Professor Baili: The FRESCO-2 study shines ESMO, and the status of fruquintinib as the third-line standard treatment for advanced bowel cancer is unshakable

With the outstanding performance of FRESCO research, the small molecule anti-angiogenesis-targeted drug fruquintinib independently developed in China was approved in China in 2018 and became the standard treatment
for patients with advanced colorectal cancer (CRC).
Since its launch for 4 years, fruquintinib has been widely used in clinical practice and has shown excellent efficacy and safety
.
At this year's European Society of Medical Oncology (ESMO) conference, fruquintinib made a stunning appearance with the global multicenter phase III FRESCO-2 study, issuing the strongest voice of China and is expected to rewrite the global CRC treatment landscape
.
On this occasion, the "medical community" specially invited Professor Bai Li of the First Medical Center of the PLA General Hospital to deeply interpret the FRESCO-2 research data and explain the impact
of the research results on the clinical practice of CRC worldwide.

A blockbuster: the FRESCO study established fruquintinib as the third-line standard treatment for CRC in China

CRC is one of the common malignant tumors in China, although after standardized first-line and second-line treatment, many patients can obtain a longer survival time, but the third-line and subsequent treatment effect is not ideal, and more efficient and safe treatment options
are still needed.
In 2018, as the first full-text study of new anti-tumor drugs in China to be published in the Journal of the American Medical Association (JAMA), the excellent results of the FRESCO study have attracted extensive attention from scholars at home and abroad ^[1].

The FRESCO study is a phase III clinical trial led by Professor Li Jin and Professor Qin Shukui and jointly participated by 28 clinical
centers across the country.
A total of 416 patients with metastatic CRC (mCRC) who had failed at least second-line standard chemotherapy were included, and about 30% of them received anti-VEGF antibody therapy
.
The results of the study showed that the median overall survival of fruquintinib for the third-line treatment of advanced CRC and above was as long as 9.
3 months, which was significantly longer than that of the placebo group by 2.
7 months, and reduced the risk of death by 35%; The median progression-free survival (PFS) reached 3.
7 months, significantly 1.
9 months longer than placebo, and reduced the risk of disease progression or death by 74%.

Furthermore, consistent OS (HR = 0.
68) and PFS (HR = 0.
24) benefits
were observed in patients previously treated with anti-VEGF antibodies.

Based on the results of this study, fruquintinib was approved for marketing in China in 2018, bringing better third-line treatment options
to Chinese mCRC patients.
Since its launch for 4 years, fruquintinib has benefited many mCRC patients in China and brought hope for countless patients to prolong their survival
.

Accumulation: The FRESCO-2 study is expected to rewrite the global landscape of CRC post-treatment in the future

At ESMO 2022, the "international version" of FRESCO's research FRESCO-2 research once again attracted global attention ^[2].

This is a randomized, double-blind, placebo-controlled phase III study conducted in the United States, Europe, Japan and Australia and included 691 patients
with refractory mCRC from 150 clinical centers in 14 countries, including the United States, Japan, Europe and Australia 。 The FRESCO-2 study design is essentially the same as the FRESCO study, but with a larger sample size and stricter inclusion criteria, requiring patients to have previously received oxaliplatin, irinotecan, fluorouracil-based chemotherapy, anti-VEGF antibodies, or anti-EGFR antibody therapy, and progression or intolerance
after TAS-102 and/or regorafenib.

Figure 1.
FRESCO-2 study design

The results of the study showed that the median OS in the fruquintinib group reached 7.
4 months, which was significantly longer than that in the placebo group by 2.
6 months, reducing the risk of death by 34%; The median PFS reached 3.
7 months, nearly doubling the 1.
9 months longer than the placebo group, reducing the risk of disease progression by 68%.

And fruquintinib confers OS and PFS benefits in all preset subgroups, including those previously treated with anti-VEGF antibodies (median OS: HR=0.
683; median PFS: HR=0.
335).

In addition, the disease control rate (DCR) in the fruquintinib group reached 55.
5%, which was also significantly better than that in the placebo group (16.
1%)
.

Figure 2.
The primary endpoint of the study was OS and subgroup benefit

Figure 3.
To study the secondary endpoint PFS and subgroup benefits

At the same time, the safety and tolerability of fruquintinib treatment were good, with a ≥ grade 3 adverse event rate of 62.
7% (placebo group: 50.
4%), and the ≥ grade 3 treatment-related adverse event rate was the lowest among the third-line common treatment regimens, fully meeting the clinical needs
of patients with advanced bowel cancer to delay disease progression while ensuring quality of life.

Is the same small molecule TKI indiscriminate in the continuation of the efficacy of frontline bevacizumab anti-angiogenic therapy? The data of large phase III studies at home and abroad may give the answer
.
Unlike the FRESCO study, which had received VEGF treatment at about 30%, FRESCO-2 basically 100% of patients received VEGF treatment on the front line, and even if the proportion of patients treated > 3rd line was significantly increased, the efficacy data of PFS 3.
7 months and OS 7.
4 months could still be obtained, which strongly proved that the efficacy of fruquintinib for the latter-line treatment of patients with advanced bowel cancer was not affected by front-line anti-angiogenic therapy.
Implement the concept of
three-line Chemo-break and anti-angiogenesis management.
In the global CORRECT phase III study of indirect comparative observation of regorafenib, 100% of patients on the same front line received bevacizumab treatment, and only obtained a median OS of 6.
4 months, which was only 1.
4 months longer than placebo; median PFS was only extended by 0.
2 months compared with placebo, up to 1.
9 months, which may indicate that the heterogeneity of small molecule TKIs is obvious, and there is indeed a difference
in the convenience of the patient's anti-angiogenesis management.

All in all, the international multicenter phase III FRESCO-2 study once again verified the results of China's pivotal phase III FRESCO study, the same study design, stable and consistent efficacy and safety, reflecting the strong anti-tumor activity of fruquintinib, which is expected to rewrite the global advanced bowel cancer treatment landscape
.
Based on the benefits of fruquintinib in ultra-long OS and PFS in two studies, in clinical practice, fruquintinib should be used as much as possible for the third-line standard treatment of advanced bowel cancer to maximize its antitumor activity and maximize patient survival benefit
.

Stand out: An ESMO mesh meta-analysis showed the longest PFS benefit with fruquintinib on third-line therapy

Among the third-line treatments for advanced bowel cancer, currently approved drugs include regorafenib, fruquintinib, and TAS-102
.
Which of the three is better or worse? How to choose the right treatment plan for patients in clinical practice? A network meta-analysis (NMA) presented at ESMO 2022 may inform clinical drug selection ^[3].

。 The analysis identified randomised controlled trials (RCTs) for inclusion in NMA through a systematic literature review conducted in February 2022, including three RCTs (ReDOs, CORRECT, and RECOURSE) including global or US-only populations and four RCTs (TERRA, Yoshino 2012, CONCUR, and FRESCO)
including Asian populations only.

Figure 4.
Study design

The investigators estimated the median PFS of different third-line regimens for advanced bowel cancer and showed that the median PFS in the fruquintinib group, regorafenib 80 mg group, regorafenib 160 mg group, TAS-102 group and the best supportive care group were 3.
9 months, 2.
8 months, 2.
1 months, 2.
0 months, and 1.
9 months
, respectively.

Figure 5.
Kaplan-Meier curve and median PFS prediction for PFS

The results of this network meta-analysis showed that among the currently approved third-line treatment drugs for advanced bowel cancer, fruquintinib had the longest median PFS and the highest risk of disease progression or death, making it the preferred third-line standard treatment for
advanced bowel cancer in clinical practice.

Create brilliance again: looking forward to fruquintinib "going abroad and going to the world"

From FRESCO research to FRESCO-2 research, fruquintinib, a small molecule anti-angiogenesis-targeted drug independently developed in China, has reached the international top stage, fully verifying the consistent efficacy and safety of fruquintinib in the treatment of advanced bowel cancer patients of different races and regions around the world, indicating that the quality of fruquintinib research data is reliable and the results are reproducible
.
This is not only a major breakthrough in the field of advanced bowel cancer treatment, but also represents the global attention and recognition
of China's voice.
It is reported that Hutchison Pharmaceutical will apply for fruquintinib overseas for the indications
for third-line and post-line treatment of advanced CRC based on the results of FRESCO and FRESCO-2 studies.
It is believed that in the future, the "Voice of China" in the field of bowel cancer will continue to resound on the world academic stage, providing Chinese solutions for solving the problem of advanced bowel cancer treatment, so that more Chinese innovative drugs can truly "go abroad and go global", bringing longer survival benefits and better quality of life to the majority of
patients.