CSCO 2021: Professor Shukui Qin reports that the first-line treatment of Akoladine has a heavier baseline and a poorer prognosis for advanced hepatocellular carcinoma

The main component of Akoladine is anhydroicaritin (anhydroicaritin), a flavonoid compound, also known as dehydrated icariin, which is naturally present in the epimedium of the Berberis family, but the content is very low
.

At present, icariin is mainly prepared with icariin as the raw material, using enzymatic hydrolysis, acid hydrolysis, combination of enzymatic hydrolysis and acid hydrolysis, and chemical synthesis

The main component of Akoladine is anhydroicaritin (anhydroicaritin), a flavonoid compound, also known as dehydrated icariin, which is naturally present in the epimedium of the Berberis family, but the content is very low

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver tumors and is characterized by a high incidence and high fatality rate.

immunity

In addition, Akoladine is also used in the treatment of various tumor diseases such as melanoma, T lymphocyte tumor, renal cell carcinoma, breast cancer , prostate cancer, and endometrial cancer
.

Its mechanism of action is shown in Figure 2.

Breast cancer

Not long ago, the international cancer academic journal Cancer Science ("Cancer Science") published online the results of the Phase II clinical trial of Icaritin Induced Immunomodulatory Efficacy in Advanced HBV-Related.
Hepatocellular Carcinoma: Immunodynamic Biomarkers and Overall Survival" (DOI:10.
1111/cas.
14641)
.

The research was led by academician Sun Yan and Prof.

The International Cancer Science Journal ("Cancer Science") published online results of Phase II clinical trial of Icaritin Induced Immunomodulatory Efficacy in Advanced HBV-Related Hepatocellular Carcinoma: "Icaritin Induced Immunomodulatory Efficacy in Advanced HBV-Related Hepatocellular Carcinoma: Immunodynamic Biomarkers and Overall Survival" (DOI:10.

manage

At the just-opening CSCO conference, in the theme report of the conference, Professor Qin Shukui brought us the latest research in the field of liver cancer, that is, "Acoradine first-line treatment with a heavier baseline and a poor prognosis for advanced hepatocellular carcinoma is a multi-center, randomized , Dual-simulation Phase III clinical study results: Marker enrichment design, overall survival, quality of life and safety"
.

A prospective, randomized controlled, double-blind, double-dummy, national multi-center phase III clinical trial of the drug compared with cinocabine in the first-line treatment of patients with advanced hepatocellular carcinoma reached the primary endpoint, showing that Akoladine is on the market Just around the corner

A prospective, randomized controlled, double-blind, double-dummy, national multi-center phase III clinical trial of the drug compared with cinocabine in the first-line treatment of patients with advanced hepatocellular carcinoma reached the primary endpoint, showing that Akoladine is on the market Just around the corner

The study included 280 patients with advanced or metastatic HCC who had not received first-line systemic treatment in the past, and they were randomized 1:1 to receive treatment with Akoladine or Cinobufosin, and biomarker testing was performed at the same time

The baseline characteristics of the enriched population showed that patients had a later stage of disease and a more complex condition.
For example, patients with visible portal vein infiltration or extrahepatic spread or both accounted for more than 60% of patients, and patients with AFP ≥ 400ng/mL accounted for more than 60% More than 80%, etc.
, the prognosis of patients is poor, and quite a few patients cannot receive existing treatments such as chemotherapy, targeting or immunization

The baseline characteristics of the enriched population showed that patients had a later stage of disease and a more complex condition.
For example, patients with visible portal vein infiltration or extrahepatic spread or both accounted for more than 60% of patients, and patients with AFP ≥ 400ng/mL accounted for more than 60% More than 80%, etc.
, the prognosis of patients is poor, and quite a few patients cannot receive existing treatments such as chemotherapy, targeting or immunization

The clinical efficacy of the enriched population showed that the median OS of the acoradine group was significantly better than that of the control group, 13.
54 vs 6.
87 months ( HR = 0.
43, P = 0.
0092), reducing the risk of death by 57% (Figure 3)
.

At the same time, in different grades of positive advanced HCC populations, it was shown that the median OS of the acoraldine group was better than that of the control group (Figure 4), which also verified the reliability of enriched markers in predicting the clinical efficacy of acoraldine

The clinical efficacy of the enriched population showed that the median OS of the acoradine group was significantly better than that of the control group, 13.

Clinical efficacy of enriched population: OS

Clinical efficacy of enriched population: OS Clinical efficacy of enriched population: OS

OS results of different enriched populations

There was no significant difference in the median TTP and median PFS assessed by the investigator in the Akoladine group, but both showed a trend of improvement compared with the control group (Figure 5).
This may be related to the small sample size of the study and also to Akola.
Lading has slower onset and longer duration
.

Enriched population: TTP and PFS

In terms of QOL, the median time to deterioration (TTD) of the enriched population was 7.
3 months vs.
2.
8 months in the acoradine group and the control group, respectively.
In the whole population, the median TTD of the two groups was 7.
3.
Months vs 3.
7 months (Figure 6)
.
Therefore, compared with the cinocabine group, the quality of life of the patients in the acoradine group was significantly improved
.

Drug-related adverse events showed that in the whole population and enriched populations, acocladine is safer than cinocabine, treatment-related adverse events (TRAE), ≥3 TRAE, leading to permanent drug withdrawal and dose The adjusted TRAE and the incidence of serious adverse events (SAE) related to the study drug were significantly lower in the acoradine group than in the control group
.

Drug-related adverse events showed that in the whole population and enriched populations, acocladine is safer than cinocabine, treatment-related adverse events (TRAE), ≥3 TRAE, leading to permanent drug withdrawal and dose The adjusted TRAE and the incidence of serious adverse events (SAE) related to the study drug were significantly lower in the acoradine group than in the control group
.

In conclusion, the oral immunomodulatory drug acoradine versus cinocabine as the first-line treatment of advanced HCC significantly prolongs overall survival, significantly improves the quality of life of patients, and prolongs the median to worsening time
.
In addition, acoradine has a significant safety advantage in the treatment of patients with advanced HCC.
Continued medication after the disease progresses can still prolong overall survival; its overall adverse reaction rate and the incidence of grade ≥3 adverse reactions are lower than existing first-line treatments Drugs
.
Peripheral blood complex markers can predict the clinical efficacy of acladine and provide precise treatment options for patients with advanced HCC
.

In conclusion, the oral immunomodulatory drug acoradine versus cinocabine as the first-line treatment of advanced HCC significantly prolongs overall survival, significantly improves the quality of life of patients, and prolongs the median to worsening time
.
In addition, acoradine has a significant safety advantage in the treatment of patients with advanced HCC.
Continued medication after the disease progresses can still prolong overall survival; its overall adverse reaction rate and the incidence of grade ≥3 adverse reactions are lower than existing first-line treatments Drugs
.
Peripheral blood complex markers can predict the clinical efficacy of acladine and provide precise treatment options for patients with advanced HCC
.
Precise

At present, Akoladine is used for unresectable hepatocellular carcinoma that has not received systemic treatment in the past, and it has obtained the priority review qualification of CDE
.

Unresectable hepatocellular carcinoma that has not received systemic treatment in the past has been qualified for priority review by CDE
.

In addition, a randomized, open-label clinical trial study of acoradine versus sorafenib in the first-line treatment of PD-L1-positive advanced hepatocellular carcinoma patients is also underway
.
According to the correlation between PD-L1 and the clinical efficacy of Akoladine found in the previous clinical studies and the results of the mechanism of Akoladine, the positive expression of PD-L1 in the immune cells of patients with liver cancer tissues at baseline was included in the inclusion criteria
.
In PD-L1 positive patients, comparing acoradine with sorafenib, the current standard treatment for advanced hepatocellular carcinoma, its main efficacy and safety endpoints are basically the same as those in the first study
.

In addition, Akoladine versus sorafenib is the first-line treatment for patients with PD-L1-positive advanced hepatocellular carcinoma.
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