The 2021 version of the CSCO ICI guidelines was released, Sintilimab wins the four recommendations of the guidelines

*Only for medical professionals to read for reference.
Pay attention to the toxicity related to immunotherapy and help standardize immunotherapy! On April 23-24, 2021, the Chinese Society of Clinical Oncology (CSCO) will hold the 2021 CSCO Guidelines Conference.

Among them, the "2021CSCO Immune Checkpoint Inhibitors Clinical Application Guidelines" and "2021CSCO Immune Checkpoint Inhibitors Related Toxicity Management Guidelines" are highly valued by experts from all over the country.

In order to let more cancer colleagues learn about the latest developments in immunotherapy and toxicity management at the first time, the Medical Oncology Channel has the honor to invite Professor Wang Baocheng from the 960th Hospital of the People’s Liberation Army and Professor Zhou Caicun from Shanghai Pulmonary Hospital to share the updated guidelines and personal academics.
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Medical community: In this year's CSCO immune checkpoint inhibitor (ICI) clinical application guidelines update, many new immunotherapy programs have been added.

For squamous and non-squamous non-small cell lung cancer (NSCLC), what are the important updates? What are the clinical significance of these updates for domestic lung cancer patients? Professor Wang Baocheng: This year the CSCO Immunotherapy Expert Committee and the Drug Safety Management Expert Committee jointly prepared the "2021CSCO Immune Checkpoint Inhibitors Clinical Application Guidelines" and "2021CSCO Immune Checkpoint Inhibitors-related Toxicity Management Guidelines", which are related to immune checkpoint inhibitors.
The application and toxicity management have been updated accordingly.■ For non-squamous NSCLC without driver gene mutations, the following points are updated: ① "Sintilimab combined with pemetrexed and platinum (1A)" first-line treatment level I recommendation; ② Lilizumab combined with pemetrexed and carboplatin (category 1A)" was upgraded to the first-line treatment level I recommendation; ③Added "atelizumab [limited to PD-L1 tumor cell positive ratio score (TPS) ≥ 50 % Or tumor-infiltrating immune cells (IC) ≥10%] (Class 1A), Tilelizumab combined with pemetrexed + platinum (Class 1A)" first-line treatment II recommendation; ④ Newly added "Navuliyu" Monoclonal antibody combined with ipilimumab, nivolumumab combined with ipilimumab and 2 cycles of chemotherapy" are the first-line treatment of stage IV non-driver gene, non-squamous NSCLC, level III recommendation (dual immunity combination is the main consideration for level III recommendation Until ipilimumab has not yet been marketed in the mainland, drug accessibility issues); ⑤The newly added "Tilelizumab" is the second-line recommendation for the second-line treatment of advanced non-squamous NSCLC (Class 1A).

■ For squamous NSCLC without driver gene mutations, the update points are as follows: ①The newly added "Tilelizumab combined with paclitaxel/albumin paclitaxel and carboplatin (Class 1A)" is the first-line treatment for advanced squamous NSCLC I Grade II recommendation; ②Newly added "Sintilizumab combined with gemcitabine and platinum (Class 1A)" as the first-line treatment of advanced squamous NSCLC II recommendation; ③Newly added "Atilizumab (limited to PD-L1 TPS≥ 50% or IC≥10%) (Class 1A), Carrelizumab combined with paclitaxel and platinum (Class 1A)" first-line treatment II recommended; ④The newly added "Tilelizumab" is advanced squamous The second-line treatment of NSCLC is recommended for level II (category 1A).

The update of this guideline is of great significance to Chinese lung cancer patients.

First of all, immunization single-drug and combined programs have fully covered the treatment of NSCLC patients with negative driver genes.

Secondly, many domestically-made innovative immunotherapy drugs have been recommended by the first-line level I of the guidelines.

The availability of these domestic drugs is very strong.
One is that they can be "buy"; the other is that the state has given very good support policies.
Many drugs have been covered by medical insurance and have become the gospel for lung cancer patients in China. In particular, it should be noted that the approval of the clinical indications of these domestic immunological drugs for lung cancer and the recommendation of the guidelines are based on China's independent research and development and the complete clinical data of the Chinese population.
The data and results obtained are similar to those in the past.
It is not the same for pharmaceuticals to use imitation for indication extrapolation or drug replacement.

Medical community: In the first-line treatment of non-squamous NSCLC, the guidelines have updated multiple new plans for PD-1 monoclonal antibody combined with chemotherapy.
What important significance does this bring to the clinical diagnosis and treatment of lung cancer in China? In conjunction with the updated guidelines, how to choose a suitable first-line immunotherapy program in clinical practice? Professor Zhou Caicun: In the past, for the first-line treatment of non-squamous NSCLC without a driver gene, chemotherapy has been a bottleneck that is difficult to break through, and the efficacy of PD-1 monoclonal antibody is limited, and it is easily restricted by the level of PD-L1 expression in patients.

The PD-1 monoclonal antibody combined with chemotherapy does not need to consider the patient's PD-L1 expression, and patients can get overall survival (OS) benefit from the combination.

Therefore, the guidelines update multiple new programs of PD-1 monoclonal antibody combined with chemotherapy in the first-line treatment of non-squamous NSCLC, marking that PD-1 monoclonal antibody combined with chemotherapy has officially become the "main theme" of domestic lung cancer treatment.

What’s more satisfying is that many of the new PD-1 monoclonal antibody + chemotherapy regimens are based on the results of phase III studies conducted in China.
The recommendation is based on a complete clinical study of the Chinese population, which not only reflects the “quantity” of domestic patients.
The characteristics of "customization" and the strong accessibility of drugs also mean that the R&D level of my country's pharmaceutical companies has gradually acquired core competitiveness.

When selecting first-line immunotherapy in the clinic, it should be based on evidence-based medicine evidence, combined with the patient's physical status (PS) score, the availability of drugs, and adverse drug reactions, etc.
, to make individualized and precise selections.

Sintilimab has been recommended by the four guidelines and recommended for lung squamous cell carcinoma based on the ORIENT-12 study.
Medical community: What do you think of the new PD-1 monoclonal antibody recommendation based on domestic clinical research data in this guideline? Taking Sintilimab as an example, what is the significance of this drug in the updated content of this guideline? Professor Wang Baocheng: According to the clinical research data based on the Chinese population, the adjustment of the new immune drug indication recommendation is the top priority of this guideline update. In the adjustment of the guidelines, imported drugs and domestically produced drugs have been adjusted.
The core is to take the actual clinical data of the Chinese as the standard, rather than copy and copy the famous international guidelines, and follow the same trend.

Take Sintilizumab as an example.
This update of the guidelines adds recommendations for four new indications of Sintilizumab, namely: Class I recommendation for the first-line treatment of non-squamous NSCLC without driver gene mutations, and no driver gene mutations.
Level II recommendation for first-line treatment of squamous NSCLC, Level II recommendation for first-line treatment of advanced hepatocellular carcinoma; and Level III recommendation for the treatment of relapsed or refractory extranodal NK/T cell lymphoma.

The above four recommendations are mainly based on the successful results of a series of clinical studies such as ORIENT-11, ORIENT-12, ORIENT-32 and ORIENT-4.

These results have been published in internationally renowned magazines and conferences, and have been highly recognized by well-known experts at home and abroad.

This also marks that my country's self-developed immunotherapy drugs have reached international standards in terms of quality, efficacy, and safety.

Medical community: At the 2020 European Society of Medical Oncology (ESMO) conference, you, as the leading PI of the ORIENT-12 study, announced the results.

Based on the research data, the indications for lung squamous cell carcinoma of Sintilimab + chemotherapy have been included in the review by the National Medical Products Administration (NMPA).

Could you please interpret the significance of this research? Prof.
Caicun Zhou: The ORIENT-12 study is the world's first randomized controlled, double-blind, phase III clinical trial to prove that the PD-1 antibody combined with gemcitabine and platinum in the first-line treatment of squamous NSCLC can significantly improve the progression-free survival (PFS) of patients , Has important clinical significance, and its efficacy is similar to that of pembrolizumab + carboplatin + paclitaxel approved based on the KEYNOTE-407 study, bringing new first-line treatment options for patients with advanced lung squamous cell carcinoma .

The study included patients with stage IIIB-IV squamous NSCLC who had not undergone chemotherapy, and were randomly divided into groups at a ratio of 1:1 to receive sintilimab (200 mg) or placebo combined with gemcitabine and platinum therapy.

The results of the study published by the ESMO conference showed that when the median follow-up time was 12.
9 months, the median PFS assessed by the IRRC (Independent Imaging Review Committee) was 5.
5 months in the sintilimab combined chemotherapy group, which was significantly better than the chemotherapy group At 4.
9 months, sintilimab combined with chemotherapy reduced the risk of disease progression or death by 46%, with a significant statistical difference (HR=0.
536, P<0.
00001), reaching the preset primary study endpoint.

The 12-month PFS rate of sintilimab combined with chemotherapy was also significantly improved (22.
3% vs 3.
1%, the combined group was 7 times that of the chemotherapy alone group).

In addition, the median PFS assessed by the investigator was 6.
7 months and 4.
9 months respectively in the two groups (HR=0.
532, 95%CI: 0.
419～0.
674, P＜0.
00001).

In addition, the sintilimab combined with chemotherapy group has a trend of overall survival (OS) benefit (HR=0.
567, P=0.
01701).

Sintilimab combined with chemotherapy group has a higher objective response rate (ORR, 44.
7% vs 35.
4%).

Medical community: In addition to lung cancer, what other important immunotherapy updates in advanced solid tumors are worth paying attention to? Professor Wang Baocheng: In addition to lung cancer, there are many updates to the guidelines.
Among them, the guidelines for several types of tumors can be updated to give more attention, including gastric cancer, hepatocellular carcinoma, urothelial cancer, and melanoma.

The incidence of these types of tumors in the Chinese population is very high, which has the characteristics of the Chinese population.

It is precisely because of the high incidence of these tumors in China that many domestically-made innovative immunological drug research and development focus on these tumors.
Therefore, on the basis of clinical research results, this guide has added a lot of domestic drug recommendations.

In the past, clinical practice often refers to international guidelines, but the clinical data of the Chinese population is often different from that of non-Asian people, and even in many diseases.

Therefore, adjustments must be made according to the actual situation of the Chinese.

In addition, domestic drugs have many advantages, such as easy purchase, access to medical insurance, and preferential prices, which greatly reduces the financial burden of patients.

Grasp the toxicity of immunotherapy drugs and guide the safe use of drugs in clinical medicine.
In addition to the indications, the handling of immunotoxicity in the guidelines is also a very important content.

May I ask how to deal with the immune toxicity caused by immune checkpoint inhibitors based on the basic principles? What adverse reactions caused by immunotherapy deserve our attention? Professor Wang Baocheng: "It is a three-point poison of medicine.
" The side effects of immune drugs can occur in almost every tissue and organ, with varying degrees.

The side effects of immunotherapy can be divided according to different dimensions: according to the degree, it can be divided into mild, moderate and severe; according to the frequency of occurrence, it can be divided into common and rare; according to the outcome, it can be divided into reversible and irreversible .

We can classify and classify the thick lines according to the above methods, so that doctors can grasp the direction of toxicity management, and handle the boundary between "effectiveness" and "life preservation".

Most of the toxic side effects are mild and reversible side effects, such as skin, digestive tract, liver function, endocrine system, bone and joint, muscle tissue and other side effects, generally do not need to stop the drug, or temporarily suspend the drug or With glucocorticoid therapy, these side effects can be alleviated, and immunotherapy can be restarted after recovery.

In such cases, the principle of medication is to "guarantee effectiveness" as much as possible to ensure the anti-tumor effect of immune checkpoint inhibitors.

The incidence of serious irreversible side effects is very low.
Clinical data statistics show that the incidence rate is less than 1%, but the severity is serious and may even have fatal reactions, such as cardiovascular, nervous system and other side effects.
Guidelines for management principles For "life-saving".

In addition, there are about two types of toxic reactions worthy of attention.
One type is relatively low in severity but very common.
For example, certain PD-1 monoclonal antibody treatments cause some small red spots on the skin, which are clinically called reactive Skin capillary hyperplasia (CCEP) can also be divided into different grades according to its severity.

The incidence of CCEP is relatively high.
Some patients may have red spots the size of pearls, and the incidence is relatively high.
Under the treatment of individual immune checkpoint inhibitors, the incidence can reach about 70%. Although it is generally mild, once the management is not good, bleeding and infection may occur, which may add some pain and inconvenience to the patient.

Another type that deserves special clinical attention is the rare but serious side effects.
Such irreversible side effects need to be identified in time and dealt with decisively.

If only the immune checkpoint inhibitor is stopped, it still does not get better, or the shock dose of glucocorticoid treatment is still not effective for hormone-resistant side effects.
Such side effects often deteriorate very quickly, and you need to be vigilant.
It is necessary to carry out multidisciplinary comprehensive diagnosis and treatment in time, so as not to miss the best opportunity for intervention.

The medical profession: Are there differences in the spectrum and incidence of adverse reactions between different drugs? Can you give an example? Taking Sintilimab as a representative, how do you evaluate the safety of the drug? Professor Wang Baocheng: This is an issue of great concern to doctors, patients, and their families.

At present, there are three main types of immune checkpoint inhibitors in clinical use: PD-1 monoclonal antibody, PD-L1 monoclonal antibody and CTLA-4 monoclonal antibody.
There are certain differences in the types and degrees of side effects between different drugs.

In general, the use of single-agent immune checkpoint inhibitors, CTLA-4 monoclonal antibody is relatively more toxic, especially the toxic side effects of the digestive system, such as colitis, diarrhea and so on.

PD-L1 monoclonal antibody is relatively less toxic, and overall the difference is not very large.

It is worth noting that when two different immune checkpoint inhibitors are used in combination, side effects will increase, and even the result of "1+1>2" will be formed, so be cautious.

Sintilimab is a new type of PD1 monoclonal antibody independently developed by my country.
In addition to the characteristics of general PD-1 monoclonal antibodies, the structure (including the FC segment, the region that binds to PD-L1), and the half-life are all It has "uniqueness".

Clinically, Sintilimab has shown good performance in terms of efficiency and safety, and its combined application compatibility is also excellent.
Therefore, Sintilimab has a good reputation in clinical applications. Medical circle: How to choose the appropriate immunotherapy drugs for patients according to the side effects of drugs? How to avoid these toxicity as early as possible? Professor Wang Baocheng: The basic principle is based on comprehensive considerations such as indications, safety, and accessibility.

First of all, we must grasp the indications and avoid random drug replacement.

Secondly, in terms of safety, how to avoid or reduce toxicity is also a very important aspect.
I have the following experience in clinical work.

First, the patient’s physical condition should be considered before medication, including physical fitness, physical fitness, major organ functions, and whether it is associated with other serious diseases.

Second, consider the patient's gene expression.

In terms of lung cancer, if it is a patient with a positive driver gene, the application of immune checkpoint inhibitors may not only be ineffective, but there may also be very serious side effects.
In some cases, super-progress may occur, which is counterproductive.

Third, when conditions permit, some genes and or related molecules can be tested, which can not only pick out the dominant population, but also avoid patients with negative gene expression or molecular expression.
This is also very important.

Fourth, during the course of immunotherapy, close clinical observation and full management should be carried out.

Education and informed consent can be carried out before medication.
Toxic and side effects in the treatment process need to be dealt with in time.

In addition, each course of treatment also requires detailed and standardized records, as well as follow-up and summary.

The domestic guidelines are in line with domestic evidence-based medical evidence and are more suitable for lung cancer patients in China.
The medical community: combined with this update of the immune checkpoint inhibitor guidelines, what do you think of the domestic and foreign guidelines regarding the treatment strategy considerations? When will China's CSCO NSCLC guidelines be updated this year, and what are the differences from the guidelines for immune checkpoint inhibitors? Professor Zhou Caicun: Whether at home or abroad, the update of the guideline comes from the blessing of evidence-based medicine.

However, foreign guidelines are more inclined to the data of the global population, while the domestic guidelines refer more to the data of the Asian population or the Chinese population.

For example, in the CSCO guidelines, multiple PD-1 monoclonal antibody programs based on the results of domestic clinical research are recommended, while the National Comprehensive Cancer Network (NCCN) of the United States abroad mainly focuses on imported drugs.

Therefore, the CSCO guidelines can be said to be the "exclusive" clinical drug reference for Chinese patients.

The difference between the update of the CSCO NSCLC guideline and the guideline for immune checkpoint inhibitors is that the former is more focused on the tumor type NSCLC, and the treatment also involves various aspects.
In addition to immunotherapy, other treatment options such as targeting will also be involved.

This year's CSCO NSCLC guidelines will not be released at the guidelines meeting and are expected to be released in the second half of the year.
Therefore, the guidelines will incorporate more evidence-based medicine released this year when they are released, and medication recommendations will be made based on the latest clinical research results.

Expert Profile Professor Wang Baocheng Chief Physician and Doctoral Supervisor Vice President of PLA 960 Hospital (former Jinan Military Command General Hospital) Former Director of Oncology Institute of Jinan Military Command Former Director of Oncology Research Institute of Jinan Military Command Executive Director of Chinese Society of Clinical Oncology (CSCO) Chairman of CSCO Immunotherapy Committee CSCO Anti-tumor Drug Safety Management Expert Committee Standing Committee Member CSCO Liver Cancer Expert Committee Standing Member CSCO Malignant Melanoma Expert Committee Standing Committee Member of the All Army Cancer Professional Committee Vice Chairman of the Central Military Commission Health Care Consultation Expert Vice Chairman of the Shandong Medical Physician Association Director of the National Drug Clinical Verification Agency " Chief Editor of Chinese Journal of Digestive Diseases and Imaging Professor Zhou Caicun Director of Oncology Department, Shanghai Pulmonary Hospital Affiliated to Tongji University Director of Oncology Institute of Tongji University School of Medicine Chairman of the Thoracic Tumor Branch, Member of the Board of Directors of the International Society for Lung Cancer Research (IASLC BOD) Member of the Standing Committee of the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association Deputy Chairman of the Oncology Drug Clinical Research Professional Committee of the Chinese Anti-Cancer Association Member of the Standing Committee of the Oncology Branch of the Chinese Medical Doctor Association Deputy Shanghai Anticancer Association Chairman, Shanghai Anti-Cancer Association, Lung Cancer Molecular Targeting and Immunotherapy Committee, Chairman, Shanghai Medical Association, Vice Chairman, Oncology Branch, Shanghai Medical Association, Vice Chairman, Shanghai Medical Association, Oncology Branch, Shanghai Leading Talent