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Liver cancer is one of the most common malignant tumors, it is reported that there will be 431,000 new cases of liver cancer and 412,000 deaths in China in 2022, due to the high rate of hepatitis B infection, love to eat pickles and other living habits, the incidence of liver cancer in China is higher, compared with only 44,000 new cases of liver cancer in the United States, 21,000 deaths
。 Whether it is China or the United States, liver cancer is still one of the malignant tumors with the worst prognosis, although after a large number of scientific research, a large number of targets have been found, a number of potential drugs have been developed, but most of them have failed, even if some products are approved for marketing, but compared with lung cancer breast cancer, the objective response rate is low, the progression-free survival, the overall survival is short, and the patient benefits are not outstanding
enough.
Due to the extremely complex signaling pathway that regulates liver cancer, few single-target targeted preparations have been developed and marketed, and the products approved for marketing are mainly multi-target small molecule targeted preparations and immune checkpoint inhibitors
.
In addition, due to the rise of nucleic acid drugs in recent years, a number of nucleic acid drugs used as the treatment of liver cancer have been in the early research stage, and it is hoped that these drugs will bring qualitative breakthroughs
.
Of course, with the continuous popularization of hepatitis B vaccine, the rate of hepatitis B infection in China has dropped significantly, and the incidence of liver cancer will gradually decrease
in the future.
Sorafenib
was approved in 2005 for anti-angiogenic therapy Sorafenib, and the indications so far are hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid cancer
.
The approved treatment for liver cancer is inoperable hepatocellular carcinoma (HCC
).
This product is a multi-target inhibitor, which can act on c-CRAF, BRAF, KIT, FLT-3, RET, RET/PTC, VEGFR1/2/3 and PDGFR-ß and other targets
.
In a clinical trial code-named SHARP, 602 inoperable HCC patients were treated with this product or placebo (1:1), and the median overall survival (mOS) was 10.
7 months vs 7.
9 months, and mPFS was 5.
5 months vs 2.
8 months
, respectively.
Regorafenib Regorafenib was approved by the FDA in 2012 for gastrointestinal stromal tumors, rectal cancer and hepatocellular carcinoma, and hepatocellular carcinoma, and the approved use of this product is HCC therapy
that has previously received sorafenib treatment 。 This product is a multi-target inhibitor, which can inhibit RET, VEGFR1/2/3, KIT, PDGFR α/β, FGFR1/2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R and other targets
。 In a multicenter clinical trial, patients enrolled were Child-Pugh grade A, Barcelona Clinic Liver Cancer stage B or C, and previous progression after sorafenib treatment (mean duration of treatment with sorafenib was 7.
8 months
).
。 The subjects were divided into 2:1 and received this product or placebo, and the results showed that the mOS was 10.
6 months vs 7.
8 months, the mPFS was 3.
1 months vs 1.
5 months, and the objective response rate (ORR) was 11% vs 4%,
respectively.
Cabozantinib Cabotinib was approved by the FDA in 2012 for the treatment of differentiated thyroid cancer, and subsequently obtained indications
for renal cell carcinoma and hepatocellular carcinoma.
In terms of hepatocellular carcinoma, the approved use of this product is HCC therapy
that has previously received sorafenib treatment.
This product is also a multi-target inhibitor, which can act simultaneously on targets such as MET, VEGFR1/2/3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2
.
In terms of efficacy, in a clinical trial code-named CELESTIAL, the enrolled patients were all Child-Pugh grade A patients who had previously received sorafenib
.
707 subjects were divided into 2:1 groups and received this product or placebo, and the results showed that mPFS was 5.
2 months vs 1.
9 months, mPFS was 10.
2 months vs 8.
0 months, and ORR was 4% vs 0.
4%.
Lenvatinib was approved by the FDA in 2015 and has so far received four indications, including first-line treatment
for inoperable hepatocellular carcinoma.
Lenvatinib is a multi-target inhibitor that simultaneously inhibits VERGF1/2/3, FGF1/2/3/4, PDGFRα, KIT, and RET
.
In a clinical trial code-named REFLECT, 954 previously untreated patients with metastatic HCC joined the trial, all of whom had not previously received systemic therapy, Child-Pugh grade A, and Barcelona Clinic Liver Cancer stage
B or C, respectively 。 The results showed that the median overall survival (mOS) was 13.
6 months vs 12.
3 months, the median progression-free survival (mPFS) was 7.
3 months vs 3.
6 months, and the ORR was 41% vs 16%,
respectively.
Donafenib Donafenib was approved by the NMPA in 2022 for the treatment
of unresectable hepatocellular carcinoma that has not previously received systemic therapy.
In a clinical study codenamed ZGDH3, 668 patients with unresectable hepatocellular carcinoma who had not previously received systemic therapy were randomly grouped into 1:1 treatment with this product or sorafenib, and all enrolled patients had BCLC stage C and Child-Pugh classification as grade
A.
The results showed that the mOS of this product and the sorafenib treatment group was 12.
1 months vs 10.
3 months, mPFS was 3.
7 months vs 3.
6 months, and the ORR was 4.
6% vs 2.
7%,
respectively.
Ramucirumab
Ramolurumab, a VEGFR2 inhibitor, was first approved in 2014 and approved by the FDA in 2022 for the treatment
of hepatocellular carcinoma with an AFP ≥ 400 ng/mL previously treated with sorafenib 。 Ramolurumab is a VEGFR inhibitor, in a clinical trial code-named REACH-2, 292 patients with Child-Pugh grade A and Barcelona stage C and B stage unresectable or interventional treatment were enrolled in the trial, and the subjects were divided into 2:1 groups and received treatment or optimal supportive care respectively, mOS 8.
5 months vs 7.
3 months, mPFS 2.
8 months vs 1.
6 months, ORR 4.
6%, respectively vs 1.
1%
。
for advanced hepatocellular carcinoma that has failed or cannot be tolerated after at least first-line systemic therapy.
In a domestic multicenter clinical trial, 400 patients (2:1) who had at least previously received first-line systemic therapy failure were randomized to receive this product or placebo
.
The results showed that mOS was 8.
7 months vs 6.
8 months, mPFS was 4.
5 months vs 1.
9 months, and ORR was 28% vs 2%,
respectively.
Bevacizumab In 2004, the FDA approved Roche's VEGFR inhibitor bevacizumab for the treatment of metastatic rectal cancer, and then Roche obtained a gastric cancer-related indication - in combination with atezolizumab for the first-line treatment of metastatic hepatocellular carcinoma through a supplementary application , see atezolizumab
for details.
In summary, almost all of the drugs approved for hepatocellular carcinoma indications are VEGFR inhibitors or multi-target inhibitors with inhibition of VEGFR, VEGFR inhibitors are inhibiting vascular growth in nature, theoretically effective for a variety of tumors, from the FDA-approved multiple products, the efficacy has indeed been significantly improved, but it has not developed from quantitative change to qualitative change
.
2.
Immune checkpoint inhibitors
Pembrolizumab (trade name: Keytruda)
Pembrolizumab was approved for marketing in 2014 and received accelerated FDA approval in 2018 for the treatment of hepatocellular carcinoma that progressed after treatment
with sorafenib.
In a clinical trial codenamed KEYNOTE-224, 104 patients with HCC who progressed after treatment with sorafenib (Child-Pugh classified as grade A) enrolled in the trial with an ORR of 17% and a 56% proportion of patients with a sustained remission time of more than 12 months
after single-arm, open-label therapy.
Nivolumab (Opdivo) + epilimumab (trade name: Yervoy)
Nivolumab was approved for marketing in 2015 and accelerated FDA approval in 2020 for the treatment of hepatocellular carcinoma
that progresses after sorafenib treatment in combination with empimumab.
In a clinical trial codenamed CHECKMATE-040, 49 HCC subgroups (all HCCs that were intolerant to sorafenib or progressed after treatment, Child-Pugh classified as grade A), after this product + espirumab combination therapy, ORR was 33%, and the proportion of patients with a duration of remission of more than 24 months was 31%.
Duvalumab (trade name: Imfinzi) + tremelimumab (trade name: Imjudo)
In 2017, AstraZeneca's PD-L1 was approved by the FDA for marketing, and in 2022, it was approved by the FDA in combination with tremelimumab (CALT4 inhibitor) for the treatment of inoperable hepatocellular carcinoma.
Clinical trial data showed that the median overall survival of 393 patients treated with this product in combination with tremelimumab was 16.
4 months, compared with 13.
8 months in 389 patients with sorafenib, and the risk of death decreased by 22%.
In terms of ORR, the combination treatment group of this product and Imfinzi was 20.
1%, while the sorafenib group was only 5.
1%, and 3.
1% of patients in the combination therapy group had a complete remission, while the sorafenib group was only 0%.
Sintilimab
In June 2021, Cindilimab was approved by NMPA in combination with bevacizumab for the first-line treatment of unresectable or metastatic hepatocellular carcinoma
that has not previously undergone systemic therapy 。 In a clinical trial codenamed ORIENT32, 571 patients who had previously undergone systemic therapy, 7 points of Child-Pu≤gh, and stage C and stage B unresectable or interventional therapy in Barcelona joined the trial, all subjects were divided into 2:1 and received this product + bevacizumab or sorafenib respectively, the results showed that the mPFS of the two groups was 4.
6 months vs 2.
8 months, and the mOS was NR vs 10.
4 months, respectively.
ORRs were 19.
1% vs 3.
8%,
respectively.
Camrelizumab
In March 2020, carrelizumab was approved by the NMPA for advanced hepatocellular carcinoma that had previously received sorafenib and/or oxaliplatin-containing chemotherapy
.
In a study code-named SHR-1210-II/III-HCC, 220 patients with metastatic HCC rated Child-Pugh with liver function rated A or better B, unsuitable for surgery or topical therapy, and who had failed or were intolerant after at least first-line systemic therapy participated in the trial, with primary endpoints of ORR and 6-month survival by the Independent Imaging Evaluation Committee (IRC
).
。 After the treatment of this product once every two weeks or once every three weeks, the ORR of the bi-weekly group or the tri-weekly group was 14% vs 17%, the mPFS was 2.
3 months vs 2.
1 months, the mOS was 14.
2 months vs 12.
6 months, and the 6-month survival rate was 79.
2% vs 73.
3%,
respectively.
Tislelizumab
In June 2021, the NMPA approved tislelizumab for the treatment
of previously treated and unresectable hepatocellular carcinoma.
In an international multicenter Phase 2 study, 249 patients with unresectable HCC, of whom 138 had previously received one systemic treatment and 111 had received at least two prior treatments, with the primary endpoint being ORR
by the Independent Imaging Evaluation Committee (IRC).
After treatment with this product, the ORR was 13.
3%, and the mPFS and mOS were 2.
7 months and 13.
2 months
, respectively.
Artylizumab (trade name: Tecentriq)
Atezolizumab was approved by the NMPA in 2021 in combination with bevacizumab for the treatment of unresectable hepatocellular carcinoma
that had not previously received systemic therapy 。 In a clinical study codenamed IMbrave150, 501 eligible patients (Child-Pugh grade A) were treated with this product + bevacizumab or sorafenib in a 2:1 group, with mOS vs 13.
2 months, 6-month survival rates of 84.
8% vs 72.
2%, mPFS of 6.
8 versus 4.
3 months, and ORR of 27.
3% vs 17.
9%,
respectively.
Immune checkpoint inhibitors are a great gift from God to liver cancer patients and have brought great progress
to the treatment of liver cancer.
Perhaps some people have questioned that China's PD-1 track is too crowded, but for liver cancer patients, the more the merrier
.
Because PD-1/L1 is not like small molecule inhibitors, it is screened at high throughput for an indication or a target, but more like a shotgun method playing "indications"
.
Due to the wide range of efficacy of PD-1/L1, perhaps the designer of PD-1/L1 does not know which tumors his product will be effective for and which tumors will be ineffective, and can only smash out
the efficacy data through a large number of clinical trials.
Therefore, different PD-1/L1 may be approved for different indications, and the efficacy in different indications will also have huge differences, either FDA-approved products are the best, only the data comparison of multiple products can obtain the product
that benefits patients the most in a certain indication area.
3.
New drugs for liver cancer in the clinical research stage
In addition to immunotherapy, there are fewer liver cancer drugs in the terminal clinical stage, including Everolimus (mTOR inhibitor, phase III), axitinib (phase 2), etc.
, of course, there are many new mechanism drugs in the early stages of research and development.
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