Professor Lin Shen and Professor Zhang Xiaotian: CheckMate-649 "Chinese Answer Sheet" refreshes history, opening a new stage for the first-line treatment of gastric cancer

*Only for medical professionals to read for reference.
At the just-concluded 2021 American Association for Cancer Research (AACR) annual meeting, the CheckMate-649 study, which broke through the bottleneck of the first decade of gastric cancer, delivered a surprising "Chinese answer".

In a clinical study of immunotherapy for gastric cancer and gastroesophageal junction cancer covering patients in mainland China, the CheckMate-649 study is the first and currently the only first-line phase III study that has achieved positive results.

So, what are the highlights of the Chinese subgroup data of this study? What impact will it bring to the development of clinical treatment of advanced or metastatic gastric cancer in China? Recently, the "medical community" is very honored to invite the main Chinese investigator of CheckMate-649 research-Professor Lin Shen, Deputy Dean of Peking University Cancer Hospital, and Professor Zhang Xiaotian, Deputy Director of the International Cooperation and Exchange Department of Peking University Cancer Hospital, to personally witness From the perspective of the author, he sheds light on the data of the Chinese subgroup and interprets layer by layer, and looks forward to the future while answering questions.

CheckMate-649: To explore the first-line efficacy of gastric cancer immunity.
More than 20 domestic centers participate in the CheckMate-649 study.
It is a phase III randomized, multi-center, open-label clinical study designed to evaluate the effect of navuli compared with chemotherapy alone (chemo).
Uumab combined with chemotherapy (nivo+chemo) or nivolumab combined with ipilimumab (nivo+ipi) is used to treat HER2-negative, advanced or metastatic gastric cancer (GC), gastroesophagus that has not been treated before Efficacy of patients with junction cancer (GEJC) or esophageal adenocarcinoma (EAC).

The CheckMate-649 study design diagram is the main Chinese researcher of the study.
Professor Lin Shen said that there were two major considerations when designing the study.
First, the study plan should be compared with the current best standard chemotherapy regimen.
Secondly, it is to establish two immunotherapy test groups.The study group includes standard chemotherapy group [capecitabine and oxaliplatin (CapeOX)/5-fluorouracil, leucovorin and oxaliplatin (FOLFOX)], PD-1 inhibitor + standard chemotherapy group (Navuliu Mab+CapeOX/FOLFOX), immunotherapy group (nivolumab+CTLA-4 inhibitor ipilimumab, the data of this subgroup has not yet been announced).

Regarding the original intention and historical significance of this research, Professor Lin Lin commented: This clinical research will solve two major issues that patients are currently very concerned about: 1.
Does PD-1 inhibitor combined with chemotherapy work in the first-line treatment of gastric cancer? How big is the effect? ​​2.
Does the dual-immune combination therapy have a good clinical effect?
At the same time, this study also answers the historical question of "Is not worthwhile to continue research in the future of immunotherapy for gastric cancer" for experts around the world.

As a research that has attracted much attention, CheckMate-649 has a high degree of participation and enrollment rate on a global scale: the study was carried out simultaneously in more than 20 centers in mainland China, and a total of 208 patients with late or metastatic GC or GEJC in mainland China were included.
Patients were randomized to receive nivo+chemo or chemo treatment.

In the CheckMate-649 study, mainland Chinese patients accounted for the highest proportion of Asian patients, reaching 60%.

Professor Lin Lin mentioned that the high proportion of Chinese patients enrolled this time is mainly due to two major reasons: one is because CheckMate-649, as a large-scale study on a global scale, has attracted a lot of attention in the country when it was launched, and domestic centers have begun to enroll.
The group worked early; second, because the research design and implementation standards were strict and reached the highest international standards, both the experimental group and the control group had clear expectations for the benefit of patients, so patients were actively enrolled in the group. CheckMate-649 Chinese answer paper: The risk of death has been reduced by nearly half, and the benefit trend is better than the first round of CheckMate-649 research published by the European Society of Medical Oncology (ESMO) Conference in 2020.
It shows that whether it is PD-L1 CPS (combined positive score) In ≥5, ≥1 or all randomized patients, there are statistically significant differences in nivolumab combined with chemotherapy: overall survival (OS) and no progression are observed in patients with PD-L1 CPS ≥5 The survival time (PFS) benefit reached the two primary endpoints of the study.

In patients with PD-L1 positive and CPS≥1 and all randomized populations, nivolumab combined with chemotherapy also showed a statistically significant OS benefit.

The results of the Chinese subgroup analysis released this time further reveal: Compared with chemo, nivo+chemo has achieved clinically significant OS (14.
3 vs 10.
3 months) and PFS (8.
3 vs.
5.
6 months) benefit.

In patients with CPS ≥ 5, it was observed that the median OS (15.
5 vs 9.
6 months) and PFS (8.
5 vs 4.
3 months) of the nivo+chemo group were more than 1.
5 times and nearly 2 times that of the control group, and they were objectively relieved.
The ORR (68% vs 48%) is significantly higher.

In CPS ≥ 1 and overall patients, OS (14.
3 vs 9.
9 months) and PFS (8.
3 vs 4.
9 months) benefits were also observed.

Regarding the efficacy results of the Chinese population, Professor Lin Shen believes that the results of the Chinese subgroup are very surprising.
The survival period can be seen in all populations and patients with PD-L1 CPS ≥ 5 or ≥ 1.
Significantly extended. The overall survival of all patients was 14.
3 months, compared with 10.
3 months in the control group, the absolute value increased by 4 months; for patients with PD-L1 CPS≥5, the overall survival improved more significantly, 15.
5 months vs.
9.
6 months (HR=0.
54), an increase of nearly 6 months-in all previous phase III randomized controlled studies of advanced gastric cancer, even if the selected population is particularly narrow, such as only for HER2-positive patients, this has not been seen Significant improvement, and the death risk of patients has been reduced by nearly 50%, which means that the death risk of half of the people has decreased, and it is also significantly better than the 29% of the global population.
It can be called a historic breakthrough.

The OS results of the Chinese population of the CheckMate-649 study The PFS results of the Chinese population of the CheckMate-649 study further compared the results of the Chinese subgroups with the data of the global population.
Professor Lin Lin pointed out: In the study, the natural survival period of Chinese patients is the control group Survival data is poor compared to the global population; and for Chinese patients in the nivo+chemo group, regardless of the PD-L1 expression level, the OS and PFS values ​​are better than the corresponding global results.

This shows that for Chinese patients, nivo+chemo is not only fully consistent with the global population on the issue of whether it can benefit, but the benefit trend is even more obvious.
This is a result that we are very happy about.

CheckMate-649 Comparison of the main efficacy data between the global and Chinese population When talking about the reasons for this difference, Professor Lin Shen believes that the reasons for this difference may be complicated.

In the future, in addition to the expression of PD-L1, we may also pay more attention to etiological factors, such as Helicobacter pylori infection, ethnic differences and tumor characteristics.

In addition, the benefit trend of the results of this subgroup is different from the results of the ATTRCTION-4 study that included Asian populations, which means that even if gastric cancer is in Asia, there are differences between countries and regions.

The above-mentioned factors and their effects have not formed widespread concern and consensus on a global scale in the past.
The results of the CheckMate-649 China subgroup have brought them back into people's vision. As the exploration of these problems continues to deepen, I believe that solving the problem of gastric cancer heterogeneity will usher in a major opportunity.
In the future, it is expected that gastric cancer can be further treated with precision and benefit patients to the greatest extent.

The whole population has benefited unanimously without the restriction of PD-L1 expression.
Professor Zhang Xiaotian proposed that the design of the CheckMate-649 study refers to the experience of previous gastrointestinal immunotherapy studies, and uses PD-L1 CPS as the standard for dividing the population.
Patients with ≥5 are the main research population; but from the final results, patients with different CPS levels have shown a high degree of consistency in the trend of benefiting from nivo+chemo, and this phenomenon is in the Chinese subgroup this time.
The results continue to be supported by data.

Professor Zhang Xiaotian: In the CheckMate-649 study, the population was divided by CPS score.

It can be seen from the results of this study that in terms of 1-year OS rate, PD-L1 CPS≥5, ≥1 and 57%, 56%, and 55% in all randomized patients are almost the same.

In the Chinese subgroup, clinically significant differences in OS/PFS were also observed, and the survival benefits were also highly consistent: the 1-year OS rate was 61% in PD-L1 CPS≥5, ≥1 and all randomized patients, respectively , 57% and 57%; the 1-year PFS rate in PD-L1 CPS≥5, ≥1 and all randomized patients were 42%, 40% and 40%, respectively.

In this regard, Professor Shen Lin pointed out: In the design of the study, we have considered the efficacy of immunotherapy in the overall population and the screened population.
However, PD-L1 expression is unlikely to be the only indicator, because in CPS<5 In the crowd, patients who have benefited can still be seen.

From the existing results, the higher the level of CPS expression, the higher the level of benefit for the population.

However, obviously, the HR (0.
61, 95% CI: 0.
44-0.
85) of OS for all random populations is also significantly different. Rewriting clinical guidelines and quickly obtaining indications, nivo+chemo creates a new benchmark for gastric cancer.
Based on the results of CheckMate-649 research, in January 2021, the first edition of the National Comprehensive Cancer Network (NCCN) 2021 gastric cancer diagnosis and treatment guidelines has been nivo +chemo (FOLFOX/XELOX) is listed as the preferred regimen for the first-line treatment of HER2-negative gastric cancer.

Then, on April 16, the FDA announced the approval of nivo+chemo as a first-line therapy for the treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma, and is not restricted by PD-L1 expression levels and HER2 overexpression levels , Opened the era of first-line immunotherapy for gastric cancer.

In addition, according to the latest news, in the newly released 2021 version of the CSCO gastric cancer diagnosis and treatment guidelines, the nivo+chemo (FOLFOX/XELOX) program has been officially listed as the first-line treatment level I recommendation (level 1A evidence) for advanced metastatic gastric cancer for HER2 Negative patients with CPS≥5 have officially established a new benchmark for the first-line treatment of advanced gastric cancer in China.

The significance is more than the present, the "stomach" has a far-reaching impact.
Before the CheckMate-649 study, a number of PD-1/PD-L1 inhibitor-based front-line treatment of gastric cancer phase III studies (KEYNOTE-061, KEYNOTE-062, Javelin Gastric 100 ) Failed to reach the primary endpoint, and the value of immunotherapy for the first-line treatment of gastric cancer is unclear.

CheckMate-649 is the study with the largest number of patients in the field of advanced gastric cancer so far, and it is also the first global study that surpasses chemotherapy to achieve significant overall survival benefits in the first-line treatment of HER2-negative gastric cancer in more than ten years; this announcement The data from the Chinese population is the first and so far only Chinese subgroup result from a Phase III study of first-line immunotherapy for gastric cancer.

This set of "first" and "only" results will not only change the current knowledge and practice of gastric cancer diagnosis and treatment, it will also have a profound impact on the future.

Professor Zhang Xiaotian mentioned: About 8 years ago, when anti-HER2 targeted drugs first obtained positive results in HER2-positive gastric cancer populations, the entire treatment field of gastric cancer, including the application of pathology detection, between the pathology department and the clinical department The collaboration and other aspects have had a far-reaching impact.

The results of CheckMate-649 showed such a big improvement in survival data, and the foreseeable significance and future impact are no less than this.

Professor Lin Lin also concluded: With such high-level medical evidence as CheckMate-649, it is inevitable and undoubted to change our clinical practice; the impact on the future is undoubtedly far-reaching.

First of all, this study confirms the efficacy of immunotherapy in gastric cancer, and also clarifies that immunotherapy-based therapies have exploratory value in gastric cancer, laying the foundation for future research.

Secondly, with the success of immunotherapy in the first-line treatment, the treatment options for the late-line of advanced gastric cancer may face a "shuffle"-under the background of the era of first-line immunity, what impact will immunotherapy have on the biological characteristics of tumors? What adjustments need to be made to the treatment plan, and how the clinical research will be designed, these questions need to be further explored.

In addition, whether the program can continue to advance to the front line, in the perioperative application of patients, that is, for neoadjuvant and adjuvant treatment of gastric cancer, is also very worth exploring: once successful, the clinical benefit is not simply prolonged survival.
For earlier patients, it may mean adding a cure.

At present, relevant clinical studies are underway, and the future prospects are promising.

The road is long and long; it should be noted that although immunotherapy has greatly improved the survival of advanced gastric cancer first-line treatment, there is still a big gap compared with other major cancer types, such as non-small cell lung cancer and breast cancer.

Fortunately, from the door opened by CheckMate-649 research, we have seen the dawn of the future.

Following this path of continuous exploration, the day when the survival of gastric cancer patients ushered in a major leap may not be too far away.

Expert profile: Professor Lin Shen, Deputy Dean of Peking University Cancer Hospital, Deputy Director of Beijing Cancer Institute, Director of Gastroenterology Oncology Department, Director of Phase I Clinical Trial Ward, Asian Gastric Cancer Diagnosis and Treatment Guidelines and GIST Diagnosis and Treatment Guidelines Chinese Drafter, National Health Commission Gastric Cancer /The author and team leader of the colorectal cancer diagnosis and treatment standard served as the secretary-general of the Chinese Anti-Cancer Association Gastric Cancer Professional Committee Chairman of the MDT Special Committee of the Chinese Medical Doctor Association Surgeons Branch Chairman of the Chinese Anti-Cancer Association Cancer Drug Clinical Research Professional Committee National Key Science and Technology Department The chief expert of the R&D plan "Research on New Technologies for Targeted Treatment of Gastric Cancer" has undertaken nearly 10 national or provincial and ministerial-level projects, more than 30 international cooperation and horizontal projects, and published more than 120 SCI papers.
Won the second prize of National Science and Technology Progress Award, Ministry of Education The first prize of scientific and technological progress, the first/second prize of China Medical Science and Technology Award and other awards.
In 2016, he was hailed as the national outstanding scientific and technological worker.
Professor Zhang Xiaotian, Doctor of Medicine, Chief Physician, Associate Professor, and Doctoral Supervisor of the Department of Digestive Oncology, Peking University Cancer Hospital, Beijing Deputy Director, Department of International Cooperation and Exchange, University Cancer Hospital, Executive Deputy Director, Department of Internal Medicine, Executive Deputy Director, Chinese Society of Clinical Oncology, Chairman, Youth Expert Committee, Chinese Society of Clinical Oncology, Chairman, Chinese Anti-Cancer Association, Gastric Cancer Professional Committee, Youth Committee, Secretary-General, Chinese Anti-Cancer Association, Cancer Support Therapy Committee, China Research Hospital Association Precision Vice Chairman of the Medical and Oncology MDT Professional Committee Chairman of the Gastric Cancer Prevention Committee of Beijing Cancer Prevention and Treatment Society, etc.