On the cloud| immunotherapy demonstrates its strength and achieves coverage of all locations, types, and disease course of tumors in the upper digestive system

The column "Cloud Discussion-Upper Gastrointestinal Cloud Dialogue Series" focuses on the latest research progress of upper gastrointestinal tumor immunotherapy, focuses on clinical hot topics and practices, and is committed to creating a standardized diagnosis and treatment position
for tumors.
Professor Guo Zengqing from the Department of Oncology of Fujian Cancer Hospital was invited to preside over this issue, and joined hands with Professor Han Shumei, Department of Gastroenterology, Shandong Cancer Hospital, and Professor Yang Kun of Gastric Cancer Center, West China Hospital of Sichuan University, to take a detailed inventory of the progress of immunotherapy in the field of upper gastrointestinal tumors in recent years and share insights in clinical diagnosis and treatment
.

CheckMate-649 research turned the tide, and first-line immunotherapy for advanced gastric cancer was on the horizon

Since immunotherapy was first used for melanoma treatment in 2011, it has completely changed the treatment model of solid tumors, covering a rapidly expanding range of indications, but the exploration of immunotherapy in gastric cancer has not been smooth
sailing.
In the process of moving the number of treatment lines forward, it has undergone hardships, and many studies have been broken one after another
.
It was not until the success of the CheckMate-649 study that advanced gastric cancer entered the era of
immunotherapy.

1

The arduous exploration process of immunotherapy in the first line of gastric cancer and the significance of the successful research of CheckMate-649

Professor Han Shumei: Gastric cancer is a highly aggressive and metastatic disease, and most patients are in the advanced stage when they are ^diagnosed1
.
Before the era of immunotherapy, the chemotherapy response rate of patients with HER2-negative advanced gastric cancer was about 40%, and the median overall survival (OS) was difficult to break through one ^year2
.
The advent of immunotherapy has brought new hope
to the treatment of advanced gastric cancer.
ATTRACTION-02 and other studies have proved that immunotherapy represented by nivolumab significantly improves the survival benefit of patients with advanced gastric cancer, laying the cornerstone
of immunotherapy in gastric cancer.
SURPRISINGLY, THE HIGHLY ANTICIPATED KEYNOTE-062 STUDY AND THE JAVELIN GASTRIC 100 STUDY HAVE FAILED ONE AFTER ANOTHER, WHICH HAS PUT THE FIRST-LINE TREATMENT EXPLORATION OF GASTRIC CANCER OF IMMUNOTHERAPY IN A QUANDARY, BUT THE RESEARCHERS CONTINUE TO MOVE FORWARD IN FAILURE
.
At the 2020 ESMO Annual Conference, CheckMate-649 research was born like a bright star, making the first-line immunotherapy of gastric cancer turn around, and successfully "gnawed" the "hard bone" of the first-line advanced gastric cancer
.

CheckMate-649 is the phase III study of first-line immunotherapy for advanced gastric cancer with the longest follow-up time, and the follow-up results have been reported
in major academic conferences.
The latest two-year follow-up results of the Chinese subgroup published in ESMO GI³ in 2022 showed that in all randomized populations, regardless of the level of PD-L1 expression, the median OS of nivolumab plus chemotherapy group reached 14.
3 months (compared with 10.
3 months in the chemotherapy group alone), and the risk of death was reduced by 37%.
In terms of median progression-free survival (PFS) and objective response rate (ORR), nivolumab plus chemotherapy was also superior to chemotherapy alone (PFS: 8.
3 versus 5.
6 months; ORR：66% vs 45%）
。 In the CPS≥5 population, the benefits were more significant: the median OS was 15.
5 months in the nivolumab plus chemotherapy group and only 9.
6 months in the chemotherapy group, with a 44% lower risk of death; The median PFS was 8.
5 months in the nivolumab plus chemotherapy group and 4.
3 months in the chemotherapy group, and the ORR was as high as 68% in the nivolumab plus chemotherapy group, which was also better than 48%
in the chemotherapy alone group.
Although the exploration of first-line immunotherapy for advanced gastric cancer has gone through twists and turns, the success of CheckMate-649 research has finally brought advanced gastric cancer into the era of
immunotherapy.
Therefore, the CheckMate-649 study is a milestone
on the road to gastric cancer immunotherapy.

Figure 1: OS, PFS,^{ORR 3} in PD-L1 CPS≥5 and ITT populations in nivolumab plus chemotherapy versus chemotherapy

Professor Guo Zengqing: It is difficult to break through the OS of advanced gastric cancer in the era of chemotherapy for 12 months, and the ToGA study broke the OS curse of 12 months, but less than 20% of HER2-positive people can benefit
from it.
The addition of immunotherapy brings new hope
to HER2-negative people.

High-quality research data support the overall benefit for the whole population

Immunotherapy has redefined the standard of
first-line treatment for advanced gastric cancer.
Based on the excellent performance of CheckMate-649 and other studies, the latest National Comprehensive Cancer Network (NCCN) and the Chinese Society of Clinical Oncology (CSCO) gastric cancer clinical diagnosis and treatment guidelines have highly recommended nivolumab combined with chemotherapy regimen for first-line treatment
of advanced gastric cancer.

2

Foreign and domestic authoritative guidelines for gastric cancer recommend the basis for the application of nivolumab in the first-line population of gastric cancer

Professor Yang Kun: The results of the CheckMate-649 study have demonstrated that nivolumab combined with chemotherapy can bring comprehensive benefits
to patients with advanced gastric cancer.
For HER2-negative people, CSCO guidelines recommend ⁴FOLFOX or XELOX in combination with nivolumab for first-line treatment of advanced gastric cancer, and different levels of recommendations are made according to PD-L1 combined with positive score (CPS): for people with CPS≥5, the guidelines make first-level recommendations for class 1A evidence.
For people with CPS<5 or inaccessible testing, it is the secondary recommendation<b12> for category 1B evidence.
The domestic authoritative guidelines for gastric cancer recommend the application of nivolumab in the first-line whole population of gastric cancer, which is roughly divided into two aspects: the efficacy of nivolumab in CheckMate-649 research and the current status of
PD-L1 detection in China.

Although CheckMate-649 Study ³ set population-wide OS as a secondary study endpoint, the statistical power of the primary endpoint could be transmitted downward sequentially, making the endpoint equally statistically significant
.
Finally, the OS P value of the whole population passed the hypothesis test
with 0.
0002.
In addition, the results of one-year follow-up in the Chinese subgroup showed that in the PD-L1 CPS<1 population, the median OS of nivolumab plus chemotherapy was 11.
8 months (compared with 10.
6 months in the chemotherapy group alone) and the risk of death was reduced by 31%.
<b13> Compared with chemotherapy alone, median PFS was also increased in the nivolumab plus chemotherapy group, at 10.
0 months and 5.
8 months, respectively, and the risk of disease progression or death was reduced by 49%.

From the perspective of detection, the morphological characteristics and molecular genetic characteristics of gastric cancer in China are complex, and the current cost of genetic testing is high, which leads to poor accessibility of PD-L1 testing
.
In addition, the proportion of people who are positive for PD-L1 in the real world is higher, and most patients who are not tested may also benefit
from nivolumab in combination with chemotherapy.
For these reasons, it is recommended in clinical practice that nivolumab in combination with chemotherapy is used
in the whole population in the first line of gastric cancer.

Professor Han Shumei: Stomach cancer is a highly heterogeneous disease with heterogeneity
in time and space.
At present, there are still questions
to be solved about the detection standards of PD-L1 and the interpretation of PD-L1 test results.
The one-year follow-up results of the Chinese subgroup based on the CheckMate-649 study showed that in the population of PD-L1 CPS<1, the OS and PFS of immunotherapy combined with chemotherapy alone were significantly beneficial, and the objective response was further improved<b12>.
Therefore, based on the various difficulties faced by the diagnosis and treatment of gastric cancer, my personal view is that it should be recommended for the whole population according to the guidelines, but it is necessary to avoid the occurrence
of serious adverse reactions.

Professor Guo Zengqing: The CheckMate-649 study achieved positive results in the whole population, achieving a leap in the efficacy of advanced gastric cancer in China in the past decade, and nivolumab combined with chemotherapy became the first approved first-line population-wide immunotherapy for advanced gastric cancer in China, and was recommended
by the highest evidence level consistent by domestic and foreign guidelines.

Immunotherapy provides a one-stop, comprehensive treatment plan for esophageal cancer

The "long tailing" effect of immunotherapy has given some advanced patients hope
for long-term survival.
Compared with gastric cancer, immunotherapy has a more significant benefit in esophageal squamous cell carcinoma, reversing the situation that no drugs are available for esophageal cancer, not only rewriting the first-line and second-line standard treatment regimens for advanced esophageal cancer, but also nivolumab has taken the lead in conquering the postoperative adjuvant therapy position, further expanding the beneficiary group
of immunotherapy.

3

Changes brought by immunotherapy to the field of esophageal cancer and future exploration directions

Professor Han Shumei: Before the era of immunotherapy, the treatment of esophageal cancer has always been mainly surgical and radiotherapy, and internal medicine treatment is more the icing on the cake
.
Once the patient's disease progresses to an advanced stage, the disease progresses
even though the chemotherapy regimen is constantly changed.
Esophageal cancer cells have high mutation rate and strong immunogenicity, which lays a good theoretical foundation
for the benefits of immunotherapy.
In practice, immunotherapy has passed all the way from advanced second-line, first-line to adjuvant therapy, constantly refreshing the survival length
of esophageal cancer patients.
In advanced first-line therapy, nivolumab in combination with chemotherapy5 achieved a median OS of 13.
2 months in the whole population, and the benefit was more significant in people with a PD-L1 tumor cell positive ratio score (TPS) of ≥1%, with OS as high as ^15.
4 months
.
These results provide great confidence
in medical treatment.

In the field of postoperative adjuvant therapy, nivolumab is effective in reducing the risk
of postoperative recurrence and distant metastases.
The CheckMate-577 study results showed that disease-free survival (DFS) reached 22.
4 months in the adjuvant immunotherapy group, a 10-month increase compared with the placebo group, and the risk of disease recurrence was reduced by 33%.

Among patients with squamous cell carcinoma, the advantage of adjuvant immunotherapy was even more pronounced, with DFS reaching 29.
7 months, nearly three times that of the placebo ^group6
.
Immunotherapy helps patients with operable esophageal cancer achieve high-quality long-term survival
.

Fig.
2 Nivolumab combined with chemotherapy versus chemotherapy group in PD-L1≥1% and OS⁵ in the total population

Figure 3 Nivolumab vs.
placebo DFS⁶ in all populations

Fig.
4 Nivolumab versus placebo for DFS⁶ in esophageal squamous cell carcinoma

Immunological monotherapy or combination chemotherapy cannot benefit all esophageal cancer patients, and accurate screening of beneficiary groups and finding more effective treatment models will be the future exploration direction
.
At present, researchers have actively carried out clinical research
such as double-free combination (such as PD-L1 monoclonal antibody combined with T cell immunoglobulin), immune combination radiotherapy and immune combination targeted therapy.
It is expected that more drugs and immune combination regimens will emerge in the future to provide patients with more individualized treatment options
.

Professor Guo Zengqing: Immunotherapy has been very successful in the field of esophageal cancer, and it has gradually expanded from the last line treatment to the front line, breaking the dilemma of advanced esophageal cancer treatment and significantly prolonging the survival time
of patients.

Immunotherapy therapy helps stage IV gastric cancer to transform more and survive longer

Conversion therapy for advanced gastric cancer has always been a research hotspot
in clinical practice.
For stage IV gastric cancer that cannot be operated at the beginning, the use of drug-based comprehensive treatment can reduce the stage of the tumor in some patients and regain the opportunity for radical surgery, thereby significantly improving the prognosis
.

4

Current status and clinical application experience of immune conversion therapy for gastric cancer

Professor Yang Kun: Paclitaxel-based three-drug chemotherapy regimen is the cornerstone
of stage IV gastric cancer conversion therapy.
The addition of immunotherapy further enhances the ORR
of conversion therapy.
The CheckMate-649 study showed that the ORR of nivolumab in combination with chemotherapy was up to 66% better than chemotherapy alone, regardless of the patient's PD-L1 expression level
.
The results of this study are a great encouragement to clinicians and patients, and it is expected that more patients with advanced gastric cancer will undergo surgery
again through conversion therapy.

It is worth noting that there are still some problems in immune conversion therapy, which need to be further explored and thought
by clinicians.
First of all, in terms of screening people who maximize the benefits of immunoconversion therapy, in addition to some biomarkers commonly used now, such as PD-L1 CPS score, tumor mutation burden, and MSI status, can the dominant population be screened by observing adverse reactions that are positively correlated with the efficacy of immunotherapy? Secondly, the scheme, course of treatment, dosage and preoperative discontinuation time of conversion therapy need to be further explored
by researchers.
In addition, clinicians should be concerned about the impact of
conversion therapy on surgery.
The existing experience of neoadjuvant therapy for gastric cancer suggests that neoadjuvant therapy may lead to problems such as tissue edema, increased vascular fragility, and increased exudate, which increases the difficulty
of surgery.
Therefore, attention should be paid to the above problems during surgery to ensure the safe operation of
surgery.

Professor Han Shumei: At present, clinical research on immune conversion therapy or neoadjuvant therapy is actively being carried out
.
In the process of academic exchange, it was found that the addition of immune drugs brought more and more cases
of pCR compared with chemotherapy alone.
Surgery for gastrointestinal tumors is traumatic and is bound to disrupt the normal function
of patients.
If the cases of pCR are screened out by endoscopy, PET-CT, ctDNA and other detection methods, so that patients can avoid surgery and obtain high-quality survival, this is also one of the directions of
clinical future exploration.

Professor Guo Zengqing

In recent years, the research and development of new drugs in the field of gastrointestinal tumors can be described as rapid development, and immunotherapy has brought great survival benefits to patients with gastrointestinal tumors and has also become its basic therapy
.
With the deepening of research, immunotherapy will become precise and individualized
in the future.

Expert profiles

Professor Guo Zengqing

• Administrative Director of Cancer Cadre Ward (20th Ward) of Fujian Cancer Hospital;

• Director of the Department of Hepatobiliary and Pancreatic Oncology, Administrative Director of the Department of Clinical Nutrition and Deputy Director of the Center for Tumor Bioimmunotherapy

• Deputy Director of Fujian Provincial Cancer Immunotherapy Quality Control Center

• Deputy Director of Fujian Clinical Nutrition Treatment Quality Control Center

• Member of the Standing Committee of the Cancer Nutrition Professional Committee of the Chinese Anti-Cancer Association

• Member of the Tumor Targeted Therapy Professional Committee of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the Biliary Tract Tumor Professional Committee of the Chinese Society of Clinical Oncology (CSCO).
  

• Member of the Cancer Nutrition Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
  

• Member of the Standing Committee of the Colorectal Cancer Professional Committee of the Southern China Cancer Clinical Research Association

• Chairman of the Professional Committee of Cancer Nutrition and Supportive Treatment of Fujian Anti-Cancer Association

• Vice Chairman of the Parenteral and Enteral Nutrition Branch of Fujian Medical Association

• Vice Chairman of the Precision Medicine Special Committee of Fujian Strait Cancer Prevention and Technology Exchange Association

• Member of the Standing Committee of the Gastric Cancer Professional Committee of Fujian Anti-Cancer Association

Professor Yang Kun

• Associate Professor, Doctoral Supervisor

• Director of Gastric Cancer Center, West China Hospital, Sichuan University

• Director of Department of Gastrointestinal Surgery, Jintang Hospital, West China Hospital, Sichuan University

• Honorary member of the Association of Surgeons of the Republic of Bashkortostan, Russian Federation

• Chairman of the Gastric Cancer Committee of Sichuan Cancer Society

• Vice Chairman of the Laparoscopic Young Physician Committee of the Endoscopist Branch of the Chinese Medical Doctor Association

• Youth member of the Minimally Invasive Surgeons Committee of the Surgeon Branch of the Chinese Medical Doctor Association

• Member of the Gastric Cancer Committee of the Chinese Anti-Cancer Association

• Member of the Minimally Invasive Science Group of the Gastric Cancer Special Committee of the Chinese Anti-Cancer Association

• Member of ERAS Group of Gastric Cancer Special Committee of Chinese Anti-Cancer Association

• Member of the MDT Group of the Gastrointestinal Stromal Tumor Special Committee of the Chinese Anti-Cancer Association

• Member of the Accelerated Rehabilitation Surgery Committee of the Chinese Medical Education Association

• Member of the Gastrointestinal Surgery Research Group of the Chinese Young Surgeons Academic Research Society

• Member of the Gastric Cancer Surgery and Treatment Collaborative Group in Western China

Professor Han Shumei

• Three wards of the Department of Gastroenterology, Shandong Cancer Hospital

• Deputy Chief Physician, Medical Doctor, Postdoctoral Fellow

• Member of the expert group for multidisciplinary diagnosis and treatment of gastric cancer in Shandong Cancer Hospital

• National second-level psychological counselor

• Member of the CSCO Oncology Support and Rehabilitation Expert Committee

• Member of the Cancer Support Treatment Professional Committee of the Chinese Anti-Cancer Association

• Member of the Professional Committee of Precision Treatment of Digestive Tract Tumors of Beijing Cancer Prevention and Control Society

• Secretary of Palliative Medicine Branch of Shandong Medical Association

• Member of Oncology and Chemotherapy Physician Branch of Shandong Medical Doctor Association

• Member of the Colorectal Cancer Branch Committee of Shandong Anti-Cancer Association

• Member of Palliative Care Branch of Shandong Anti-Cancer Association

• Member of the Radiation Oncology Professional Committee of Shandong Pain Medical Association

References

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Ba Yi, Zhou Likun.
Chemotherapy selection for advanced gastric cancer[J].
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)

2.
Bang YJ, Van Cutsem E, Feyereislova A, et al.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3,open-label, randomised controlled trial[J].
Lancet, 2010,376(9742): 687-697.

3.
Lin Shen, Yuxian Bai, Xiaoyan Lin, et al.
First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis 2-year follow-up.
ESMO World Congress on Gastrointestinal Cancer 2022 Abstr P-86.

4.
Chinese Society of Clinical Oncology (CSCO) Gastric Cancer Diagnosis and Treatment Guidelines 2022 Edition.

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Doki Yuichiro,Ajani Jaffer A,Kato Ken et al.
Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.
[J].
N Engl J Med,2022,386:449-462.

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Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.
N Engl J Med.
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Organized by the Chinese Society of Clinical Oncology Guidelines Working Committee.
Guidelines for the diagnosis and treatment of gastric cancer of the Chinese Society of Clinical Oncology (CSCO)-2022[M].
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