Professor Lv Jing | Stomach Lai Xianfeng (9): In-depth analysis of CheckMate-649 Chinese subgroup data and the differences between Chinese and global data

CheckMate-649 is a landmark study in the world's first-line immunotherapy for advanced gastric cancer, first published in The Lancet, a top medical journal, in 2021¹, and the two-year long-term follow-up data in 2022 topped the journal Nature²
.
The Chinese subgroup data of the study have been disclosed at previous international conferences and have received extensive attention
from domestic experts in the field of gastric cancer.
The full article of this publication provides us with a detailed analysis of the complete data of the CheckMate-649 Chinese subgroup and the reasons for the discrepancy between the data of the Chinese population and the global population³.

It is well known that there are differences in clinical factors in patients with gastric cancer in the East and West, such as more lower parts and fewer middle parts of the initial tumor location of gastric cancer; Histology Lauren classification diffuse type less; Surgical modalities: more proximal gastrectomy, less total gastrectomy, and so on
.
In addition, a previous meta-analysis showed a more pronounced survival benefit in Asian populations than in non-Asian populations in patients with gastric or gastroesophageal junction cancer treated with immune checkpoint inhibitor monotherapy⁴^,⁵
.
This may be because the two populations have different tumor immune signatures that are associated with T cell function⁶
.
Therefore, in the global clinical study of gastric cancer immunotherapy, it is necessary
to preset Chinese subgroup analysis.

The CheckMate-649 study included a total of 1581 patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma worldwide, including 208 patients in China
.
Studies have shown that the Chinese subgroup is consistent with global studies showing benefits of nivolumab in combination with chemotherapy in the whole population of China
.

Figure 1: CheckMate-649 Chinese subgroup study design

In the CPS≥5 population, the median OS of the Chinese group increased by 5.
9 months (HR=0.
54) from 9.
6 months to 15.
5 months, the median PFS increased by 4.
2 months (HR=0.
55) from 4.
3 months to 8.
5 months, and ORR increased by 20% from 48% to 68%.

。

In the CPS≥1 population, the median OS of the Chinese group increased by 4.
4 months (HR=0.
59) from 9.
9 months to 14.
3 months, the median PFS increased by 3.
4 months (HR=0.
59) from 4.
9 months to 8.
3 months, and the ORR increased from 47% to 65%, an improvement of 18%.

It is worth mentioning that this paper discloses for the first time the benefit data
of the CPS<1 population of the Chinese subgroup CheckMate-649.

In the CPS<1 population, the median OS of the Chinese group increased by 1.
2 months from 10.
6 months to 11.
8 months (HR=0.
69).
The median PFS increased by 4.
2 months from 5.
8 months to 10.
0 months (HR=0.
51).
ORR improved by 39% from 36%
to 75%.
Although this part of the population is very limited, the span of the forest map is large; In addition, it is indeed not as significant as the benefit of people with CPS≥1; But we can also see that even if the PD-L1 expression is negative in Chinese gastric cancer patients, there is still a trend to benefit from nivolumab combined with chemotherapy.

In the 2022 CSCO gastric cancer guidelines, for patients with HER2-negative, PD-L1 CPS<5 or gastric cancer that cannot be detected, the first-line treatment level II recommendation also adds nivolumab combined with chemotherapy⁷.

In clinical practice, patients with large tumor burden need to reduce tumor burden as soon as possible to relieve symptoms; Alternatively, patients with initially inoperable T4b or oligometastasis, but with potential transformation potential assessed by MDT, and whose treatment goal is tumor-free status (NED), may still be considered in combination with nivolumab
.

Figure 2: Analysis of OS, PFS, and ORR of the PD-L1 CPS subgroup by the CheckMate-649 Chinese subgroup

Data from the Chinese subgroup show that the trend of benefit from nivolumab combined chemotherapy in Chinese patients is more pronounced than in the global population, which is consistent
with the results of the meta-analysis mentioned earlier.
The reason may be due to the difference in baseline characteristics of patients with gastric cancer in the East and the West, including stage, location and tumor microenvironment
.

Overall, data from the Chinese subgroup of the CheckMate-649 study showed that nivolumab in combination with chemotherapy showed comprehensive benefit in five endpoints in Chinese patients with advanced gastric cancer: median OS extension for half a year; ORR nearly 70%; Double PFS; DoR doubled; Safe 0 deaths
.
The publication of this full paper further consolidates the position
of nivolumab in the first-line treatment of advanced gastric cancer in China.

Figure 3: Five-star benefit of nivolumab in combination with chemotherapy

Yimaitong: Could Professor Lu share his clinical experience in first-line immunotherapy for advanced gastric cancer based on clinical experience?