Mace inventory: 10 classes of 23 anti-tumor drugs that are not limited to cancer

In the past cognition, targeted drugs and immunotherapy drugs were drugs
that could only be used for specific cancers, specific gene mutations, specific targets, and specific pathways.
Many patients have no ideal target for genetic test results, lose the opportunity to take drugs, or try to take drugs across indications, but cannot be reimbursed or donated across
indications.
Now, the successful development and marketing of broad-spectrum anticancer drugs (also known as anti-tumor drugs with no limit to cancer) has given everyone new hope! Break the cancer restriction so that more patients have access to medicine!

This treatment strategy that is not bad for cancer, also known as "precision treatment", is mainly due to the results of
genetic testing.
According to the results of genetic testing, once the corresponding target is found, a corresponding targeted therapy drug
can be used.

Target detection was initially common from breast cancer and lung cancer, and now gradually expands to all cancers, including ovarian cancer, gastric cancer, etc
.
For example, patients with non-small cell lung cancer are tested for EGFR, ROS1, and ALK, breast cancer is tested for HER2, and gastric cancer is tested for HER2
.
However, compared to hundreds of cancer driver genes, there are still too few genetic mutations in each type of cancer that can be used to treat them, far from meeting the needs
of all patients 。 Solid tumors mainly include PD-1/PD-L1, EGFR, ROS1, RET, ALK, MET, BRAF V600E, NTRK, BRCA1/2, KRAS, MSI-H and dMMR, Claudin 18.
2, FGFR, BCMA, GPC3, Mesothelin, TP53; Hematological tumors include CD19, CD7, etc.
, many target drugs are still in the process of development, Mace Xiaobian takes you to inventory these drugs
.

However, with the improvement of antibody production technology and gene therapy technology, targeted new drugs have shown an accelerating trend, and the "broad-spectrum anti-cancer" without limiting cancer species will become more and more frequent
in the future.

At present, there are 10 "broad-spectrum anticancer drugs" with solid tumor indications that have been marketed (approved by the FDA or NMPA), namely PD-1 inhibitors pymoodumab (Keytruda), dostarlimab-gxly, serplulimab and envolimab, NTRK inhibitors lalotinib and entrectinib (Entrectinib), Dabrafenib + trametinib, Pemigatinib tablets, selpercatinib (serpatinib).

There are also a large number of cancer drugs in the process
of being marketed.
At present, nearly 20 drugs are listed here, and 10 of them are in the process of research and development before marketing, but because there is great hope, they are also included in the inventory
.

1.
PD-1/PD-L1 class

PD-1, as a representative of immunotherapy drugs, PD-1 inhibitors have opened a new door
for the precision treatment of cancer.
Such drugs can mobilize the patient's own immunity to kill cancer cells, with good efficacy and few side effects, and can be combined with other types of cancer treatment drugs to achieve better results
.

In terms of "broad-spectrum anti-cancer", PD-1 inhibitors are actually at the forefront
.
The first drug approved for solid tumor indications is not lalotinib or entretinib as we think of it, but pembrolizumab
.

1.
Pembrolizumab (Keytruda): solid tumors of MSI-H and dMMR

In May 2017, the FDA approved the solid tumor indication of pembrolizumab for patients with solid tumors with high microsatellite instability (MSI-H) or mismatch repair defects (dMMR) and no other treatment options, becoming the world's first immune drug
that does not distinguish between tumor origins.
As a basis for approval, the overall response rate of pembrolizumab in patients with various solid tumors was 39.
6%, of which 78% of patients continued to remission for more than 6 months
.

In June 2020, Keytruda's second "unlimited cancer" new indication was approved
.
For the treatment of adult and pediatric patients
with unresectable or metastatic solid tumors with a high tissue tumor mutational burden (TMB-H) ≥ 10 mutations/megabases (using FDA-specified tests).
The approval of TMB as a molecular marker means that the broad-spectrum anti-cancer range has been expanded again, and more patients will benefit
.

However, due to factors such as detection technology limitations, Keytruda's unlimited cancer species has not become mainstream
.
What really pushes this class of drugs to the "frontline" of anti-cancer is actually the latter two NTRK inhibitors
.
News about Keytruda: Reporting by Keytruda

2.
Dostalimab: solid tumor of dMMR

On August 18, 2021, the FDA accelerated its approval of dostalimab (Dostarlimab-gxly, Jemperli) for the treatment of adult patients
with recurrent or advanced solid tumors with mismatch repair defects (dMMR).
Patients should have been treated with the current standard regimen and have no better alternatives
.

As a basis for approval, the Phase I GARNET trial verified the efficacy of
dostalimab in patients with solid tumors, endometrial cancer and other non-endometrial cancers.

The results showed that dostalimab achieved a response rate of 41.
6% in patients with solid tumors with dMMR, including a complete response rate of more than 9%.
In addition, more than 95.
4% of patients had remissions lasting more than half a year, and the median duration of remission was as long as 34.
7 months, nearly 3 years! For details, see: NEJM: PD-1 immunotherapy completely disappeared 14 patients with advanced rectal cancer

Previously, in April 2021, dostalimab has accelerated the approval of dMMR for recurrent and advanced endometrial cancer, and after this approval, the indication has been extended to all types of recurrent and advanced solid tumors
.

3.
Subcutaneous injection of PD-L1 envoli monoclonal antibody

In December 2021, Envolimab (Envida) was approved for MSI-H/dMMR advanced colorectal cancer, gastric cancer and other solid tumors
.
This is the first and only PD-L1 antibody drug
approved for subcutaneous injection.

Clinical data showed that the objective response rate (ORR) of Envida treatment in patients with second-line and above was 44.
7%, and 12 cases (11.
7%)
had complete response.
89.
3%, 100%, 100%, 100% and 93.
2% of patients with advanced CRC, advanced gastric cancer, other advanced solid tumors and all patients, respectively, were still in continuous remission, with obvious persistence
.

4.
Serplulimab: solid tumor of MSI-H

On March 24, 2022, the Chinese NMPA conditionally approved the PD-1 inhibitor serplulimab (H drug, Serplulimab, HLX10) developed by Henlius Biologics of Shanghai for monotherapy in patients
with unresectable, metastatic highly microsatellite instable (MSI-H) solid tumors after standard therapy failure.

The approval is based on the results of the
Phase II ASTRUM010 trial.
A total of 108 patients were enrolled in the trial; Among them, 68 patients were the main efficacy analysis population, and the overall response rate was 39.
7%.

In addition, among the subjects, the objective response rate (ORR) of 45 colorectal cancer subgroup with sensitivity efficacy analysis was as high as 46.
7%; The 12-month survival (OS) rate of 58 patients with sensitivity and efficacy analysis reached 82.
4%, and the disease control time was long
.
Domestic experts believe that such efficacy is completely comparable to PD-1 at home and abroad
.
Details: JAMA: Longest OS result for serplulimab in extensive-stage small cell lung cancer (ASTRUM-005 study)

5.
Various dual-target drugs derived from PD-1

What the two PD-1 inhibitors can do, the "double antibodies" of PD-1 and other targets will naturally not be inferior
.
At present, the most common PD-1 "biantibody" target combinations include PD-1/CTLA-4, PD-1/VEGF, etc.
, which have their own characteristics and have shown excellent efficacy
in clinical trials for some indications.

In addition, there are some new immunotherapy targets under development, and once successfully developed, they may be natural tumors
.

2.
NTRK inhibitors

The approval of the first NTRK inhibitor larotinib truly puts the concept of "broad-spectrum anti-cancer" in front
of patients.
The craze of lalotinib not only brought the concept of broad-spectrum anti-cancer with "fire", but also raised the value of NTRK as a target to the highest
.

Since its success, more and more new drugs have followed in the footsteps of lalotinib, and second-generation NTRK inhibitors that can sequentially follow first-generation NTRK inhibitors such as lalotinib and are used to treat drug-resistant patients.

The second-generation drugs TPX-0005, AB-106, ICP-723, SIM-1803, HG030, etc.
, have achieved very excellent efficacy or have shown promising efficacy
.

1.
Larotinib: NTRK mutated solid tumor

At the end of 2018, a new drug known as the "miracle drug" Larotrectinib (Larotrectinib, Vitrakvi, Vitekai) came out, and the FDA approved it for the treatment of solid tumors in adults and children with neurotrophic receptor tyrosine kinase (NTRK) gene fusion, causing global exclamation
.
"The first broad-spectrum anti-cancer drug", "remission rate of 75%" and many other halos have put lalotinib and the target NTRK behind it on the stage
of anti-cancer.
Details: UK NICE RECOMMENDS THE TRK INHIBITOR VITRA KVI (LAROTRECTINIB) FOR SOLID TUMORS WITH POSITIVE NTRK GENE FUSION

The biggest three highlights of this drug that are impressive are:

First, there is no restriction on cancer types
.
As long as NTRK fusion is present, 17 cancer types, including breast, colorectal, lung, and thyroid cancer, can be used for both adults and children
.
And for infant fibrosarcoma and thyroid cancer, the effective rate of gastrointestinal stromal tumors can be as high as 100%!

Second, the overall response rate was as high as 75%.

According to the results of three clinical trials (NCT02122913, NCR02576431 and NCT02637687) based on the approval, the overall response rate of lalotinib treatment was 75% for patients with NTRK-positive solid tumors, including 22% complete response rate and 53% partial response rate; The duration of response was very long, with a median duration of response of 35.
2 months and a median progression-free survival of 25.
8 months
.

Third, fast and durable response
.
This medicine works very quickly, and once it works, it brings obvious
relief.
The data showed that the average time to onset of action was only 1.
84 months, and 73% of patients responded for a duration of more than 6 months
.
(One case report showed that a 2-year-old spindle cell sarcoma girl experienced a rapid response and rapid improvement
in symptoms within 24 hours of receiving lalotinib.
) ）

In fact, in the treatment of as many as 17 types of cancer, larotinib is quite effective!

With high overall response rate, high complete response rate, long duration of response, and long duration of patient benefit from treatment, lalotinib fully meets patients' expectations for a targeted therapy drug, coupled with broad-spectrum anti-cancer properties, it is also called a "cure-system" drug
.
It is currently available
in China.

2.
Ntratinib: NTRK mutated solid tumors

On August 15, 2019, the FDA accelerated the approval of entrectinib (Luo Shengquan) for patients with NTRK mutations in solid tumors, which is the third drug
that is not restricted to cancer.

In patients with NTRK fusion-positive solid tumors, entrectinib (entrectinib, RXDX-101) had an objective response rate of ORR (tumor shrinkage) of 57.
4%, and objective responses (tumor shrinkage)
were observed across 10 different tumor types.
In patients with brain metastases, entrectinib had an intracranial objective response rate of 54.
5% ORR, of which more than one-quarter achieved complete remission (total disappearance of lesions).

The investigators reported a median duration of response of 20 months (95% CI, 13-38.
2) and a median progression-free survival (PFS) of 13.
8 months (95% CI, 10.
1-19.
9).

Emtratinib has a deeper Asian background and has published efficacy analysis results specifically for Asian patients
.
Among NTRK-positive patients, the overall response rate of patients with brain metastases at baseline was 75.
0%, including 100% of intracranial lesions and 66.
7% of patients without brain metastases at baseline.
Patients who achieved clinical response lasted 10.
4 months, and all patients had a median progression-free survival of 14.
9 months
.

The same NTRK inhibitor, entretinib is more than half a year late in the market, so naturally you need to
come up with some advantages that are different from larotinib.
In fact, entretinib is a multi-target drug that treats ROS1-mutated cancers with excellent results
.
In addition, cerebral activity is also one of the advantages of
entretinib that deserves attention.
In July 2022, it was also approved for listing
in China.
Details: The preliminary efficacy of the second-generation inhibitor VC004 of the golden target NTRK is gratifying, and many domestic companies have similar pipelines

3、Selitrectinib

It is a second-generation NRTK class inhibitor.

At the 2019 American Association for Cancer Research (AACR) annual meeting, the latest clinical trial results
of Selitrectinib were reported.
As of December 3, 2018, a total of 31 (7 children, 24 adults) cancer patients, including 11 types of tumor patients such as sarcoma, gastrointestinal stromal tumor, pancreatic cancer, and breast cancer, were treated
with Selitrectinib.
Selitrectinib treated patients with TRK kinase domain mutations with an ORR of 45%, and adverse events (TEAEs) during treatment were dizziness, loss of appetite, nausea, vomiting, anemia, myalgia, abdominal pain, fatigue, and lymphopenia
.
For details, see: Second-generation broad-spectrum anti-cancer TRK inhibitors, which may address the problem of entretinib or larotinib resistance

4、ICP-723

ICP-723 is a new generation of NTRK inhibitor independently developed by China Nuocheng Jianhua, which can treat advanced or metastatic solid tumors carrying NTRK fusion genes, including breast cancer, colorectal cancer, lung cancer, thyroid cancer, etc.
, as well as patients
resistant to the first-generation NTRK inhibitors lalotinib and entnetrutinib.

As of February 11, 2022, a total of 17 patients in the Phase I dose escalation trial were treated with ICP-723 at a dose of 1~8 mg once
daily.
The safety profile was good, and no dose-limiting toxicity (DLT)
was observed.
Of the 17 patients, 5 were confirmed positive for NTRK gene fusion, with an objective response rate (ORR) of 80%, including 4 partial responses, and a disease control rate (DCR) of 100%.

In the group of doses of 4 mg and above, the objective response rate was 100%.

Third, RET inhibitors

RET protein is a membrane receptor tyrosine kinase, and mutation and fusion of the RET gene can lead to overactivation of the RET signaling pathway, leading to tumor initiation and progression
.
Mutations in the RET gene can cause a variety of tumors, including NSCLC, papillary TC, colorectal cancer, ovarian cancer, pancreatic cancer, pleural mesothelioma, gastric cancer, cholangiocarcinoma, etc
.

1.
selpercatinib (LOXO-292, serpatinib).

On May 8, 2020, the FDA approved selpercatinib (Retevmo), also known as LOXO-292, for patients with advanced RET fusion-positive non-small cell lung cancer, RET mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer
.
Detail: Lancet Oncol: Selpercatinib has promising efficacy in RET fusion-positive solid tumors

Retevmo is also the first precision therapy
approved specifically to treat cancer patients with RET gene variants.
The latest results show that selpercatinib is also a veritable broad-spectrum anticancer drug, showing amazing clinical efficacy
for a variety of solid tumors.
Details: FDA approved Selpercatinib for the treatment of patients with locally advanced or metastatic solid tumors with RET gene fusions regardless of cancer species

In November 2021, Selpercatinib submitted a listing application in China and was accepted and included in the priority review
.

2.
Pratinib

In June 2018, CStone entered into an exclusive collaboration and licensing agreement with Blueprint Medicines, acquiring exclusive rights to
develop and commercialize platinib in Greater China.

In March 2021, platinib was approved for the first time in China for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had previously received platinum-containing chemotherapy with transfection rearrangement (RET) gene fusion, becoming the first highly selective RET inhibitor
approved for marketing in China.
At the same time, platinib has also become the first drug
in China to use Lecheng's real-world data to assist in review and approval.

In March 2022, platinib was expanded to new indications for the treatment of adults and children 12 years of age and older with advanced or metastatic RET mutated medullary thyroid cancer (MTC) requiring systemic therapy, as well as for adults and children 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer requiring systemic therapy and refractory to radioactive iodine (if radioactive iodine is applicable
).
It has become the first and only selective RET inhibitor
approved for RET mutated medullary thyroid cancer and RET fusion-positive thyroid cancer in China.

The results of the trial presented at the 2021 ASCO Annual Meeting showed a lasting clinical benefit
in patients with RET fusion-positive NSCLC.
In 68 patients without systemic treatment, the overall response rate (ORR) was 79%.

HRD drugs (BRCA1/2 gene, homologous recombination repair, and PARP inhibitors)

About BRCA1/2 gene, homologous recombinant repair (HRR; "Homologous recombination" is HR, and the latter R is repair, i.
e.
"repair"), homologous recombination repair defects (HRD), and PARP inhibitors, which can be classified into this category
.

HRD can exist in
many types of cancer.
Breast, ovarian, prostate, pancreatic cancer is the most common, and there is a certain proportion of other cancers, in general, when the indications of PARP inhibitors are expanded from BRCA mutations to HRD, and then to HRR-related gene mutations, they may reach almost all solid tumors
.

1.
Dostalimab

In August 2021, dostarlimab-gxly (Jemperli, dostalimab) was marketed for patients with recurrent mismatch repair defects (dMMR) who had relapsed or advanced solid tumors who had previously been treated and had no satisfactory alternative options;

The results showed that dostalimab achieved an excellent response rate of 41.
6% in patients with solid tumors with dMMR, including a complete response rate of more than 9%.
In addition, more than 95.
4% of patients had remissions lasting more than half a year, and the median duration of remission was as long as 34.
7 months, nearly 3 years! For details, see: NEJM: PD-1 immunotherapy completely disappeared 14 patients with advanced rectal cancer

5.
FGFR: hepatobiliary digestive tract tumor

FGF/FGFR signaling pathway exists in the development of almost all organs, the production of blood vessels and the production of lymphatic vessels, and is one of
the most important pathways in the human body.
There are more than 22 "members" of the FGF family, activated
by four important genes (FGFR1, FGFR2, FGFR3 and FGFR4).

FGFR is one of the most common mutation types of cholangiocarcinoma, which is also of vital significance in the targeted therapy of liver cancer, and also has certain potential for pancreatic cancer, which can be said to be a "small broad-spectrum" target for hepatobiliary digestive tract tumors
.

Some studies have pointed out that FGFR 1~3 mutation accounts for about 11%~45% of cholangiocarcinoma, so it has become one of
the most important research directions for targeted drug treatment of intrahepatic cholangiocarcinoma.
FGFR4 is also specific in liver cancer
.
The disclosure of the efficacy of the two blockbuster drugs provides proof
of the treatment ideas of this target.

Bemarituzumab: 9.
5 months of progression-free survival

Bemarituzumab is a first-of-its-kind humanized IgG1 monoclonal antibody
against FGFR2b, an FGF receptor.
On April 20, 2021, the FDA awarded Amgen the designation of Bemarituzumab breakthrough therapy for the first-line treatment of patients with FGFR2b-positive, HER2-negative locally advanced or metastatic gastric and gastroesophageal junction cancer
in combination with the modified FOLFOX6 regimen (mFOLFOX6).
5%~10% of gastric cancer patients have FGFR2b high expression or FGFR2 gene amplification, and in HER2- patients, the proportion is as high as 30%.

According to the results of the FIGHT study published at the 2021 Symposium on Gastrointestinal Oncology, among a total of 155 patients treated with intention-to-treat (ITT), patients treated with Bemarituzumab + mFOLFOX6 had a median progression-free survival of 9.
5 months and a 1-year progression-free survival rate of 52.
5%; Patients treated with placebo + mFOLFOX6 had a median progression-free survival of 7.
4 months and a 1-year progression-free survival rate of 33.
8%.

Details: Lancet Oncol: Bemarituzumab combined with mFOLFOX6 is expected to have a promising effect in the treatment of advanced adenocarcinoma of the stomach or gastroesophageal junction

(1) Subgroup analysis: higher expression level and longer survival

Subgroup analyses also supported this result
.
In the subgroup with higher expression of FGFR2b, i.
e.
, immunohistochemistry (IHC)2+/3+ accounting for more than 10% of the sample, the median progression-free survival of Bemarituzumab + mFOLFOX6 was 14.
1 months, and the 1-year progression-free survival rate was 57.
0%, significantly exceeding the 7.
3 months and 26.
4%
of placebo + mFOLFOX6 patients.
The median overall survival of patients in the combination therapy group had not yet been reached, compared with 11.
1 months
in the placebo group.

In the subgroup with high FGFR2b expression levels, i.
e.
, immunohistochemistry (IHC)2+/3+ accounting for more than 5% of the sample, the median progression-free survival of Bemarituzumab + mFOLFOX6 patients was 10.
2 months, and the 1-year progression-free survival rate was 56.
3%, significantly exceeding the 7.
3 months and 28.
6%
of patients treated with placebo + mFOLFOX6.

(2) Remission rate: as high as 47%, lasting 12.
2 months

In terms of response rate and duration, the overall response rate of Bemarituzumab + mFOLFOX6 treatment was 47%, and the median response lasted 12.
2 months, significantly exceeding the 33% and 7.
1 months
of placebo + mFOLFOX6 treatment.

(3) Median overall survival (OS) was 19.
2 months vs 13.
5 months (HR: 0.
60, 95% CI: 0.
38-0.
94)

The FDA said in the announcement that more than 10% of patients with locally advanced or metastatic gastric and gastroesophageal junction cancer have FGFR2b overexpression, and the Bemarituzumab program will provide a new solution
for this part of the patient.

2, pemigatinib (Pemigatinib): remission rate 36%

On April 17, 2020, the first targeted drug for cholangiocarcinoma received accelerated approval from the FDA and officially entered the clinic
.
Pemigatinib (Pemazyre) is an FGFR2-targeted drug approved for the treatment of treated patients
with FGFR2 mutant cholangiocarcinoma.
This is the first targeted drug approved for the treatment of cholangiocarcinoma, bringing a breakthrough of zero for the treatment of advanced cholangiocarcinoma
.
In April 2022, Innovent announced that its introduction of Pemigatinib tablets (trade name: Dabertan) has been approved for marketing in China for the treatment
of adult patients with advanced, metastatic or unresectable cholangiocarcinoma who have received at least one previous systemic therapy and have been tested for FGFR2 fusion or rearrangement.

A total of 107 patients with unresectable or metastatic FGFR2-positive cholangiocarcinoma were enrolled in the FIGHT-202 trial, all of whom had received at least one frontline treatment regimen and had progression
.
The results showed that the overall response rate of patients was 36%, of which 3 patients achieved clinical complete remission; The median duration of response was 9.
1 months, and of those who achieved clinical response, seven patients lasted more than 12 months
.

3.
Infigratinib: remission rate 23.
1%, progression-free survival 7.
3 months

On May 29, 2021, the FDA announced the approval of Infigratinib (Truseltiq) for the treatment of previously treated patients with locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion and rearrangement mutations
.

The results showed an overall response rate of 23.
1% and a median progression-free survival of 7.
3 months in patients treated with Infigratinib, and 32.
0% of patients who responded with a response lasting more than 6 months, with a median duration of response of 5.
0 months
.

The results of subgroup analysis showed that the overall response rate of patients who had received second-line treatment was 34%, and the overall response rate of patients with third-line treatment or above was 13.
8%.
The largest number of patients have received 8 frontline treatment modalities
.
Details: Pemigatinib for the treatment of FGFR2 fusion or rearranged advanced cholangiocarcinoma, CHMP has a positive evaluation

4.
Futibatinib: remission rate 37.
3%, progression-free survival 7.
2 months

On April 1, the FDA granted the FGFR inhibitor Futibatinib (TAS-120) breakthrough therapy designation for the treatment of patients with locally advanced or metastatic cholangiocarcinoma with treated FGFR2 gene rearrangements and fusion mutations
.

According to the results of the study presented at the 2020 ESMO conference, the overall objective response rate of all patients treated with Futibatinib reached 37.
3% during a minimum 6-month follow-up period, of which 1.
5% was complete and 35.
8%
was partial.

Overall, disease control was 82.
1% for all patients, with a median duration of response of 8.
3 months; the median time from initiation of treatment to being judged to be in clinical response was 2.
5 months
for all patients who achieved clinical remission.
The median progression-free survival for all patients was 7.
2 months; the 6-month progression-free survival rate was 61%, and the 6-month overall survival rate was 86%.

5.
BLU-554: It has a good effect on liver cancer, and the cholangiocarcinoma trial is ongoing

BLU-554 is an FGFR4 inhibitor, which has achieved certain efficacy
in clinical trials for liver cancer indications.

According to the data of a study published at the International Conference on Liver Cancer, BLU-554 treated patients with advanced liver cancer with high expression of FGF 19 (ligand of FGFR4), with an overall response rate of 16% and a disease control rate of 68%.

To date, there are three approved pan-FGFR inhibitors worldwide: Pemazyre (Pemigatinib) from Incyte, Balversa from Johnson & Johnson and Infigratinib from QED Therapeutics
.
In addition to the above three drugs, there are 15 pan-FGFR inhibitor drug candidates in various stages of clinical development
.
Domestic there are ABSK091, Gunagratinib, Fisogatinib, Roblitinib

VI.
HER2

HER2 and EGFR (also known as HER1) belong to the same HER family
.
Cancer caused by abnormal HER2 can be said to be "from head to toe", with a detection rate of about 2.
5% in lung cancer, about 15%~25% in breast cancer, about 20% in gastric cancer, about 20% in cholangiocarcinoma, about 27% in ovarian cancer, and 18%~80%
in endometrial cancer.

The cancer caused by this type of mutation is so extensive, it is naturally also in
the field of broad-spectrum cancer prevention.

1, Zanidatamab (zenidatumab): impact solid tumor indications

At present, the first HER2 inhibitor to impact solid tumor indications is the HER2 bispecific antibody Zanidatamab
.
Zanidatamab was developed based on Zymeworks' Azymetric platform that can bind two nonoverlapping epitopes of HER2 simultaneously, which is known as bispecific binding
.
This innovative design has led to multiple new mechanisms of action, including dual HER2 signal blocking, enhanced binding and clearance of HER2 proteins from the cell surface, and potent effector functions to generate encouraging anti-tumor activity
in patients.
, which has received FDA breakthrough therapy designation
in December 2020 for indications for cholangiocarcinoma.

At the 2021 ESMO conference, researchers announced data
from Zanidatamab's first-line treatment of HER2-positive gastroesophageal adenocarcinoma.
In 36 patients, Zanidatamab combined with chemotherapy regimens such as CAPOX (capecitabine/oxaliplatin) or FP (5FU/cisplatin) or mFOLFOX6 (5FU/folinic acid/oxaliplatin) resulted in an overall response rate of 75% and a disease control rate of 89%; The median duration of response was 16.
4 months and median progression-free survival was 12 months
.

Among them, Zanidatamab combined with CAPOX or FP regimens has the highest disease control rate of 100%.

Details: Treatment of gastroesophageal adenocarcinoma achieves a disease control rate of 90.
9%, and Zymeworks HER2-targeted bispecific antibody shows "miracle effect"

This is just a cancer data, and we are very much looking forward to this new drug, which is called "with broad-spectrum anti-cancer potential", and can show its strength
in more adaptations.

VII.
KRAS class

KRAS is the most commonly mutated oncogene in human cancer, with mutations occurring in
approximately 25% of NSCLCs.
KRASG12C mutations occur in
approximately 14% of adenocarcinomas and 0.
5-4% of squamous NSCLCs.
This mutation also occurs in
3-4% of colorectal cancers and 1-2% of biliary tract and pancreatic cancers.
KRAS mutations are involved in a wide variety
of cancers.
Common types of cancer, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, etc.
, as well as relatively rare endometrial cancer and testicular germ cell carcinoma, may be caused by
KRAS mutations.

Known members of the RAS gene family include KRAS, NRAS and HRAS, with KRAS mutations being the most common, accounting for about 85 percent
.
Among all KRAS mutations, the KRAS p.
G12C single nucleotide variant (glycine replaced by cysteine at codon 12) is the most common variant in NSCLC, and the mutation carries about 13%
in lung adenocarcinoma.

From the perspective of researchers, the development of drugs targeting KRAS is very difficult, and the efficacy of drugs studied in the past is not ideal, and even KRAS was once regarded as an "undruggable" target; From the patient's point of view, patients with such mutations are very difficult to treat, insensitive to many common treatment options, and patient survival is difficult to guarantee
.

However, with the development of targeted therapy research, this problem has gradually been overcome, so far a KRAS inhibitor Sotorasib has been approved for marketing, and another similar drug Adagrasib has also submitted an application, taking the last step
before marketing.

Sotorasib: ORR is 37.
1%.

Sotorasib is the first target to enter clinical trials KRAS p.
G12C oral inhibitors, which have made their stunning debut at ASCO in September 2019, have been approved by the FDA in May 2021 for the treatment of patients with locally advanced or metastatic NSCLC with KRAS p.
G12C mutations who have received at least one prior systemic therapy
.

For patients with KRAS p.
G12C mutant NSCLC who had received more than three treatment regimens, the ORR of sotorasib was 37.
1%, the median PFS was 6.
8 months, and the median OS data - 12.
5 months
.
For details, see: NEJM: Promising clinical data of Sotorasib in the treatment of KRASp.
G12C-mutated advanced non-small cell lung cancer

2.
Adagrasib: median DoR is 8.
5 months

The drug half-life of sotorasib is 5 hours versus 23 hours for adagraci, dose-dependent prolonged exposure of adagraci, and adagraci's potential central nervous system (CNS) penetration
.
Adgrasib continues to be evaluated
as monotherapy and in combination with other therapies in NSCLC and other advanced solid cancers.

As of October 15, 2021, a total of 116 patients with advanced NSCLC with KRASG12C mutations were treated with a median follow-up of 12.
9 months
.
Of these patients, 98.
3% had previously received chemotherapy and immune checkpoint inhibitors
.
Of the 112 patients with measurable disease at baseline, 48 (42.
9%) had a confirmed objective response
.

The median DoR was 8.
5 months (95% confidence interval [CI] 6.
2 to 13.
8) and the median PFS was 6.
5 months (95% CI 4.
7 to 8.
4).

As of 15 January 2022, the median follow-up was 15.
6 months and the median OS was 12.
6 months (95% CI 9.
2 to 19.
2).

Among 33 previously treated patients with stable CNS metastases, the objective response rate confirmed intracranially was 33.
3% (95% CI 18.
0 to 51.
8).

Details: NEJMLung cancer, KRAS new drug adagrasib shows its edge again, ORR as high as 42.
9%

3.
JDQ443: Disease control rate 82.
1%

The investigators published data
on JDQ443 in the treatment of patients with a variety of KRAS G12C-positive solid tumors as of January 5, 2021.
The 39 patients were divided into 4 dose groups, including 200 mg once daily, 400 mg once daily, 200 mg twice daily, and 300 mg twice
daily.

At all dose levels, the overall response rate was 28.
2%
for both confirmed and unconfirmed.
By the time the results were announced, two of the patients had not completed their assessment
.
Among the current patients, the overall response rate that has been confirmed is 20.
5% and the disease control rate is 82.
1%.

Based on the results of this phase, the researchers set the recommended dose at 200 mg twice
a day.

4、D-1553

It is a new, highly effective and oral KRAS G12C inhibitor
independently developed by Yifang Biologics.
At the 2022 American Association for Oncology Research (AACR) annual meeting, Yifang Biotech announced for the first time the clinical phase I data of its oral KRAS G12C inhibitor D-1553 in cancer patients, making D-1553 the first domestic KRAS inhibitor
to publish clinical data.

In an international multicenter phase I study of patients with advanced or metastatic solid tumors with KRAS G12C mutations, D-1553 was well tolerated in 22 patients without any dose-limiting toxicity
.
In 21 evaluable patients, an objective response rate of 19.
0% confirmed tumors was observed, achieving a disease control rate
of 85.
7%.
Tumor remission
has been observed at dose levels as low as 300 mg per day.

In another study analysis of patients with non-small cell lung cancer (NSCLC) with KRAS G12C mutation, 59 patients were included in the study analysis of non-small cell lung cancer (NSCLC) with KRAS G12C mutation, of which 52 were evaluable patients, and the objective response rate of tumor reached 40.
4%, and the disease control rate was as high as 90.
4%.

These patients are all patients with advanced or metastatic cancer, and most have received second-line or more systemic anticancer drugs
.

The data showed that at PR2D (600 mg/BID, BID twice daily) doses, D-1553 achieved an objective response rate of 40.
6% and disease control rate of 84.
4%
in 32 patients.
In terms of safety, D-1553 is well tolerated and does not reach dose-limiting toxicity
.

5、JAB-21822

It is a KRAS G12C inhibitor
independently developed by Jacobio.
Preclinical research data show that it can be used alone to treat solid tumors containing KRAS G12C mutations, and the combination of SHP2 inhibitors is expected to effectively overcome and reverse the problem
of KRAS inhibitor resistance after the development of resistance in KRAS G12C inhibitor treatment.

As of April 1, 2022, a total of 72 patients with
advanced solid tumors have been enrolled.
Among them,a total of 32 patients with KRA S G12C mutation with non-small cell lung cancer who had efficacy evaluation had an objective response rate (ORR) of 56.
3% (18/32) and a disease control rate (DCR) of 90.
6% (29/32).

In the 400 mg/day and 800 mg/day dose groups, the objective response rate was 66.
7% (8/12) and the disease control rate was 100% (12/12).

In addition, JAB-21822 had no dose-limiting toxicity (DLT) in the dose escalation phase, and 2.
5% (1/40) of the adverse effects associated with grade III or IV therapy in the 400 mg/day and 800 mg/day dose groups.

8.
BRAF V600E mutation

The mutation rate of the BRAF gene in all human tumors is about 8%, but it varies greatly
between tumors.
It is more common in hairy cell leukemia (100%), melanoma (50%), papillary thyroid carcinoma (45%), colorectal cancer (about 10%), and non-small cell lung cancer (about 10%)
.
More than 40 BRAF mutations have been discovered, of which more than 80% are in the form of V600E mutations
.

1.
Dabrafenib in combination with trametinib

In June 2022, dabrafenib in combination with trametinib was used for the treatment of adult and pediatric patients
aged 6 years and older with unresectable or metastatic solid tumors, with BRAF V600E mutations that have progressed after prior treatment and for whom there are no satisfactory alternative treatment options.
It can cover 20 types of adult and pediatric tumors
.

This is the world's first and only drug combination approved for the treatment of BRAF V600E mutant adult and pediatric pantumors, and it is also the first time that BRAF/MEK inhibitors have been approved for the treatment of
pediatric patients.

The approval is based on the results of the Phase II ROAR (Rare Oncology Agnostic Study) basket study, the NCI-MATCH subprotocol study, and the
X2101 study.
Clinical efficacy and safety
demonstrated in three clinical trials.
In the Phase II ROAR (Rare Oncology Agnostic Study) basket study and the NCI-MATCH subprotocol study, dabrafenib + trametinib resulted in an overall response rate of up to 80% in patients with BRAF V600E solid tumors, including high- and low-grade gliomas, biliary tract cancers, and certain gynecologic and gastrointestinal cancers
.
Another study (Study X2101) demonstrated the clinical benefit and acceptable safety
of the combination of dabrafenib + trametinib in pediatric patients.

The results of the trial showed that the objective response rate (ORR) of the three groups (group A VS B GROUP VS C GROUP) WAS 27% VS 63% VS 61%, THE COMPLETE RESPONSE RATE (CR) WAS 1% VS 4% VS 3%, THE PARTIAL RESPONSE RATE (PR) WAS 26% VS 60% VS 58%, THE SUSTAINED RESPONSE TIME (DOR) WAS 21 MONTHS VS 36 MONTHS VS 22 MONTHS, AND THE PROPORTION OF PATIENTS WITH A OR 6-MONTH OR OR DOR ≥ 6 MONTHS WAS 52% VS 64% VS 59%.

。 Details: The new indication of "dual-target combination" has been approved in China, and "dabrafenib" combined with "trametinib" brings a new choice to patients with BRAF V600 mutant non-small cell lung cancer

9.
TP53 Y220C mutation

TP53 is a tumor suppressor gene that, when mutated, causes p53 to be inactivated, leading to tumorigenesis
.
The mutated p53 has carcinogenic properties, giving cancer cells a growth advantage and resistance to
anti-cancer treatments.
It is estimated that more than 50% of cancers carry mutations in the p53 protein, including breast, lung, prostate, colorectal and uterine cancers
.
However, p53 is also one of the most difficult targets to target, and there is currently no effective therapy
approved for targeting p53 worldwide.

Note: Schematic diagram of the mechanism of action of TP53

TP53 mutations are the most common genomic event of all human cancers, with approximately 30% containing hotspot mutations
.
TP53 Y220C is a key hotspot, TP53 missense mutation that makes p53 unstable, found in about 1% of solid tumors
.

1、PC14586

On July 29, 2022, OncLive Medical Online published the antitumor activity and safety
of PC14586 in patients with TP53 Y220C mutant locally advanced or metastatic solid tumors.

PC14586 is a first-in-class small molecule p53 reactivator designed to selectively bind to the gaps present in the TP53 Y220C mutant protein and restore p53 wild-type (normal) conformational and transcriptional activity, resulting in potent preclinical antitumor activity
.
The U.
S.
Food and Drug Administration (FDA) has granted Fast Track designation to PC14586 for the treatment of patients
with locally advanced or metastatic solid tumors with TP53 Y220C mutations.

PYNNACLE is an open-label, multicenter phase I/II clinical trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy
of PC14586 in patients with advanced solid tumors with TP53 Y220C mutations.

Population characteristics of enrolled patients included a median age of 62 years, with most patients being female (n = 25; 61%) and Caucasian (n = 31; 76 percent).

Most patients had an ECOG score of 1 (n=23; 56%); The median number of prior treatments was 3 (n=23; 57.
5%); 93% of patients were negative
for germline TP53 Y220C mutations.

In these studies, the main cancer types were the ovaries (n=11; 26.
8%), followed by the pancreas (n=8; 19.
5%), the mammary gland (n=6; 14.
6%), the prostate (n=5; 12.
2%), the colon (n=5; 12.
2%), the endometrium (n=2; 4.
9%), the head and neck (n=2; 4.
9%), small cell lung (n=1; 2.
4%), and germ cells (n=1; 2.
4%)
.

In patients with evaluable efficacy (n=33/41), the investigator-assessed objective response rate (ORR) was 24.
2% (n=8), including six partial responses (PR) and two unproven PRs
, according to the RECIST v1.
1 criteria.
Fifteen patients were stable (SD) and seven had disease progression (PD).

Other results showed that when broken down by dose level, no response was observed in evaluable patients receiving 150 mg to 600 mg per day (n = 8/10); 4 patients SD and 4 PD.

In patients receiving an evaluable response in the dose range of 1150 mg to 1500 mg (BID) (n=25/31), the ORR was 32.
0% (n=8), including 6 PRs and 2 unconfirmed PRs; Eleven cases of SD and 3 cases of PD
were also reported.

Regarding the duration of treatment, 13 patients were still on treatment at the time of data cut-off, and 6 of the 8 responders were continuing treatment
.

Claudin 18.
2: Gastrointestinal tumors

Claudin 18.
2 belongs to a subtype of the tight junction protein family, which is highly expressed in a variety of tumor tissues, such as gastric cancer (60%~80%), pancreatic cancer (50%), esophageal cancer (30%~50%) and lung cancer (40%~60%), but it is almost not expressed in normal tissues, so it has excellent therapeutic potential
.

Compared with the old target HER2, the biggest feature of Claudin 18.
2 is that the number of patients with this target accounts for about 50%~60% of
all gastric cancer patients.
This means that more than half of patients are able to cross the threshold of "mutation type" and have the opportunity to use the drug
for this target.

The research direction for Claudin 18.
2 target is mainly divided into two categories
: targeted drugs and CAR-T cell immunotherapy.
For details, see: 6 domestic Claudin18.
2 innovative drugs were approved for clinical trials within half a year, the global research boom, cancer therapy targeting claudins, and Nat Med: CARsgen Claudin18.
2 CAR-T cell therapy for solid tumors made an initial breakthrough

Brief summary:

The above 10 targets are currently the most interesting cross-indication targets for solid tumors (except hematological tumors), but there are still many new targets under development, and different research progress
has been made.
The greatest value of broad-spectrum cancer drugs is that they allow many cancer patients to no longer have to wait for the drug to be approved for marketing, and patients with many types of cancer can benefit
from just one approval.
Especially for some "small tumors", because few companies develop specific therapeutic drugs
for small tumors.

The confirmation of genotyping and targeted therapy signaling pathways provides new ideas
for targeted therapy of "different diseases and treatment".
The emergence of new pan-cancer drugs has brought new hope and treatment options
to more fortunate patients.

Moreover, targeted therapy through targets is also an important trend
in tumor treatment in the future.
With the increasing number of targeted drugs, a patient may have multiple effective therapeutic targets, so the future combination of multi-target drugs is also worth looking forward to
.

Resources:

Tumor agnostic treatment,

Inventory of new anti-tumor drugs approved by the US FDA from 2017 to 2021, style="color: #121212;" data-pid="qd9gp8oH" _msthash="320231" _msttexthash="980694">https://zhuanlan.
zhihu.
com/p/534241874