TRAP research opens up new ideas, and big coffee gathers to discuss colorectal cancer targets and the present and the future

From September 9 to 13, 2022, the annual meeting of the European Society of Medical Oncology (ESMO) was held in Paris, France, and a series of latest studies
in the field of oncology were announced.
Colorectal cancer has been attracting attention as a gastrointestinal tumor with the highest incidence and mortality rate
.
There are also a number of new studies at this ESMO conference! Among them, the tyrosine kinase inhibitor (TKI) combined immunotherapy research initiated by Chinese scholars can be described as a new one
.
In order to timely convey cutting-edge progress and discuss new strategies and new trends, this platform has launched the column "Big Coffee Talks, Care is Always Present", specially inviting big coffee in the field of colorectal cancer to discuss and deeply analyze the new progress in the diagnosis and treatment of advanced colorectal cancer!

At this ESMO conference, the preliminary results of the TRAP study of tyrosine kinase inhibitor (TKI) combined with PD-1 inhibitor in the treatment of microsatellite stability or mismatch repair normal (MSS/pMMR) metastatic colorectal adenocarcinoma in the treatment of TKI response by the team of Professor Zhang Jingdong of Liaoning Provincial Cancer Hospital brought new ideas
to TKI combined immunotherapy.
Professor Zhang Jingdong, the main investigator of the study, and his team member Professor Dong Qian, together with Professor Li Jian of Peking University Cancer Hospital, are invited to interpret the research, collide ideas, and unlock new ideas!

Interview video

The immune efficacy of MSS colorectal cancer is limited, and the anti-vascular combined immune strategy is highly anticipated

Professor Zhang Jingdong: Immunomonotherapy has now become the standard treatment
for patients with microsatellite highly unstable (MSI-H) bowel cancer.
Unfortunately, MSI-H accounts for only about 5% of mCRC patients, and for the vast majority of people with MSS bowel cancer, it is especially expected that they can benefit
from immunotherapy.
Due to the relatively poor overall immune microenvironment of MSS advanced bowel cancer, the overall effective rate of immunotherapy alone is relatively low, so it is also expected that anti-angiogenic drugs can be combined with immunotherapy to obtain better benefits
.
Although the objective effective rate (ORR) of immune combined with antiangiogenic drugs exceeded 30% in the REGONIVO study ^[1], most subsequent studies failed to replicate such good results
.
This may be related to the lack of clarity in the dominant population of antiangiogenesis and immune
combinations.

The mainstay of the third-line treatment of bowel cancer, fruquintinib and FRESCO-2 research strength confirmed

Professor Dong Qian: Fruquintinib is a small molecule TKI independently developed in China against VEGFR-1, 2 and 3, which has solid evidence-based medical evidence
in both preclinical and clinical research.
In terms of guideline recommendation level, fruquintinib is currently the standard of care for the third-line treatment of colorectal cancer
.
Its marketing registration study, FRESCO Research, is well known
.
In the FRESCO study ^[2], fruquintinib confered significant benefits in both progression-free survival (PFS) and overall survival (OS) for advanced third-line colorectal cancer; In the real world, the clinical research data has also been further verified
.

The FRESCO-2 study presented at the 2022 ESMO ^{Annual Meeting [3]} further verified the efficacy and safety
of fruquintinib in patients with advanced colorectal cancer based on the Western population.
The published data are similar to the FRESCO study, and there are clear benefits
for both PFS and OS.
In other words, whether it is an Eastern or Western population, whether it is a randomized controlled clinical study, or real-world research data, fruquintinib is one of the
third-line standard treatments for advanced colorectal cancer.

The new perspective screens immunodominant populations, and the preliminary results of the TRAP study are gratifying

Professor Dong Qian: The design of the TRAP study is derived from clinical practice
.
At that time, we found in the backline treatment of colorectal cancer that combined immunotherapy on the basis of effective TKI can achieve a very long remission period, and PFS in some cases can even reach more than
1 year.
In view of this, Professor Zhang Jingdong designed this study based on the combination of basic research and evidence-based medicine
.

First of all, lesion shrinkage is a manifestation of
effective treatment.
Second, in patients with stable disease (SD), changes may also occur inside the tumor
.
For example, patients with lung metastases who undergo antiangiogenic therapy have cavitation-like changes in the lesion; The reduction in the density of lesions in patients with liver metastases all reflect the efficacy of anti-angiogenic therapy, and we also summarize them as effective imaging findings
.
In addition to anti-angiogenic drugs, they also exert their own anti-tumor effects, as well as immunomodulatory effects, which also lays the foundation
for the immune activation microenvironment for immunotherapy.
Based on the above factors, Professor Zhang Jingdong screened out the immunology-benefiting advantageous population on the basis of effective imaging performance, and combined immunotherapy sequentially in order to exert better efficacy
.
In the follow-up study, we also saw obvious efficacy
in the screened advantageous population.
Compared with the exploration of molecular biology, we believe that the performance of effective imaging may be more in line with the needs of clinical practice and more convenient for clinical application, which is the design consideration
of the TRAP study.

Professor Li Jian: As Professor Dong Qian said, the selection criteria for effective populations in the TRAP study are not completely limited to the traditional RECIST evaluation criteria, but combine some other perspectives and indicators to evaluate the effectiveness of treatment, and the design is very novel.

In conventional thinking, for the screening of dominant or effective populations, we often select some immune microenvironments that are better, or even apply immune biomarkers for screening, but in the research of Professor Zhang Jingdong's team, the idea is completely different, but according to the efficacy of TKI to select the treatment population
.

Professor Zhang Jingdong: At the beginning of the design, we also considered
the overall efficacy process of immunotherapy.
First of all, the effective population of TKI treatment is not the same as conventional chemotherapy, and patients with both lung metastasis and liver metastases have seen obvious changes in imaging, such as cavities of lung metastases, significant reduction in the density of liver metastases, etc.
, suggesting that tumors may be necrosis
.
After tumor necrosis, the release of tumor antigens is very obvious, which increases the immunogenicity
of cold tumors.
Second, once effective, TKI can play a significant role
in reducing tumor burden.
Third, for people with TKI effect, in terms of anti-angiogenesis itself, blood vessels are normalized and immunosuppressed states can be lifted; At this time, the combination with immunization may prolong and amplify
the progress of TKI effectiveness.
In order to better reflect the long tailing effect of immunotherapy benefit, we selected 9-month PFS rates instead of objective response rates
for the design endpoints.

Professor Dong Qian: Before the submission deadline of the 2022 ESMO Conference, that is, as of April 2022, a total of 35 patients were screened [^4], and 33 were assessable
.
Among them, 15 patients were in the first group of the study, that is, the imaging obvious response group, and the late sequential PD-1 monoclonal antibody, that is, the population
of the 9-month PFS rate study.
As of August 2022, the objective response rate in this group was 20%, all of which were partial response (PR), and the 9-month PFS rate was 55%, which was double (27.
1%)
compared with the historical control group from the FRESCO study.
At the last follow-up, the 9-month PFS rate in this group had reached 73%, and the median PFS was 13.
2 months
.
This paper further validates the hypothesis that
sequential PD-1 monoclonal antibody in the dominant population can achieve a state of lasting remission.
In terms of adverse reactions, grade 3~4 adverse reactions are mainly hypertension, proteinuria, hand and foot skin reactions, immune-related hypothyroidism, etc.
, which can be significantly alleviated after effective treatment, that is, the safety and tolerability of the program are good
.

Prof.
Li Jian: The data is really amazing
.
For immunotherapy, we not only hope to increase the response rate, but more importantly, we hope to play the greatest advantage of immunotherapy, that is, once effective, it can bring a longer tumor control time
.
According to the research data of Professor Zhang Jingdong's team, patients not only have improved efficiency, but also have a durable tumor control time, and it is obvious that immunotherapy plays an important role in it; And it may be possible to reverse the advantage of TKI combined with immunotherapy, the research idea is novel, which will bring better inspiration
for similar research in the future.

Anti-angiogenic combined immunotherapy has a unique mechanism and significant synergistic benefits

Professor Zhang Jingdong: TKI drugs have their own characteristics, bevacizumab is usually not used alone, unlike TKI, which can not only be used alone, but also has better efficacy
.
In the TRAP study, the efficacy of people who responded to TKI was further improved
after sequential combined immunotherapy.
In the population that did not respond to the pre-TKI treatment, the tumor immune microenvironment did not actually change, so the possibility of subsequent effectiveness was relatively low
.
The synergistic mechanism of anti-angiogenesis and immunity has been explored
.
In my opinion, TKI tends to shape the environment
in which immunotherapy is effective in terms of tumor burden reduction, vascular normalization, and reduction of immunosuppressive factors in the immune microenvironment.
During TKI treatment, the patient's physical status is good, and adverse reactions can be well treated, so the efficacy of combined immunotherapy for people who are effective for TKI can be further improved on the basis of the past, and because patients have good tolerance to TKI, the safety of combined immunization on this basis is also guaranteed
.

Antiangiogenesis runs throughout, and combination immunotherapy can further enhance efficacy

Professor Zhang Jingdong: With the increase of therapeutic drugs, the arrangement of third-line or post-treatment is indeed an important issue
for clinicians to consider.
As far as the current guidelines for the treatment of colorectal cancer ^[5] are concerned, in the first-line treatment, RAS or BRAF wild-type and left colon are mainly anti-EGFR; RAS or BRAF mutants, or right colon, are predominantly
antiangiogenesis.
Antiangiogenic therapy can be continued with second-line therapy
.
In the third-line treatment, although the application of TKI is still in the anti-angiogenic pathway, its drug mechanism of action is different from that of bevacizumab anti-EGFR drugs, so it can bring different efficacy
to patients.
In the TRAM study, the regimen was in line with guideline recommendations, and people who responded to TKI were tried in combination with immunotherapy to further improve their survival time
.
Improving quality of life can also help
with late-line treatment.
There are very few cases regarding the superposition of TKI with immunotherapy adverse effects, and the overall safety of this drug combination is
manageable.
In the future, the pre-application
of this combination may be further explored.

New drugs are constantly emerging, and the options are becoming more and more abundant, and reasonable decisions should be fully considered

Professor Zhang Jingdong: At present, there are many application data of bevacizumab in the first and second lines; Allibercept is also conducting relevant clinical studies in China, but it has not yet been marketed; Ramoximab is currently mainly approved for liver cancer and gastric cancer; Fruquintinib and regorafenib are both approved TKIs
for colorectal cancer.
In the treatment of patients in the later line, the patient's quality of life needs to be considered, including the control
of adverse effects.
There is no more in-depth study of the head-to-head study of the two TKIs, so it can only refer to historical data and make reasonable choices
based on different populations in clinical practice.

Based on China to the world, China's innovative drugs can be expected in the future

Professor Zhang Jingdong: In recent years, China's new drug research and development has developed rapidly, and the original research and innovation capabilities of domestic pharmaceutical companies have been strong, and a number of representative and excellent national pharmaceutical companies
have emerged.
Leaders such as Professor Shen Lin, Professor Xu Ruihua, Professor Li Jin, Professor Qin Shukui and other leaders also actively lead China's new drug research, whether in the design of the test protocol, or in the overall organization of the strict density, the speed of the research process and the quality of the test are outstanding, leading China's esophageal cancer, gastric cancer, liver cancer and other drug research to the forefront of the world
。

In the past, many imported drugs were used for more than ten years, but now new drugs are developed extremely rapidly, usually in two or three or four years
.
The independent innovative drugs represented by fruquintinib not only based on China to do excellent FRESCO research, but also go global, further verify its effectiveness and safety in the global population through FRESCO-2 research, fully demonstrating the strong strength
of China's innovative drugs.
For the independent research and development of new anti-tumor drugs, we believe that more drugs will be based in China, go to the world, and be recognized
by the world in the future.

Professor Dong Qian: At present, in the research and development of new anti-tumor drugs, China's new drugs and technologies such as bispecific antibodies and antibody conjugate drugs (ADCs) are at the forefront of the world, and we are very proud
of this.
The progress of molecular biotechnology, not only the efforts of domestic scholars, including the progress of international advanced biological technology, but also laid a research foundation
for the research and development of new drugs in China.
Under the concept of global sharing, with reference to foreign research results, China's new drug research and development has also seen more innovation and further improvement
.
New technological innovations and target combinations based on molecular biology research and development can bring more new drugs and better therapeutic effects
.

summary

Professor Li Jian: In this interview, Professor Zhang Jingdong and Professor Dong Qian shared their research ideas without reservation based on their latest research results, which played a positive guiding role
for us to carry out new clinical research in the future, especially in the screening of immune-benefiting people.
In addition, the two professors discussed the application prospect of anti-angiogenic drugs, especially TKI drugs and immune combination therapy, in the treatment of MSS bowel cancer.
With the help of TKI drug-related research results, an in-depth analysis
was conducted on how to bring better treatment to patients with advanced colorectal cancer.
At the same time, the relevant mechanism of action was better analyzed and displayed
.
It is believed that the future of colorectal cancer immunotherapy dilemma will be broken, bringing better treatment opportunities
to patients.

References:

[1] 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].
J Clin Oncol,2020,38(18):2053-2061.

[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[J].
JAMA, 2018 ,319(24):2486-2496.

[3]Dasari NA,Lonardi S, Garcia-Carbonero R,et al.
FRESCO-2: a global phase III multiregional clinical trial (MRCT) evaluating the effificacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer.
2022 ESMO LBA25 .

[4]J.
Zhang, Q.
Dong, Y.
WANG, et al.
Tyrosine kinase inhibitor (TKI) plus PD-1 blockade in TKIresponsive MSS/pMMR metastatic colorectal adenocarcinoma (mCRC): Preliminary results of TRAP study.
2022ESMO; 428P.

[5] Guidelines for the diagnosis and treatment of colorectal cancer of the Chinese Society of Clinical Oncology (CSCO) (2022 edition)[M].
Beijing:People's Medical Publishing House,2022.

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