Nature: First-line treatment of advanced gastric cancer opens the "door" of immunotherapy?

*For medical professionals to read and reference, what is the future for the diagnosis and treatment of HER-2 positive gastric cancer? Gastric cancer is one of the top 3 cancers in terms of morbidity and mortality in China
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Data show that in 2020, the number of new cases of gastric cancer in China will account for about 50% of the world, and most patients will progress to the middle and advanced stages when the disease is discovered
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Among them, about 10%-20% of advanced gastric cancer patients have HER-2 gene amplification or protein overexpression
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Unfortunately, for patients with HER-2-positive advanced gastric cancer, treatment options are limited and the prognosis is usually poor
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On December 15, the results of the first interim analysis of the KEYNOTE-811 study were published in the internationally renowned journal Nature
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This will be another landmark study in the field of HER-2 positive advanced gastric cancer after the ToGA study
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Taking this opportunity, the Medical Oncology Channel specially invited Professor Xu Jianming, Director of the Division of Digestive Oncology, Fifth Medical Center of the PLA General Hospital, to interpret and discuss the interim analysis results of the KEYNOTE-811 study and issues related to the diagnosis and treatment of HER-2 positive advanced gastric cancer
.

 Since 2010, there have been few breakthroughs in the diagnosis and treatment of HER-2-positive gastric cancer.
HER-2-positive gastric cancer is a relatively special type of gastric cancer.
Professor Xu Jianming said in an interview: "HER-2 gene is an important cell in a variety of solid tumors.
Proliferation-driving gene, encoding HER-2 protein.
HER
-
2 protein is a transmembrane glycoprotein that plays an important role in cell proliferation, differentiation, angiogenesis and other processes
.

Therefore, compared with HER-2-negative gastric cancer, HER-2-positive gastric cancer has a higher overall degree of malignancy
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For such patients, domestic guidelines recommend that patients receive chemotherapy combined with targeted therapy
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"In 2010, the ToGA study [1] broke the bottleneck of chemotherapy alone in patients with HER-2 positive advanced gastric cancer, established the status of trastuzumab as the first-line standard treatment in such patients, and opened the door for HER-2 positive gastric cancer.
The door to quasi-targeted therapy
.
The
ToGA study showed that compared with chemotherapy alone, trastuzumab combined with chemotherapy significantly prolonged median overall survival [OS, 13.
8 months (95%CI 12-16) vs.
11.
1 months (95%CI 10-13), HR 0.
74, 95%CI 0.
60-0.
91, p=0.
0046], the objective response rate (ORR) also increased from 34.
5% to 47.
3%
.

The ToGA study proved that HER-2 positive Patients with advanced gastric cancer can benefit from anti-HER-2 therapy, and a combination therapy for HER -2-positive advanced gastric cancer has been found that is superior to chemotherapy alone
.

A bottleneck, many studies of targeted therapy for HER2-positive advanced gastric cancer have failed
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Whether it is the JACOB study with Pertuzumab combined with trastuzumab and chemotherapy[2], or the use of Lapa The LOGiC study of tinib combined with capecitabine and oxaliplatin [3] failed to further prolong the OS data of patients
.

In this regard, Professor Xu Jianming pointed out: "Pertuzumab combined with trastuzumab can be effective In different parts of HER-2, it blocks the formation of homo- and heterodimers, thereby blocking its downstream signaling and inhibiting tumor cell proliferation
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In the results of the JACOB study, the benefit trend of patients' OS can be observed, but due to the problems of the study sample size and study design, the JACOB study finally failed to obtain positive results
.

"But this more or less frustrating stalemate, perhaps with the announcement of the interim results of the KEYNOTE-811 study, let people see hope for a breakthrough! The KEYNOTE-811 study may bring treatment to patients with HER-2-positive advanced gastric cancer New Select KEYNOTE-811 study A randomized, double-blind, placebo-controlled phase III study evaluating pembrolizumab or placebo in combination with trastuzumab and chemotherapy in patients with advanced HER-2-positive advanced gastric cancer or Efficacy and safety of first-line treatment for adenocarcinoma of the gastroesophageal junction
.

With the release of the interim data of this study, immunotherapy represented by pembrolizumab may be able to break this deadlock and become the first-line treatment for HER-2-positive advanced gastric cancer.
Patients bring new opportunities
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The results of the KEYNOTE-811 interim analysis, which announced the efficacy of the first 264 patients enrolled, showed that the ORR of patients in the pembrolizumab group was 74.
4% (95%CI 66.
2%) -81.
6%), the complete remission (CR) rate was 11.
3%, and the partial remission (PR) rate was 63.
2%; the ORR in the control group was 51.
9% (95% CI 43.
0%-60.
7%), the CR rate was 3.
1%, and the PR rate was 51.
9% (95% CI 43.
0%-60.
7%).
The rate was 48.
9%, and the ORR was improved by 22.
7% in the pembrolizumab group (95% CI 11.
2%-33.
7%; P = 0.
00006)
.

The median duration of response (DoR) in the pembrolizumab group was 10.
6 month, the disease control rate (DCR) was 96.
2% (95% CI 91.
4%-98.
8%); compared with 9.
5 months and 89.
3% (95% CI 82.
7%-94.
0%) in the placebo group
.

Table 1 Disease remission data in the two groups In terms of safety, the incidence of grade 3-5 adverse events in the pembrolizumab group and the control group were 57.
1% and 57.
4%, respectively, and 24.
4% and 25.
9% of patients in each group.
Adverse reactions leading to treatment discontinuation occurred, with the most frequent adverse events in the two groups being diarrhea, nausea, and anemia
.

Table 2 The adverse reaction data of the two groups of patients is based on the interim analysis results of the KEYNOTE-811 study.
The US Food and Drug Administration (FDA) accelerated the approval of pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive patients.
Indications for first-line treatment of unresectable locally advanced/metastatic gastric and gastroesophageal junction (GEJ) cancer
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Professor Xu Jianming said: "This publication is only the interim data analysis of KEYNOTE-811, but we can observe very obvious ORR benefit data
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Based on this data, the FDA accelerated the approval of pembrolizumab in May this year .
Relevant treatment indications have also had a significant impact on domestic clinical practice
.

" "Because the treatment regimen adopted in this KEYNOTE-811 study is immunosuppressive combined with trastuzumab and chemotherapy, which is different from the previous JACOB and LOGiC, etc.
This study has different treatment mechanisms.
It is believed that the combination of pembrolizumab combined with trastuzumab and chemotherapy will not only bring benefits to patients with ORR, but also hope to bring PFS and even PFS to patients in the future.
It is the benefit of OS
.

" Professor Xu Jianming emphasized
.

 Regarding the diagnosis and treatment of HER-2-positive gastric cancer, these issues still need to be further explored.
If the data of the KEYNOTE-811 study in the future show that pembrolizumab can bring further survival benefits to patients, it is very important for these patients with HER-2-positive advanced gastric cancer.
The clinical diagnosis and treatment will still face many challenges
.

Professor Xu pointed out that although we have seen the positive side of the KEYNOTE-811 study, it also brought us several issues worth thinking about.

.

First, how to screen out which patients can benefit from pembrolizumab in clinical practice? In theory, pembrolizumab will not benefit all patients, which also depends on the PD-L1 expression in the patient's tumor lesions
.

For gastric cancer, the PD-L1 expression level is generally high in most patients, but for a small number of patients with negative PD-L1 expression, whether pembrolizumab can also bring such obvious therapeutic benefits to the patients is not yet relevant.
Research data gives the answer
.

Based on current clinical practice experience, pembrolizumab may not bring significant benefit to these patients
.

Second, how should patients respond when they develop drug resistance? Although the interim data released by the KEYNOTE-811 study show that pembrolizumab combined with trastuzumab and chemotherapy have a good effect on patients with HER-2-positive advanced gastric cancer, any anti-tumor treatment regimen is The problem of drug resistance will inevitably arise.
How to formulate treatment strategies for patients when patients develop drug resistance to targeted therapy and immunotherapy is a new challenge that oncologists are facing! Third, the exploration of the combination regimen of immunosuppressants
.

Each patient's condition is different, and the human immune system is extremely complex
.

Different patients receiving immunosuppressive therapy and combining some drugs that activate or inhibit immune pathways according to the specific conditions of the patients may bring better curative effect to patients, but this still needs to be verified by relevant studies
.

In addition, the combined application of immunosuppressants and antibody-drug conjugates (ADCs) is also worth exploring
.

A number of research data show that ADC drugs targeting HER-2 such as T-DM1 and T-Dxd can bring relatively good clinical efficacy to patients.
However, according to the current clinical practice experience, the efficacy of ADC drugs combined with chemotherapy may indeed be better than the efficacy of chemotherapy alone
.

Therefore, it is necessary to further explore whether the number of ADC drug treatment lines can be advanced and used in combination with immunosuppressive agents
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Expert Opinions Essentials The ToGA study opened the door to precise targeted therapy for patients with HER-2 positive gastric cancer, but after that, the research on the diagnosis and treatment plan for such patients has again fallen into a bottleneck.
Although there are studies that can improve the efficacy of patients trend, but it has not been able to bring substantial breakthroughs to patients
.

The interim results of the KEYNOTE-811 study show that the treatment regimen of pembrolizumab combined with trastuzumab and chemotherapy has brought significant ORR benefits to patients, and is expected to bring PFS and even OS benefits to patients , may be able to break this deadlock and open the door to immunotherapy for patients
.

In the future, how to screen clinical patients, improve the precision of immunotherapy, how to solve the problem of drug resistance of patients, and explore the combination of immunotherapy will be the direction of further exploration and research in the future
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  Expert Profile Professor Xu Jianming Director, Professor, Doctoral Supervisor, Department of Gastrointestinal Oncology, Fifth Medical Center, PLA General Hospital, Vice Chairman, Big Data and Real World Professional Committee, China Anti-Cancer Association, Vice Chairman, Chinese Research Hospital Oncology Professional Committee, Chinese Society of Clinical Oncology References of the former chairman of the Professional Committee of Gastroenteropancreatic Neuroendocrine Tumors:[1] Bang YJ, Van Cutsem E, Feyereislova A, et al.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
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