Asia vs West, gastric cancer survival data PK

Stomach cancer and gastroesophageal adenocarcinoma are the fourth leading cause
of cancer death worldwide.
The incidence of gastric/gastroesophageal adenocarcinoma varies by region, with the highest rates currently in Asia Pacific and lowest
in North America.
Over the past few decades, the overall incidence has declined globally, but advanced unresectable stomach cancer often has a poor
prognosis.
In recent years, the treatment landscape for advanced/metastatic gastric cancer has changed
dramatically.
New treatments are emerging, including immunotherapy, targeted therapy, etc
.
It is important to note that gastric/gastroesophageal adenocarcinoma is a highly heterogeneous disease
in terms of geographical location.
Based on previous studies, patients with gastric cancer in Asia (including Japan, China, and Korea) and the West (mainly Caucasians from North America or Western Europe/Northern Europe) have different prognosises
.
According to subgroup analysis of multi-country randomized controlled studies, Asian patients had longer progression-free survival (PFS) and overall survival (OS).

In contrast, Western patients have shorter survival and a poorer
response to systemic therapy.

Knowing the difference in survival outcomes and treatment outcomes is critical for clinicians, but the available research is insufficient to help clinicians make accurate judgments about the most appropriate treatment for
patients.
A recent systematic review meta-analysis quantitatively evaluated the efficacy (OS and PFS) of various systemic therapies in patients with unresectable gastric/gastroesophageal adenocarcinoma in Asia and the West, and sought to verify the correlation
between survival parameters and geography.

Research methods

The study searched PubMed-MEDLINE, EMBASE, Web of Science, and Cochrane Library for clinical studies up to October 31, 2021, and reviewed conference abstracts from the 2001-2021 American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) Annual Meetings, with the following selection criteria:

Inclusion Criteria:

1) randomized or non-randomized controlled clinical trials enrolling Asian and Western patients (patients from North America, Oceania, or Western/Northern Europe) with pathologically confirmed unresectable gastric cancer or gastroesophageal adenocarcinoma;

2) assess the clinical benefits of systemic therapies (including chemotherapy, targeted therapy, immunotherapy, or any combination regimen);

3) Subgroup survival outcomes (OS or PFS) stratified by geography (including Asia)
were reported.

Exclusion Criteria:

1) Single-arm design test;

2) did not recruit Asian or Western patients;

3) lack of subgroup analysis;

4) Studies involved non-systematic interventions (e.
g.
local radiotherapy, tumor shrinkage surgery).

The search identified 1654 relevant literatures, and 20 studies (17 phase III clinical trials, 3 phase II trials) met the criteria, and a total of 9033 patient data were finally meta-analysed, with OS and PFS
as the main assessment indicators.
Random-effects models were used to calculate risk ratios and 95% confidence intervals for OS and PFS in Asian and Western populations
.
A linear regression model was used to compare OS and PFS
in Asian and Western patients.

Figure 1 Summary of included studies

Asia vs West, gastric cancer survival data PK

1.
Overall population: There is no significant difference in survival benefits between Asian and Western populations

OS and PFS were analysed for patients stratified by region based on 18 and nine studies, each comparing the effects
of a specific type of systemic treatment with standard care.
The results of the analysis showed that the HR of OS in Asian patients was 0.
89, 95% CI was 0.
80-0.
99, and heterogeneity was not obvious (I2=36%, P=0.
06), the HR of OS in Western patients was 0.
86, and the 95%CI was 0.
80-0.
93), and there was no heterogeneity between studies (I2=²¹%, P=0.
20).

。 Contrary to the results of the meta-analysis of OS, the treatment regimen in the trial group did not improve the PFS benefit in Asian and Western patients, with an HR of 0.
71 in Asian and Western patients, respectively; 95% CI, 0.
48-1.
04 and 0.
80; 95% CI, 0.
62-1.
04
。

2.
Immunotherapy is used for first-line treatment, and Asian patients have obvious benefits

In the six studies focused on immunotherapy, there was no difference in OS between Asian and Western patients (interaction test P = 0.
32) (Figure 2A).

Compared with controls, receiving immunotherapy resulted in improved
OS in both Asian patients (HR, 0.
80; 95% CI, 0.
65-0.
98) and Western patients (HR, 0.
90; 95% CI, 0.
81-1.
00).
Of the studies mentioned above, two were of immunotherapy in first-line therapy, and further subgroup analysis of OS by treatment line showed clear differences between regions (Figure 2).

In first-line therapy, there was an improvement in OS in Asian patients (HR, 0.
65; 95% CI, 0.
53 to 0.
79), while there was no significant benefit in OS in Western patients (HR, 0.
86; 95% CI, 0.
72 to 1.
04, interaction test P = 0.
04) (Figure 2A).

In addition, Asian patients (HR, 0.
98; 95% CI, 0.
78-1.
23) and Western patients (HR, 0.
92; 95% CI, 0.
83-1.
06) did not benefit from second-line and subsequent immunotherapy (cross-test P=0.
66) (Figure 2B).

Fig.
2 Differences
in OS in different regions when immunotherapy is used in the first and posterior lines.
(A) Frontline; (B) Second line and beyond
.

Of the included immunotherapy-related studies, five evaluated monotherapy and two sought combination therapy (in KEYNOTE-062, immunotherapy or immunotherapy plus chemotherapy was compared with chemotherapy alone).

Results showed that Asian patients (HR, 0.
87; 95% CI, 0.
66-1.
14) and Western patients (HR, 0.
94; 95% CI, 0.
83-1.
06) did not benefit from OS from immunomonotherapy, and there was no significant difference between regions (interaction test P = 0.
60).

However, immunocombination therapy improved OS in Asian patients (HR, 0.
56; 95% CI, 0.
54-0.
87) and Western patients (HR, 0.
77; 95% CI, 0.
63-0.
93) (interaction test P = 0.
22).

3.
Second-line treatment of anti-angiogenic drugs, Western patients benefit more

Four studies explored the efficacy of antiangiogenic drugs, with an evenly balanced benefit for OS in Asian and Western patients (interaction test P = 0.
44).

Although none of the antiangiogenic agents significantly improved the benefit in Asian patients (HR, 0.
95; 95% CI, 0.
79 to 1.
14) and Western patients (HR, 0.
86; 95% CI, 0.
71 to 1.
03), a trend
in OS benefit was shown.
Of the four studies, two were first-line and two were second-line
.
Analysis showed no survival benefit from first-line treatment in Asian patients (HR, 0.
94; 95% CI, 0.
75 to 1.
19) and Western patients (HR, 0.
91; 95% CI, 0.
66 to 1.
26).

。 In the second-line treatment, Western patients treated with antiangiogenic drugs showed longer survival (HR, 0.
79; 95% CI, 0.
64 to 0.
97), while Asian patients (HR, 0.
96; 95% CI, 0.
72 to 1.
28) did not show a similar benefit, with no statistically significant differences between regions (interaction test P = 0.
29).

4.
There was no significant benefit of anti-HER2 therapy and there was no regional difference

In four studies exploring anti-HER2 therapy, although there was a trend towards survival benefit of anti-HER2 treatment compared with control, the OS benefit was not significantly improved in Asian (HR, 0.
87; 95% CI, 0.
69 to 1.
10) and Western (HR, 0.
83; 95% CI, 0.
65 to 1.
06) populations, and there was no regional difference (interaction test P = 0.
77).

5.
Overall, Asian patients benefited more from OS, and there was no difference in PFS benefits between Asian patients and Western patients

Eleven eligible studies provided median OS data for 22 pairs of Asian and Western patients, including 11 trial and 11 control groups
.
Median OS prolongation in Asian and Western patients was statistically significantly associated with treatment (r=0.
867, P< 0.
001).

Five eligible studies provided median PFS data for 10 pairs of Asian and Western patients, including five trial and five control groups
.
Median PFS prolongation in Asian and Western patients was statistically significantly associated with treatment (r = 0.
942, P<0.
001).

Reflect and summarize

This is the first meta-analysis
to comprehensively compare the efficacy of multiple treatment strategies in patients with unresectable gastric/gastroesophageal adenocarcinoma in different settings.
A meta-analysis of 20 clinical trials showed that both Asian and Western patients benefited from immunotherapy, anti-HER2 and anti-angiogenic drugs with no regional differences
in efficacy.

It is unclear
why the efficacy of immune checkpoint inhibitors, anti-HER2 drugs, and antiangiogenic drugs varies so little between regions.
Patient response to treatment is often determined by biomarkers, and while markers such as PD-L1 and HER2 differ little in Asian and Western gastric cancer patients, there are many undiscovered factors that can have an impact on
prognosis.
The complexity of the tumor microenvironment attenuates the influence of a single factor, and multiple factors may cancel each other out
.

From the pooled results of two large RCTs (CheckMate-649 and KEYNOTE-062), Asian patients appear to be more sensitive to first-line immunotherapy, consistent with data from clinical trials of some other cancer types, although this result is still unexplained
.
Previous studies have suggested regional differences
in clinicopathologic features of gastric/gastroesophageal adenocarcinoma.
Proximal tumors are more common in Western patients, while antral tumors predominate
in Asians.
For the Lauren classification, Asians have a higher
proportion of intestinal types.
In terms of molecular subtypes, the Cancer Genome Atlas (TCGA) proposed that the distribution ratios of four gastric cancer subtypes (EBV-positive, genome-stable, microsatellite-unstable MSI and chromosomal instability) were similar in the East and West (Korea is special, and the MSI or EBV positive rate of gastric cancer is significantly higher).

Genetic polymorphisms and epigenomic traits are also regional.

All of these factors can contribute to differences
in immunotherapy sensitivity between Asian and Western populations.
In addition, based on the results of CheckMate-649 and KEYNOTE-062, response to immunotherapy cannot be judged solely by traditional indications such as PD-L1 or TMB, as a large number of patients with PD-L1-negative or low TMB tumors in the CheckMate-649 and KEYNOTE-062 studies produced abnormal lasting remissions
。 Given the differences in immunity between treatment-naïve and severely treated patients, the investigators speculate that there is some immune environment in the treatment-naïve patient that is conducive to first-line immunotherapy, and that this unspecified special immune environment is more common
in Asian patients.
This possible race-specific feature can be used in conjunction with traditional indications such as PD-L1 and TMB to predict prognosis
.
The development of new markers for predicting immunotherapy response must take into account unique immunogenomic features
not possessed by Western patients.
As immune checkpoint inhibitors play an increasingly critical role in the treatment of a wide range of advanced cancers, the correlation between geographic region and treatment response warrants further investigation
.

According to this meta-analysis, patients with unresectable gastric/gastroesophageal adenocarcinoma in Asia had longer OS than Western patients, regardless of treatment, which is highly consistent
with previous studies.
ONE POSSIBLE EXPLANATION IS THAT PATIENTS WITH ADVANCED/METASTATIC GASTRIC/GASTROESOPHAGEAL ADENOCARCINOMA IN ASIA GENERALLY RECEIVE MORE CYTOTOXIC THERAPY AND PALLIATIVE CARE AFTER DISEASE PROGRESSION (AS EVIDENCED BY THE RAINBOW AND AVAGAST TRIALS).

In addition, Asian patients had better baseline physical condition than Western patients, which may indicate better
tolerance and responsiveness to subsequent treatments.
However, the above assumptions require further analysis in prospective studies
.

Overall, although Asian and Western patients with unresectable gastric/gastroesophageal adenocarcinoma have different clinical and genetic profiles, they respond similarly to systemic therapy, with limited
regional variation.
Notably, Asian patients are more responsive to first-line immunotherapy
.
In addition, Asian patients had higher OS than Western patients, and there was no significant difference in
PFS.
These results may influence the design of
multi-country clinical trials.
It is expected that based on the above results, future study designs can give more detailed results with smaller sample sizes, so as to better promote clinical diagnosis and treatment progress and promote more benefits
for patients.

Expert reviews

THIS META-ANALYSIS EXPLORED THE SIMILARITIES AND DIFFERENCES IN SURVIVAL DATA FOR GASTRIC CANCER PATIENTS WITH DIFFERENT THERAPEUTIC DRUGS AND TREATMENT LINES IN ASIA AND THE WEST; The results showed a greater benefit for OS in Asian patients; In particular, the use of immunologic drugs for first-line treatment has significantly benefited Asian patients compared with Western patients; From the published data of a number of large phase III clinical studies also have similar phenomena: such as CheckMate649 and CheckMate649 (Chinese group), KEYNOTE-062, ORIENT16, we can see that there are differences between different races, especially in Asia, especially Chinese groups in the chemotherapy combined immunotherapy mode, the benefit is higher; May be different
from the primary site and immune microenvironment of gastric cancer in Asian populations.
At the same time, anti-HER2 drugs are seen to be no different in Asian and Western populations, and there are two possible reasons:

(1) only ToGA, a subgroup analysis of positive results, was included in the studies included in anti-HER2 therapy, and other clinical studies of anti-HER2 treatment were used in either the first line or the second line;

(2) The included studies all combined with different drugs based on trastuzumab may differ between Asian and Western populations
if anti-HER2 ADC drugs with stronger anti-tumor activity are included.
For second-line antiangiogenic therapy, Western patients benefit more than Asian populations, which may be related to the imbalance in the sample size of the included studies, such as REGARD and RAINFALL, where sample sizes are significantly higher than in Asian populations
.
It is expected that in the future, there will be more detailed exploration of the different clinical and genetic characteristics of patients with unresectable gastric cancer/gastroesophageal adenocarcinoma in Asia and the West, and promote clinical experts to make treatment decisions
that can bring more benefits to patients.