The 2022 CSCO satellite will | the preferred third-line treatment for advanced bowel cancer from the FRESCO-2 study

In 2018, with the breakthrough success of FRESCO research, fruquintinib, China's original anti-angiogenic small molecule tyrosine kinase inhibitor (TKI), was rapidly approved for the third-line treatment of advanced colorectal cancer (CRC) patients in China, and in 4 years, fruquintinib has brought survival benefits and significant improvements
in quality of life to more than 60,000 Chinese patients with advanced colorectal cancer (mCRC).
。 With the release of positive data from the FRESCO-2 international multi-center phase III clinical study in September this year, fruquintinib will bring longer survival benefits
to patients with advanced bowel cancer worldwide.
On the occasion of the 2022 China Clinical Oncology (CSCO) Annual Conference, the 2022 CSCO and Huang Medicine Satellite Conference was grandly held, and big names in the field of gastrointestinal tumors gathered in the cloud to explore the latest frontier progress
of gastrointestinal tumors.

Professor Li Jin of the Dongfang Hospital Affiliated to Tongji University and Professor Shen Lin of Peking University Cancer Hospital were specially invited to serve as the chairpersons
of the conference.
Professor Li Jin said in his opening speech that in the past few years, anti-vascular targeted drugs have made significant progress, from FRESCO research to FRESCO-2 research, in recent years, large-scale global clinical studies led by Chinese experts are gradually changing the global mCRC diagnosis and treatment pattern
.
Professor Shen Lin said that although the multi-line therapeutic drug options in the mCRC field today are rich, they still do not fully meet the needs
of patients.
The positive results of the FRESCO-2 study announced at this year's ESMO Annual Meeting are another proof
that Chinese pharmaceutical companies are based in China and going global.
Today's conference will also focus on the application and frontier progress of anti-angiogenic drugs in the field of mCRC, exchange experience in the diagnosis and treatment of bowel cancer, and seek the future development of
the discipline.

Figure 1 Statement by the President of the General Assembly

From FRESCO to FRESCO-2

Based on China, go global

Professor Wang Feng from Sun Yat-sen University Cancer Hospital gave a wonderful sharing
entitled "Anti-angiogenic Therapy Helps Optimize the Management Strategy of mCRC".
Professor Wang Feng said that abnormal angiogenesis of tumors plays an important role in the occurrence and development of mCRC, and the VEGF-VEGFR pathway also plays an important role
in CRC angiogenesis.
In the field of first-line and second-line therapy, the research and clinical application of macromolecular antiangiogenic drugs combined with chemotherapy have been quite mature, which can bring significant median overall survival (mOS) and median progression-free survival (mPFS) benefits to patients
.

Figure 2: Professor Wang Feng shared FRESCO research data

In the field of third-line therapy, the success of the FRESCO study led by Professor Li Jin and Professor Qin Shukui is undoubtedly a boon
for advanced CRC patients in China.
In the FRESCO study, the mOS of patients in the fruquintinib group was 9.
30 months, significantly longer than that of the placebo group by 2.
73 months (P<0.
001), and the risk of death was reduced by 35% (hazard ratio HR = 0.
65).
<b11> Fruquintinib also significantly prolonged PFS (3.
71 versus 1.
84 months, P<0.
001) and reduced the risk of disease progression by 74% (HR=0.
26).
<b12> At the same time, the objective response rate (ORR) and disease control rate (DCR) were also significantly higher than those in the placebo group ^[1].

In clinical practice, for mCRC patients who have previously received antivascular targeted therapy, whether they can continue to benefit from fruquintinib in the third-line and later-line therapy is the focus
of clinicians.
In the subgroup analysis data of the FRESCO study, it is not difficult to see that the median OS of third-line treatment with fruquintinib in patients with mCRC who have previously received targeted therapy is 7.
69 months, which can significantly prolong overall survival and reduce the risk of death by 37%.

The FRESCO-2 study presented at this year's ESMO Annual Meeting is an important study
for the source innovation of fruquintinib and the global bloom.
As the "international version" of the FRESCO study, fruquintinib has brought benefits very close to the FRESCO study data in the context of more rigorous screening of enrolled patients (previous chemotherapy failure with oxaliplatin, irinotecan, fluorouracil, failure of anti-VEGF antibody or anti-EGFR antibody therapy, and progress after TAS-102 and/or regorafenib).
It reflects the consistent efficacy of fruquintinib in patients with CRC in different regions and races around the world, which further confirms the survival benefit and objective efficacy of this drug for advanced CRC ^[2].

Finally, Professor Wang Feng also shared his wonderful views on anti-angiogenic drug resistance and coping exploration
.
After the development of resistance to front-line bevacizumab, it induces the formation of compensatory angiogenic pathways that do not depend on VEGF; The small molecule TKI multi-target is directly based on its direct effect on tumor cells, and combined immunity can better improve tumor hypoxia, regulate tumor immune microenvironment and other mechanisms of action, and can better continue the concept and efficacy
of antivascular full management.
At the same time, for most patients with MSS type mCRC who are not sensitive to immunotherapy, small molecule TKI combined with immunity can significantly improve and strengthen the efficacy of immunotherapy in mCRC patients, and the "golden partner" of "anti-vascular + immunity" may become an important direction
for future research.

Innovation at the source, blooming globally

From the FRESCO-2 study, the third-line treatment of advanced bowel cancer is preferred

Professor Xicheng Wang from Peking University Cancer Hospital delivered a wonderful speech
entitled "Source Innovation, Global Bloom - Optimal Third-line Treatment of Advanced Bowel Cancer from FRESCO-2 Research".
Professor Wang Xicheng said that for the FRESCO study, which published positive data in 2018, its efficacy data and important value need not be said
.
It is precisely based on the excellent efficacy and safety shown in the above studies that fruquintinib is the first to be approved for the third-line treatment
of mCRC in China.
In the FRESCO-2 study launched globally in 2020, the answer was also given to whether patients with multi-line therapy failure, large tumor burden and early antivascular therapy could further benefit from fruquintinib therapy
.

• Overall survival (OS) of the primary endpoint of the study: At a median follow-up of 11.
  3 months, the median OS of patients in the fruquintinib group reached 7.
  4 months, which extended the OS of patients by 2.
  6 months compared with placebo, and reduced the risk of death by 34% (HR=0.
  662, 95% CI: 0.
  549~0.
  800; P<0.
  001
  ).
  

• The secondary endpoint of the study, progression-free survival (PFS): median PFS of 3.
  7 months in the fruquintinib group doubled the patient's PFS and reduced the risk of disease progression by 68% (HR=0.
  321, 95% CI: 0.
  267~0.
  386; P<0.
  001
  ).
  

• Disease control rate (DCR): The DCR of patients treated with fruquintinib was 55.
  5%, significantly higher than that of 16.
  1%
  in the control group.
  

• Subgroup analysis of benefits of OS and PFS: almost all subgroups of patients were able to benefit
  significantly from fruquintinib.
  

Figure 3 Professor Wang Xicheng shared the FRESCO-2 research data

In terms of safety, the data from the FRESCO-2 study were similar to those in the FRESCO study, with ≥ grade 3 adverse event rates of 62.
7% and 50.
4% in the fruquintinib group and placebo group, respectively
.
Professor Wang Xicheng said that the incidence of adverse reactions in patients between the two groups was similar, which shows that most of the above serious adverse reactions are caused by tumor diseases themselves rather than therapeutic drugs
.
In the FRESCO subgroup of liver metastases, fruquintinib significantly prolonged OS and PFS (OS up to 8.
61 months and PFS up to 3.
71 months) in patients with liver metastases mCRC.

The results of the FRESCO-Hybrid real-world study showed that the PFS of patients in the fruquintinib group was significantly longer than that of the other TKI groups: 3.
71 months versus 2.
49 months, HR was 0.
67, and the P value was statistically significant
.
In the subgroup analysis, the extension of mPFS in the fruquintinib group was generally consistent with the results of the general population, and the mPFS was significantly prolonged
in the fruquintinib group compared with other TKI drug groups.
The above research data all reflect the antitumor activity of fruquintinib ^[3].

This paper once again verifies the preferred position
of fruquintinib in the third-line standard treatment of advanced bowel cancer.

Discussion: Continuing benefits from drug resistance breakthroughs,

The exploration direction of fruquintinib and the prospect of "going to sea"

Professor Liu Hao from Sichuan Provincial People's Hospital, Professor Ye Feng from the First Affiliated Hospital of Xiamen University, and Professor Zhu Liangjun from Jiangsu Cancer Hospital had wonderful discussions
on "How to break through drug resistance to achieve survival benefits in mCRC continuous antiangiogenic drug treatment, the future exploration direction of fruquintinib and the prospect of 'going to sea'" 。 Based on the evidence-based evidence of fruquintinib and their own clinical practice, the three professors highly praised fruquintinib as the standard treatment for patients with advanced bowel cancer: since the launch of fruquintinib in 2018, we have observed that the survival and quality of life improvement of patients are similar to the data in the FRESCO study during clinical use, bringing real survival benefits
to patients 。 Due to the important role of anti-angiogenic mechanism in anti-tumor treatment, fruquintinib is also exploring the possibility of anterior treatment indications, and expects more clinical research data to benefit more patients with gastrointestinal tumors, and also expects FRESCO-2 research to help fruquintinib "go to sea" successfully and go to the world
.

Figure 4 Professor Liu Hao's speech during the discussion session

Figure 5 Professor Ye Feng's speech during the discussion session

Figure 6 Professor Zhu Liangjun's speech during the discussion session

At the end of the conference, the chairmen of the conference, Professor Li Jin and Professor Shen Lin, summarized
the content of the conference.
The two professors said that at this meeting, we saw the important position of anti-angiogenic drugs in the whole process management of mCRC, and looked forward to the success of various therapies such as fruquintinib combined with immunity in the field of various solid tumors in the future, and also hoped that Hutchison Pharmaceutical, as a local R&D enterprise "based in China and going global", can create more and better domestic original anti-tumor drugs to go global and benefit more patients
.

References:

[1] 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.

[2] Dasari NA, et al.
FRESCO-2: A global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer.
ESMO Congress 2022, LBA25.

[3] Jin Y, 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.

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