Professor Miao Liyun: The remission rate of combined therapy is 72%!

*For medical professionals to read only for reference.
For non-small cell lung cancer (NSCLC) patients with negative driver genes, recombinant human endostatin is an important treatment option.

The previous treatment for patients with advanced non-small cell lung cancer (NSCLC) with negative driver genes was chemotherapy, but the efficacy was limited.
In recent years, a variety of PD-1/L1 inhibitors have been approved for indications in my country, and the treatment of NSCLC patients has been greatly improved effect.

In the new era of immunotherapy, anti-angiogenesis drugs such as recombinant human endostatin have shown great potential for synergism with immunological drugs [1].

In this issue, the "medical community" is fortunate to invite Professor Miao Liyun from the Drum Tower Hospital of Nanjing University School of Medicine to review the application status and development prospects of recombinant human endostatin and other anti-angiogenic drugs under the new situation based on his clinical diagnosis and treatment experience.
Professional sharing.

Driver gene-negative lung cancer patients have a poor prognosis, and more effective treatments are urgently needed.
With the development of precision medicine, targeted drugs have been available for multiple genes that play a key role in the progression of NSCLC disease.
For epidermal growth factor receptor (EGFR), In patients with advanced NSCLC with positive driver genes such as anaplastic lymphoma kinase (ALK), most targeted drug treatments can effectively prolong patient survival and improve the quality of life of patients, but targeted drugs cannot benefit patients with negative driver genes [2].

 Professor Miao Liyun said, “In the past ten years, patients with NSCLC driver gene-negative can only use chemotherapy, but the objective response rate (ORR) of first-line chemotherapy is only 30%, and the remission can only be maintained for 4-6 months.
The effectiveness of chemotherapy is getting worse.

Some patients say that “advanced lung cancer has no friends for a year”, which reflects that the driver gene-negative patients only use chemotherapy, and the median overall survival (OS) and progression-free survival (PFS) are both Relatively short status quo.

Moreover, most patients have poor tolerance to the side effects of chemotherapy.
Ordinary people would describe it as “chemotherapy and chemotherapy, once it’s done”.
It has not been until recent years that drug development and symptomatic support treatment have made progress, reducing the incidence and incidence of chemotherapy-related side effects.
Severity, improved the survival of NSCLC patients with negative driver genes.

"Although a variety of PD-1/L1 inhibitors have been approved in China for the treatment of advanced NSCLC patients with negative driver genes, even immunotherapy has obvious limitations, and more clinical treatment options are still needed to further improve the prognosis of patients.

Recommended by the guidelines, anti-angiogenic drugs have become an important option for the treatment of lung cancer.
Since the first clinical indication was approved, anti-angiogenic drugs have been developed for more than ten years, and a large amount of evidence has been accumulated in the field of lung cancer.
They are combined in the first-line treatment The standard chemotherapy regimen has successfully broken the bottleneck of lung cancer patients' survival of no more than one year in the chemotherapy era.

 At present, three anti-angiogenic drugs have been approved in China for the treatment of advanced NSCLC, which are vascular endothelial growth factor (VEGF) inhibitors.
Vallizumab, recombinant human endostatin (trade name: Endo) and small molecule multi-target tyrosine kinase inhibitor (TKI) anlotinib, but the mechanisms of action of the three drugs are different.
There are also differences in the batch indications.

 Recombinant human endostatin is a targeted drug independently developed in China.
It inhibits the migration of blood vessel-forming endothelial cells and limits the formation of tumor neovascularization.
It has been approved for use in combination with platinum-containing dual-drug chemotherapy.
In patients with advanced NSCLC whose histological type is squamous cell carcinoma or adenocarcinoma [3].

Professor Miao Liyun pointed out, “From the perspective of indications, recombinant human endostatin has a wide range of options, and its combination with platinum-containing dual-drug chemotherapy The program has also been recommended by the "Chinese Expert Consensus on Anti-angiogenic Drugs for Advanced Non-small Cell Lung Cancer (2020 Edition)" [4].

 Figure 1.
Anti-angiogenic drug treatment for advanced non-small cell lung cancer.
Chinese expert consensus.
The specific recommendations of specific recommendations have synergistic advantages.
Recombinant human endostatin is still of great value.
Although immunotherapy is increasingly used in driver gene-negative NSCLC patients However, Professor Miao Liyun pointed out that “the current use of immunotherapy for these patients still has some shortcomings.
For example, for patients with PD-L1 expression level ≥50%, the guidelines recommend PD-1/L1 inhibitor monotherapy However, the ORR of monotherapy is generally not more than 50%, and more than half of the patients still have tumors that cannot shrink.
Therefore, there are many recent studies exploring the efficacy of immunity + anti-angiogenesis.

"Preclinical studies have confirmed immunotherapy and anti-angiogenesis.
The combined use of drugs has a synergistic mechanism that can achieve 1+1>2 efficacy [5].
Therefore, a variety of imported and domestic PD-1/L1 inhibitors that have been approved are actively carrying out relevant research.

For example, in a clinical phase Ib study conducted by Chinese scholars, the ORR of anlotinib + PD-1 inhibitor combined treatment of NSCLC patients with driver gene-negative NSCLC exceeded 70%, and the disease control rate (DCR) reached 100% [6].
It is close to the efficacy of targeted drugs in treating patients with positive driver genes.

 Recombinant human endostatin has also been explored in combination therapy.
For example, the Enpower study announced at the 2020 Chinese Society of Clinical Oncology (CSCO) annual meeting showed that recombinant human endostatin + standard platinum-containing dual-drug chemotherapy (Peimei Tracet+carboplatin/cisplatin)+PD-1 inhibitor sintilimab, the ORR of the first-line treatment of driver gene-negative advanced non-squamous NSCLC patients is 72%, the control group (recombinant human endostatin monotherapy ) Has an ORR of 66%.

Table 1.
Results of the Enpower study In terms of safety data, the incidence of ≥3 grade adverse events during treatment was about 3%, mainly due to hematological toxicity, and no unexpected adverse events occurred [7].

Professor Miao Liyun said, “This staged research results show that recombinant human endostatin + chemotherapy + immunotherapy is expected to provide new treatment options for NSCLC patients with negative driver genes and solve the problem of low ORR immunotherapy.

"According to experience to solve the problem, recombinant human endostatin will continue to explore the clinical application of recombinant human endostatin in the treatment of lung cancer in China for more than ten years.
It has the characteristics of good curative effect and low side effects.
Clinicians have accumulated Quite a wealth of application experience, and the method of use is constantly being updated.

Professor Miao Liyun said, “Although the drug instructions still suggest that the application method of recombinant human endostatin is 1 day/branch for 14 days, this method has been Not suitable for the current fast-paced clinical diagnosis and treatment.

Therefore, based on some research data, we often adopt the method of continuous intravenous micropump injection for 3 days, which can also guarantee the effect.

"Professor Miao Liyun also talked about some new models actually used in clinical practice, "In clinical practice, for some specific patients, the use of recombinant human endostatin cross-line therapy has a relatively good effect, especially for patients with squamous cell carcinoma.

For example, in the first-line treatment, the regimen is recombinant human endostatin combined with chemotherapy, and then recombinant human endostatin monotherapy is maintained.

If the patient's condition progresses, chemotherapy is repeated, but the recombinant human endostatin is not stopped at the same time.

In clinical practice, this cross-line application is effective for many patients, but I hope that there will be some multi-center, randomized controlled studies to confirm the effect of this treatment model.

Finally, Professor Miao Liyun pointed out that there are still some problems to be solved in the overall application of anti-angiogenic drugs: “First of all, there is currently no Biomarker (biomarker) that can guide the use of anti-angiogenic drugs, so it is impossible to determine which patients are in advance.
Can benefit from treatment, and basic research has lacked progress for many years; secondly, the resistance mechanism of anti-angiogenic drugs is still not clear, whether it involves bypass activation, pro-angiogenic factors, etc.
, also requires basic research and clinical exploration Come to crack.

"Expert profile Dr.
Miao Liyun, Chief Physician, Department of Respiratory and Critical Care Medicine, Drum Tower Hospital, Nanjing University School of Medicine, Member of the Lung Cancer Group, Respiratory Branch of Jiangsu Medical Association, Member of the Respiratory Rehabilitation Committee of Jiangsu Association of Rehabilitation Medicine, Jiangsu Research Member of the Standing Committee of the Lung Nodules and Lung Cancer MDT Professional Committee of the Society of Type Hospitals, Member of the Oncology Rehabilitation Branch of the Chinese Society of Gerontology and Geriatrics, Youth Member, Member of the Pulmonary Tumor Committee of the Chinese Medical Education Association References for committee members: [1]Wu J, Zhao X, Sun Q, et al.
Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model[J ].
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[2]Yuan M, Huang LL, Chen JH, et al.
The emerging treatment landscape of targeted therapy in non-small-cell lung cancer[J].
Signal Transduction and Targeted Therapy, 2019, 4(1): 1-14.
[3]Ling Y, Yang Y, Lu N, et al.
Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk -1 of endothelial cells[J].
Biochemical and Biophysical Research Communications, 2007, 361(1):79-84.
[4] Chinese Expert Consensus on Anti-angiogenic Drug Therapy for Advanced Non-small Cell Lung Cancer (2020 Edition)[J].
Chinese Journal of Oncology,2020,42(12):1063-1077.
[5]Manegold C, Dingemans AMC, Gray JE, et al.
The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC[J].
Journal of Thoracic Oncology, 2017, 12(2): 194-207.
[6]Chu T, Zhong R , Zhong H, et al.
Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC[J].
Journal of Thoracic Oncology, 2021, 16(4): 643-652.
[7] Recombinant human blood vessels Endostatin combined with chemotherapy, plus or without PD-1 monoclonal antibody for first-line treatment of driver gene mutation-negative advanced non-squamous non-small cell lung cancer controlled clinical study (Enpower study) phased results report.
2020 CSCO, abstract number: 7557.
194-207.
[6]Chu T, Zhong R, Zhong H, et al.
Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC[J].
Journal of Thoracic Oncology, 2021, 16(4 ): 643-652.
[7] Recombinant human endostatin combined with chemotherapy, plus or without PD-1 monoclonal antibody for first-line treatment of driver gene mutation-negative advanced non-squamous non-small cell lung cancer controlled clinical study (Enpower study) stage Sexual results report.
2020 CSCO, abstract number: 7557.
194-207.
[6]Chu T, Zhong R, Zhong H, et al.
Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC[J].
Journal of Thoracic Oncology, 2021, 16(4 ): 643-652.
[7] Recombinant human endostatin combined with chemotherapy, plus or without PD-1 monoclonal antibody for first-line treatment of driver gene mutation-negative advanced non-squamous non-small cell lung cancer controlled clinical study (Enpower study) stage Sexual results report.
2020 CSCO, abstract number: 7557.