Immunologic drugs help first-line treatment benefits for patients with advanced colorectal cancer, domestic PD-L1 inhibitors bring new treatment options

*Only for medical professionals to read and refer to the launch of the domestically-made innovative drug Envolimab, which will bring benefits to patients with advanced solid tumors of MSI-H/dMMR! Colorectal cancer (CRC) is one of the most common malignant tumors in the world.
The latest statistics of the World Health Organization (WHO) in 2020 show that the number of new cases of CRC in China exceeds 550,000, ranking second among all malignant tumors in China
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Compared with tumors such as melanoma, kidney cancer, lung cancer, CRC, the disease progresses relatively slowly, and some of the CRC patients with MSI-H/dMMR are the dominant populations for immunotherapy
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Such patients are more sensitive to immunotherapy and have relatively better curative effects
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Previously, single-agent immunotherapy has been recommended for the first-line treatment of MSI-H/dMMR advanced colorectal cancer in China, and the approval of Envolimab has brought another "weapon" to the treatment of advanced colorectal cancer
.

What new treatment methods does immunotherapy bring to patients with advanced CRC? How will immunotherapy develop in the future? The general trend of precision therapy, immunotherapy has become the first-line treatment for patients with advanced CRC.
Starting in 2015, the KEYNOTE-016 study was the first to find that the PD-1 monoclonal antibody pembrolizumab can bring significant clinical benefits to patients with MSI-H/dMMR mCRC.
, CRC immunotherapy opened a new chapter
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The "2021 Chinese Society of Clinical Oncology (CSCO) Colorectal Cancer Diagnosis and Treatment Guidelines" separately lists MSI-H/dMMR patients with advanced CRC.
No matter whether it is first-line, second-line or third-line treatment, immune checkpoint inhibitor therapy is recommended, and immunotherapy has a further status Improvement: For the treatment of patients with initial unresectable metastatic colorectal cancer (partial patients with T4b and M0 cannot achieve radical cure even with combined organ resection), a new note "Based on the results of the KEYNOTE-177 study, MSI-H/ dMMR patients in palliative treatment or conversion treatment may be considered PD-1 monoclonal antibody immunotherapy "
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Table 1 Recommended first-line palliative treatment for MSI-H/dMMR patients.
At the 2020 American Society of Clinical Oncology (ASCO) annual meeting, the preliminary data of the clinical phase III KEYNOTE-177 study was selected into the blockbuster study abstract (LBA) published by the plenary meeting, confirming Pa Bolivizumab in the first-line treatment of MSI-H/dMMR mCRC patients can significantly improve the median progression-free survival compared with standard chemotherapy (mPFS 16.
5 months vs 8.
2 months, HR=0.
59, 95%CI 0.
45-0.
79) [1 ], which became the basis for pembrolizumab to be approved for this indication in the United States in June 2020
.

The KEYNOTE-177 study established the first-line treatment status of immune monotherapy in patients with advanced CRC of MSI-H/dMMR
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Comparing the data of the three studies of KEYNOTE-177, KEYNOTE-164 and CheckMate-142 horizontally, it can be found that for patients with MSI-H/dMMR mCRC, immunotherapy can obtain better clinical benefits than chemotherapy ± targeted therapy.
Combined therapy with dual immunity is better than therapy with single immunity, and some patients even get a chance to be cured
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To fill the gap in the treatment of colorectal cancer after MSI-H/dMMR, Envolimab showed amazing efficacy across tumors.
On November 24, 2021, the National Medical Products Administration (NMPA) of China passed the priority review and approval procedure.
The PD-L1 inhibitor Envolimab was launched for the treatment of unresectable or metastatic MSI-H/dMMR adult patients with advanced solid tumors, including those after previous treatment with fluorouracil, oxaliplatin and irinotecan Patients with advanced CRC who have advanced disease and other advanced solid tumor patients who have experienced disease progression after previous treatment and have no satisfactory alternative treatment options
.

In the pivotal phase II study of envolimab [2], the objective response rate of envolimab as a single agent (administered at 150 mg QW) for 65 patients with MSI-H/dMMR colorectal cancer as second-line treatment (ORR) is 43.
1%
.

The 12-month PFS rate was 43.
7% (95%CI 31.
2%~55.
4%), and the 12-month OS rate was 72.
9% (95%CI 60.
1%~82.
2%)
.

Table 2 Efficacy of envolimab in the treatment of Chinese patients with MSI-H/dMMR solid tumors It is proved that it has good therapeutic value in MSI-H/dMMR solid tumors
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The ORR of Envolimab as a single agent (150mg QW administration) for 103 patients with MSI-H/dMMR treatment above the second-line treatment was 44.
7%, the median progression-free survival (PFS) was 11.
1 months, and the 1-year overall survival The rate is 74.
6%, and the efficacy is equivalent to that of approved PD-1 inhibitors
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This also shows that Envolimab has extraordinary clinical potential
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Domestic immunologic drugs are on the track, and the original PD-L1 inhibitor shows good safety.
Envolimab is not only effective, but as a PD-L1 inhibitor, Envolimab is safer than PD-1 inhibitors and CTLA -4 Inhibitors and other immunotherapy drugs have certain advantages
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With the continuous deepening of the research and development of PD-1/PD-L1 inhibitors, researchers have discovered that there are certain differences in the mechanism of action between PD-1 inhibitors and PD-L1 inhibitors
.

Although PD-1/PD-L1 inhibitors block the binding of PD-1 and PD-L1, PD-1 inhibitors can block PD-1 while blocking the binding of PD-1 and PD-L1.
Combining with PD-L2 leads to excessive immune activation and side effects such as interstitial pneumonia
.

PD-L1 inhibitors, because they work by inhibiting the PD-L1 site, do not affect the combination of PD-1/PD-L2, retain immune homeostasis to a certain extent, and help prevent autoimmune reactions [3] , Immune-related side effects will be lower
.

In addition, in addition to blocking the interaction between PD-L1 and PD-1, PD-L1 inhibitors can also block the binding of PD-L1 to B7.
1, inhibit the activity of dendritic cells to generate T cells, and enhance the immune response
.

Therefore, the theoretical advantages of PD-L1 inhibitors compared to PD-1 inhibitors make it one of the hot spots of research and development of domestic pharmaceutical companies
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Table 3 2021 CSCO Immunotherapy Toxicity Management Guidelines As the first domestically-developed PD-L1 inhibitor, Envolimab also demonstrated good tolerability and safety in the pivotal phase II clinical study: Grade 3-4 The incidence of adverse events (TRAE) during drug-related treatment was 16%, no grade 5 TRAE, immune pneumonia and colitis occurred; Envolimab was administered by a unique subcutaneous injection method, and the incidence of injection site reactions was 9%, and all are 1-2 grades
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In general, domestic immunotherapy has developed rapidly in recent years, and a number of immunotherapy drugs independently developed by China have been approved for marketing, bringing more choices and benefits to patients with advanced CRC
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With the advent of the precision era of tumor immunotherapy, the role of MSI-H/dMMR as a predictor of the efficacy of tumor immunotherapy has become increasingly prominent and has become a hot spot of clinical concern
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We also look forward to envolimab's ability to carry out more large-sample clinical studies, and move forward in the treatment of MSI-H/dMMR CRC patients, and extend it to first-line treatment or preoperative neoadjuvant treatment, which will benefit more patients
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References[1]André T, Shiu KK, Kim TW, et al.
Pembrolizumab in microsatellite-instability–high advanced colorectal cancer[J].
New England Journal of Medicine, 2020, 383(23): 2207-2218.
[2 ]Li J, Deng Y, Zhang W, et al.
Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors[J].
Journal of Hematology & Oncology, 2021, 14(1): 95.
[3 ]Chen DS, Irving BA, Hodi FS.
Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1[J].
Clin Cancer Res,2012 ,18(24):6580-6587.
* This article is only used to provide scientific information to medical professionals and does not represent the views of this platform