MSS/pMMR colorectal cancer immunotherapy needs to be broken through, and small molecule anti-vascular targeted drugs may be the key to breakthrough

*For medical professionals only for reference According to the data released by the International Agency for Research on Cancer (IARC) of the World Health Organization, there will be about 560,000 new cases of colorectal cancer in China in 2020, which has become the second largest cancer after lung cancer [1], seriously affecting the life and health of the people.

.

In recent years, with the continuous progress in research related to the diagnosis and treatment of colorectal cancer and the continuous improvement of the standardized diagnosis and treatment system for colorectal cancer in China, it can be seen that China has made great progress in the diagnosis and treatment of colorectal cancer
.

The medical community specially invited Professor Bai Li of the First Medical Center of the PLA General Hospital and Professor Liao Wangjun of the Southern Hospital of Southern Medical University to introduce the research progress in the field of colorectal cancer diagnosis and treatment in recent years, as well as the current situation and future of the construction of standardized diagnosis and treatment of colorectal cancer in China and prospects.

.

Targeted therapy and immunotherapy have made gratifying progress.
Looking back at the clinical research on colorectal diagnosis and treatment in recent years, although there are few breakthroughs in chemotherapy, many breakthroughs have been made in immunotherapy and targeted therapy
.

It is well known that KRAS gene mutations account for a high proportion of tumor patients, but targeted therapy has rarely made breakthroughs in patients with KRAS gene mutations in the past, which also led to KRAS being once considered an "undruggable" target
.

However, a study called KRYSTAL-1 [2] announced at the 2021 European Society for Medical Oncology (ESMO) Congress showed that a specific optimized oral inhibitor for KRAS G12C mutation, Adagrasib (MRTX849) alone or in combination with Western Tuximab resulted in a disease control rate (DCR) of 87% and 100%, respectively, in patients with KRAS G12C-mutant colorectal cancer
.

In this regard, Professor Liao Wangjun said that Adagrasib has shown great potential for the treatment of colorectal cancer, and the prospect of combined application with cetuximab is worth looking forward to
.

At the same time, Professor Bai Li also said that KRAS gene mutation accounts for a high proportion of colorectal cancer patients, and the difficulty of targeted therapy for KRAS gene mutation must be overcome in the future clinical practice
.

Not only the KRAS G12C mutant type, but also the KRAS G12V and KRAS G12D mutant types, which account for a higher proportion in colorectal cancer, must also seek new breakthroughs
.

In addition to targeted therapy, immunotherapy has also made encouraging new progress in the field of colorectal cancer diagnosis and treatment in recent years
.

The results of the KEYNOTE-177 study [3] showed that compared with chemotherapy alone, pembrolizumab combined with chemotherapy could prolong the median progression-free survival (PFS) of patients from 8.
2 months to 16.
5 months
.

In terms of overall survival (OS), after a median follow-up of 44.
5 months, the median OS of patients in the pembrolizumab group was still not reached, while the median OS of patients who received chemotherapy alone was 36.
7 months, although Prespecified statistical assumptions were not met, but were also better than those who received chemotherapy alone
.

Professor Wangjun Liao pointed out that based on the KEYNOTE-177 study, pembrolizumab has laid the foundation for the application of first-line treatment in patients with microsatellite high instability (MSI-H)/mismatch repair deficiency (dMMR) and promoted this strategy.
approved and recommended by guidelines
.

Regarding colorectal cancer immunotherapy, Professor Bai Li said that the KEYNOTE-016 study identified MSI-H/dMMR as a molecular marker for metastatic colorectal cancer immunotherapy.
However, for patients with microsatellite stable (MSS)/normal mismatch repair (pMMR), which account for a higher proportion in colorectal cancer, whether it is suitable to receive immunotherapy still needs to be explored in the future
.

Small molecule anti-angiogenesis targeted drugs may shine in the future.
Professor Wangjun Liao pointed out that anti-angiogenesis therapy is a very important means in the treatment of advanced colorectal cancer, which runs through first-line, second-line and third-line treatment
.

In the first- and second-line treatment of colorectal cancer, bevacizumab combined with chemotherapy has become the standard treatment; in the third-line treatment, small molecule anti-angiogenic targeted drugs such as fruquintinib and regorafenib are also listed in the "CSCO" Recommended in Colorectal Cancer Diagnosis and Treatment Guidelines 2021 [4]
.

Two small studies on small molecule anti-angiogenic targeted drugs combined with immune checkpoint inhibitors in the late-line treatment of colorectal cancer patients, presented at the 2021 American Society of Clinical Oncology (ASCO) annual meeting, allow clinicians and patients It has seen a new direction and is expected to be the key to breaking the deadlock that MSS patients are generally less effective in immunotherapy
.

The results of a phase Ib study of fruquintinib combined with sintilimab in the treatment of advanced colorectal cancer [5] showed that for patients with metastatic colorectal cancer who failed at least second-line treatment with fluorouracil, oxaliplatin or irinotecan , the treatment regimen of fruquintinib combined with sintilimab can bring patients an objective response rate (ORR) of 22.
7%, and the median PFS of patients can reach 5.
6 months, receiving phase II clinical recommended dose (RP2D) The ORR and median PFS of treated patients were 27.
3% and 6.
9 months, respectively
.

In addition, another study of fruquintinib combined with Geptanolimab (GB 226) in the treatment of metastatic colorectal cancer [6] showed that patients treated with this regimen had an ORR of 26.
7%, a DCR of 80%, and an intermediate The median PFS was 7.
33 months; in MSS patients, ORR and DCR were 25.
0% and 75%, respectively, and the median PFS was 5.
45 months, and 2/3 of the patients in this study had received more than 2 lines of treatment
.

In this regard, Professor Bai Li said that although the sample size of these two studies was small, they showed promising data results, which brought new opportunities for the current difficult post-line treatment of colorectal cancer and immunotherapy for MSS patients.
Dawning, it is worth conducting research with larger sample size in the future
.

Professor Liao Wangjun also said that in the future, he hopes to see a large sample study on the efficacy of fruquintinib monotherapy or fruquintinib combined with immunotherapy compared with the current standard third-line treatment regimen
.

In addition, as a complementary chemotherapy regimen with targeted therapy, in order to better exert its value and reduce the secondary resistance of chemotherapy drugs, our Southern Hospital has discovered clinical resistance to chemotherapy drugs based on the exploration of tumor evolution under treatment pressure.
Drug clues
.

At present, a large database of tumor tissue dynamic specimens has been established, and relevant studies have been carried out based on dynamic tissue specimens and some research results have been published.
It is hoped that our follow-up work can contribute to the proposal of chemoresistance solutions for colorectal cancer
.

In the future, it is necessary to further introduce guidelines suitable for China's national conditions and ensure that they are implemented.
Colorectal cancer has become one of the three major malignant tumors in China, and a considerable number of patients are diagnosed at an advanced stage.
At the same time, colorectal clinical diagnosis and treatment are constantly seeking new Therefore, the implementation of standardized diagnosis and treatment can achieve better treatment outcomes for patients with colorectal cancer
.

Professor Bai Li pointed out that the standardized diagnosis and treatment system for colorectal cancer in China is relatively complete, and the update of the Chinese Society of Clinical Oncology (CSCO) colorectal cancer diagnosis and treatment guidelines is very timely, which can enable more patients to use the latest treatment for colorectal cancer in a more timely manner.
medication or regimen
.

Regrettably, most of the evidence-based medical evidence in the current CSCO colorectal cancer diagnosis and treatment guidelines comes from research conducted by foreign scholars.
Study data of domestic patients
.

In addition, Professor Bai Li also said that standardized diagnosis and treatment of colorectal cancer has brought better therapeutic efficacy and survival benefits to most patients, but the clinical application management of anti-tumor drugs and the individualization of very special patients Sufficient attention should also be paid to clinical treatment needs, so as to strengthen the implementation of standardized diagnosis and treatment of colorectal cancer while taking into account the individualized clinical diagnosis and treatment needs of different patients
.

Regarding the standardized diagnosis and treatment of colorectal cancer in China, Professor Liao Wangjun also pointed out that there are still the following deficiencies in the clinical practice of colorectal cancer in China
.

First of all, due to technical means, inspection instruments, doctors' diagnosis and treatment level, and patients' economic conditions, some patients have not really received the diagnosis and treatment recommended by the guidelines
.

Secondly, the currently used patient stratification indicators are mainly TNM staging and the mutation status of certain genes.
These indicators are not precise, comprehensive and efficient enough to cover all clinical scenarios, accurate molecular typing and effective stratification indicators.
The establishment of it is a key research direction in the future
.

Professor Liao Wangjun then emphasized that with the progress of clinical research on rectal cancer, clinicians and patients have more treatment options
.

How to further standardize the practice of colorectal cancer diagnosis and treatment in China in the future, and to launch a colorectal cancer diagnosis and treatment guideline suitable for China's national conditions is the common expectation of both doctors and patients
.

This requires the joint efforts of Chinese oncologists.
The CSCO colorectal cancer diagnosis and treatment guidelines fully take into account clinical evidence, China's national conditions and operability, and are an important basis for clinical diagnosis and treatment.
I hope that it will be better and better in the future
.

Summary In recent years, targeted therapy and immunotherapy have made continuous progress in the field of clinical treatment of colorectal cancer.
With the release of a number of research data, it can be seen that small molecule anti-angiogenesis targeted drugs may be able to break the efficacy of immunotherapy in MSS patients.
Bad key
.

In the future, with the continuous progress of tumor treatment methods, the drugs and programs for colorectal cancer treatment will become more and more abundant, thus giving more hope to the diagnosis and treatment of colorectal cancer patients
.

Expert Profile Prof.
Bai Li Chief Physician, Professor, Ph.
D.
, Doctoral Supervisor, Department of Medical Oncology, First Medical Center, PLA General Hospital, Chairman, Beijing Cancer Prevention Society, Director of the Precision Treatment Committee for Digestive Tract Tumors, China Anti-Cancer Association (CSCO) Director, China Member of the Standing Committee of the Pancreatic Cancer Professional Committee of the Oncology Branch of the Medical Association Member of the Standing Committee of the Pancreatic Cancer Professional Committee of the Cancer Branch of the Medical Association Director of Medical Oncology, University Southern Hospital, National Key Clinical Specialist, Leader Deputy Director of the Chemotherapy Professional Committee of the Cancer Association Member of the Standing Committee of the Clinical Chemotherapy Professional Committee of the China Anti-Cancer Association Member of the Internal Medicine Group of the Colorectal Cancer Professional Committee of the China Anti-Cancer Association As the project leader, he has undertaken 5 projects of the National Natural Science Foundation of China, focusing on tumor microenvironment evaluation and remodeling.
He has published 58 SCI-indexed papers as the first author or corresponding author, including 4 ESI highly cited papers and 1 AACR best paper, with cumulative IF415, h-index: 33
.

References: [1] https://gco.
iarc.
fr/today/online-analysis-pie?v=2020&mode=cancer&mode_population=continents&population=900&populations=160&key=total&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group% 5B%5D=0&ages_group%5B%5D=17&nb_items=7&group_cancer=1&include_nmsc=1&include_nmsc_other=1&half_pie=0&donut=0[2]KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation.
2021 ESMO.
Abstract LBA 6.
[3] Diaz LA Jr, Shiu KK, Kim TW, et al.
Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE -177): final analysis of a randomised, open-label, phase 3 study.
Lancet Oncol.
2022 Apr 12: S1470-2045(22)00197-8.
[4]CSCO Colorectal Cancer Diagnosis and Treatment Guidelines 2021[5]Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.
2021 ASCO.
Abstract Poster 2514.
[6]A phase ib trial of assessing the safety and preliminary efficacy of a combination therapy of geptanolimab (GB226) plus fruquintinib in patients with metastatic colorectal cancer (mCRC).
2021 ASCO.
Abstract e15551.
*This article is only for medical professionals Provide scientific information and do not represent the views of this platform*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform