Professor Shen Lin deeply commented on CheckMate -649: Opening a new era of upper gastrointestinal tumor diagnosis and treatment

Tumor lookout

Recently, based on the results of the CheckMate-649 study, Odivor (navuliyumab) combined chemotherapy in China has been approved for the first-line treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma, regardless of PD-L1 expression level. This is the first and currently the only PD-1 inhibitor approved for first-line indications for advanced gastric cancer in China; it is also the first major breakthrough in this field in more than a decade.

How would you rate the design and results of the landmark study CheckMate -649? What impact will the approval of this indication have on the first-line clinical practice of advanced gastric cancer in China and the future exploration of upper gastrointestinal tumor treatment? During the 2021 CSCO Conference, Professor Shen Lin, the leading Chinese investigator of the CheckMate-649 study and vice president of Peking University Cancer Hospital, is expected to give an oral presentation on the results of the Chinese subgroup of the study at 11:45 a.m. on September 27 at 11:45 a.m., in the online conference room 3 of the conference; previously, we also had the honor to invite Professor Shen Lin to conduct an in-depth analysis of this study and its far-reaching implications.

High standards of experimental design drive high-quality research results

CheckMate-649 is a global multicenter, randomized, open-label, three-arm phase III clinical study designed to evaluate the efficacy of a navulilizumab-based regimen for the treatment of patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma compared with chemotherapy alone.

Research Highlight 1: The world's largest scale, China's participation the most

The CheckMate-649 overall study included a total of 2032 patients (of which 13.4% were Chinese) from 176 research centers in many countries and regions around the world. CheckMate -649 is the largest randomized, global Phase III study to date of first-line treatment of gastric and esophageal cancer based on immune checkpoint inhibitors. CheckMate-649 is also the world's largest multicenter multicenter gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma study in China.

CheckMate -649 overall study design

In this regard, Professor Shen Lin commented: In the history of global gastric cancer research, there has never been a clinical trial with such a large sample size of CheckMate-649 research. The previous advanced metastatic gastric cancer study enrolled a maximum of 700 to 800 cases, and the study of locally advanced gastric cancer also enrolled about 1,000 cases, while the CheckMate-649 study enrolled more than 2,000 cases overall. This may be considering the characteristics of the high heterogeneity of gastric cancer, under such a large sample size of clinical study design, even if the overall population does not benefit, it is still possible to explore the target population that really benefits; and the study finally achieves both OS and PFS benefits in the overall population, which is surprising. At the same time, the CheckMate-649 study included 208 Chinese patients, which ranked first among all countries, and the results of the study can also be extrapolated to Chinese group.

Research highlight 2: PFS, OS dual endpoint design

The primary endpoints of the CheckMate-649 study were double endpoints, PFS and OS in cps≥5 populations, where the α segmentation values were 0.02 and 0.03, respectively, that is, the positive clinical endpoint of this study could only be considered to be met when both the primary endpoints PFS and OS needed to meet higher statistical assumptions. The findings also lived up to expectations and are the only studies to date to confirm the dual benefits of combination immunotherapy versus chemotherapy for PFS and OS.

Global data showed that in patient populations with a combined positive score (CPS) of ≥5: the median OS of the Navulilizumab combined chemotherapy group was 14.4 months, compared with the chemotherapy group alone (11.1 months), the risk of death was reduced by 29%, and the median PFS of the navulijulumab combined chemotherapy group was 7.7 months, compared with the chemotherapy group alone (6 months), the risk of cancer progression or death was reduced by 32%, and both primary endpoints passed the hypothesis test with a p<0.0001 result.

Global population data link (☟ click on the link to jump to read)

In terms of the design of the double endpoint study, Professor Shen Lin said: Our previous similar clinical studies were mostly designed for a single endpoint, and the double endpoint design of CheckMate -649 actually increased the difficulty of the study. Setting the double endpoint earlier to obtain PFS data can provide the FDA or CDE with earlier primary endpoint data, laying the foundation for timely approval and earlier drug accessibility. Overall, as a clinical study, a two-endpoint design is more difficult and the results are more reliable.

The data is eye-catching and confirms that the drugs in Chinese groups are effective and safe

CheckMate-649 study China subgroup results showed clinically significant overall survival versus progression-free survival benefits, as well as higher objective response rates, compared with chemotherapy alone in combination with chemotherapy alone in previously untreated advanced Patients in China. Moreover, Chinese group as a whole showed a trend of greater benefit, for example, the risk of death in the population as a whole decreased by 39% (compared with 20% globally) and the risk of disease progression or death by 43% (compared with 23% globally).

China subgroup data link (☟ click on the link to jump to read)

For the results of the CheckMate -649 study Chinese group, Professor Shen Lin pointed out that in the study results, after the combination of immunotherapy and chemotherapy in patients with advanced gastric cancer in China, it can be seen that the risk of disease progression is significantly reduced, the results are better than the global population data, and better efficacy trends can be observed in OS, PFS and ORR, which may be related to the more sensitive characteristics of gastric cancer in Chinese population to immunotherapy, and may also be related to the acquired factors and genetic background of Chinese. Although it is not yet possible to identify the exact influencing factors from a single study, it is indeed a very gratifying result for the majority of Chinese patients at this stage.

In terms of safety, CheckMate-649 studies the safety profile of navulilizumab combined with chemotherapy consistent with known safety profiles, and the Chinese population is consistent with the world, and no new safety signals are observed. In addition, in the Chinese subgroup studied, no treatment-related deaths were reported in the navulilizumab plus chemotherapy group.

Professor Shen Lin also said that the mild immune response caused by the Chinese population is no different from that of foreign populations, and the incidence of skin allergies, diarrhea and immune enteritis can be observed to be lower. The above conclusions have enabled the efficacy and safety of navuliliumab combined chemotherapy in the treatment of patients with advanced gastric cancer in China.

It was quickly approved to reshape the first-line treatment pattern of advanced gastric cancer in China

On April 16, 2021, based on the CheckMate-649 study, the U.S. Food and Drug Administration (FDA) approved Odivo (Navuliyumab injection) in combination with fluorouracil and platinum chemotherapy drugs for the first-line treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, regardless of PD-L1 expression status; then, just over four months later, the State Drug Administration (NMPA) approved the same indication in China.

In this regard, Professor Shen Lin said that the biggest significance of this approval is to meet the huge needs of current patients and fill the gap in the field of front-line treatment of gastric cancer: Recently, CDE issued the "Clinical Value-Oriented Clinical Research and Development Guidelines for Clinical Research and Development of Anti-tumor Drugs" Draft for Comment, pointing out that clinical value-oriented and patients can really benefit from the ultimate goal of clinical research and drug treatment. CheckMate-649 research has achieved great success worldwide, and with the participation of Chinese patients, it has laid a solid foundation for the rapid approval of indications in China; coupled with the long-term huge gap in the first-line treatment of HER2-negative gastric cancer patients in China, this rapid approval profoundly reflects the importance attached to the needs of patients with high-incidence cancer at the national level and meets the huge expectations of patients.

In the future, the innovative achievements of navuliyuzumab will lead the reform of upper gastrointestinal tumor diagnosis and treatment

In addition to the CheckMate -649 study, the Phase III study CheckMate -577/648 has set its sights on the field of esophageal cancer, which is also a high incidence of cancer in China, and has successively achieved the world's first postoperative adjuvant immunotherapy phase III research results for esophageal cancer, and the world's first-line "chemotherapy-free" (immune Gemini "O+Y" scheme) Phase III research results. The clinical evidence of navuliyumab in these representative studies covers all first-line populations in the upper gastrointestinal tract (different sites, pathological types), as well as adjuvant therapy after surgery for esophageal cancer and gastroesophageal junction cancer.

Previously, China's high incidence of upper gastrointestinal tumors was not taken seriously globally due to its low incidence in Western countries: taking esophageal cancer as an example, cisplatin+5-FU regimen has not been challenged for more than 50 years since it became a first-line standard chemotherapy in the 1960s. Today, with the rapid development of immunotherapy, the diagnosis and treatment of upper gastrointestinal cancer is ushering in an unprecedented era full of opportunities.

Finally, Professor Shen Lin also concluded in the prospect of immunotherapy for gastrointestinal tumors: CheckMate -649 research confirms the value of gastric cancer immunotherapy, which has triggered an overall wave of drug and clinical research in the field of gastric cancer, and many ongoing gastric cancer-related similar studies have significantly accelerated the progress, and made clinicians and researchers begin to pay more attention to the immune microenvironment of gastric cancer. The evidence of heavy clinical research, represented by the CheckMate -649 study, has become an important basis for changing clinical guidelines, and will eventually profoundly change clinical practice. The success of checkMate-649 research will be a new starting point in the field of gastric cancer and even upper digestion tumors, for gastric cancer populations, it is necessary to further deepen the analysis of clinical characteristics and sensitive populations, present more detailed results, and let specific patients achieve greater benefits in specific treatment models. In addition, we have also seen the first-line immunotherapy results of esophageal squamous cell carcinoma represented by CheckMate -648, which not only benefits as much as stomach cancer, but also achieved the first success of the double immune "chemotherapy-free" program, which is a very bold exploration and has also achieved very gratifying results. These clinical studies give us new hope in the field of upper gastrointestinal tumors. But we still need to continue to explore, and look forward to the near future, there will be new data, new results continue to present.