Ask the big coffee, life is far-reaching| Professor Bi Feng: Mechanics is practiced, perseverance: the road of targeted therapy exploration for colorectal cancer

In recent years, various new drugs/therapies around colorectal cancer treatment have emerged one after another, especially targeted therapy has now become the "mainstay" in the field of colorectal cancer, opening the "life channel"
of many patients.
At the just-concluded 2022 European Society for Medical Oncology (ESMO), a number of targeted therapy research results for colorectal cancer have been unveiled, which has attracted widespread attention
from the academic community.
In this regard, Yimaitong specially invited Professor Bi Feng of West China Hospital of Sichuan University to sort out the evolution of targeted therapy for colorectal cancer and comment on the new progress
of targeted therapy for colorectal cancer.

Expert profiles

Prof.
Bi Feng

Director of Department of Medical Oncology, West China Hospital, Sichuan University

Director of the Laboratory of Signal Transduction and Molecular Targeted Therapy

Chairman of the Special Committee of Tumor Molecular Targeted Therapy of the Chinese Society of Biomedical Engineering

Vice President of Oncology Branch of Chinese Geriatric Association

Vice Chairman of the Colorectal Oncology Treatment Committee of the Chinese Medical Doctor Association

Vice Chairman of the CSCO Biliary Tract Oncology Expert Committee

Recipient of the National Science Foundation for Outstanding Young Scholars

Expert in the review of major special projects of the Ministry of Science and Technology of the People's Republic of China

National Science and Technology Progress Award Review expert

Targeted exploration to witness the 18-year history of colorectal cancer

Prof.
Bi Feng: Professor Bi introduced that targeted therapy has opened a new chapter
in precision tumor treatment.
Among them, colorectal cancer patients are one of
the first to receive targeted therapy.
After years of radiotherapy and chemotherapy, cetuximab and bevacizumab were approved for marketing in 2004, and colorectal cancer treatment officially entered the era
of precision targeted therapy.
Clinical studies have shown that cetuximab + chemotherapy versus bevacizumab + chemotherapy significantly improves patient outcomes compared with conventional therapies1
.

In the following ten years, a number of colorectal cancer targeted drugs have been launched, providing patients with more treatment options
.
In particular, the introduction of regorafenib in 2012 has ushered in new changes
in the field of colorectal cancer.
Regorafenib is a small molecule tyrosine kinase inhibitor (TKI) that can inhibit multiple tyrosine kinase targets, and based on its good efficacy and safety data, the United States and China have successively approved the drug for marketing
.
Subsequently, more anti-angiogenic drugs such as ramoximumab and fruquintinib have gradually entered the clinic
.

In 2017, the advent of immune checkpoint inhibitors based on targets such as PD-L1/PD-1 once again set off a research boom in the field of colorectal cancer, and MSI-H/dMMR patients ushered in a new dawn
.
The exploration of TKI combined with immunotherapy has pushed the treatment of colorectal cancer to a new era
of target-immune combination.

Figure 1 Timeline of approval of colorectal cancer treatment drugs by the US FDA 1

Reasonable layout and optimized sequential: Priority use of regorafenib brings longer survival to patients with advanced colorectal cancer

Professor Bi Feng: Professor Bi introduced that for the back-line treatment of colorectal cancer, the drugs commonly used include regorafenib, fruquintinib, and TAS-102
.
However, how these drugs should be arranged so that patients can benefit more is a question
worth thinking about clinicians.
At this year's ESMO conference, a study called FRESCO-2 attracted widespread attention
from the academic community.
Professor Bi pointed out that the FRESCO-2 study has made a good exploration
of the problem of drug "formation".
In this prospective study, 48% of the included patients had previously received regorafenib or/and TAS-102, and 48% of those patients had received regorafenib at the frontline
.
Data showed that prior treatment with regorafenib followed by fruquintinib resulted in a greater risk reduction in the risk of death and disease progression, and greater survival benefit2
.

Patients who were previously treated with regorafenib versus no regorafenib had a greater risk of death after fruquintinib: HR 0.
62 (38% reduction) versus HR 0.
72 (28% reduction);

Patients who were previously treated with regorafenib versus no regorafenib had a greater risk reduction in disease progression with fruquintinib: HR 0.
28 (72% reduction) versus HR 0.
36 (64% reduction);

Fig.
2 Survival outcomes
of front-line regorafenib-treated versus fruquintinib in patients without regorafenib

Professor Bi said that the re-use of fruquintinib in patients treated with regorafenib can achieve better results, which is the result of a prospective phase III clinical study, and the root cause may be mainly as follows:

First, regorafenib is an anti-angiogenic multi-target small molecule TKI
.
Unlike other TKIs, regorafenib not only blocks VEGFR1/2/3, but also has inhibitory activity against oncogenes and tumor microenvironment kinases including TIE-2, RAF-1, BRAF, BRAFV600, KIT, RET, PDGFR, and FGFR, which individually or synergistically affect tumor growth, interstitial microenvironment formation, and disease progression3
.

Second, different medication sequences often lead to different treatment outcomes
.
The survival benefit of regorafenib for colorectal cancer patients is undoubted
.
In the whole process of management of cancer patients, "good drugs first" may often lead to better outcomes for patients, because as the number of treatment lines goes on, many patients lose the opportunity to
try other drugs.

In addition, Professor Bi also pointed out that regorafenib can regulate tumor immunity through multiple mechanisms and comprehensively improve the tumor immune microenvironment, which is expected to become a "good partner"
for immunotherapy (such as PD-1/PD-L1 inhibitors).
However, due to the intervention of immunotherapy drugs, the "formation" of colorectal cancer patients needs more thinking and exploration
.

Play a good "combination box" of treatment, and combine strong to achieve the long-term survival of colorectal cancer patients

Prof.
Bi Feng: The data show that pMMR/MSS CRC accounts for a high proportion, and the tumor microenvironment is mainly immuno-exclusion and immunosuppressive
.
However, the efficacy of pMMR/MSS mCRC alone is not satisfactory, and target-free combination may be one of the important directions for future exploration4
.
Several studies are currently underway
.

At this year's ESMO meeting, a Phase I clinical trial
of regorafenib, ipilimumab and nivolumab (RIN) in chemotherapy-resistant MSS metastatic colorectal cancer (mCRC) was reported 。 For the results of the study, Professor Bi introduced that the median OS of the combined immunization regimen based on regorafenib was nearly one and a half years, while the combination of regorafenib combined with double immunity (RIN) showed stronger anti-tumor activity, with an objective response rate (ORR) of 31% and a disease control rate (DCR) of 65.
5%.
The median OS of the total population was 19.
6 months and the median PFS was 4 months; In patients without liver metastases, the median PFS is 5.
0 months, and the median OS has not been reached, but it has been more than 20 months
.
In terms of safety, the adverse reactions of regorafenib combined with double exemption were controllable and manageable5
.

Fig.
3 PFS and OS
of RIN protocol

Professor Bi also mentioned that although the results of RIN research have been significantly improved compared with traditional treatment options, because the study is still in the phase I study stage, the sample size is relatively small, and the efficacy of non-liver metastases patients is better, so it is expected that a larger sample size study will further verify the results
.
In addition, which patients are more likely to benefit from targeted combination therapy? Which patients may not tolerate the side effects of target-immune combination? These questions also deserve more research to explore and validate
.

References:

1.
Ciardiello F, Ciardiello D, Martini G, et al.
Clinical management of metastatic colorectal cancer in the era of precision medicine[J].
CA Cancer J Clin.
2022 Jul; 72(4):372-401.

2.
Dasari NA, Lonardi S, Garcia-Carbonero R, et al.
LBA25 FRESCO-2: A global phase III multiregional clinical trial （MRCT） evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer[J].
Annals of Oncology, 2022, 33: S1391-S1392.

3.
LI Chunyi,HUANG Xinen,WANG Ping.
Research progress on colorectal cancer-related molecular targets and targeted therapy[J].
Shandong Medical Journal.
2021,61(17):108-112.
)

4.
Kim CG, Jang M, Kim Y, et al.
VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers[J].
Sci Immunol.
2019 Nov 8; 4(41):eaay0555.

5.
Fakih MG, Sandhu J, Lim D, et al.
A phase I clinical trial of regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy resistant MSS metastatic colorectal cancer (mCRC) .
2022 ESMO abstract 320MO.