “switch”) into The active conformation, in turn, inhibits all tested KIT and PDGFRA mutants. Ripretinib’s effectiveness in preclinical cancer models and initial clinical trials also validated that Ripretinib can inhibit the universal KIT mutation in patients with drug-resistant GIST.

Data from the Phase III study (INVICTUS) showed that patients receiving Ripretinib had a 85% lower risk of tumor progression or death compared to placebo, with a median OS of 15.1 months, and 6.6 months in the placebo group. Late GIST fourth-line or above treatment brings dual benefits of PFS and OS, and Ripretinib shows better tolerability.


The world’s first targeted drug that does not distinguish tumor sources for initial treatment-Vitrakvi ® (larotrectinib, hereinafter referred to as larotinib), has been approved by the global tumor community since it was approved for marketing in November 2018 Doctors and patients have brought new hopes and choices.

The biggest attraction of the drug is that it is a new anti-cancer drug that targets specific gene mutations but not specific cancer types. The NTRK gene fusion solid tumors that it can treat include 17 types of cancers including breast cancer, colorectal cancer, lung cancer, and thyroid cancer, and can be used for both adults and children. NTRK gene fusion exists in 0.7% ~ 3.6% of digestive tract tumors.


Therefore, if you do a genetic test, you can first see if there are any mutations that may bring a miracle of survival, you can call the medical department of the Global Oncologist Network to interpret the report.

I believe that with the advent of more and more targeted drugs, patients with gastrointestinal stroma
l tumors can get more treatment options and longer survival benefits. I also hope that these drugs can be listed in China as soon as possible and be included in medical insurance for the benefit of more patients.

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