Professor Fang Shencun and Professor Shen Hua talked about the latest research results of 3-day continuous intravenous pumping of recombinant human vascular endostatin to help elderly NSCLC patients benefit!

Recombinant human vascular endostatin 3-day continuous intravenous pumping combined with platinum-containing double-agent chemotherapy adds new evidence!

As the malignant tumor with the highest incidence in China, the overall 5-year survival rate of lung cancer is only 10%~15% ^[1], and most lung cancer patients are diagnosed in an advanced stage, and the traditional chemotherapy regimen has little
effect.
Anti-angiogenic drugs can act on the tumor microenvironment, degenerate existing tumor blood vessels, and inhibit tumor neoangiogenesis, which has become one of the
indispensable treatment methods for patients with advanced NSCLC.

Recombinant human vascular endothelial instatin acts on vascular endothelial cells to inhibit the migration of endothelial cells that form blood vessels, inhibit the generation of tumor neovascularization, and block the nutrient supply of tumor cells, thereby inhibiting tumor proliferation or metastasis^[2].

Recombinant human vascular endostatin has been used for a long time in the treatment of non-small cell lung cancer (NSCLC) in China, and its efficacy and safety have been clinically verified
.

Recently, the Chinese Journal of Geriatrics published a study exploring the efficacy and safety of 3-day continuous intravenous pumping of recombinant human vascular endostatin combined with platinum-containing double-agent chemotherapy in patients with advanced non-small cell lung cancer aged 60 years and older ^[3], adding evidence
to optimize the administration of recombinant human vascular endostatin 。 The Medical Oncology Channel is honored to invite the main investigators of the study, Professor Fang Shencun of Nanjing Chest Hospital and Professor Shen Hua of Shaw Hospital Affiliated to Nanjing Medical University, to share the application value of anti-angiogenic drugs in advanced NSCLC and the main results of
the study.

Professor Shen Hua's wonderful video

Multiple evidence suggests a therapeutic benefit of recombinant human vascular endostatin

Professor Shen Hua shared, "Targeted anti-angiogenic drugs mainly inhibit the generation of tumor neovascularization by inhibiting the migration of endothelial cells that form blood vessels, among which recombinant human vascular endostatin is an intravenous anti-angiogenic targeted drug
independently developed and marketed in China.
Angiogenesis is closely related to tumor growth and provides essential nutrients and oxygen
to the tumor.
At the same time, tumor cells can secrete a large number of angiogenic factors, resulting in abnormal growth of blood vessels, but tumor blood vessels are often abnormal in structure and function, and can create a hypoxic, acidosis tumor microenvironment, which will limit the anti-tumor activity of drugs ^[4-6].

Recombinant human vascular endostatin is a multi-target antiangiogenic drug that inhibits vascular endothelial cell proliferation by inhibiting the VEGF/VEGFR signaling pathway, and inhibits vascular endothelial cell migration and invasion
by inhibiting integrin, matrix metalloproteinase 2 (MMP2).
By inducing blood vessel normalization, recombinant human vascular endostatin can improve tumor hypoxia, reduce penetration, and inhibit tumor migration by intertissue pressure, thereby improving drug delivery and improving the sensitivity of
patients with chemoradiotherapy and chemotherapy.
In addition, recombinant human vascular endostatin can also improve the immune microenvironment of patients, reduce the number of immune-suppressing cells such as myeloid-derived suppressor cells (MDSC) and M2 tumor-associated macrophages (TAMs), increase the number of cells that promote immunity in M1 type TAM, myeloid dendritic cells (mDC), CD8+T and other cells, and improve the immune suppressing microenvironment inside the tumor to an immune microenvironment.
In turn, the efficacy of immunotherapy is improved ^[7].

”

Speaking about the efficacy of recombinant human vascular endostatin, Professor Fang Shencun said: "A phase III.
clinical study led by Academician Sun Yan of China to explore the efficacy and safety of recombinant human vascular endostatin combined with vinorelbine + cisplatin (NP) in the treatment of advanced NSCLC confirmed that the recombinant human vascular endostatin combined with NP regimen alone can prolong the overall survival (OS) (13.
75 months vs.
9.
77 months) for nearly 4 months, and both treatment-naïve and retreated people can benefit, squamous cell carcinoma, Non-squamous cell carcinoma can benefit ^[8,9].

In addition, a phase IV clinical study of recombinant human vascular endostatin combined with commonly used platinum-containing chemotherapy regimens in the treatment of advanced NSCLC showed that recombinant human vascular endostatin combined with NP, paclitaxel plus cisplatin (TP), docetaxel plus cisplatin (DP), gemcitabine plus cisplatin (GP), and other platinum-containing regimens had a significant survival benefit and a good safety profile ^[10]
。

In a retrospective analysis evaluating the effectiveness of recombinant human vasoendostatin plus different chemotherapy regimens in the treatment of advanced NSCLC in the real-world setting, objective response rates (ORRs) were 28%, 22%, 41%, 27%, and 31% in patients treated with recombinant human vasoendostatin plus NP (n=25), DP (n=49), GP (n=90), and paclitaxel plus cisplatin (PP) (n=89), respectively, Disease control rates (DCRs) were 72 percent, 57 percent, 72 percent, 76 percent, and 74 percent, and median progression-free survival (PFS) was 7.
9 months, 6.
8 months, 5.
6 months, 13.
7 months, and 5.
4 months, respectively ^[11].

”

Recombinant human vascular endostatin 3 days of continuous intravenous pumping combined with chemotherapy escorts elderly tumor patients

The data show that the elderly group accounts for about 70% of new lung cancer patients, and the prognosis of elderly patients is relatively worse, with the continuous development of NSCLC drug treatment, more and more elderly NSCLC patients can be treated, and the overall survival of elderly patients with advanced NSCLC is still not significantly prolonged
。 Professor Fang Shencun pointed out: "The diagnosis and treatment of elderly NSCLC patients is a concern of many clinicians, lung cancer is the highest incidence and mortality malignant tumor in the world and in people over 60 years old in China.

Changes in the physiology of elderly patients have an impact on drug absorption, distribution, metabolism, and clearance, and may lead to a decline in the tolerance of treatment in elderly patients ^[12].

The Chinese expert consensus on the medical treatment of elderly advanced lung cancer (2022 edition) pointed out that platinum-containing dual therapy is better than single-agent chemotherapy in elderly patients with advanced NSCLC, while anti-angiogenic therapy drugs alone or in combination with chemotherapy, EGFR-TKIs or immune checkpoint inhibitors have shown certain efficacy in elderly patients, but it is necessary to consider the patient's physical condition to choose different treatment options and pay attention to adverse reactions ^[13].

The traditional administration of recombinant human vascular endostatin is 7.
5 mg/^m2 intravenously for 3 to 4 hours and intravenously for 14 days
.
Continuous prolonged hospitalization seriously affects the patient's
quality of life and compliance.
Previous studies have shown that 7-day or 5-day continuous intravenous pumping of recombinant human vascular endostatin has better efficacy and safety advantages
than intravenous drip for 14 days.
The study by our team showed that recombinant human vascular endostatin received 3-day continuous intravenous pumping in combination with platinum-double-agent chemotherapy in elderly patients with advanced NSCLC also showed a good clinical efficacy and survival benefit, and a good safety profile, similar to previously reported studies [^14-16].

”

Commenting on the results of the study of 3-day continuous intravenous pumping of recombinant human vascular endostatin combined with platinum-containing double-agent chemotherapy in the treatment of elderly patients with advanced NSCLC ^[3], Professor Shen Hua said: "This study explores the efficacy and safety
of 3-day continuous intravenous pumping of recombinant human vascular endostatin combined with platinum-containing double-agent chemotherapy in advanced NSCLC over 60 years of age.
A total of 93 patients were included in the study, including 60 patients with squamous cell carcinoma and 33 patients with non-squamous cell carcinoma.
There were 28 patients with stage III and 65 patients with stage IV
.
The results of the study showed that the ORR was 38.
7% and the DCR was 78.
5%
after treatment.
Among them, the ORR of squamous cell carcinoma patients was 46.
7% and DCR was 83.
3%; The ORR of non-squamous cell carcinoma patients was 24.
2% and DCR was 60.
6%.

The median PFS of 93 patients was 6.
8 months (95% CI: 6.
4~7.
3) and the median OS was 16.
5 months (95% CI: 15.
8~17.
2).

Ninety-three patients were included in the observation of adverse reactions, of which 72 had adverse reactions, and the overall incidence of adverse reactions was 77.
4%.

Most of the common side effects are caused by chemotherapy, including: leukopenia (60.
2%), anemia (33.
4%), thrombocytopenia (31.
2%), nausea and vomiting (34.
4%), diarrhea (5.
4%), abnormal liver function (9.
7%), arrhythmias (2.
2%), myocardial ischemia (1.
07%), blood in sputum (1.
07%), rash (4.
3%), and fever (2.
2%)
。 Most of the adverse reactions were grade 1~2, and the adverse reactions related to recombinant human vascular endostatin included arrhythmia in 2 cases (2.
2%), myocardial ischemia in 1 case (1.
07%) and bleeding in 1 case (1.
07%), all of which were grade 1~2, and improved on their own after stopping the drug
.
Hypertension, proteinuria, and blood clots
were absent.
”

TP53 mutations, circulating endothelial cells (CECs) may be potential biomarkers for antivascular therapy

Based on the study, Professor Fang Shencun shared the factors that may affect the efficacy of patients, saying: "Unfortunately, for many years, no good biomarkers have been found clinically to predict the efficacy
of anti-angiogenic drugs.
In this study by our team ^[3], the patient's tumor stage and the presence or absence of TP53 mutations were independent influencing factors affecting OS, and TP53 mutations were closely related to high VEGF expression and involved in tumor neovascularization
.
In addition, CEC refers to vascular endothelial cells detected in peripheral blood, including mature endothelial cells derived from the vascular wall, bone marrow endothelial cells, or endothelial precursor cells
.
When blood vessels are damaged, the number of shedding from damaged vessels increases significantly, which can reflect the pathological process
of vascular endothelial injury.
Therefore, the quantity and quality of CECs and their subpopulations can effectively reflect the status of endothelial cells (ECs) and serve as potential biomarkers for antiangiogenic therapy
.
In addition, the CXC chemokine family, angiopoietin, and serum lactate dehydrogenase (LDH) may affect patient efficacy ^[17].

Biomarkers are a prerequisite
for selecting advantageous populations and achieving precise antiangiogenic therapy.
It is expected that more therapeutic and resistant targets, efficacy and adverse reaction biomarkers will be discovered in the future, laying the foundation
for anti-angiogenic drugs to optimize precision therapy.
”

Antiangiogenic combinations still need to be further explored for optimal delivery patterns

Talking about the prospect of anti-angiogenic combination therapy in the treatment of lung cancer, Professor Fang Shencun shared: "Anti-angiogenic drugs are indispensable for the treatment of NSCLC, whether it is combination chemotherapy, targeted or immunological, whether it is placed in the first-line, second-line or post-line treatment, anti-angiogenic drugs
are indispensable.
Previous studies have demonstrated that antiangiogenic therapy combined with chemotherapy, targeted therapy, and immunotherapy for the treatment of advanced NSCLC can be effective and further prolong survival
。 At present, there are also many expert consensus and guidelines to guide the treatment regimen of anti-angiogenic combination targeted therapy and chemotherapy, but there are still many problems in the combination of anti-angiogenic drugs and immunotherapy, and the three major classes of anti-angiogenic drugs include small molecule multi-target angiogenesis inhibitors, large molecule single-target angiogenesis inhibitors and endogenous pan-target angiogenesis inhibitors, and different combinations between PD-1/PD-L1 may bring different efficacy and safety.
Specific joint plans are also one of the
key directions for future exploration.
”

Professor Shen Hua pointed out: "At present, anti-angiogenic drugs combined with new targeted drugs and emerging tumor immunotherapy are important strategies for the clinical treatment of advanced NSCLC, especially the application prospects of first-line treatment of advanced NSCLC are promising
.
In the future, the optimal combination of different kinds of anti-angiogenic drugs, targeted drugs, immunotherapy drugs, the best application in different subgroups of populations and different treatment stages, and the optimal dosing mode of anti-angiogenic drugs in patients with advanced NSCLC still need to be further explored
.
”

summary

In summary, the efficacy and safety of 3-day continuous intravenous pumping of recombinant human vascular endostatin combined with platinum-containing dual-agent chemotherapy in the treatment of advanced elderly age were verified for the first time through retrospective studies, and the ORR and DCR of 3-day continuous pumping of recombinant human vascular endostatin combined with chemotherapy were 38.
7% and 78.
5%, and the median PFS and OS were 6.
8 months and 16.
5 months, respectively, and the overall efficacy rate was higher than that of the previous recombinant human vascular endostatin phase III and IV studies
。 Among them, the ORR of squamous cell carcinoma was 46.
7%, and that of non-squamous cell carcinoma was 24.
2
%.
At the same time, the study also showed that the safety of 3-day continuous pumping of recombinant human vascular endostatin was controllable, and did not increase the risk of
cardiotoxicity or bleeding.
The results of this study further optimize the administration of recombinant human vascular endostatin, improving the survival benefit and compliance of patients
.
It is expected that in the future, anti-angiogenic drug combination therapy can further accumulate clinical evidence and help more patients benefit
.

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