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Although hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, it has not historically been the focus of new drug development.
In the past few years, with the announcement of many landmark Phase 3 studies, some systemic therapies that can be used for advanced HCC have emerged.
Hepatology (impact factor: 14.
971), a high-scoring journal in the field of liver disease, published a review discussing the progress of systemic treatment of advanced HCC.
Based on this review, this article introduces the development of systemic treatment of advanced HCC, and at the same time looks forward to the future of treatment of advanced HCC.
Yesterday: Sorafenib "Outstanding" In 2007, sorafenib was approved for the first-line treatment of advanced HCC, which is an important step forward in the management of advanced HCC.
After many phase 3 clinical studies of advanced HCC failed, the SHARP study finally came up with a positive result.
The study showed that sorafenib compared with placebo treatment of advanced HCC prolonged the median overall survival (OS) period by 2.
8 months (10.
7 vs 7.
9).
However, in the next ten years, most similar drugs could neither defeat sorafenib as a first-line drug, nor be better than a placebo as a second-line drug in improving survival.
Today: Multiple therapies finally approved.
Starting from the 2016 RESORCE study, a number of new protocols for the treatment of advanced HCC have been approved.
Table 1 lists the results of clinical studies that led to the U.
S.
Food and Drug Administration (FDA) approval for the treatment of advanced HCC. Table 1 The study leading to FDA approval for advanced HCC 01 The single-agent multi-kinase inhibitor REFLECT study is a global multi-center, open-label, randomized, non-inferior phase III clinical trial.
The results show that compared with sorafenib , The oral multi-kinase inhibitor lenvatinib (lenvatinib) reached the statistical standard of non-inferiority in terms of overall survival (OS) (Table 1).
In addition, lenvatinib had a median progression-free survival (PFS) (7.
4 months vs.
3.
7 months, P<0.
00001), and a median time to disease progression (8.
9 months vs.
3.
7 months, P<0.
00001) And the objective response rate (24.
1% vs.
9.
2%, P<0.
00001) was significantly better than sorafenib in the three secondary study endpoints.
It is worth noting that in the trial, lenvatinib was administered according to body weight (≥60kg: 12mg/d; <60kg: 8mg/d), and 50% or more of liver-occupied tumor patients and patients with biliary/portal vein invasion were not Included in this trial.
Regorafenib is another oral multi-kinase inhibitor.
Its mechanism of action is similar to that of sorafenib, but its inhibitory effect on VEGFR kinase is stronger and the kinase activity is wider.
It can act on RAF, KIT, RET , PDGFR, VEGFR1 and TIE2 signaling pathways.
The phase III RESORCE trial included patients with advanced HCC who developed tolerance or disease progression after receiving sorafenib.
Compared with placebo, regorafenib improved the median OS to 10.
6 months.
Cabozantinib is a small molecule multi-target tyrosine kinase inhibitor that can inhibit vascular endothelial growth factor receptor (VEGFR) and has a strong inhibitory effect on MET and AXL.
In the phase III CELESTIAL trial, patients with advanced HCC enrolled had previously received sorafenib treatment.
The study showed that the median OS was 10.
2 months in the cabozantinib group and 8.
0 months in the placebo group (HR 0.
76; 95% CI 0.
63-0.
92; P = 0.
0049). Similarly, the improvement in OS was accompanied by an improvement in median PFS (5.
2 months for the cabozantinib group and 1.
9 months for the placebo group; HR 0.
44; 95% CI 0.
36-0.
52).
The objective response rates of the two groups were respectively 4% and <1% (P=0.
009).
02 The single-drug VEGFR targeting antibody ramucirumab is an anti-VEGFR2 monoclonal antibody.
The REACH-2 trial included patients who had failed sorafenib treatment with a baseline alpha-fetoprotein concentration ≥400 ng/dL.
The results of the phase III trial showed that the median OS of ramucirumab was 8.
5 months, while that of the placebo group was 7.
3 months (HR 0.
710; 95% CI 0.
531-0.
949; P = 0.
0199).
Compared with the placebo group, the PFS of the ramucirumab group also achieved significant improvement (median PFS: 2.
8 months vs 1.
6 months, HR=0.
45; 95%CI 0.
339-0.
603; P<0.
0001).
03 The single-agent immune checkpoint inhibitor nivolumab (nivolumab) is an anti-PD-1 monoclonal antibody.
The CheckMate 040 I/II study showed that the objective response rate of the nivolumab group under the RECIST criteria was 15% (MRECist 18%).
As a second-line treatment, the patient's median OS is 15.
6 months, and the treatment is usually well tolerated, and the side effects are not much different from those of patients with other diseases using nivolumab.
Based on these results, the US FDA decided to accelerate the approval of nivolumab for advanced HCC patients who had previously received sorafenib treatment.
Pembrolizumab (pembrolizumab) is another anti-PD-1 monoclonal antibody that has received accelerated approval from the US FDA for the second-line treatment of advanced HCC.
04 Immune checkpoint inhibitor combined with anti-VEGF antibody In May of this year, NEJM reported the complete data of the clinical phase III trial IMbrave150.
Studies have shown that the PD-L1 inhibitor Atezolizumab (Atezolizumab) is combined with the anti-VEGF antibody bevacizumab (bevacizumab).
Studies have shown that compared to sorafenib, PD-L1 inhibitor Atezolizumab (Atezolizumab) combined with anti-VEGF antibody bevacizumab (bevacizumab) can significantly reduce the risk of death by 42% (OS stratification HR=0.
58; 95% CI: 0.
42-0.
79; p=0.
006), significantly reducing the risk of disease progression and death by 41% (PFS stratified HR=0.
59; 95% CI: 0.
47-0.
76; p<0.
0001), the patient’s 12-month survival rate Increased to 67.
2%.
Based on this result, the US FDA approved atelizumab combined with bevacizumab for unresectable HCC patients who have not received systemic treatment in the past.
05 Combining PD-1 antibody and CTLA-4 antibody In March of this year, the US FDA approved nivolumab combined with anti-CTLA-4 antibody ipilumimab for HCC patients who have previously received sorafenib treatment .
The approval is mainly based on the results of the nivolumab combined with ipilimumab cohort in the CheckMate-040 Phase I/II study, which aims to evaluate the immuno-oncology (IO) combination therapy for previous sorafenib treatment The efficacy of patients with advanced hepatocellular carcinoma (HCC).
Among them, nivolumab + ipilimumab showed a long-lasting effect in HCC patients treated with sorafenib.
After at least 28 months of follow-up, the objective remission rate reached 31%, and the median remission continued The duration was 17 months, the disease control rate was 49%, and the 24-month OS rate was 40%.
Tomorrow: What other treatments are worth paying attention to? 01Combined immune checkpoint inhibitors and multikinase inhibitors Some immune checkpoint inhibitors and multikinase inhibitor combinations have entered phase III trials.
These multi-kinase inhibitors have different target kinase profiles, but they can all inhibit VEGFR.
The 2019 European Society of Medical Oncology (ESMO) annual meeting announced the results of a phase Ib trial of lenvatinib combined with pembrolizumab in unresectable HCC (uHCC).
In patients with unresectable HCC, lenvatinib combined with pembrolizumab showed strong anti-tumor activity, the objective response rate under mRECIST criteria was 46%, and the median PFS was 9.
7 months (95% CI 5.
3-13.
8), the median OS was 20.
4 months (95% CI 11.
0-NE).
A phase III trial (LEAP-002; NCT03713593) is currently underway to evaluate the efficacy of this therapy versus lenvatinib as the first-line treatment for uHCC patients.
02 Combination of other immune checkpoint inhibitors (IO-IO combination) In an early trial, the objective response rate of PD-L1 antibody durvalumab + CTLA-4 antibody tremelimumab in the treatment of advanced HCC was 17.
5% .
The HIMALAYA Phase III trial is ongoing to compare the efficacy and tolerability of this therapy with sorafenib as the first-line treatment for patients with advanced HCC (NCT03298451).
In addition, many studies are currently evaluating checkpoint inhibitors for single or combined use in the early stages of the disease, such as in combination with local treatments, or as adjuvant treatments after therapeutic resection or ablation.
At present, considering the risk of rejection of immune checkpoint inhibitors, they should not be used for the treatment of HCC recurrence after liver transplantation.
Yimaitong compiled and compiled from: Finn RS, Zhu AX.
Evolution of Systemic Therapy for Hepatocellular Carcinoma.
Hepatology.
07 May 2020.
https://doi.
org/10.
1002/hep.
31306 Reference materials: https:// .
org/doi/full/10.
1056/NEJMoa1915745
In the past few years, with the announcement of many landmark Phase 3 studies, some systemic therapies that can be used for advanced HCC have emerged.
Hepatology (impact factor: 14.
971), a high-scoring journal in the field of liver disease, published a review discussing the progress of systemic treatment of advanced HCC.
Based on this review, this article introduces the development of systemic treatment of advanced HCC, and at the same time looks forward to the future of treatment of advanced HCC.
Yesterday: Sorafenib "Outstanding" In 2007, sorafenib was approved for the first-line treatment of advanced HCC, which is an important step forward in the management of advanced HCC.
After many phase 3 clinical studies of advanced HCC failed, the SHARP study finally came up with a positive result.
The study showed that sorafenib compared with placebo treatment of advanced HCC prolonged the median overall survival (OS) period by 2.
8 months (10.
7 vs 7.
9).
However, in the next ten years, most similar drugs could neither defeat sorafenib as a first-line drug, nor be better than a placebo as a second-line drug in improving survival.
Today: Multiple therapies finally approved.
Starting from the 2016 RESORCE study, a number of new protocols for the treatment of advanced HCC have been approved.
Table 1 lists the results of clinical studies that led to the U.
S.
Food and Drug Administration (FDA) approval for the treatment of advanced HCC. Table 1 The study leading to FDA approval for advanced HCC 01 The single-agent multi-kinase inhibitor REFLECT study is a global multi-center, open-label, randomized, non-inferior phase III clinical trial.
The results show that compared with sorafenib , The oral multi-kinase inhibitor lenvatinib (lenvatinib) reached the statistical standard of non-inferiority in terms of overall survival (OS) (Table 1).
In addition, lenvatinib had a median progression-free survival (PFS) (7.
4 months vs.
3.
7 months, P<0.
00001), and a median time to disease progression (8.
9 months vs.
3.
7 months, P<0.
00001) And the objective response rate (24.
1% vs.
9.
2%, P<0.
00001) was significantly better than sorafenib in the three secondary study endpoints.
It is worth noting that in the trial, lenvatinib was administered according to body weight (≥60kg: 12mg/d; <60kg: 8mg/d), and 50% or more of liver-occupied tumor patients and patients with biliary/portal vein invasion were not Included in this trial.
Regorafenib is another oral multi-kinase inhibitor.
Its mechanism of action is similar to that of sorafenib, but its inhibitory effect on VEGFR kinase is stronger and the kinase activity is wider.
It can act on RAF, KIT, RET , PDGFR, VEGFR1 and TIE2 signaling pathways.
The phase III RESORCE trial included patients with advanced HCC who developed tolerance or disease progression after receiving sorafenib.
Compared with placebo, regorafenib improved the median OS to 10.
6 months.
Cabozantinib is a small molecule multi-target tyrosine kinase inhibitor that can inhibit vascular endothelial growth factor receptor (VEGFR) and has a strong inhibitory effect on MET and AXL.
In the phase III CELESTIAL trial, patients with advanced HCC enrolled had previously received sorafenib treatment.
The study showed that the median OS was 10.
2 months in the cabozantinib group and 8.
0 months in the placebo group (HR 0.
76; 95% CI 0.
63-0.
92; P = 0.
0049). Similarly, the improvement in OS was accompanied by an improvement in median PFS (5.
2 months for the cabozantinib group and 1.
9 months for the placebo group; HR 0.
44; 95% CI 0.
36-0.
52).
The objective response rates of the two groups were respectively 4% and <1% (P=0.
009).
02 The single-drug VEGFR targeting antibody ramucirumab is an anti-VEGFR2 monoclonal antibody.
The REACH-2 trial included patients who had failed sorafenib treatment with a baseline alpha-fetoprotein concentration ≥400 ng/dL.
The results of the phase III trial showed that the median OS of ramucirumab was 8.
5 months, while that of the placebo group was 7.
3 months (HR 0.
710; 95% CI 0.
531-0.
949; P = 0.
0199).
Compared with the placebo group, the PFS of the ramucirumab group also achieved significant improvement (median PFS: 2.
8 months vs 1.
6 months, HR=0.
45; 95%CI 0.
339-0.
603; P<0.
0001).
03 The single-agent immune checkpoint inhibitor nivolumab (nivolumab) is an anti-PD-1 monoclonal antibody.
The CheckMate 040 I/II study showed that the objective response rate of the nivolumab group under the RECIST criteria was 15% (MRECist 18%).
As a second-line treatment, the patient's median OS is 15.
6 months, and the treatment is usually well tolerated, and the side effects are not much different from those of patients with other diseases using nivolumab.
Based on these results, the US FDA decided to accelerate the approval of nivolumab for advanced HCC patients who had previously received sorafenib treatment.
Pembrolizumab (pembrolizumab) is another anti-PD-1 monoclonal antibody that has received accelerated approval from the US FDA for the second-line treatment of advanced HCC.
04 Immune checkpoint inhibitor combined with anti-VEGF antibody In May of this year, NEJM reported the complete data of the clinical phase III trial IMbrave150.
Studies have shown that the PD-L1 inhibitor Atezolizumab (Atezolizumab) is combined with the anti-VEGF antibody bevacizumab (bevacizumab).
Studies have shown that compared to sorafenib, PD-L1 inhibitor Atezolizumab (Atezolizumab) combined with anti-VEGF antibody bevacizumab (bevacizumab) can significantly reduce the risk of death by 42% (OS stratification HR=0.
58; 95% CI: 0.
42-0.
79; p=0.
006), significantly reducing the risk of disease progression and death by 41% (PFS stratified HR=0.
59; 95% CI: 0.
47-0.
76; p<0.
0001), the patient’s 12-month survival rate Increased to 67.
2%.
Based on this result, the US FDA approved atelizumab combined with bevacizumab for unresectable HCC patients who have not received systemic treatment in the past.
05 Combining PD-1 antibody and CTLA-4 antibody In March of this year, the US FDA approved nivolumab combined with anti-CTLA-4 antibody ipilumimab for HCC patients who have previously received sorafenib treatment .
The approval is mainly based on the results of the nivolumab combined with ipilimumab cohort in the CheckMate-040 Phase I/II study, which aims to evaluate the immuno-oncology (IO) combination therapy for previous sorafenib treatment The efficacy of patients with advanced hepatocellular carcinoma (HCC).
Among them, nivolumab + ipilimumab showed a long-lasting effect in HCC patients treated with sorafenib.
After at least 28 months of follow-up, the objective remission rate reached 31%, and the median remission continued The duration was 17 months, the disease control rate was 49%, and the 24-month OS rate was 40%.
Tomorrow: What other treatments are worth paying attention to? 01Combined immune checkpoint inhibitors and multikinase inhibitors Some immune checkpoint inhibitors and multikinase inhibitor combinations have entered phase III trials.
These multi-kinase inhibitors have different target kinase profiles, but they can all inhibit VEGFR.
The 2019 European Society of Medical Oncology (ESMO) annual meeting announced the results of a phase Ib trial of lenvatinib combined with pembrolizumab in unresectable HCC (uHCC).
In patients with unresectable HCC, lenvatinib combined with pembrolizumab showed strong anti-tumor activity, the objective response rate under mRECIST criteria was 46%, and the median PFS was 9.
7 months (95% CI 5.
3-13.
8), the median OS was 20.
4 months (95% CI 11.
0-NE).
A phase III trial (LEAP-002; NCT03713593) is currently underway to evaluate the efficacy of this therapy versus lenvatinib as the first-line treatment for uHCC patients.
02 Combination of other immune checkpoint inhibitors (IO-IO combination) In an early trial, the objective response rate of PD-L1 antibody durvalumab + CTLA-4 antibody tremelimumab in the treatment of advanced HCC was 17.
5% .
The HIMALAYA Phase III trial is ongoing to compare the efficacy and tolerability of this therapy with sorafenib as the first-line treatment for patients with advanced HCC (NCT03298451).
In addition, many studies are currently evaluating checkpoint inhibitors for single or combined use in the early stages of the disease, such as in combination with local treatments, or as adjuvant treatments after therapeutic resection or ablation.
At present, considering the risk of rejection of immune checkpoint inhibitors, they should not be used for the treatment of HCC recurrence after liver transplantation.
Yimaitong compiled and compiled from: Finn RS, Zhu AX.
Evolution of Systemic Therapy for Hepatocellular Carcinoma.
Hepatology.
07 May 2020.
https://doi.
org/10.
1002/hep.
31306 Reference materials: https:// .
org/doi/full/10.
1056/NEJMoa1915745
