Medical Voice and Medical Road| Down-to-earth, Looking Up at the Stars - Exploring the Trail of Late Colorectal Cancer Treatment in China

*For medical professionals only

Chinese patients, Chinese research, fruquintinib domestic original research drugs to help the diagnosis and treatment of advanced colorectal cancer in China

With the excellent efficacy shown in the CONCUR study[^1], FRESCO study^[2], and TERRA study^[3], regofinib, fruquintinib, and TAS-102 (trafluuridine tipitrine) have been approved for marketing, adding treatment options
for the third-line treatment of advanced colorectal cancer in China.
The choice of third-line treatment drugs is unprecedentedly rich, which is no longer what it used to be, but it also brings clinicians the confusion of how to choose drugs for third-line treatment and the question of where to go after the
line.

In this context, the "Medical Community" specially planned a series of activities on medical sound and medical road, inviting Professor Wang Yusheng from Shanxi Provincial Cancer Hospital and Professor Wang Zhenghua from the First Affiliated Hospital of Jinzhou Medical University to share important views and treatment experiences
on the treatment of advanced coloral cancer.

How to choose a third-line drug?

Refer to the guidelines to recommend and study the evidence, and make an individualized choice after comprehensive consideration

"In the past, patients with advanced colorectal cancer generally went to the third line of treatment, although the patient's physical condition was still very good, but there was basically no drug to choose from
.
Now, there are more options for third-line treatment! ”

What about three oral medications – fruquintinib, regofinib, and TAS-102? What about two small molecules TKI, regofinib and fruquintinib? It has always been a problem that plagues clinicians
.
"For the choice of third-line drugs, the FRESCO Hybrid study ^[4] announced at the Chinese Society of Clinical Oncology (CSCO) conference last year can provide some help and reference information
.
" Professor Wang Yusheng explained that the FRESCO Hybrid study conducted a tendential matching analysis
of patients in the trial group treated with fruquintinib in the Phase III FRESCO study with patients who used other TKIs in the real world.
The results showed that the median overall survival (mOS) was significantly longer in the fruquintinib group (9.
3 months vs 6.
6 months), the progression-free survival time (PFS) in the fruquintinib group was significantly longer than that in other TKI groups (3.
71 months vs.
2.
49 months), and fruquintinib showed significant PFS
and OS benefit.
In terms of safety, FRESCO research results show that fruquintinib is safe, real-world applications also show that fruquintinib is safer, common adverse reactions are hypertension, hand and foot skin reactions, and basically mild
.

Professor Wang Yusheng said that in the choice of drugs in clinical practice, the first consideration is "both symptomatic and medical insurance priority"
.
Medicines within the scope of health insurance are both evidence-based medical evidence and accessible, making them the first treatment options
to consider.
In addition, it is also necessary to consider the patient's constitution, economy, tumor burden, and analyze the previous treatment of drugs in order to select drugs
that may benefit in subsequent treatment.
At the same time, for some drugs that are not currently in health insurance, clinical choices are often made
.
For example, in patients with advanced bowel cancer with microsatellite height instability (MSI-H), first-line therapy may select immune checkpoint inhibitors
for patients based on current clinical study data and guidelines.
Although these drugs do not enter the medical insurance and are not as accessible as the drugs within the scope of medical insurance, there is sufficient evidence that MSI-H patients can benefit more from immune checkpoint inhibitor therapy, and it will be clinically recommended that these patients choose drugs
that they are more likely to benefit.
Therefore, I hope that these well-documented drugs can enter medical insurance as soon as possible and benefit more patients!

Professor Wang Zhenghua pointed out that clinical guidelines are recommended based on large-scale Phase III clinical trials, and clinically, when selecting therapeutic drugs, while fully referring to the recommendations or recommendations given by clinical guidelines, it is also necessary to choose according to the real situation, and real-world data is also an important basis for
drug selection.
In addition, in the choice of third-line treatment drugs, it is necessary to consider not only the efficacy, but also the toxic side effects, quality of life, whether important organs have metastasis, medication routes, etc.
, and appropriate treatment plans
should be selected after comprehensive consideration.
In terms of medication routes, if intravenous and oral administration can achieve roughly similar efficacy, it is more beneficial to patients to choose oral, more convenient drugs, especially in the stage
of outbreak.

What do you think of antivascular therapy?

Anti-angiogenesis therapy continues throughout the course and benefits from third-line TKI

"Now, although there are many kinds of bowel cancer drugs, the overall plan is relatively single
.
In palliative care for advanced unresectable metastatic colorectal cancer, treatment options need to be selected according to the status of MSI/MMR, RAS and Braf, and immune checkpoint inhibitors are recommended for MSI-H/dMMR, while for MSS or MSI-L/pMMR, the first and second lines are mainly chemotherapy ± targeted therapy
.
The selection of targeted drugs is mainly anti-EGFR drugs and anti-VEGF drugs
.
Professor Wang Zhenghua explained that under normal circumstances, patients in the first and second lines, basically choose anti-EGFR and anti-VEGF
.
If the patient RAS and Braf are both wild-type and the primary focus is located in the left half colorectum, the first line will choose anti-EGFR drugs, and if the disease progresses, the second line will be replaced by anti-VEGF drugs
.
If the patient has a mutation in RAS or Braf, the primary site is generally not considered: the first line will directly select anti-VEGF drugs, and the second line will also select anti-VEGF drugs
across the line.

The more treatment lines in patients with advanced colorectal cancer, the longer the overall survival, and when receiving third-line therapy, some patients have received first-line anti-angiogenesis therapy, and some patients have received second-line anti-angiogenesis therapy
.
Even so, Professor Wang Zhenghua emphasized: "Heavy clinical studies such as FRESCO show that there are still significant benefits of third-line anti-angiogenesis therapy
.
It can be seen that anti-angiogenesis therapy plays a very important role
in the whole management of advanced unresectable metastatic bowel cancer.
”

At the same time, FRESCO studies have also shown that for patients with advanced bowel cancer with liver metastasis, even if the first and second lines have undergone anti-angiogenesis therapy, the third-line fruquintinib treatment still has a beneficial advantage
.
In other words, whether the first and second lines have been treated with anti-angiogenesis therapy, and whether the patient has concomitant liver metastases, the third-line fruquintinib treatment has a survival benefit
.
In general, anti-angiogenesis therapy is throughout the treatment of advanced colorectal cancer and has a very important role
in all lines.

Professor Wang Yusheng also said that in patients with coloral cancer liver metastasis, the research evidence of third-line fruquintinib treatment is sufficient and has obvious advantages
.
In addition, she added that coloral cancer liver metastases are very common, with about 15% to 25% of colorectal cancer patients having liver metastases at the time of diagnosis, while another 15% to 25% of patients will have liver metastases after radical resection of the primary colorectal cancer focus, of which the vast majority (80% to 90%) of liver metastases are initially unable to obtain radical resection ^[5].

Therefore, liver metastasis has always been a "stumbling block" to limit the long-term survival of patients with advanced coloral cancer
.
At present, liver metastasis of MSS colorectal cancer is commonly used in first-line and second-line chemotherapy combined with targeted therapy
.
Cituximab may be used in patients with wild RAS/RAF, or bevacizumab, depending on whether it is left or right colon cancer
.
At the third line, the treatment strategy will change
.
Because the effect of bevacizumab continuing cross-line therapy is not necessarily better than the current three-line selection, clinical continuous intravenous administration will also increase the psychological pressure of patients and affect the patient's psychological state, so oral small molecule drugs are a more suitable third-line option, especially in patients who have previously used VEGF inhibitors (such as bevacizumab), including patients with
liver metastasis.

How does the third or rear line go?

"1+1>2", anti-angiogenesis combination therapy can be expected in the future

From the guideline, the third-line treatment is mainly monotherapy, including anti-angiogenic TKI and chemotherapy drugs
.
"The FRESCO study showed that the median PFS was significantly longer in the fruquintinib group than in the placebo group (3.
71 months vs 1.
84 months) and OS was extended by 2.
73 months (9.
3 months vs 6.
57)[2].

In fact, the above excellent clinical data can not fully meet the requirements and wishes
of clinicians for the extension of patient survival time.
If the patient's physical condition is still relatively good, we hope to give the patient more treatment methods, so that the patient has more treatment benefits
.
Professor Wang Zhenghua pointed out that in the post-line treatment, the improvement of the tumor microenvironment cannot be satisfied by antivascular therapy alone, and the combination treatment mode is an important choice
.
For example, chemotherapy combined with targeted, targeted combined immunization, or chemotherapy combined with targeted combined immunization
.
It is not difficult to see that in the improvement of tumor microenvironment, a simple pathway and a treatment mechanism are far from meeting the clinical needs, and it may be necessary to combine treatment modes of "1+1>2" or even "1+1+1>3" to bring survival benefits
to patients.

Professor Wang Zhenghua also pointed out that after the third-line treatment, relevant clinical studies, including the REGONIVO study^[6], also showed the initial effectiveness of anti-angiogenesis multi-target TKI combined with PD-1 inhibitor therapy, and the above combination therapy strategy has the value of
further research and exploration.

Professor Wang Yusheng added that the REGONIVO study has opened up ideas
for the exploration of third-line combination treatment strategies for advanced coloral cancer.
The REGONIVO study explores and attempts anti-angiogenic small molecule TKI drugs + immune checkpoint inhibitors to improve efficacy in patients with advanced colorectal cancer, especially for patients with microsatellite stabilization (MSS), which is expected to benefit
。 At the 2021 American Society of Clinical Oncology (ASCO) conference, Professor Li Jin reported a clinical study that explored the preliminary application results of fruquintinib combined with cidilizumab in the treatment of advanced coloral cancer and achieved good efficacy; The overall objective response rate (ORR) of 22.
7%, disease control rate (DCR) of 86.
4%, median PFS of 5.
6 months, and median OS of 11.
8 months in the study group of 44 patients ^[7] indicates that fruquintinib combined with cidilizumab is highly promising
for MSS-type advanced colorectal patients after failure of standard therapy.
The two professors agreed that anti-angiogenesis combination therapy is the future development direction, whether it is combined chemotherapy or combined with immune checkpoint inhibitors, it is worth further exploration!

Expert Profile
Professor Wang Yusheng

Department of Gastroenterology, Shanxi Provincial Cancer Hospital

Chief Physician Master Supervisor

Shanxi Provincial Cancer Hospital is the person in charge of clinical research and digestion

Vice Chairman of the Ethics Committee of Shanxi Provincial Cancer Hospital

Deputy Director of Shanxi Provincial Gastric Cancer Diagnosis and Treatment Center

He is the chairman of the Youth Committee of the Tumor Chemotherapy Professional Committee of Shanxi Anti-Cancer Association

Leader of the liver cancer group of the Hepatology Branch of Shanxi Medical Doctor Association

Secretary General of the Oncology Professional Committee of Shanxi Medical Association

Deputy Leader of the Oncology Group of the Digestive Committee of Shanxi Medical Association

Vice Chairman of the Youth Committee of the Colorectal Cancer Professional Committee of Shanxi Anti-Cancer Association

Vice Chairman of the Youth Committee of the Liver Cancer Committee of Shanxi Anti-Cancer Association

Vice Chairman of the Youth Committee of the Hepatology Physicians Branch of Shanxi Medical Doctor Association

Member of Pancreatic Cancer Committee of the Chinese Society of Clinical Oncology (CSCO).

Member of the Gastrointestinal Mesenchymoma Committee of the Chinese Society of Clinical Oncology (CSCO).

Member of the Standing Committee of the Esophageal Cancer Committee of the Beijing Society for Cancer Prevention and Control

Expert Profile
Wang Zhenghua Professor
Chief Physician Master Tutor The First Affiliated Hospital of Jinzhou Medical University Leader of the Department of Oncology Science of the First Affiliated Hospital of Jinzhou Medical University, Director of the Department of Oncology, Director of the Department of Oncology,
the First Affiliated Hospital of Jinzhou Medical University Standing Committee of Gastrointestinal Tumor Professional Committee of Chinese Health Science and Technology Promotion Association, Vice Chairman of Gastrointestinal Tumor Branch of Liaoning Life Science Society, Academic Committee of Tumor Hyperthermia of China Anti-Cancer AssociationAcademic Member, Youth Committee of Tumor Big Data and Real-World ResearchYouth Committee of Liaoning Anti-Cancer Association, Standing Committee Member of Liaoning Anti-Cancer Association, Standing Committee Member of the First Professional Committee of Tumor Immunology of Liaoning Provincial Society of Immunology, Standing Committee Member of the Third Tumor Metastasis Professional Committee of
Liaoning Anti-Cancer Association
Member of the Standing Committee of the Liaoning Branch of the First Tumor Hyperthermia Professional Committee of the Chinese Anti-Cancer Association

References

[1].
Li J, Qin S, Xu R, et al.
Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Oncol.
2015 Jun; 16(6):619-29.

[2].
Li J, Qin S, Xu RH, et al.
Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial.
JAMA.
2018 Jun 26; 319(24):2486-2496.

[3].
Xu J, Kim TW, Shen L, et al.
Results of a Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Trifluridine/Tipiracil (TAS-102) Monotherapy in Asian Patients With Previously Treated Metastatic Colorectal Cancer: The TERRA Study.
J Clin Oncol.
2018 Feb 1; 36(4):350-358.

[4].
Jin Y, Li J, Shen L, et al.
A multi-center effectiveness comparison study of fruquintinib with constructed external control cohort of other TKIs using real-world data in 3+ line treatment of metastatic colorectal cancer.
2021 CSCO.

[5] Surgeon Branch of Chinese Medical Doctor Association, Gastrointestinal Surgery Group of Surgery Branch of Chinese Medical Association, Colorectal Surgery Group of Surgery Branch of Chinese Medical Association, etc.
Guidelines for the diagnosis and comprehensive treatment of liver metastasis of colorectal cancer in China (2020 edition)[J].
Chinese Journal of Practical Surgery,2021,41(1):1-11.

[6].
Fukuoka S, Hara H, Takahashi N, et al.
Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial ( REGONIVO, EPOC1603).
J Clin Oncol.
2020 Jun 20; 38(18):2053-2061.

[7].
Ye Guo, Weijie Zhang, Jieer Ying, et al.
Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.
2021 ASCO Abstract 2514.

*This article is for the sole purpose of providing scientific information to medical professionals and does not represent the views of this platform