The 2021 edition of the NCCN Guidelines promotes the application status of MSI-H/dMMR. Has the global gastrointestinal tumor immunotherapy era arrived?

*It is only for medical professionals to read for reference.
The recommendation status of MSI-H/dMMR testing continues to increase, which further promotes the treatment of gastrointestinal tumors into the immune era.

Highly unstable microsatellite (MSI-H)/mismatch repair defect (dMMR) is currently one of the most important biomarkers for predicting the efficacy of immunotherapy, and has been applied to a variety of advanced entities including gastric cancer and colorectal cancer Screening of superior populations for tumor immunotherapy.

The latest 2021 National Comprehensive Cancer Network (NCCN) gastric cancer and colon cancer guidelines have successively updated the diagnosis and treatment of people benefiting from MSI-H/dMMR immunity [1,2], and the immunotherapy of gastrointestinal tumors ushered in a new era.

Tumor immunotherapy, MSI detection is the first in recent years, tumor immunotherapy represented by PD-1/PD-L1 inhibitors has become the fifth largest tumor treatment after surgery, radiotherapy, chemotherapy, and targeted therapy, and it is also currently The most popular tumor treatment method.

However, when using PD-1/PD-L1 inhibitors alone, only 20%-40% of patients will respond to immunotherapy [3,4].
How to screen out this part of patients who respond is a clinical challenge and needs to be resolved.
The problem.

Microsatellite instability (MSI) refers to the phenomenon that the length or base composition of MS sequence changes due to insertion or deletion mutations during DNA replication, often caused by mismatch repair defects (dMMR) [5].

According to the degree of instability, MSI can be divided into three categories: microsatellite highly unstable (MSI-H), microsatellite low instability (MSI-L), and microsatellite stable (MSS) [6].

MSI-H has a higher incidence in solid tumors such as endometrial cancer, colorectal cancer, and gastric cancer [7].

A large number of clinical studies have confirmed that patients with MSI-H/dMMR solid tumors receiving immune checkpoint inhibitor (ICI) treatment represented by PD-1/PD-L1 inhibitors have significant benefits [8-10].

Moreover, the key influencing factor of whether ICIs benefit is whether the patient is MSI-H, which has nothing to do with specific cancer types [11].

In 2017, the U.
S.
Food and Drug Administration (FDA) approved the PD-1 inhibitor pembrolizumab for patients with advanced or metastatic solid tumors of MSI-H/dMMR who had disease progression after previous standard treatment and did not have satisfactory alternative treatment options.
This is the first anti-tumor therapy that is not based on tumor source, but based on biomarkers.
Since then, MSI has officially entered clinical practice.

At the end of January 2021, the National Medical Products Administration (NMPA) approved China's first MSI detection kit based on "multiplex fluorescent PCR-capillary electrophoresis" [12], making MSI once again the focus of immunotherapy.

MSI application guidelines recommend upgrading, opening the door for gastrointestinal immunotherapy.
Based on the molecular characteristics of MSI-H/dMMR, it has a strong predictive value in tumor immunotherapy.
Many domestic and foreign guidelines recommend that patients with advanced solid tumors receive immunotherapy should be tested for MSI State [5,13,14].

The latest 2021 V1 NCCN Gastric Cancer Guidelines have raised the recommended level of MSI/MMR testing.
It is recommended that all newly diagnosed gastric cancer patients should undergo MSI polymerase chain reaction (PCR) testing or mismatch repair protein (MMR) immunohistochemistry (IHC) ) Detection (Figure 1) [3].

The previous version of the guidelines recommended for MSI/MMR testing only in patients with suspected metastasis.

The recommendations of the new version of the guidelines mean that for patients with MSI-H/dMMR, ICIs are not only suitable for rescue treatment of stage IV patients, but also for preoperative neoadjuvant treatment earlier than stage IV.

Figure 1.
Recommendations of the 2021 V1 NCCN Gastric Cancer Guidelines Compared with the 2020 version of the NCCN Colon Cancer Guidelines, the 2021 V1 NCCN Colon Cancer Guidelines add nivolumab±ipilimumab (O±Y) or pembrolizumab (Preferred) for the adjuvant treatment of MSI-H/dMMR patients (Figure 2), it provides a new immune adjuvant therapy program for the MSI-H/dMMR population [4].

Figure 2.
2021 V1 NCCN Colon Cancer Guidelines Recommendations For non-resectable advanced or metastatic colon cancer suitable for high-intensity chemotherapy, 2021 V1 NCCN Colon Cancer Guidelines add O±Y or Pembrolizumab for MSI-H /dMMR is the first-line treatment for the population, among which pembrolizumab is listed as the preferred recommendation (Figure 3) [4].

This means that immunotherapy has broken the dominant position of traditional chemotherapy ± targeting, and provides more new options for colon cancer patients.

Figure 3.
Recommendations for 2021 V1 NCCN Colon Cancer Guidelines are the icing on the cake: Domestic immunotherapy drugs shine in the field of MSI-H/dMMR In the field of MSI-H/dMMR solid tumor treatment, domestic immunotherapy drugs have also made significant progress.

Compared with the PD-1/PD-L1 inhibitors currently on the market and under research, the subcutaneously injected PD-L1 nanobody envolimab, which is independently developed in my country, has obvious differentiating advantages.
It has a small molecular weight and high water solubility.
, High affinity, strong tissue penetration, convenient drug delivery and other characteristics, showing good anti-tumor efficacy and safety.

A total of 103 patients with advanced MSI-H/dMMR cancer were included in the Phase II clinical trial of Envolimab for the treatment of advanced solid tumors of MSI-H/dMMR in China, of which 65 patients with advanced colorectal cancer were treated for first-line and above, and first-line and above There were 18 patients with advanced gastric cancer after treatment, and 20 patients with advanced non-colorectal cancer and non-gastric cancer after first-line treatment.

The results of the study show that Envolimab injection has a significant effect on advanced solid tumors of MSI-H/dMMR that have failed at least first-line standard treatment in the past.
The overall population, advanced colorectal cancer, advanced gastric cancer and other solid tumors have been independently reviewed The objective response rates (ORR) assessed and confirmed by the committee (BIRC) were 42.
7%, 43.
1%, 44.
4%, and 40.
0%, respectively.

In the overall population assessed by BIRC, the duration of remission (DOR) was not reached, and the 12-month DOR rate was 92.
2%.

The overall population median progression-free survival (PFS) was 11.
1 months.

The median overall survival (OS) of the overall population and each subgroup was not reached.
The 12-month OS rates of the overall population, advanced colorectal cancer, advanced gastric cancer, and other solid tumors were 74.
6%, 72.
9%, 83.
3%, and 75.
0% (Figure 4) [15].

Figure 4.
Target lesion load changes in all 103 subjects (BIRC assessment) In terms of safety, 16 patients (15.
5%) had grade 3-4 drug-related adverse events during treatment (TEAE), and no study drug For related grade 5 TEAEs, 3 subjects (2.
9%) were permanently discontinued due to drug-related TEAEs.

The incidence and occurrence of immune-related adverse events (irAE) are similar to similar products.

In addition, envolimab was administered by subcutaneous injection without infusion reactions; the incidence of injection site reactions was low (8.
7%), both grade 1-2, and there were no serious drug-related adverse events or events leading to permanent drug withdrawal (table 1).

Table 1.
Safety results of Envolimab in the treatment of MSI-H/dMMR solid tumors in China.
Based on the good efficacy and safety of Envolimab on MSI-H/dMMR advanced solid tumors, November 2020, Envoli The monoclonal antibody injection submitted a new drug marketing application (NDA) to NMPA, and the indications for the application are for the treatment of MSI-H/dMMR advanced colorectal cancer, gastric cancer and other advanced solid tumors that have failed the previous standard treatment.

In the context of the ever-increasing application status of MSI-H/dMMR, it is believed that the future listing of Envolimab will further promote the clinical practice of domestic solid tumor immunotherapy, allowing more MSI-H/dMMR populations to benefit from ICIs treatment .

References: [1] NCCN Guidelines Version 1.
2021 Gastric Cancer.
[2] NCCN Guidelines Version 1.
2021 Colon Cancer.
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