Research and Development . . . A list of small molecule-targeted drug development patterns for gastrointestinal methoblastoma (GIST).

Gastroenteromelioma (GIST) is a common interloleaf-derived tumor in the gastrointestinal tract, originating in Cajal interstitial cells (ICC Cells, ICC), which accounts for one-half of the soft tissue sarcoma.
the annual incidence rate of GIST reported abroad is 7 parts per million, the annual incidence rate of GIST reported in China is 1.28 per 100,000, although lower than foreign, but with the understanding of GIST and the progress of diagnostic technology, the incidence rate is increasing year by year.
C-kit gene mutation and PDGFRA gene mutation are the most common pathogenesis of GIST, and GIST, which has not detected mutations in the C-kit and PDGFRA genes, is called wild-type GIST.
C-kit gene mutations accounted for 75%-80% in GIST, PDGFRA gene mutations for 5%-10%, wild GIST for 10%-15%.
different types of gene mutations were closely related to the clinical pathological characteristics, therapeutic efficacy and prognosis of gastrointestinal mesomas.
C-kit gene exon 9 mutant type gastrointestinal intercomoma spherloid is mostly occurring in the small intestine and is insensitive to the therapeutic dose of 400 mg/day of conventional mfofonate imartinib.
PDGFRA gene 18 exon D842V mutant type gastrointestinal intercomoma is resistant to the now-listed tyrosine kinase inhibitors Imatinib, shonetinib and Regfini.
GIST Targeted Therapeutics - The classic Imatinib generation of "god drug" Imatinib became the first FDA-approved first-line treatment for non-surgical and transfer of GIST in 2002.
treatment of advanced GIST in Imatinib, 80% of patients receive a treatment response after 2-3 months of treatment, with median OS being 57-60 months and about 50% of patients having a survival of more than 5 years.
compared to other gene mutation types, the C-kit exon 11 mutation is the most sensitive to Imatinib treatment and has the best prognosis.
C-kit exon 9 mutation and wild-type GIST imatinib are less effective, the No. 9 exon mutation can benefit from the treatment of Imatinib at 800 mg/day.
about 10-15% of the transferred GIST is resistant to the imatinib, usually PDGFRA exon 18 D842V mutation or wild TYPE GIST.
a large proportion of patients with effective metastasis giST in initial treatment of Imatinib develop disease progression within 2-3 years, the most common mechanism is secondary resistance caused by secondary gene mutations, which often occur at the kinase ATP binding site and activation rings (C-kit exons 13, 14, 17 and 18).
Sunitinib Sunitinib is a second-generation gastrointestinal methioma targeted treatment drug developed by Pfizer for imateini resistance, with a pyrethylie structure, and is a multi-target tyrosine kinase inhibitor for KIT, PDGFR, VEGFR, and FLT-1/KDR.
in the late GIST III study of sunitinib treatment for failure or intolerance against a placebo, the sunitinib group compared to the placebo group, with 27.3 and 6.4 months of TTP (HR 0.33, p.0001), respectively. Common side effects
include fatigue, diarrhea, hand and foot syndrome, and hypothyroidism, which can be tolerated.
based on the above study schonotinib was approved as a 2-line drug to treat imatinib treatment failure or intolerance of late GIST.
studies have shown that the type of gene mutation is associated with the treatment response of sunitinib, 9 exon and wild type benefit greater, the coding kinase ATP binding region 13 or 14 exon mutation is sensitive to sunitinib, and the 17 or 18 exosome mutation seditinibly encoded activation ring is resistant to sunitinib.
Regorafenib, a new generation of oral multi-target tyrosine kinase inhibitors developed by BAYER after Sorafini, was approved in 2013 for the treatment of gastrointestinal methomas. In addition to inhibiting KIT and PDGFRA kinase targets,
can also act on TARGETs such as RET, BRAF, RAF1, VEGFR, FGFR, PDGFRP, etc.
A phase II study of late GIST that failed treatment of Imatinib or shonetinib showed good results, with a clinical benefit rate of 79% (full remission, partial remission, disease stabilization of 16 weeks), median PFS for 10 months, and the most common level 3 toxicity reactions were hypertension and hand and foot syndrome. Long follow-up
phase II studies above found that Regfini had significant efficacy with C-kit 11 exosome mutation GIST and SDH defective GIST.
A phase III study of Rigfini's placebo-controlled placebo found that the median PFS in the Rigfini group was significantly higher than the 0.9 months in the placebo group, but there was no significant difference between the two groups of OS.
based on the above studies, Regfini was approved as a third-line treatment for imatinib and shonesinib treatment failures or intolerance to advanced GIST.
in addition to the above three targeted therapeutic drugs, Soolafinini, Dashatinib, nilotinib, papaltinib, cabotinib and so on can be used as a GIST backline treatment options.
GIST-targeted therapeutic drug - New GuiRipretinib May 16, 2020, Reding Pharmaceuticals partner Deciphera Pharmaceuticals announced that the FDA has approved its broad-spectrum KIT and PDGFR alpha kinase inhibitor Ripretinib (Qinlock, DCC-2618) three months ahead of schedule, becoming the first drug specifically approved for four-line treatment sEDST.
Ripretinib is suitable for adult patients who have previously been treated with three or more kinase inhibitors, including Imatinib, Shoneib, Rigofinib, etc.
Ripretinib (DCC2618) is a "switch-controlled" kinase inhibitor that forces the activation ring (or activate 'switch') into an inactive conformation.
Ripretinib inhibits all tested KIT and PDGFRA mutants, especially as a type II kinase inhibitor, which can widely inhibit activation ring mutations in KIT and PDGFRA, which were previously thought to be possible only by type I inhibitors.
The Key Phase III INVICTUS (NCT03353753) study of The Ripretinib's quadrage treatment of GIST showed that Ripretinib showed a very significant efficacy advantage, with a median PFS of 6.3 months, an 85% reduction in disease progression or death risk, or R 9.4%.
in previous studies, the ORR for the second-line shonetinib treatment was only 6.8 percent, the median PFS was about 6 months, the ORR of the third-line rigafini was only 4.5 percent, and the median PFS was only 4.8 months.
Ripretinib's data for four-line and above treatments can be compared to second- and third-line treatments, and the results are amazing.
in addition, patients with Ripretinib treatment in this study had long durations of continuous remission.
currently, Ripretinib has written the latest 2020 NCCN guidelines recommended as a four-line standard treatment.
domestic, Reding Pharmaceuticals has obtained the development rights of Ripretinib in Greater China, making Ripretinib clinical research in China rapidly advancing, and we look forward to Ripretinib's early approval of indications in China for the benefit of Chinese GIST patients.
Avapritinib (BLU-285) January 9, 2020, the FDA announced the approval of the oral strong selective KIT and PDGFR alpha inhibitor avapritinib developed by Blueprint Medicines for the treatment of patients carrying platelet-derived growth factor receptor alpha (PDGFRA) anichild 18 mutation (including PDGFRA D842V mutation) of non-removable or interstituatoral gastroenteroma."
, however, on April 28, 2020, Blueprint published new data from Avapritinib and Rigofini Head-to-Head Trials (VOYAGER), which failed to reach the end of its clinical study.
in this open VOYAGER clinical study, Avapritinib had a higher response rate than Rigofini (17% vs 7%), but mPFS was weaker than the latter.
this also suggests that the mechanism of GIST is complex, although the total response rate of UP 86% of the GIST of the PDGFRA exon 18 mutation orR was achieved, but for other GIST, the improvement relative to Rigofani was not demonstrated.
, the FDA has rejected the NDA application for Arapitinib's four-wire treatment for GIST.
Blueprint has decided to terminate all clinical studies of all GIST indications in addition to the continued commercialization of approved indications.
, Keystone Pharmaceuticals announced that the State Drug Administration (NMPA) has accepted applications for the listing of new drugs for avapritinib, including two indications, for non-surgical or metastatic GIST adult patients carrying platelet-derived growth factor receptor alpha (PDGFRA) exosome 18 mutations (including PDGFRA D842V mutations), and four-line non-surgical or metastatic GIST adult patients.
the preliminary data of the China I/II phase bridge study conducted by Keystone Pharmaceuticals, the safety and pharmacokinetic characteristics data of patients with advanced GIST in China are consistent with THE NAVIGATOR global research data and are well tolerated.
GIST targeted therapeutic drug - clinical phase drug HQP1351 HQP1351 by the domestic Asian medicine in the original 1 new drug, oral third generation BCR-ABL inhibitor, is the first three-generation BCR-ABL targeted drug resistance CML treatment drug, BCR-ABL and a variety of BCR-ABL mutations including T315I mutation starring prominent effect.
July 2019, the species was approved by the FDA for clinical trials and went directly to Phase Ib clinical studies.
May this year, HQP1351 was awarded the U.S. FDA's orphan drug qualification and review fast track qualification.
June 18, this year, based on two key registered clinical studies, AXA Pharmaceuticals announced that it will submit to the National Drug Administration (NMPA) New Drug Review Center (CDE) a new drug listing application (NDA) for the treatment of chronic myeloid leukemia (CML) chronic and accelerated patients with T315I mutations.
currently, clinical phase I trials are under way for HQP1351 to treat patients with imatinib primary drug resistance (PDGFRAD842V mutation or NF1 mutation) or giST patients who have failed treatment with Imatinib or Imatinib and at least one other TKI treatment.
Crenolanib Crenolanib (CP-868596) is a PDGFRA D842V mutation-specific inhibitor developed by Arog Pharmaceuticals and can reduce the expression of KIT/PDGFRA.
a Phase II study included 16 patients with PDGFRA D842V mutation GIST, with a clinical benefit rate of 31% (2 PR, 3 SD) after treatment with Crenolanib.
currently, Crenolanib's Phase III clinical trial for GIST treatment NCT02847429 is in the process and is expected to be completed in August 2020.
Masitinib Masitinib, a multi-target kinase inhibitor primarily targeted at KIT, PDGFR alpha/beta and FGFR, exhibited higher activity and selectivity against KIT than imartinib in in vitro experiments.
masitinib's first-line treatment of advanced GIST, the median PFS was 41 months, comparable in safety and efficacy to imartinib.
a small sample study of 2 phases with Shnitini in its early years, which focused on OS.
Masitinib's Phase 2 clinical study oS reached 29.8 months, but its PFS was only 3.7 months.
conducted a Phase 2,3 clinical study of Masitinib and Shoneib (NCT01694277), which is currently under way for 5 years of OS.
conclusion, GIST therapy will enter the era of gene-driven precision therapy, and It is believed that more targeted new drugs to overcome drug resistance will emerge, bringing clinical benefits to GIST patients.
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