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Author: Cornflower This article is published by Yimaitong authorized by the author, please do not reprint without authorization
.
Neurotrophic Tyrosine Receptor Kinase (NTRK) is the first drug-available mutation gene that has been discovered and approved to co-occur in all cancers
.
Because it is found in a variety of tumors, it is an ideal target for tumor treatment
.
However, currently there is no NTRK targeted drug on the market in China
.
Now this status quo is about to be broken
.
On May 26, the official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration showed that the marketing application of larotrectinib (code name LOXO-101) was planned to be included in the priority review for the treatment of adult and pediatric patients with solid tumors carrying NTRK fusion genes.
It is expected to become the first NTRK inhibitor to be marketed in China1
.
What is NTRK gene? NTRK genes include NTRK1, NTRK2 and NTRK3, which respectively encode three proteins of the tropomyosin receptor kinase (TRK) family TRKA, TRKB and TRKC
.
In healthy tissues, the NTRK pathway is involved in the development and function of the nervous system and cell survival, and plays an important role in healthy tissues
.
When any gene in the NTRK gene family has a fusion mutation with other genes, it will cause abnormal activity of cancer cells and drive the occurrence of tumors
.
The mutation frequency of NTRK gene has been found that NTRK fusion exists in more than 25 types of cancer, including breast cancer, colorectal cancer, lung cancer, thyroid cancer, etc.
, and it exists in solid tumors in adults and children.
.
Wherein, NTRK adult secretory breast carcinomas and salivary secretion, infant fibrosarcoma and mutation frequency of up to 75%, it is strongly recommended that these types of patients detecting gene NTRK 2
.
The distribution and frequency of NTRK fusion in adult and pediatric tumors (Source: Reference 2) Larotrectinib-just look at the target, regardless of the cancer species.
Larotrectinib is a new generation of highly specific oral TRK inhibitors that can bind with high selectivity The protein product encoded by the NTRK fusion gene blocks the activation and transmission of downstream signaling pathways, thereby inhibiting the growth and proliferation of cancer cells with these mutations, and exerting anti-cancer effects
.
On November 26, 2018, the U.
S.
Food and Drug Administration (FDA) accelerated the approval of larotrectinib for the treatment of adults and children with locally advanced or metastatic solid tumors carrying NTRK gene fusions, regardless of the area where the cancer occurred
.
This is the first FDA-approved broad-spectrum anti-cancer targeted drug that does not distinguish cancer types and only looks at mutations, and has been proven to be effective in 17 types of pediatric and adult tumors; it is also the first target for NTRK fusion mutations Xiang medicine
.
Larotrectinib's three "fame battles" were the LOXO-TRK-14001 test, the SCOUT test and the NAVIGATE test
.
For patients with NTRK-positive solid tumors, the overall response rate (ORR) of larotrectinib treatment is 75%, with a complete response (CR) rate of 22% and a partial response (PR) rate of 53%; and the duration of the patient's response Very long, the median duration of response (DOR) reached 35.
2 months, and the median progression-free survival (PFS) was 25.
8 months 3
.
NTRK inhibitors open up a broad-spectrum anti-cancer craze.
In addition to larotrectinib, there are also many NTRK inhibitors that have shown good efficacy
.
01Entrectinib, a new broad-spectrum targeted anticancer drug, entrectinib is a new, orally effective, tyrosine receptor kinase inhibitor with central nervous system (CNS) activity
.
It is used for targeted treatment of solid tumor patients who carry NTRK-encoded fusion protein or proto-oncogene tyrosine protein kinase 1 (ROS 1) gene-encoded fusion protein and anaplastic lymphoma kinase (ALK)-encoded protein gene rearrangement
.
In August 2019, entrectinib received accelerated approval from the FDA for the treatment of central nervous system tumors, neuroendocrine tumors, salivary gland tumors, pancreatic cancer, non-small cell lung cancer, thyroid cancer, colorectal cancer, cholangiocarcinoma, breast cancer, etc.
nearly 20 A variety of tumors
.
In the phase II STARTRK-2 trial, the phase Ib STARTRK-1 trial and the phase I ALKA-372-001 trial, the ORR of entrectinib in patients with NTRK gene fusion protein-positive local progression or metastatic solid tumors was 57.
4%
.
Among them, the intracranial ORR of patients with brain metastases was 54.
5%
.
25% of patients achieved complete lesion disappearance (CR)
.
For patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC), 37.
7% of patients had an ORR of 77.
4% and a DOR of 24.
6 months 4
.
02Selitrectinib (LOXO-195) LOXO-195 is the second-generation NTRK targeted drug, designed to solve the first-generation NTRK targeted drug resistance problem
.
The 2019 AACR annual meeting reported the efficacy and safety data of 31 patients with NTRK-targeted drug resistance who received LOXO-195 treatment.
Among them, 20 patients came from the phase I clinical trial of LOXO-195, and 11 patients came from the sympathetic medication plan, ORR Up to 50%
.
It is invalid for bypass mutations that do not depend on the NTRK gene
.
03Repotrectinib (TPX-0005) Repotrectinib is an oral multi-target targeted drug.
The targets include ROS1, NTRK and ALK.
In 2017, it obtained the orphan drug designation issued by the US FDA
.
Pre-clinical studies have shown that repotrectinib can strongly inhibit NTRK wild-type and mutant types, and the inhibitory concentration is much lower than other NTRK-targeted drugs, and the NTRK G595R/F589L compound mutation that is refractory to the second-generation NTRK-targeted drug LOXO-195 can still be treated.
Effectively inhibit 5
.
In 2019, researchers published on ASCO the efficacy data of repotrectinib compared with other ROS1 inhibitors in the treatment of ROS1-positive NSCLC patients
.
In the first-line treatment, the ORR of repotrectinib reached 82%, compared with the first-line ORR targeted by other ROS1 inhibitors (72% for crizotinib, 62% for ceritinib, 77% for entrectinib, and 62% for lorlatinib) , The ORR of repotrectinib is far ahead
.
As a second-line program, the ORR of repotrectinib also reached 39%
.
With the rapid development of tumor treatment, the evolution and breakthroughs of various innovative therapies have brought more and newer treatment options to the majority of patients, helping them to achieve a longer survival and a higher quality of life
.
At present, the international NTRK inhibitors continue to send good news.
Two targeted drugs with excellent curative effect, larotrectinib and entrectinib, are also on the market.
We look forward to coming to China as soon as possible, so that more patients will be reborn through these broad-spectrum anti-cancer drugs
.
References: 1.
http:// Reviews Clinical Oncology 2018, 15, 731-747.
3.
Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.
Lancet Oncol, 2020.
DOI: 10.
1016/S1470-2045(19)30856-3.
4.
Drugs 2019, 79(13), 1477-1483.
5.
Cancer Discovery 2018, 8 (10), 1227-1236.
.
Neurotrophic Tyrosine Receptor Kinase (NTRK) is the first drug-available mutation gene that has been discovered and approved to co-occur in all cancers
.
Because it is found in a variety of tumors, it is an ideal target for tumor treatment
.
However, currently there is no NTRK targeted drug on the market in China
.
Now this status quo is about to be broken
.
On May 26, the official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration showed that the marketing application of larotrectinib (code name LOXO-101) was planned to be included in the priority review for the treatment of adult and pediatric patients with solid tumors carrying NTRK fusion genes.
It is expected to become the first NTRK inhibitor to be marketed in China1
.
What is NTRK gene? NTRK genes include NTRK1, NTRK2 and NTRK3, which respectively encode three proteins of the tropomyosin receptor kinase (TRK) family TRKA, TRKB and TRKC
.
In healthy tissues, the NTRK pathway is involved in the development and function of the nervous system and cell survival, and plays an important role in healthy tissues
.
When any gene in the NTRK gene family has a fusion mutation with other genes, it will cause abnormal activity of cancer cells and drive the occurrence of tumors
.
The mutation frequency of NTRK gene has been found that NTRK fusion exists in more than 25 types of cancer, including breast cancer, colorectal cancer, lung cancer, thyroid cancer, etc.
, and it exists in solid tumors in adults and children.
.
Wherein, NTRK adult secretory breast carcinomas and salivary secretion, infant fibrosarcoma and mutation frequency of up to 75%, it is strongly recommended that these types of patients detecting gene NTRK 2
.
The distribution and frequency of NTRK fusion in adult and pediatric tumors (Source: Reference 2) Larotrectinib-just look at the target, regardless of the cancer species.
Larotrectinib is a new generation of highly specific oral TRK inhibitors that can bind with high selectivity The protein product encoded by the NTRK fusion gene blocks the activation and transmission of downstream signaling pathways, thereby inhibiting the growth and proliferation of cancer cells with these mutations, and exerting anti-cancer effects
.
On November 26, 2018, the U.
S.
Food and Drug Administration (FDA) accelerated the approval of larotrectinib for the treatment of adults and children with locally advanced or metastatic solid tumors carrying NTRK gene fusions, regardless of the area where the cancer occurred
.
This is the first FDA-approved broad-spectrum anti-cancer targeted drug that does not distinguish cancer types and only looks at mutations, and has been proven to be effective in 17 types of pediatric and adult tumors; it is also the first target for NTRK fusion mutations Xiang medicine
.
Larotrectinib's three "fame battles" were the LOXO-TRK-14001 test, the SCOUT test and the NAVIGATE test
.
For patients with NTRK-positive solid tumors, the overall response rate (ORR) of larotrectinib treatment is 75%, with a complete response (CR) rate of 22% and a partial response (PR) rate of 53%; and the duration of the patient's response Very long, the median duration of response (DOR) reached 35.
2 months, and the median progression-free survival (PFS) was 25.
8 months 3
.
NTRK inhibitors open up a broad-spectrum anti-cancer craze.
In addition to larotrectinib, there are also many NTRK inhibitors that have shown good efficacy
.
01Entrectinib, a new broad-spectrum targeted anticancer drug, entrectinib is a new, orally effective, tyrosine receptor kinase inhibitor with central nervous system (CNS) activity
.
It is used for targeted treatment of solid tumor patients who carry NTRK-encoded fusion protein or proto-oncogene tyrosine protein kinase 1 (ROS 1) gene-encoded fusion protein and anaplastic lymphoma kinase (ALK)-encoded protein gene rearrangement
.
In August 2019, entrectinib received accelerated approval from the FDA for the treatment of central nervous system tumors, neuroendocrine tumors, salivary gland tumors, pancreatic cancer, non-small cell lung cancer, thyroid cancer, colorectal cancer, cholangiocarcinoma, breast cancer, etc.
nearly 20 A variety of tumors
.
In the phase II STARTRK-2 trial, the phase Ib STARTRK-1 trial and the phase I ALKA-372-001 trial, the ORR of entrectinib in patients with NTRK gene fusion protein-positive local progression or metastatic solid tumors was 57.
4%
.
Among them, the intracranial ORR of patients with brain metastases was 54.
5%
.
25% of patients achieved complete lesion disappearance (CR)
.
For patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC), 37.
7% of patients had an ORR of 77.
4% and a DOR of 24.
6 months 4
.
02Selitrectinib (LOXO-195) LOXO-195 is the second-generation NTRK targeted drug, designed to solve the first-generation NTRK targeted drug resistance problem
.
The 2019 AACR annual meeting reported the efficacy and safety data of 31 patients with NTRK-targeted drug resistance who received LOXO-195 treatment.
Among them, 20 patients came from the phase I clinical trial of LOXO-195, and 11 patients came from the sympathetic medication plan, ORR Up to 50%
.
It is invalid for bypass mutations that do not depend on the NTRK gene
.
03Repotrectinib (TPX-0005) Repotrectinib is an oral multi-target targeted drug.
The targets include ROS1, NTRK and ALK.
In 2017, it obtained the orphan drug designation issued by the US FDA
.
Pre-clinical studies have shown that repotrectinib can strongly inhibit NTRK wild-type and mutant types, and the inhibitory concentration is much lower than other NTRK-targeted drugs, and the NTRK G595R/F589L compound mutation that is refractory to the second-generation NTRK-targeted drug LOXO-195 can still be treated.
Effectively inhibit 5
.
In 2019, researchers published on ASCO the efficacy data of repotrectinib compared with other ROS1 inhibitors in the treatment of ROS1-positive NSCLC patients
.
In the first-line treatment, the ORR of repotrectinib reached 82%, compared with the first-line ORR targeted by other ROS1 inhibitors (72% for crizotinib, 62% for ceritinib, 77% for entrectinib, and 62% for lorlatinib) , The ORR of repotrectinib is far ahead
.
As a second-line program, the ORR of repotrectinib also reached 39%
.
With the rapid development of tumor treatment, the evolution and breakthroughs of various innovative therapies have brought more and newer treatment options to the majority of patients, helping them to achieve a longer survival and a higher quality of life
.
At present, the international NTRK inhibitors continue to send good news.
Two targeted drugs with excellent curative effect, larotrectinib and entrectinib, are also on the market.
We look forward to coming to China as soon as possible, so that more patients will be reborn through these broad-spectrum anti-cancer drugs
.
References: 1.
http:// Reviews Clinical Oncology 2018, 15, 731-747.
3.
Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.
Lancet Oncol, 2020.
DOI: 10.
1016/S1470-2045(19)30856-3.
4.
Drugs 2019, 79(13), 1477-1483.
5.
Cancer Discovery 2018, 8 (10), 1227-1236.
