Professor Zhou Aiping: MSI-H/dMMR digestive system cancer treatment adds another weapon, the domestic PD-L1 nanoantibody Envolimab debuts

*Only for medical professionals to read for reference.
Envolimab has a clear effect on MSI-H/dMMR digestive system tumors, giving patients a new treatment option! Digestive cancers such as colorectal cancer, gastric cancer, and esophageal cancer are all high-incidence tumors in China, and most patients are already at an advanced stage when diagnosed, and cannot receive radical surgery.
At the same time, traditional treatment options such as chemotherapy have limited efficacy
.

Fortunately, in recent years, PD-1/L1 inhibitors have made a strong march and significantly improved the therapeutic effect
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Among them, China's independent research and development, the first PD-L1 nanobody envolimab administered by subcutaneous injection, has shown good efficacy
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 Recently, the Phase II registered clinical study of Envolimab in the treatment of patients with high-grade microsatellite instability (MSI-H)/mismatch repair defects (dMMR) solid tumors was officially published [1], and the "Medical Oncology Channel" invited the The main participant of the research branch, Professor Zhou Aiping, Department of Oncology, National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences, shared the development of immunotherapy for gastrointestinal tumors and the actual performance of envolimab in clinical research
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 Professor Zhou Aiping’s wonderful video clearly selects the MSI-H/dMMR "superior population" to give full play to the value of immunotherapy.
Professor Zhou Aiping pointed out: "MSI-H/dMMR patients are the most certain dominant population for immunotherapy.
As early as 2017, the US Food and Drug Administration The FDA approved immune checkpoint inhibitors for patients with solid tumors with such characteristics.
The objective response rate (ORR) of monotherapy can reach 30%-40%, and most patients have a long-lasting response.
Another PD-1 inhibitor + CTLA-4 inhibitor dual immunization program has been successfully used in MSI-H/dMMR patients with advanced colorectal cancer, and the objective remission rate can reach 60% [2]
.

"Based on the above, the definitive guide to Europe since 2017 for MSI-H / dMMR patients with advanced colon cancer is recommended to use the immune checkpoint inhibitors
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2021 National Comprehensive Cancer Network (NCCN) guidelines of colorectal cancer specific recommendations as follows: in For unresectable advanced or metastatic MSI-H/dMMR advanced colon cancer, pembrolizumab or nivolumab + ipilimumab is recommended, and for simple liver and/or lung metastasis colon cancer surgery Former neoadjuvant or conversion therapy, immunotherapy is also one of the recommended treatment methods
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In the phase III study, the ORR of pembrolizumab single-agent first-line treatment is close to 45%, which is significantly better than the chemotherapy control group, and the patients have no The progression survival time is twice that of the chemotherapy group [3]
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Since ipilimumab has not yet been approved for metastatic colorectal cancer (mCRC) indications in China, the 2021 version of the CSCO guidelines mainly recommends immune checkpoint inhibitor monotherapy
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 Based on Immunotherapy has outstanding efficacy in MSI-H/dMMR advanced colorectal cancer.
There have been clinical studies to further advance the application of immunotherapy for neoadjuvant/adjuvant treatment of patients with MSI-H/dMMR colorectal cancer during the perioperative period, such as the earliest The reported NICHE study used nivolumumab + low-dose ipilimumab as a neoadjuvant program to treat all 7 patients with stage I-III dMMR colon cancer to achieve major pathological remission (MPR), of which 4 cases (57%) Pathological complete remission (pCR) [4], suggesting that the treatment downgrade is effective, but the efficacy and long-term benefits still need to be further confirmed by prospective studies with a larger sample size
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Many centers in China are exploring immunotherapy or immunotherapy combined with chemotherapy as a study of neoadjuvant therapy of MSI-H / dMMR cancer
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pair of surgical treatment of colorectal cancer neoadjuvant be careful to select people, the need for accurate staging and comprehensive patient assessment, try to avoid over-treatment and serious adverse reactions
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 Accurate treatment testing is the first priority.
What issues should be paid attention to in MSI-H/dMMR testing? Finding MSI-H/dMMR patients through precise detection is the basis for immunotherapy.
Professor Zhou Aiping pointed out: “About 15% of operable colorectal cancers are MSI-H/dMMR[5], 80% of which are sporadic.
, 20% of patients with hereditary Lynch syndrome
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At present, the NCCN and CSCO guidelines in the United States recommend MSI-H/dMMR testing for all colorectal cancer patients to help judge clinical prognosis and formulate treatment strategies
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"Currently in clinical practice.
The detection methods for MSI-H/dMMR mainly include immunohistochemistry (IHC) detection of mismatch repair proteins, PCR and next-generation sequencing (NGS), among which PCR method is MSI-H as the gold standard for detection, and NGS method can be used simultaneously To obtain other gene mutations in tumor tissues, tumor mutation burden (TMB) and other information, the two detection methods have high reproducibility
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 The IHC method is simple and fast, but has certain limitations.
Affected by issues such as tissue fixation and staining technology, it cannot detect a small number of gene abnormalities that cause MSI-H but do not affect the expression of mismatch repair proteins.
It is used in small tissue biopsy samples.
The accuracy of the test may sometimes be inferior to that of large specimens removed by surgery
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Professor Zhou Aiping pointed out: “Clinical needs to choose appropriate detection methods according to the situation.
For example, when the IHC method does not match the clinical manifestations, PCR or NGS methods should be used.
The disadvantages of NGS include complex technology, high cost, and the inability to detect MLH1 gene A.
The two types of methods are sometimes complementary
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"The effect of single-agent therapy is significant.
Envolimab provides a new treatment option for patients with MSI-H/dMMR.
Envolimab (envafolimab) It is a PD-L1 nanobody independently developed in China.
Compared with the PD-1/PD-L1 antibodies that have been marketed and under research, Envolimab has unique advantages.
It maintains the high efficacy and safety of PD-L1 antibody drugs.
It has the advantages of good sex, and has the characteristics of small molecular weight, high affinity, good stability, and convenient subcutaneous injection
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 A domestic clinical phase II study that recently published detailed data showed that the ORR of envolimab as a single agent for the second-line treatment of MSI-H/dMMR patients was 42.
7%, and the median progression-free survival was 11.
1 months, 1 The annual overall survival rate is 74.
6% [1]
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Professor Zhou Aiping said: "The efficacy data of envolimab in this study are basically equivalent to those of PD-1 inhibitors approved abroad, and the safety is relatively good.
The administration method of envolimab is Subcutaneous injection once a week, the drug is stable at room temperature, and the injection site is less restricted.
The administration can be easily completed, which can improve the patient's treatment compliance and quality of life
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"Table 1 Envolimab treatment of Chinese MSI-H/dMMR solid tumors Patient efficacy In addition, the recent clinical phase I study data of envolimab also provided the pharmacokinetic results of 300 mg every 3 weeks (Q3W) or 400 mg Q4W subcutaneously
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The study found that the half-life of the drug after the first dose of Q3W or Q4W is about 14 days, and the steady-state half-life of the drug after 5 cycles of administration is 23 days, which supports the use of Envolizumab at 300 mg Q3W or 400 The fixed-dose dosing regimen of mg Q4W for follow-up clinical exploration is expected to further improve the convenience of envolimab medication and enhance the medication experience of patients [6]
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Professor Zhou Aiping’s center also participated in the registration clinical study of envolimab and provided a typical case.
Professor Zhou Aiping said: “Envolimab treatment has shown impressive efficacy while being convenient for medication.
, Achieved lasting relief"
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 Case information: The second-line treatment with envolimab resulted in a significant remission.
A 53-year-old male patient with PFS for nearly two years was diagnosed with “right colon cancer” during colonoscopy in May 2008 and received right colon cancer.
Radical surgery, postoperative pathology showed moderately differentiated adenocarcinoma, no lymph node metastasis (specifically unknown), postoperative chemotherapy with FOLFOX regimen for 6 cycles, tumor recurrence was found due to "intestinal obstruction" in 2009, surgery was performed again, pathological results and surgery The post-chemotherapy situation is unknown
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 In March 2018, the patient experienced lower abdominal pain again, blood in the stool and progressive increase.
Combined with the medical history, it was considered as the second primary possibility.
PET-CT in the outside hospital showed a high-metabolic soft tissue density mass of the descending colon.
Consider malignant tumor.
Colon cancer or postoperative recurrence is likely to be associated with lymph node metastasis, left common iliac lymph node metastasis, left colon cancer radical resection in May 2018, postoperative pathology showed moderately differentiated adenocarcinoma, see multifocal Vascular infiltration, focal nerve invasion, invasion of the entire intestinal wall, penetrating the serosal membrane and invading the entire layer of the adjacent small intestine to the serosal layer; peri-intestinal lymph node metastasis 3/17; metastatic mucinous adenocarcinoma is seen retroperitoneally
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 The patient’s staging at this time was pT4bN1bM1, genetic testing: RAS, BRAF wild-type, ERBB2 (2.
2686C>T), PTEN (c.
963delA), TP53 (c.
844C>T) mutations, immunohistochemistry showed: MLH1+, PMS2+, MSH6+, MSH2-, dMMR
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From August to December 2018, the patient received 6 cycles of XELOX+bevacizumab treatment in the external hospital, but the treatment response was not good.
The CT scan in April 2019 showed that the patient’s retroperitoneal metastatic lesion invaded the left ureter and secondary hydronephrosis.
There are low-enhancing small nodules in S5 and 6 segments of the liver.
Re-examination of MRI in our hospital revealed multiple liver metastases
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 From May 8, 2019, the patient received 150 mg of envolimab subcutaneous injection Q7d, Q28d treatment until now, the pain in the left groin of the patient disappeared after 1 cycle of treatment, and the efficacy evaluation after 4 cycles and 16 cycles of treatment were all relieved (PR), remission will continue until March 2021, the progression-free survival (PFS) of patients receiving envolimab second-line treatment is ≥23 months, and the duration of remission is ≥20 months, suggesting that envolimab is good The effect of the treatment, and the degree of adverse reactions is slight.
The patient has only reported the occurrence of a rash, which is rated as level 1.
It is currently recommended that the patient continue to use envolimab treatment
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 The future development prospects are promising.
Envolizumab will fully attack the future clinical exploration directions and fields of Envolizumab.
Professor Zhou Aiping believes: “The currently accepted indication applications for Envolizumab are the previous standard treatment.
For the failed MSI-H/dMMR advanced colorectal cancer, gastric cancer and other advanced solid tumors, the ORR of the treatment reached 42.
7%.
Therefore, the future exploration should use combined immune checkpoint inhibitors, chemotherapy, targeted drugs and other treatments to continue to improve On the other hand, it is necessary to continue to refine the selection of treatment advantage groups and use molecular markers to improve the accuracy of treatment
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" Based on the good efficacy of envolimab in the treatment of advanced MSI-H/dMMR patients, follow-up clinical studies are also It will continue to move forward for first-line treatment or neoadjuvant/adjuvant treatment during perioperative period
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In addition to MSI-H/dMMR solid tumors, envolimab will inevitably carry out clinical research on the treatment of other cancers, such as the treatment of pleomorphic sarcoma (UPS)/ The ENVASARC study of patients with fibrous histiocytosarcoma (MFS) completed the first administration in the United States in December 2020
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Professor Zhou Aiping pointed out: "The subcutaneous administration of envolimab is convenient and quick, and the safety is generally good.
It should be explored in the application of elderly patients, poor general conditions, poor liver and lung function and other special patient populations
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" Expert profile Professor Zhou Aiping Chief Physician, Chinese Academy of Medical Sciences Tumor Hospital/National Cancer Center, Deputy Director of Internal Medicine, Vice Chairman of the Chinese Society of Clinical Oncology (CSCO) Urothelial Cancer Professional Committee, Standing Member of the Chinese Society of Clinical Oncology (CSCO) Colorectal Cancer/Stomach Cancer/Smart Medical Professional Committee Vice Chairman of Abdominal Tumor and Colorectal Cancer Branch of Chinese Medical Education Association Vice Chairman of Gastrointestinal Tumor MDT Branch of China Healthcare International Exchange Promotion Association Vice Chairman of Geriatric Oncology Committee (CGOS) of Chinese Society of Gerontology, Vice Chairman of Gastrointestinal Expert Committee Areas of expertise: chemotherapy, biological targeting and immunotherapy for gastric cancer, colorectal cancer, esophageal cancer, hepatobiliary and pancreatic cancer and other malignant tumors such as kidney cancer, bladder cancer, and lung cancer
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Rich experience in clinical research on new anticancer drugs
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References: [1] 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.
[2] Lenz HJ, Lonardi S, Zagonel V, et al.
Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: Clinical update[J].
Journal of Clinical Oncology, 2020, 38(4_suppl): 11.
[3] 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.
[4] Chalabi M, Fanchi LF, Van den Berg JG, et al.
Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer[J].
Annals of Oncology, 2018, 29(S8): viii731.
[5] Cercek A,Fernandes GDS, Roxburgh CS, et al.
Mismatch repair–deficient rectal cancer and resistance to neoadjuvant chemotherapy[J].
Clinical Cancer Research, 2020, 26(13): 3271-3279.
[6] Papadopoulos KP, Harb W, Peer CJ , et al.
First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors[J].
The Oncologist, 2021.
*This article is only for Scientific information provided by medical professionals does not represent the views of this platform