K-drug single-agent first-line treatment is recommended by CSCO guidelines: A new standard for the treatment of MSI-H/dMMR metastatic colorectal cancer is born

*Only for medical professionals to read and reference.
The Chinese Society of Clinical Oncology (CSCO) Colorectal Cancer (CRC) Diagnosis and Treatment Guidelines (2021 Edition) was officially released at the CSCO Guidelines Conference on April 24, 2021.

An important update of this guideline is to separately list the initial unresectable metastatic colorectal cancer (mCRC) with highly microsatellite instability (MSI-H)/mismatch repair defect (dMMR) gene characteristics, and to give PD-1 Immune checkpoint inhibitor pembrolizumab (commonly known as K drug in China) single-agent first-line treatment recommended by level I experts, level of evidence 1A.

The 2021 version of the CSCO CRC diagnosis and treatment guidelines recommends this is a milestone update, because this is the CSCO CRC diagnosis and treatment guidelines to classify treatment plans based on genetic characteristics, and it is also the first time that the guidelines have given the highest-level experts of PD-1 immune checkpoint inhibitor drugs.
recommend.

 The CSCO guidelines only recommend K drugs and a PD-1 immune checkpoint inhibitor as the first-line treatment for mCRC with MSI-H/dMMR gene characteristics.
The evidence-based medical evidence is derived from an international multi-center, randomized controlled, open label The results of the Phase III clinical study KEYNOTE-177.

The results of the study were first released at the 2020 American Society of Clinical Oncology (ASCO) conference and published in the December 2020 issue of the New England Journal of Medicine.

Screenshot of article title KEYNOTE-177 is a project designed to evaluate K-drug single-drug versus standard treatment (FOLFOX or FOLFIRI chemotherapy ± targeted bevacizumab or cetuximab) first-line treatment (MSI-H) for advanced mCRC Phase III clinical study.

The primary endpoints of the study were progression-free survival (PFS) as assessed by RECIST and overall survival (OS).

Secondary endpoints include objective response rate (ORR) and safety as assessed by RECIST v1.
1.The updated data reported by the American Society of Clinical Oncology Symposium on Gastrointestinal Tumors (ASCO-GI) in 2021 showed that the median PFS of the K drug group was 16.
5 months, which was twice that of the control chemotherapy group (8.
2 months) (HR =0.
60; 95%CI: 0.
45~0.
80; P=0.
0002); PFS2 of the K drug group (the time from randomization to progression to later-line treatment or death from any cause) did not reach, and the control group was 23.
5 months (HR= 0.
63; 95%CI: 0.
45~0.
88); the ORR of the K drug group was 43.
8%, and the chemotherapy group was 33.
1%; the K drug group had a treatment-related adverse event (TRAE) rate of 22% and above, which was the control group (66 %).

 KEYNOTE-177 research PFS, PFS2, and ORR data results.
During the publication of the guidelines, the Medical Oncology Channel invited Professor Yuan Ying, deputy chairman of the CSCO Colorectal Cancer Expert Committee and director of the Department of Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, to discuss KEYNOTE -177 The significance of the research results, the importance of MSI-H/dMMR detection, and the development trend of MSI-H/dMMR mCRC immunotherapy are introduced.

The medical profession: The CSCO guidelines recommended the highest-level experts for the first-line treatment of pembrolizumab for mCRC with MSI-H/dMMR gene characteristics.
Does this mean that immunotherapy has become the first-line standard treatment for this type of mCRC population? ? Professor Yuan Ying: Yes, there is no doubt about it.

KEYNOTE-177 clearly tells us that for mCRC patients with MSI-H/dMMR molecular phenotype, K drug has advantages over traditional chemotherapy or chemotherapy combined with targeted therapy.

After the research results were released, the National Comprehensive Cancer Network (NCCN) guidelines updated the treatment recommendations for this group of people.

The CSCO guidelines give the highest-level expert recommendation for the first-line treatment of pembrolizumab, and the evidence level is 1A, which means that this treatment plan will become the new standard for the first-line treatment of this type of patient population in China.

Medical community: What percentage of CRC patients show MSI-H/dMMR? What's special? Professor Yuan Ying: Among the CRC patients, about 15% of the patients have the MSI-H/dMMR molecular phenotype, of which 3% are hereditary and 12% are sporadic.

There are many differences between this type of tumor and ordinary bowel cancer-it usually occurs in the right colon, is pathologically manifested as mucinous adenocarcinoma, and there are more lymphocyte infiltrations around the tumor.
Therefore, the immune microenvironment of this part of tumor patients is Common bowel cancer is different.

Medical profession: In clinical practice, is MSI-H/dMMR a mandatory item? Professor Yuan Ying: Actually, we are no strangers to MSI-H in CRC treatment.

In 1993, there were many articles in Science and Nature describing the molecular phenotype of MSI-H, but scholars who only had hereditary CRC at that time paid more attention to this topic, because at that time they only knew about this type of phenotype and hereditary CRC.
Lynch syndrome is clearly related.

In hereditary CRC such as Lynch syndrome, 95% manifested as MSI-H, so the main function of this marker at the time was to help clinicians find and diagnose patients with Lynch syndrome, but they did not know it.
For predicting the value of treatment efficacy.

 However, as research continued to deepen, it was discovered around 2005 that the status of MSI-H was also related to the sensitivity of fluorouracil chemotherapy drugs.

The study found that fluorouracil monotherapy as a postoperative adjuvant treatment for patients with stage II MSI-H CRC not only did not bring survival benefits to patients, but also brought survival damage; therefore, stage II colon cancer has been required since then After surgery, patients undergo MSI-H testing before adjuvant chemotherapy.

 In 2015, the United States "New England Journal of Medicine" published the results of a study of pembrolizumab in the treatment of dMMR solid tumors (including CRC), which clarified the relationship between MMR status and the efficacy of immunotherapy.

The relationship between MMR status and immunotherapy efficacy.
Therefore, the current domestic and foreign CRC diagnosis and treatment guidelines will recommend MSI-H/dMMR testing for two types of patients: the first type is patients before adjuvant chemotherapy after radical surgery, especially stage II Patients; the second category is all untreated mCRC patients.

Medical community: Does the MSI-H/dMMR test only provide guidance for the first-line treatment of mCRC immunity? Professor Yuan Ying: For the first time this year’s CSCO guidelines list MSI-H/dMMR patients in the first-line, second-line, and third-line treatment of mCRC palliative care, which means that MSI-H/dMMR is a molecular marker that must be clarified first.
The treatment needs of these patients are different from other types of patients; whether it is first-line, second-line or third-line treatment, immunotherapy should be given priority.

For patients with microsatellite stable (MSS) or pMMR, we also need to test the mutation status of RAS and BRAF to determine whether the chemotherapy regimen is combined with bevacizumab or cetuximab.

Medical community: This year's ASCO-GI conference announced the PFS2 data of the KEYNOTE-177 study with a median follow-up of 32.
4 months (24.
0-48.
3).

Compared with the control group, the PFS2 of the pembrolizumab treatment group was significantly prolonged.

Will OS data also bring surprises? Professor Yuan Ying: The PFS2 data results of KEYNOTE-177 show that the two curves of the pembrolizumab treatment group and the control group still maintain a very clear separation, and it seems that subsequent signs of OS positive can be seen; especially considering the chemotherapy Nearly 60% of patients in the targeted therapy control group received PD-1 monoclonal antibody treatment after treatment progressed.

 The OS data of KEYNOTE-177 may be published at this year's ASCO meeting.
We are looking forward to the final OS data.

If it is a positive result, it will prove that the first-line immune treatment of mCRC can bring better OS benefits than the second-line treatment, and will undoubtedly further establish the status of pembrolizumab as the first-line treatment.

Medical community: What enlightenment does the results of the KEYNOTE-177 study bring to conversion therapy strategies for patients with unresectable MSI-H/dMMR CRC? Professor Yuan Ying: The ORR of pembrolizumab single-agent first-line treatment reached 43.
8%, which is 10% higher than the 33.
1% effective rate of two-drug chemotherapy combined with targeted therapy; for CRC patients with potentially transformable resection lesions , This 10% improvement is commendable.

Therefore, a note has been added to the CSCO guidelines of the 2021 edition: When these patients need conversion therapy, we also recommend pembrolizumab monotherapy.

Medical community: What are the directions worth exploring for future CRC immunotherapy as the results of the KEYNOTE-177 study? Professor Yuan Ying: While KEYNOTE-177 changes the clinical practice of CRC treatment, there are still unanswered questions.

 First of all, although the ORR of 43.
8% brought by pembrolizumab alone is 10% higher than the ORR of 33.
1% of chemotherapy ± targeted therapy, more than half of the patients are still interested in immunotherapy.
No answer.

Therefore, how to further improve ORR is the direction that needs to be studied in the next step.

For example, on the basis of pembrolizumab, combined with traditional chemotherapy or anti-angiogenesis drugs, or whether the dual immunization regimen can further improve ORR.

 Secondly, the standard deviation of PFS in the pembrolizumab group is very large, the shortest is 5.
4 months, and the longest is 32.
4 months.
The range of 27 months is thought-provoking. What caused such a huge difference in PFS? Are there patients with other molecular phenotypes in this part of the population, and these patients may not benefit from single-agent immunotherapy? The results of subgroup analysis of KEYNOTE-177 showed that patients with MSI-H/dMMR combined with KRAS/NRAS mutations did not benefit significantly from immune monotherapy; then, whether the KRAS/NRAS mutation status is related to the efficacy of immunotherapy ? For the treatment of this part of the population, is it possible to choose pembrolizumab combined with traditional chemotherapy or anti-angiogenic drugs? In addition, for patients with microsatellite stable (MSS) and normal mismatch repair (pMMR), can pembrolizumab combined with EGFR monoclonal antibody treatment also achieve better results? These issues need to be further explored.

At the International Academic Forum on Colorectal Cancer of Zhejiang University to be held in May, experts from home and abroad will also conduct in-depth discussions on these issues.
Please pay attention to the follow-up conference information.

Medical community: Immunotherapy research is developing rapidly.
What updates are expected to bring to CSCO guidelines next year? Professor Yuan Ying: This year, there have been major breakthroughs and changes in immunotherapy in the CRC diagnosis and treatment guidelines.

If immunotherapy combined with other treatments can obtain more data on mCRC treatment of MSI-H/dMMR, the guidelines may be further updated next year.

 The second possible update is the treatment of CRC patients with MSS, such as whether the combination of immunity, traditional chemotherapy and anti-angiogenic drugs can be included in the guidelines.
Of course, this still needs further exploration and more evidence-based medical evidence to support.

 The third possible update is the adjuvant treatment after stage III radical surgery for MSI-H/dMMR.

At present, there have been researches on new programs of this type of adjuvant therapy, that is, on the basis of half a year of FOLFOX treatment, plus one year of immunotherapy, we are also looking forward to the release of the research results.

Medical circles: "Zhejiang University International Academic Forum on Colorectal Cancer" will be held in Hangzhou from May 13 to May 16.

What are the highlights of this year's conference? Professor Yuan Ying: "Zhejiang University Colorectal Cancer International Academic Forum" has entered its 11th year this year and has gradually become an influential brand conference in the field of colorectal cancer treatment.

This year's theme still focuses on the two key topics of standardized treatment of colorectal cancer and multidisciplinary diagnosis and treatment.

 Due to the new crown pneumonia epidemic, this year's conference is still held in a combination of online and offline mode, with 1 main venue and 22 branch venues, and the conference is grand.

At the same time, this year's conference will also invite well-known foreign experts to share the latest treatment concepts and research progress of colorectal cancer online, and look forward to the attention and participation of colleagues! Expert profile Professor Yuan Ying, director of the Department of Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, deputy director of the Key Laboratory of Malignant Tumor Early Warning and Intervention of the Ministry of Education, CSCO director, CSCO colorectal cancer expert committee deputy director, Chinese Anti-Cancer Association (CACA) Member of the Standing Committee of the Colorectal Cancer Special Committee, leader of the genetics group, member of the CACA Cancer Targeted Therapy Special Committee, chairman of the Colorectal Tumor Genetics Special Committee of the Chinese Medical Doctor Association, and expert of the 2017 Colorectal Cancer Diagnosis and Treatment Standards Group of the Health and Family Planning Commission.