The first-line, neoadjuvant treatment of advanced gastric cancer is progressing rapidly, and innovative therapies are expected to change clinical practice. 2021ASCO Gastric Cancer Special

*Only for medical professionals to read and refer to Fudan Cancer Experts Interpretation of 2021 ASCO New Progress in Gastric Cancer Diagnosis and Treatment! The 2021 American Society of Clinical Oncology (ASCO) Annual Meeting will be held online from June 4th to 8th.
As one of the largest and most popular events in the oncology field, it will show scholars from all walks of life the latest cutting-edge progress in the field of oncology every year
.

"Experts on complex tumors will take you to the 2021 ASCO-Stomach Cancer Special" Invited Professor Dazhi Xu, Professor Chen Jie, Professor Huang Mingzhu, and Professor Wang Chenchen from Fudan University Affiliated Tumor Hospital to interpret the blockbuster research of gastric cancer from different perspectives and convey the cutting edge Dynamic
.

Scan the code to watch the live broadcast.
Professor Xu Dazhi: CheckMate649 expands the results of the study to explore the efficacy and safety of NIVO+ chemotherapy in the first-line treatment of advanced newly-treated GC/GEJC/EAC patients (abstract number: 4002) The results of the CheckMate649 study in 12020 are announced for the first time, marking gastric cancer immunity The starting point of treatment The CheckMate649 study is a global, large, randomized controlled Phase III clinical study to explore PD-1 inhibitor-based treatment options for first-line treatment of advanced gastric cancer/gastric junction cancer/esophageal adenocarcinoma (GC ／GEJC/EAC) the efficacy and safety of patients, the results show that in the PD-L1 combined positive score (CPS) ≥5, ≥1 and all randomized populations, nivolumab (NIVO) + chemotherapy is compared with chemotherapy Overall survival (OS) and disease progression-free survival (PFS) have better benefits, and the safety is acceptable
.

Based on this, the US Food and Drug Administration (FDA) approved it as a first-line treatment for GC/GEJC/EAC patients
.

 CheckMate649 study design 22021ASCO: CheckMate649 extended study results again prove the advantage of NIVO + chemotherapy Now, at the 2021 ASCO conference, the CheckMate649 study extended results section, that is, the data of all randomized populations has been published
.

 In terms of efficacy results, among all the expanded randomized populations, patients in the NIVO+ chemotherapy group have an advantage in OS compared with patients in the chemotherapy group, and the increase in PFS is also more clinically significant
.

Especially in the group of patients with PD-L1 CPS≥5, the median OS of the NIVO+ chemotherapy group and the chemotherapy group were 13.
8 months and 11.
6 months, respectively, and the median PFS were 7.
7 months and 6.
0 months, respectively
.

 CheckMate649 study OS and PFS results (all randomized population) After subgroup analysis of OS, it can be found that in almost all subgroups, the NIVO+ chemotherapy group has an advantage in OS compared to the chemotherapy group
.

 CheckMate649 study OS subgroup analysis results (all randomized populations) In terms of treatment response and duration of remission (DoR), among all randomized populations, the objective response rate (ORR) of patients in the NIVO+ chemotherapy group was higher (58% vs 46%) ), the DoR time is longer (8.
5 months vs 6.
9 months)
.

 CheckMate649 study treatment response and duration of remission (all randomized populations) The most striking thing is that the results of the subgroup analysis of the efficacy of all randomized populations show that the NIVO+ chemotherapy group has indeed benefited from OS and PFS compared with the chemotherapy group.
It is more obvious in people with higher PD-L1 CPS, but the ORR benefit is the same in all subgroups, that is, regardless of the patient's PD-L1 CPS expression
.

It is worth noting that the vast majority of the randomized population included in the study are patients with PD-L1 CPS ≥ 5, which does not correspond to the PD-L1 expression of patients in the real world.
Therefore, you need to be cautious when interpreting the study.

.

This is also the reason why the National Cancer Comprehensive Network (NCCN) guidelines recommend that this program be used only in people with PD-L1 CPS≥5
.

 The results of the efficacy subgroup analysis of the CheckMate649 study (all randomized populations) In terms of safety, in all organ categories, the proportion of patients in the NIVO+ chemotherapy group that experienced grade 3 to 4 treatment-related adverse reactions (TRAEs) was ≤5%
.

The vast majority of non-endocrine selective TRAEs that occurred in the NIVO+ chemotherapy group can be controlled with existing symptomatic treatments (median time to remission is 2 to 23 weeks), and the addition of NIVO to chemotherapy does not increase the toxicity of the treatment Response
.

 Safety results of the CheckMate649 study (all randomized populations) In terms of symptom deterioration control, the NIVO+ chemotherapy group can reduce the risk of symptom deterioration by 23% compared with the chemotherapy group
.

  Symptom worsening risk results of the CheckMate649 study (all randomized populations) In summary, the research data of the CheckMate649 study in all randomized populations show that NIVO+ chemotherapy can be used as a potential first-line treatment option for advanced HER2-negative GC/GEJC/EAC compared with chemotherapy.
China is also involved in this study.
Therefore, an in-depth interpretation of the research results has guiding significance for clinical practice in China
.

 Professor Chen Jie: NEO-AEGIS-International Research on Neoadjuvant Therapy for Esophageal Adenocarcinoma and Esophageal Gastric Junction Cancer (Abstract No.
4004) was confirmed by the emergence of the CROSS study in the journals of NEJM in 2012 and The Lancet in 2015 For resectable esophagus and esophagogastric junction cancer, compared with patients undergoing surgery alone, patients receiving neoadjuvant radiotherapy and chemotherapy have a significant survival benefit.
However, 75% of the patients enrolled in the CROSS study are glandular Cancer, after adjusting the risk ratio (HR), the P value is 0.
07.
Therefore, although the neoadjuvant radiotherapy and chemotherapy model of the CROSS study can also benefit patients with adenocarcinoma, the benefit is not as much as the data surface
.

Another landmark study, the MAGIC study has confirmed that neoadjuvant chemotherapy can benefit patients with adenocarcinoma.
So, which model is more suitable for patients with esophageal adenocarcinoma and esophagogastric junction cancer, NEO-AEGIS study Thus was born
.

 1 The NEO-AEGIS study is the first locally advanced esophageal adenocarcinoma and esophageal-gastric junction cancer neoadjuvant radiotherapy vs.
chemotherapy treatment model study.
NEO-AEGIS study is a head-to-head, international, phase III randomized controlled clinical study.
The patients were 377 cases of adenocarcinoma of the esophagus and esophagogastric junction with cT2～3N0～3M0 from 25 medical centers in 5 countries, with masses ≤8cm
.

The patients were randomly divided into perioperative chemotherapy + surgery group (group A, MAGIC study mode) and neoadjuvant chemoradiation + surgery group (group B, CROSS study mode).
The study hypothesized that the CROSS mode can bring 10 % of survival benefit, the OS for the primary endpoint, disease-free survival is a secondary endpoint (the DFS), time to failure, toxicity and the like
.

NEO-AEGIS study design 2OS results: There was no statistical difference between MAGIC mode vs CROSS mode in neoadjuvant therapy.
There were 184 and 178 patients in groups A and B with evaluable efficacy, respectively.
During a median follow-up time of 24.
5 months, a total of 143 patients died, including 73 in group A and 70 in group B.
The 3-year OS rates of the two groups were 57% and 56% [HR (95%CI) 1.
02 (0.
74～1.
42)], no statistics Learn the difference
.

For this reason, the study will stop enrollment in December 2020, and the final survival analysis will be announced in July 2022
.

 3TRAEs results: The incidence of TRAEs in MAGIC mode is higher, especially in neutropenia and diarrhea.
Compared with CROSS mode, the incidence of MAGIC mode is higher, and there is a statistical difference
.

 NEO-AEGIS study TRAEs results 4 Postoperative complications: There is no significant difference between MAGIC mode and CROSS mode.
There were 3 cases and 5 cases of MAGIC mode and CROSS mode respectively.
Postoperative deaths occurred, which may be related to acute respiratory distress syndrome (ARDS) Related, there was no significant difference in postoperative complications between the two groups
.

 NEO-AEGIS study postoperative complications results 5 postoperative pathological evaluation: CROSS mode is better than MAGIC mode, CROSS mode and MAGIC mode, R0 resection (95% vs 82%) and TRG1&2 (41.
7% vs 12.
1%) in the two groups P <0.
001
.

 NEO-AEGIS study postoperative pathological results.
In short, CROSS mode compared with MAGIC mode showed no survival advantage in patients with locally advanced esophageal adenocarcinoma and esophagogastric junction adenocarcinoma.
At the same time, there were no significant postoperative complications in the two groups.
The difference is only in the postoperative pathological response, the CROSS mode is more superior
.

The reason for the insignificant difference in survival between the two groups may be due to the close pathological complete remission (pCR) postoperatively and the death of postoperative patients in CROSS mode.
In addition, the postoperative spread of adenocarcinoma patients may be more, and the surrounding Postoperative chemotherapy during surgery can bring benefits
.

 Professor Huang Ming: Exploration of KENOTE811 study using pembrolizumab + trastuzumab + chemotherapy for HER2-positive metastatic gastric or esophagogastric junction cancer (interim analysis results) (Abstract number: 4013) for HER2-positive metastasis For gastric or gastroesophageal junction (G/GEJ) tumors, the previous standard first-line treatment was anti-HER2 trastuzumab + fluorouracil + platinum.
The MSKCC study and the PANTHERA study suggested the addition of trastuzumab to pembrolizumab After the monoclonal antibody + chemotherapy, the anti-tumor activity can be improved, and the safety is controllable
.

Therefore, the KENOTE811 research kicked off
.

 KENOTE811 Study Design The KENOTE811 study is a global multicenter, double-blind, phase III, for unresectable or metastatic HER2-positive G/GEJ patients, using pembrolizumab + trastuzumab + chemotherapy (pembrolizumab) Monoclonal antibody group) vs placebo + trastuzumab + chemotherapy (placebo group) as a comparative study of first-line treatment
.

It is worth noting that nearly 1/3 of the patients in this study are Asian patients, mainly gastric primary, and CAPOX is the more choice in the choice of chemotherapy
.

 1ⅠA1 analysis showed that after ≥8.
5 months of follow-up time, the proportion of continuous treatment in the pembrolizumab group was higher.
The first interim analysis (ⅠA1) of the 264 patients included in the initial study showed that between 8.
5 months and 19.
4 months During the follow-up period, the proportions of patients in the pembrolizumab group and placebo group who received continuous treatment were 40.
6% and 28.
5%, respectively
.

 2ⅠA1 analysis shows that the pembrolizumab group is better for tumor remission.
Although the waterfall chart shows that whether it is pembrolizumab group or placebo group, the proportion of all grades of tumor regression has reached more than 90%, and More than 80% of patients with tumor regression reached 32% and 15%, respectively.
However, in ORR (74.
4% vs 51.
9%, P=0.
00006), complete remission [CR, 15 (11%) vs 4 (3%)] , Partial remission [PR, 84 (63%) vs64 (49%)], pembrolizumab group was better
.

 The 3ⅠA1 analysis showed that there was no significant difference in safety between the two groups.
Both groups had treatment-related adverse reactions of grade 3 and above, 57%, but the proportion of immunotherapy-related adverse reactions above grade 3 was 10% in the pembrolizumab group.
Security is generally acceptable
.

 ⅠA1 analysis of efficacy results In summary, the ⅠA1 results of the KENOTE811 study indicate that for untreated, unresectable or metastatic HER2-positive gastric and gastroesophageal junction cancers, pembrolizumab combined with trastuzumab + chemotherapy can become potential New treatment options
.

 Professor Huang Ming: The PLATFORM study explores the use of duvalizumab for maintenance therapy after first-line platinum-based chemotherapy for advanced esophagogastric junction adenocarcinoma (Abstract No.
4015) The PLATFORM study is a prospective, open-label, multi-center The adaptive phase II clinical study aims to explore the efficacy of maintenance treatment for esophageal cancer, gastroesophageal junction cancer (GOJ) and gastric adenocarcinoma after first-line chemotherapy.
This time, it mainly focuses on A3 (duvaliumab) vsA1 (Observation) part of the report
.

 PLATFORM study design As of February 2021, a total of 205 patients were enrolled in the A1 and A3 groups, with a median follow-up time of 24.
2 months.
The proportion of metastatic patients in both groups accounted for more than 90%, and more than 80% of the first-line patients The duration of chemotherapy is 18 weeks
.

 The median duration of continuous treatment in the first-degree varizumab group was longer, and the median duration of continuous treatment in the varizumab group and observation group were 3.
5 months and 2.
8 months, respectively, and the rate of treatment interruption was 97 cases (94%).
And 94 cases (94%), the proportion of treatment interruption due to progress was 62 cases (60%) and 82 cases (82%), respectively
.

Five patients were re-challenged with duvalizumab after treatment was discontinued
.

 PLATFORM study A1 group and A3 group treatment situation 2 degrees of Vallizumab maintenance treatment can not bring OS benefit.
Whether it is PFS or OS curve, it can be seen that the two groups fit closely, and there is no statistical difference in value.
Of course, with the increase of PD-L1 CPS, there is a tendency to benefit more in the maintenance treatment of duvalizumab
.

The incidence of serious adverse reactions in the duvalizumab group and the observation group were 36% and 15%, respectively
.

 PLATFORM study the efficacy of group A1 and group A3.
In summary, for patients with advanced gastric adenocarcinoma, esophagogastric junction cancer and esophageal cancer, maintenance treatment with duvalizumab after 18 weeks of first-line chemotherapy did not significantly prolong PFS and OS.
However, as the expression of PD-L1 increased, the PFS of patients on maintenance treatment of duvalizumab also increased, indicating that PD-L1 CPS may be a marker for screening of patients on maintenance treatment of duvalizumab
.

 Prof.
Chenchen Wang: The FIGHT study explores the use of Bemarituzumab + mFOLFOX6 as the first-line treatment for FGFR2B-positive advanced gastric cancer/gastric junction adenocarcinoma (Abstract No.
4010).
For FGFR2B inhibitor Bemarituzumab, previous studies have confirmed that FGFR2B-positive gastroesophageal junction cancer , Bemarituzumab can achieve an overall remission of 18% in the back line.
Now, it challenges the first-line treatment of FGFR2B-positive advanced gastric cancer/gastroesophageal junction adenocarcinoma
.

 The FIGHT study is a double-blind, placebo randomized controlled phase II clinical study.
After admission, patients were randomly divided into Bemarituzumab+mFOLFOX6 (Bemarituzumab group) and placebo+mFOLFOX6 (placebo group).
The two groups were enrolled in 77 cases.
And 78 patients, the baseline characteristics of the two groups were balanced, 83.
2% of the patients immunohistochemically showed FGFR2B overexpression, but ctDNA was negative
.

 FIGHT Study Design FIGHT Study Flow Chart 1 FGFR2B positive degree is higher, more benefit from bemarituzumab The PFS time and OS time of the overall population of the Bemarituzumab group and the placebo group are 9.
6 months vs 7.
4 months respectively [HR 0.
68 (0.
44, 1.
04)] and did not reach vs12.
9 months [HR 0.
58 (0.
35, 0.
95)], PFS had a trend of benefit but did not reach the statistical cut-off value, while OS had a statistical difference
.

On ORR, the bemarituzumab group and placebo group were 36% and 26%, respectively
.

 Regardless of PFS, OS, ORR, it is suggested that patients whose IHC expression of FGFR2B exceeds 10% are more likely to benefit from the Bemarituzumab group
.

 FIGHT Study Efficacy Results 2 Among all subgroups, the PFS and OS in the Bemarituzumab group had more obvious benefits.
Among them, the IHC positive was more beneficial than the ctDNA positive.
The analysis of the FIGHT subgroup analysis results 1 FGFR2B IHC expression higher, the two groups of OS achieved The more obvious the difference in benefit.
In the overall intention population and FGFR2B IHC2+/3+ >5% and >10% population, the median OS of the Bemarituzumab group and the placebo group was 19.
2 months vs.
13.
5 months, and under-achieved months vs.
12.
5 months and 25.
4 months vs 11.
1 months
.

 FIGHT study patients OS benefit trend In short, regardless of the status of FGFR2 gene amplification in ctDNA, first-line treatment with Bemarituzumab can improve the therapeutic effect of patients with advanced gastric cancer/gastroesophageal junction adenocarcinoma with overexpression of FGFR2.
However, it is necessary to pay attention to the specific toxicity of Bemarituzumab Corneal toxicity, dry eye syndrome
.

 Prof.
Chenchen Wang: EXELOX study-the exploration of the XELOX vs EOX regimen for the first-line treatment of advanced gastric cancer patients (Abstract No.
4014) The EXELOX study is an open-label, multi-center, randomized controlled, prospective phase III clinical study aimed at exploring advanced gastric cancer The pros and cons of the first-line use of XELOX and EOX for gastric cancer patients
.

The primary endpoint is that the XELOX regimen on PFS is not inferior to the EOX regimen
.

 EXELOX study design 1 The XELOX regimen non-inferiority on PFS reached the primary endpoint in the EOX regimen study.
The pFS of the XELOX regimen group and the EOX regimen group were 5.
0 months and 5.
5 months, respectively, and the non-inferiority P value was 0.
0032
.

The median OS time of the two groups was 12.
0 months, and the P value was not statistically different
.

On ORR, the XELOX program group and EOX program group were 37.
4% and 45.
1%, respectively
.

Stratified analysis showed that for patients with poor differentiation and liver metastases, the use of three-drug chemotherapy has a trend of benefit for PFS and OS
.

 EXELOX study curative effect results 2XELOX regimen group patients have better quality of life and lower toxic reactions.
EXELOX study safety results.
In short, this is the first non-inferiority comparative study on the first-line use of XELOX regimen and EOX regimen in patients with advanced gastric cancer.
The curative effect of the regimen is not inferior to the three-drug regimen, and the patient's quality of life is higher, and the toxicity is lower.
However, for patients with poor differentiation and liver metastasis, the three-drug regimen may have more advantages
.