The second-line treatment of liver cancer has added "fierce general"! The successful approval of the indication for remoxizumab has brought more hope to patients in China

Liver cancer is a high-incidence tumor in
China.
China's population is less than 20% of the world's population, but the annual new cases of liver cancer occupy half of the world's "half of the country"
.
Many patients are initially terminal, have a low 5-year survival rate, and a high disease burden ^[1,2
].
With the vigorous development of anti-tumor treatment drugs, a variety of new drugs/new therapies have come out, bringing new dawn
to liver cancer patients.
In the field of first-line treatment of liver cancer, drugs such as sorafinil and lenvatinib have been introduced, providing clinicians and patients with more choices
.
At the same time, there are still many unmet needs for the second-line treatment of liver cancer, and new drugs or treatment methods are urgently needed to be applied to the clinic
.

On October 8, 2022, the State Drug Administration (NMPA) approved the use of remoxizumab monotherapy for the treatment of hepatocellular carcinoma (HCC) patients who have previously received sorafenib and whose alpha-fetoprotein (AFP) ≥ 400 ng/mL has opened a new chapter
in the second-line treatment of liver cancer in China.

Remoxizumab breaks the deadlock with challenges to second-line HCC therapy: the REACH-2 study yields eye-catching data in people with elevated HCC at baseline AFP

As we all know, AFP is a diagnostic marker of liver cancer, and its expression is closely related to
the occurrence and development of liver cancer.
AFP can affect the differentiation, growth, metastasis, invasion and apoptosis of liver cancer cells through a variety of ways, and the prognosis of HCC patients with high AFP is poor
.
Elevated AFP levels are often associated with increased vascular endothelial cell growth factor receptor (VEGFR) expression and angiogenesis of
HCC.
After treatment with sorafenib, about half of patients have AFP≥400 ng/ml, and effective therapeutic agents are urgently needed for such patients ^[2,3
].

The advent of remoxizumab brings new hope
to patients with advanced HCC with baseline AFP ≥ 400 ng/ml who have failed or intolerant of sorafenib therapy.
Remoxizumab is a fully human IgG1 monoclonal antibody that specifically binds to VEGFR-2 and blocks the binding
of VEGF-A, VEGF-C, and VEGF-D to VEGFR-2.
Thus, remoxizumab inhibits VEGFR-2 activation stimulated by ligands, thereby inhibiting ligand-induced endothelial cell proliferation and migration^[4].

Its therapeutic status in advanced HCC is based on a global multicenter, randomized, double-blind, placebo-controlled Phase III clinical study (the "REACH-2 Study"
).
A total of 292 patients with advanced HCC who advanced after treatment with sorafenib and whose AFP ≥ 400 ng/mL were randomized to be treated with raimoxilizumab (8 mg/kg every 2 weeks) or placebo at
a 2:1 randomization.
The primary endpoints were overall survival (OS), and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), safety and the time to worsening of the hepatobiliary scale 8 (FHSI-8) score of the cancer treatment function evaluation system, and the time to the deterioration of the ECOG physical status score
.

The results showed that the study reached the main positive endpoint of OS, and the survival benefit
of patients with advanced liver cancer with advanced liver cancer with remoxizumab single-agent second-line treatment AFP≥ 400 ng/ml was significantly higher than placebo 。 Among them, the median OS of patients in the remoxilizumab group was 8.
5 months, which was significantly longer than that in the placebo group by 1.
2 months (HR=0.
710, 95% CI 0.
531-0.
94, P=0.
0199), and the risk of disease death was reduced by 29%; The median PFS was 2.
8 months in the remosimumab group, which was significantly better than that in the placebo group for 1.
6 months (HR=0.
452, 95% CI 0.
339 to 0.
603, P<0.
0001), and the risk of disease progression was reduced by 55%^[3].

Figure 1.
Kaplan-Meier total survival curve

Figure 2.
Kaplan-Meier has a progression-free survival curve

At the 2021 CSCO conference, the study's Chinese population data
were again published.
The results showed that the median OS of 9.
07 months vs 6.
18 months HR=0.
854 in the remoxizumab group and placebo group and the median PFS were 2.
76 months vs 1.
45 months, respectively, showing a survival benefit
consistent with the main cohort of the global REACH-2 study.
In terms of safety, patients are well tolerated and toxic as a whole, both in the global population and in Chinese ^{populations [5].}

The success of the REACH-2 study is of landmark significance:

First, remoxizumab is the first drug to be approved for liver cancer indications based on biomarker-enriched populations, which is conducive to more precise treatment;

Second, the REACH-2 study confirmed that even in patients with high levels of baseline AFP with a very poor prognosis, ramoxizumab still achieved statistically significant improvements in OS and PFS.

In addition, both in the global population and in the Chinese population, most patients with remoxilizumab are well tolerated after the use of remoxizumab, which also lays the foundation
for the combination of other drugs.

It is based on the results of the REACH-2 study that remoxizumab has been included in the treatment guidelines
for primary hepatocellular carcinoma in many countries and regions at home and abroad.
The 2022 edition of the CSCO guidelines for liver cancer includes remoxilizumab (limited to AFP ≥ 400 ng/ml of HCC) as a second-line treatment option (class II expert recommendation, class 1A evidence) ^[6].

The exploration never stops, and remoxilizumab will provide patients with more individualized treatment options

In addition to the above-mentioned published data, an exploratory study
on the treatment of HCC with extrahepatic spread (EHS) in China was also disclosed at the recent International Liver Cancer Association 2022 Annual Meeting (ILCA 2022).
The results of the study showed that HCC patients with high AFP in China who received second-line treatment with remoxilizumab could benefit from
OS compared with placebo, regardless of the presence or absence of EHS.
Among them, the median OS of patients receiving remoxizumab plus optimal supportive care (BSC) was 6.
9 months, while the median OS of patients receiving placebo plus BSC was 4.
4 months (HR, 0.
719; 95% CI, 0.
477-1.
085).

Moreover, the study also demonstrated good tolerance and controllable safety ^[7].

The approval of remoxizumab is expected to change the overall treatment pattern of advanced liver cancer, and it is expected that more studies will be carried out and more research data will be disclosed, so as to benefit more liver cancer patients
.

References (swipe up to view):

1.
Liver Cancer Professional Committee of Chinese Anti-Cancer Association, Chen Minshan.
Expert consensus on multidisciplinary comprehensive treatment of liver cancer in China[J].
Electronic Journal of Comprehensive Oncology Therapy, 2021, 7(2):9.

2.
Qian Liyuan, Li Changfei, Luo Yunjing, et al.
Research progress of alpha-fetoprotein in the diagnosis and treatment of liver cancer[J].
Chinese Journal of Bioengineering, 2021, 37(9):19.

3.
Zhu A X, Kang Y K, Yen C J, et al.
Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial[J].
The Lancet Oncology, 2019, 20(2): 282-296.

4.
CYRAMZA (ramucirumab)  Directions,FDA.

5.
Shukui Qin, Guoliang Shao, Yuxiao Bail,et al.
Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated α-fetoprotein: Chinese subpopulation analysis of the REACH-2 trial.
2021CSCO.

6.
Guidelines Working Committee of Chinese Society of Clinical Oncology, Guidelines for the Diagnosis and Treatment of Primary Liver Cancer 2022.
People's Medical Publishing House

7.
NielsenMH, Møllerhøj MB, Oro D ,et al.
SEMAGLUTIDE PREVENTS THE PROGRESSION OF HEPATOCELLULAR CARCINOMA IN THE GAN DIET-INDUCED OBESE AND BIOPSY-CONFIRMED MOUSE MODEL OF NASH.
2022 ILCA P-106.

Editor: Candy

Reviewer: Fish balls

Typesetting: Youshi

Execution: Uni