When discussing the "three perfections" of tumor immunotherapy in the upper gastrointestinal system

This interview comprehensively interprets the data of CheckMate-649, CheckMate-648 and CheckMate-577, aiming to evaluate the clinical guidance significance
of this series of classic studies for the treatment of upper gastrointestinal in China 。 Professor Qu Xiujuan from the Department of Medical Oncology of the First Affiliated Hospital of China Medical University was invited as the host, and Professor Zhang Miaozun from the Department of Gastrointestinal Surgery of Lihuili Hospital of Ningbo Medical Center and Professor Han Quanli from the Department of Internal Medicine of the Chinese General Hospital of the People's Liberation Army (301 Hospital) were invited as interview guests to discuss the progress and application prospects
of the "three comprehensive" era of tumor immunotherapy in the upper gastrointestinal system.

The CheckMate-649 study strengthens nivolumab as a first-line treatment for gastric cancer

The burden of digestive tract tumors in China is serious, showing the characteristics of "double high" morbidity and mortality1
.
Digestive tract tumors are heterogeneous and show significant differences in Chinese and Western populations, while new drugs and therapies progress slowly, and China's anti-gastrointestinal tumor cause has been facing a huge therapeutic bottleneck
.
The advent of immunotherapy has injected new vitality into the diagnosis and treatment of gastrointestinal tumors, significantly improved the survival benefits of patients, and promoted the "three complete" era
of all-place, all-type and full-course immunotherapy of upper gastrointestinal tumors in China.

1 CheckMate-649 studies the latest data and highlights of the Chinese subgroup

Professor Zhang Miaozun: The CheckMate-649 study has created a new standard for first-line immunotherapy for advanced gastric cancer, and its global research results were first published at the 2020 European Oncology Society (ESMO) Congress, and the data has been continuously updated in recent years
.
The results of the 2-year overall survival (OS) of the Chinese cohort were announced at the 2022 ESMO GI Conference, with a median follow-up of 25.
1 months
for the Chinese population as of May 27, 2021.
The results of the Chinese subgroup analysis showed that nivolumab plus chemotherapy significantly improved the OS of patients compared with chemotherapy alone, consistent with
global results.
In the PD-L1 CPS≥5 population, the 2-year OS rates in the nivolumab plus chemotherapy and chemotherapy groups were 39% and 15%, respectively; In the whole population, the 2-year OS rates in the nivolumab plus chemotherapy and chemotherapy groups were 35% and 15%,
respectively.
In both CPS≥5 and the whole population, nivolumab plus chemotherapy has doubled the two-year survival rate compared with chemotherapy alone
.
In addition, nivolumab plus chemotherapy significantly improved progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) compared with chemotherapy alone2
in both PD-L1 CPS≥5 and the whole population.

Figure 1: OS, PFS, ORR, and DOR in PD-L1 CPS≥5 and ITT populations in the nivolumab plus chemotherapy group versus chemotherapy group

Professor Han Quanli: Although immunotherapy has achieved excellent efficacy in the field of gastric cancer treatment, the exploration path of immunotherapy is not smooth, and many studies have broken the sand
.
The success of CheckMate-649 research sweeps away the dust before and is a milestone, opening a new era of first-line immunotherapy combined with chemotherapy for advanced gastric cancer, bringing sustainable survival benefits
to more patients.

Professor Qu Xiujuan: In the era of chemotherapy, the treatment of gastric cancer has always been two-drug chemotherapy, and three-drug chemotherapy has also been tried, but three-drug chemotherapy is more toxic and can tolerate fewer patients; In the era of targeting, trastuzumab combined with chemotherapy has achieved certain efficacy in the treatment of Her2+-positive gastric cancer patients, but the dominant population is small, and it is hoped that a treatment plan can be found that benefits more patients; With the advent of the immune era, CheckMate-649 research has established the therapeutic status
of first-line immunotherapy combined with chemotherapy for advanced gastric cancer.

Multiple breakthroughs, significant benefits highlight the "food" power

The success of CheckMate-649 research has opened the way to first-line immunotherapy for advanced gastric cancer; Esophageal cancer is also a common digestive tract tumor, and the history of drug development is also tortuous, in the past few decades, the response rate of single-agent chemotherapy for advanced esophageal cancer is only 10%, and even if the effective rate of double-agent chemotherapy is only about 30%.

In recent years, immunotherapy has gradually improved in the field of esophageal cancer, and the publication of a number of research results has consolidated the position
of immunotherapy in postoperative adjuvant and advanced first-line treatment of esophageal cancer.

2 Highlights of the CheckMate-648 and CheckMate-577 studies and implications for clinical practice

Prof.
Quanli Han: China is a big country with esophageal cancer, and the CheckMate-648 study is a phase III, randomized, global clinical study to evaluate the efficacy
of nivolumab-based immune combination therapy compared with chemotherapy alone for first-line treatment of advanced or metastatic esophageal squamous cell carcinoma.
Nivolumab in combination with chemotherapy continued the excellent performance in the CheckMate-649 study, with OS benefit observed in all populations; At the same time, the OS benefit was not limited by PD-L1 expression in all randomized patients3

In addition, postoperative adjuvant therapy for esophageal cancer has lacked large-scale clinical research data, and the effect of postoperative traditional chemotherapy is not good
.
The CheckMate-577 study was designed to evaluate the efficacy and safety
of nivolumab as adjuvant therapy for patients with oesophageal cancer and gastroesophageal junction cancer who do not achieve complete pathologic response after neoadjuvant chemoradiotherapy (CRT).
。 The median disease-free survival (DFS) of 22.
4 months in the nivolumab group was 22.
4 months, doubling the benefit (11.
0 months) compared with the placebo group, and the median DFS in the nivolumab group was 29.
7 months, compared with the placebo group (10.
6 months), demonstrating that immunotherapy was effective in overcoming postoperative recurrence and distant metastasis to achieve the desired effect
.
In addition, patients with or without PD-L1 expression could benefit from immunotherapy from the results of the study4
.

Figure 2: DFS4 in the nivolumab group versus placebo

Professor Qu Xiujuan: Squamous cell carcinoma is a high-incidence group in China's esophageal cancer, and the efficacy of traditional treatment methods is not satisfactory
.
In recent years, we have also been looking for breakthroughs, and the CheckMate-648 study not only benefits ORR, but also brings significant survival benefits, providing strong evidence
for first-line immunotherapy in advanced esophageal cancer.
In addition, the evidence for postoperative adjuvant therapy for esophageal cancer is low, and the CheckMate-577 study is the first to establish the importance of immunotherapy in postoperative adjuvant therapy for esophageal cancer
.

Conversion therapy may lead to surgery for patients with advanced gastric cancer

Immune combination chemotherapy has become the first-line standard of care for upper gastrointestinal tumors, and it is worth noting that immune combination chemotherapy has a higher ORR rate than previous first-line regimens, such as nearly 70%
ORR in the whole population in the CheckMate-649 study.
In recent years, the application of conversion therapy in advanced gastric cancer has received more and more attention, however, conversion therapy is still being explored, and immune-based conversion therapy can be expected
in the future.

3How will surgeons screen and evaluate patients who are suitable for conversion therapy for advanced gastric cancer?

Professor Zhang Miaozun: The ORR of nivolumab combined with chemotherapy in the first-line treatment of advanced gastric cancer in China in the CheckMate-649 study was close to 70%.

Since the drug is so effective, it is worth considering whether the drug can be applied to conversion therapy for surgeons
.
According to the biological behavior of gastric cancer, Japanese scholar Yoshida et al.
divided stage IV.
gastric cancer into four types: type I is potentially resectable, type II is borderline resectable, type III is potentially unresectable, and type IV is extensive metastasis5
.
At present, it is generally believed that preoperative chemotherapy for type I patients can be classified as the concept of neoadjuvant chemotherapy, and the indications for conversion therapy are mainly type II patients, including some type III and a very small number of type IV patients
.
How effective neoadjuvant immunotherapy is and whether immunotherapy can be applied after surgery are all directions
that need to be explored later.

In clinical practice, how to screen patients with advanced gastric cancer transformation involves Biomarker
.
The perioperative treatment chapter of the 2022 CSCO Guidelines for the Diagnosis and Treatment of Gastric Cancer separates patients with highly unstable microsatellite (MSI-H), which may benefit from immunotherapy, but a smaller
proportion.
Overall, the emergence of immunotherapy has increased the choice of surgical conversion therapy, and immune-based regimens have great promise
in gastric cancer conversion therapy.

Professor Qu Xiujuan: Stage IV gastric cancer is a systemic disease that requires the rational use of a variety of different treatment methods for comprehensive treatment, and the immune-based program has made great achievements in gastric cancer conversion therapy, and it is hoped that immunotherapy can provide survival benefits
for more gastric cancer patients.

Nivolumab ushers in a new era of immunotherapy for upper gastrointestinal tumors

Immunotherapy has brought earth-shaking changes to the field of upper gastrointestinal tumors, not only setting a new standard for advanced treatment, but also gradually gaining a foothold in perioperative treatment, and immunotherapy drugs represented by nivolumab are leading the treatment of upper gastrointestinal tumors in China into a new era
.

4How to understand the significance of the "three complete" era of all places, all types and all course of the disease? What are the directions of upper gastrointestinal immunotherapy?

Professor Han Quanli: The "three completes" of all positions, all types and all disease courses fully reflect the excellent results
of nivolumab in the field of upper gastrointestinal tumor treatment.
Digestive tract tumors are characteristic high-incidence tumors in China, with high aggressiveness and high heterogeneity, and the success of CheckMate-649, CheckMate-577 and CheckMate-648 studies has made nivolumab a number of heavy indications
.
At the same time, nivolumab covers esophageal cancer, gastroesophageal junction cancer, gastric cancer, and there is sufficient evidence-based medical evidence in the course of the disease from the postoperative adjuvant stage to the advanced first line and posterior line, which is valuable in highly heterogeneous upper gastrointestinal tumors, and provides a full-coverage treatment option
for patients with upper gastrointestinal tumors in China.

Professor Zhang Miaozun: Since the era of chemotherapy, there have been fewer
drugs for the treatment of gastric cancer.
With the advent of the immune era, different clinical trials have been carried out from the back line to the first line, or from squamous cell carcinoma to adenocarcinoma, and effective results
have been achieved.
Therefore, surgeons not only have a "scalpel", but also a "gene knife", hoping that future clinical trials can be carried out more extensive and more in-depth, bringing personalized and precise medical services
to patients.

Professor Qu Xiujuan: As the application of immunotherapy drugs becomes more and more extensive, it is necessary to further promote the standardization of immune combination therapy regimens, rationalize the layout of immunotherapy under whole-process management, streamline the management of adverse reactions related to immunotherapy combined with chemotherapy, and accurately select many PD-1 monoclonal antibody drugs based on evidence-based medical evidence, so as to improve the multidisciplinary comprehensive treatment model
for gastric cancer.

epilogue

Although immunotherapy drugs represented by nivolumab have changed the treatment pattern of upper gastrointestinal tumors, in clinical practice, immunotherapy still faces many unsolved problems, such as how to arrange the four treatment methods of radiotherapy, surgery, chemotherapy and immunity in esophageal cancer? Is maintenance therapy used after the first line of advanced stages, and what regimen is maintenance therapy? The treatment cycle and frequency of traditional ECF regimens (epidoxorubicin, cisplatin, fluorouracil) combined with PD-1 monoclonal antibody in the perioperative period of gastric cancer are the future directions of discussion, which need to be continuously improved and optimized to bring better survival benefits
to gastric cancer and esophageal cancer patients.

Expert profiles

Professor Qu Xiujuan

Director of the Department of Medical Oncology, The First Affiliated Hospital of China Medical University

Chief physician, professor, doctoral supervisor

Deputy Director of the Department of Oncology

CSCO Board of Trustees

Member of the Standing Committee of the CSCO Gastric Cancer Expert Committee

Member of the CSCO Immunotherapy Committee

Member of CSCO Smart Healthcare Expert Committee

Member of CSCO Antitumor Drug Safety Management Committee

Vice Chairman of the Youth Committee of the CACA Tumor Targeted Therapy Professional Committee

Member of the Gastric Cancer Group of the Oncology Branch of the Chinese Medical Association

Member of the Colorectal Cancer Professional Committee of the Chinese Medical Doctor Association

Chairman of Oncology Branch of Liaoning Immunology Society

Chairman-elect of Biomarker Professional Committee of Liaoning Anti-Cancer Association

He presided over 1 major science and technology project, 5 national natural projects, and 2 provincial science and technology progress awards

He has published more than 100 SCI papers as the first or corresponding author in JCO and other journals

Professor Han Quanli

Department of Internal Medicine, General Hospital of the People's Liberation Army (301 Hospital) of Chinese People's Liberation Army

Deputy Chief Physician, Department of Medical Oncology, PLA General Hospital, M.
D

Member of the Clinical Research Committee of Oncology Drugs of the Chinese Anti-Cancer Association

Member of the Tumor Marker Professional Committee of the Chinese Anti-Cancer Association

Member of the Precision Medicine and Oncology MDT Professional Committee of the China Association for the Promotion of Rehabilitation Technology Transformation and Development

Member of MDT Professional Committee of Precision Medicine and Oncology of China Research Hospital Association

Professor Zhang Miaozun

Deputy Chief Physician of Department of Gastrointestinal Surgery, Lihuili Hospital, Ningbo Medical Center

Doctor of Surgery, Master Supervisor

Member of the Special Committee for Minimally Invasive Diagnosis and Treatment of Tumors of Zhejiang Anti-Cancer Association

Member of the Cancer Support Treatment Committee of Zhejiang Mathematical Medical Association

Member of the Cancer MDT Special Committee of Zhejiang Medical Doctor Association

Member of Gastrointestinal Surgery Committee of Ningbo Integrative Medical Association

Research interests: minimally invasive treatment of gastrointestinal surgery in a number of natural and provincial natural topics in participating countries

He has presided over 3 bureau-level projects, and published more than 20 SCI and domestic core journals, including more than 10 papers indexed by SCI

References:

1.
ZHOU Jiachen, ZHENG Rongshou, WANG Shaoming, et al.
Comparison of major gastrointestinal tumor burden in China and some countries in the world in 2020[J].
Electronic Journal of Comprehensive Oncology Therapy, 2021, 7(2): 26-32.

2.
Shen L, 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 GI 2022.
Abstr P-86.

3.
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.

4.
Kelly RJ, Ajani JA, Kuzdzal J, et al.
Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.
N Engl J Med.
2021; 384(13):1191-1203.

5.
YAMAGUCHI K, YOSHIDA K, TANAKA Y, et al.
Conversion therapy for stage IV gastric cancer-the present and future［J］.
Transl Gastroenterol Hepatol, 2016, 1: 50.