Lai Su Zhiwang Professor Zhang Xiaotian: Innovative targeted combined immunization is expected to capture the "fortress" for the treatment of advanced gastric cancer

*Only for medical professionals to read for reference.
Big coffee interprets ASCO and analyzes the latest developments in Chinese research in the field of gastric cancer.

From June 4th to June 8th, 2021, the annual American Society of Clinical Oncology (ASCO) annual meeting will be held, and many clinically valuable research results will be presented at this meeting.

Among them, a project led by Professor Lin Shen from Peking University Cancer Hospital is the treatment of advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma with sofantinib combined with teriprizumab after platinum and fluoropyrimidine first-line chemotherapy.
The Phase II clinical trial (Abstract Number: e16040) [1] showed that the efficacy and safety of sofantinib combined with teriprizumab are excellent, and it is expected to break the treatment dilemma of patients with advanced gastric cancer.

The "medical community" specially invited Professor Zhang Xiaotian from Peking University Cancer Hospital to give a wonderful interpretation of this research and talk about the future treatment direction of gastric cancer.

Study design The patients included in the study were: 18-75 years old; advanced solid tumors confirmed by histology or cytology [A total of eight tumor types were included in the group, namely neuroendocrine tumors (NENs), biliary tract cancer, gastric cancer, thyroid cancer, Small cell lung cancer, soft tissue sarcoma, endometrial cancer and esophageal squamous cell carcinoma]; all patients have failed or intolerated standard treatment, or no effective standard treatment is available, or refused standard treatment; Eastern Cooperative Oncology Group (ECOG) The performance status (PS) score is 0 or 1; there are measurable lesions (according to RECIST 1.
1); the expected survival time is more than 12 weeks.

Enrolled patients received 250 mg of sofatinib once a day (QD), and 240 mg of combined teriprizumab, intravenously every 3 weeks.

The primary study endpoint was the objective response rate (ORR) assessed by RECIST v1.
1.

Secondary research endpoints include: duration of remission (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety.

The exploratory research endpoints include biomarkers and resistance mechanisms.

The results of the study as of December 31, 2020, a total of 21 patients with G/GEJ adenocarcinoma were enrolled.

The median duration of treatment was 3 months (Sofantinib, 3 months, Teriplimumab, 3 months).

Among the 15 patients who received at least one post-baseline efficacy evaluation, according to RECIST v1.
1, 2 cases were confirmed partial remission (PR), 3 cases were unproven PR, 6 cases were stable disease (SD), and 3 One case was disease progression (PD), and one case was not evaluated.

According to irRECIST, 5 cases were PR, 7 cases were SD, and 2 cases were PD.

The confirmed and unconfirmed ORR were 13.
3% and 33.
3%, respectively.

According to RECIST v1.
1, DCR is as high as 73.
3%.

The median PFS was 3.
71 months.

In terms of safety, 14.
3% (3/21) of patients had ≥3 treatment-related adverse events (TRAEs).

Research conclusions Sofatinib combined with teriprizumab showed encouraging activity in advanced G/GEJ adenocarcinoma, and its safety was controllable.

This combination program may become a promising treatment strategy.

Expert profile Professor Zhang Xiaotian, chief physician of the Department of Digestive Oncology, Peking University Cancer Hospital, doctoral supervisor, doctor of medicine, deputy director of the International Cooperation and Exchange Department of Peking University Cancer Hospital, and deputy director of the Department of Internal Medicine, Chinese Society of Clinical Oncology Youth Expert Committee Chairman, Chinese Anti-Cancer Association Gastric Cancer Chairman of the Youth Committee of the Professional Committee Secretary-General of the Cancer Supporting Treatment Committee of the Chinese Anti-Cancer Association; Deputy Chairman of the Precision Medicine and Tumor MDT Professional Committee of the Chinese Research Hospital Association; Chairman of the Gastric Cancer Prevention and Treatment Committee of the Beijing Cancer Prevention and Treatment Society, etc.
The new mainstream drug "medical community" for gastric cancer: Could you please talk about the current status of the treatment of advanced gastric cancer? Are there any unmet clinical needs? Professor Zhang Xiaotian: The morbidity and mortality of gastric cancer are among the forefront of malignant tumors in our country, and our country has a wide area, and there are certain differences in screening and diagnosis and treatment strategies in various regions.
This has led to a low overall early diagnosis rate of gastric cancer, about 60%.
%-70% of patients are already at an advanced stage when they are diagnosed.

Therefore, whether it is preoperative, postoperative, initial treatment, recurrence and metastasis, drug therapy is an important treatment.

The current efficacy of traditional first-line chemotherapeutic drugs has reached a plateau, and there is a huge unmet need.
Even if it is to improve the formulation or develop new chemotherapeutic drugs, it is difficult to make a major breakthrough in the short term.

Therefore, to improve the current status of treatment for patients with advanced gastric cancer, the direction of efforts should focus on targeted and immunotherapy.

And for targeted or immunotherapy, we all call for precision treatment.
In a nutshell, the current unmet clinical need is to more accurately screen the beneficiaries and more clearly target the target marker population to improve the efficacy.

 Hand in hand, targeted immune combination may impact the front-line "medical community": Please explain to us the results of the study of Sofantinib combined with Teriprizumab in advanced gastric cancer at this ASCO meeting.

And talk about how do you view its efficacy and safety? Professor Zhang Xiaotian: Targeted and immune combination therapy is a hot direction in the field of tumor therapy.
The breakthrough of this combination program in gastric cancer has always attracted attention.

From the point of view of targets, effective targeted therapy for gastric cancer currently focuses on anti-human epidermal growth factor receptor-2 (HER2) and anti-vascular endothelial growth factor (VEGF) pathways.

HER2 positive belongs to a special population in gastric cancer, and HER2 negative accounts for more than 80%.

There are many attempts to target anti-angiogenesis drug therapy, and representative ones include tyrosine kinase inhibitors (TKI) such as apatinib and sofatinib.

This study explores the combined application of sofantinib and teriprizumab in advanced G/GEJ adenocarcinoma.
The results published by ASCO show that although the sample size of the study is small, the confirmed and unconfirmed ORRs are 13.
3.
% And 33.
3%, suggesting that there is still a lot of room for improvement in the field of advanced second-line gastric cancer, and the DCR assessed by RECIST v1.
1 is as high as 73.
3%, and the median PFS is 3.
71 months.
The results are satisfactory.
We look forward to follow-up to provide more data.

In terms of adverse events related to anti-angiogenesis and immunotherapy, the patients were generally well tolerated.

Based on the good efficacy and safety, it is hoped that this combination scheme can be verified in clinical studies with a larger sample size in the future.

 In addition, for patients with advanced gastric cancer in China, the whole population of Chemo-free (no chemotherapy) program still has risks.
If the program is to be further advanced to front-line treatment, it is necessary to screen the beneficiaries more accurately, through the perspective of clinical characteristics Or from the perspective of molecular biomarkers, including the characteristics of the tumor itself and the characteristics of the tumor microenvironment to screen some patients, for this type of population, the Chemo-free joint strategy may continue to advance.

 With continuous advancement, sofantinib has a unique mechanism and has become the best assisting "medical community" in immunotherapy: Could you please talk about what enlightenment this research can bring us? Professor Zhang Xiaotian: The application of PD-1 monoclonal antibody in gastric cancer, from the third-line approval to the second-line overall negative, to the benefit of some people, to the success of the first-line combined chemotherapy, PD-1 monoclonal antibody is on the road of gastric cancer research and development.
Constantly break through.

But in the end it will still face the outcome of drug resistance, whether it is primary drug resistance or secondary drug resistance.
Therefore, most gastric cancers will not try single-drug therapy unless they are highly microsatellite instability (MSI-H Patients with unresectable or metastatic solid tumors with) or mismatch repair defects (dMMR), overall 90%-95% of gastric cancer patients require combination therapy.

The CheckMate-649 study [2] provides the exploration direction of immune combined chemotherapy, but chemotherapy always has large cytotoxic adverse reactions, which also has a greater impact on the quality of life of patients, and the combined program still needs to be optimized.

At the 2019 ASCO meeting, the announcement of the results of the REGONIVO study [3] detonated the audience, providing us with ideas for anti-angiogenesis targeted drugs combined with immunotherapy.

Sofatinib, as a new type of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), has two mechanisms of action.
One is to completely inhibit VEGFR-1/2/3 and FGFR-1.
Inhibit tumor angiogenesis.

The second is to inhibit colony stimulating factor 1 receptor (CSF-1R), regulate tumor-associated macrophages (TAM), increase CD8+ T cell infiltration, and activate the body's immune response to tumor cells.

Based on the dual mechanism that sofatinib can not only fight tumor angiogenesis, but also improve the immune microenvironment, on this basis, the combination of PD-1 monoclonal antibody can exert a 1+1+1＞＞3 synergistic anti-tumor effect.

The new drug combination program of sofatinib and teriprizumab was able to obtain excellent results in terms of efficacy and safety in this study, which also reflects a research trend.

Moreover, our expectations for it do not stop there.
We hope that this combined strategy can try more translational research explorations in the future, can truly screen the beneficiaries, and further clarify the mechanism of sofatinib to improve the efficacy of immunotherapy.

 Of course, the phase I clinical study of this combination scheme for advanced solid tumors [4] has been announced at the 2020 American Association for Cancer Research (AACR) annual meeting.
All kinds of advanced solid tumors have definite curative effect and good safety.

In the Phase II study data released at this meeting, gastric cancer is the first tumor type that has shown obvious curative effect.
I believe that the data of other tumor types will be displayed accordingly.

Come to Suzhiwang, lead clinical research and clinical practice to explore the "medical community": What significance does the release of the research results have for the clinical practice of advanced gastric cancer in China? What are the future exploration directions in the field of advanced gastric cancer? Professor Zhang Xiaotian: The clinical practice of advanced gastric cancer in China is mainly based on the "Guidelines for Diagnosis and Treatment of Gastric Cancer" and "Chinese Society of Clinical Oncology (CSCO) Guidelines for Diagnosis and Treatment of Gastric Cancer".
At present, the treatment strategies provided by these two standards are still relatively limited.
Chemotherapy It is still the main treatment recommendation, and the options and scope of targeted and immunotherapy are limited.
Sofantinib combined with teriprizumab can provide new treatment options for patients with advanced gastric cancer.

Therefore, for areas that are not covered by the guidelines in clinical practice, the gastric cancer cohort of our phase II study can be used as solid evidence-based medicine to provide oncologists with medication guidance, and in research design, research implementation, data interpretation, and future The accompanying translational research and other aspects have an important impact on the research of gastric cancer in China.
At the same time, the appearance of this research on the international stage is an affirmation of the efficacy and safety of domestically developed original drugs.
It will also greatly enhance the voice of Chinese scholars and strengthen our relationship with the international community.
Exchanges.

 In addition, I hope that this research can be the beginning of a breakthrough.
In the future, Chemo-free combination treatment plan represented by sofatinib can achieve more precise treatments, establish predictive models based on biomarkers, and enrich the population with advantages.
It will be the main direction of gastric cancer clinical practice and clinical research for a long time in the future.

In this direction, I hope everyone can make concerted efforts to do research on the Chinese themselves in order to achieve major breakthroughs and bring more well-being to Chinese patients.

References: [1] Shen L, Lu M, Chen ZD, et al.
Phase II trial of surufatinib plus toripalimabfor disease progression after first-line chemotherapy with platinum and fluoropyrimidine in advanced gastric or gastroesophageal junctionadenocarcinoma.
2021 ASCO.
e16040.
[2 ] MoehlerM.
, Shitara K.
, Garrido M.
LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo)versus chemo as first-line (1L) treatment for advanced gastriccancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma(EAC): first results of the CheckMate 649 study.
Ann Oncol.
2020;31:S1191.
[3] FukuokaS, Hara H, Takahashi N, et al.
Regorafenib Plus Nivolumab in Patients WithAdvanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation , andDose-Expansion Phase Ib Trial (REGONIVO, EPOC1603).
J Clin Oncol.
2020 Jun20;38(18):2053-2061.
[4] Lu M,Cao YS, Gong JF,et al.
A Phase I Trial of Surufatinib plus Toripalimab inPatients with Advanced Solid Tumor.
AACR 2020.
Abstract No.
9563.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform