Liver cancer innovation "Damo Unlimited" | hepatobiliary surgery "big coffee" reviews 2022 ESMO blockbuster progress

The 2022 ESMO Academic Event came to an end, and many heavy research data in the field of liver cancer treatment were brilliantly displayed, lighting up the speculative light

Systemic treatment of liver cancer is booming

Helps improve five-year survival

Expert profile

Zheng Shusen Academician

• Academician of the Chinese Academy of Engineering

• Foreign member of the French National Academy of Medical Sciences

• Professor of Surgery of Zhejiang University is currently the director of the Key Laboratory of Organ Transplantation Diagnosis and Treatment of the Chinese Academy of Medical Sciences

• Deputy Director of the Academic Committee of Zhejiang University

• Director, Institute of Organ Transplantation, Zhejiang University,

• Director of the Academic Committee of the First Affiliated Hospital of Zhejiang University, Director of Hepatobiliary and Pancreatic Surgery

• President of Shulan Medical General Hospital

• Vice President of Chinese Medical Association

• Vice President of Chinese Medical Doctor Association

• President of the Organ Transplant Physicians Branch of the Chinese Medical Doctor Association

• Fellow of the American Society of Surgeons (FACS)

• Member of the International Executive Committee on Living Donor Liver Transplantation

• Member of the International Hepatobiliary and Pancreatic Association

Question 1: Liver cancer is the second highest number of deaths per year after lung cancer

Zheng Shusen Academician

Shulan (Hangzhou) Hospital

China is a big country with liver cancer, and nearly half of the world's new liver cancer patients are in China

In terms of prevention and treatment, Chinese liver cancer patients have Chinese characteristics, mostly caused

First of all, early screening and early diagnosis of liver cancer is the key

Secondly, the treatment of liver cancer has entered a new era

More importantly, the concept of doctors has also improved with the advancement of treatment methods, and the concepts

In short, the five-year survival rate of liver cancer in China has been significantly improved with the joint efforts of all walks of life, but there is still a long way to go, and we clinicians need to further explore the essential characteristics of liver cancer and further explore accurate and effective treatment methods

Question 2: In the field of liver transplant therapy, how do you view the value of systematic therapy?

Zheng Shusen Academician

Shulan (Hangzhou) Hospital

The incidence of liver cancer in China is high, and the demand for liver transplantation for liver cancer is large

The update of systematic treatment drugs has brought breakthroughs
in the down-of-phase treatment, bridging therapy and prevention and treatment of tumor recurrence of liver cancer liver transplantation.

A number of real-world studies have shown that a combination of treatment based on lenvatinib has a positive effect
on preventing tumor recurrence after transplantation.

However, whether immunotherapy can be used in liver transplant patients is still controversial and needs to be explored
.

Systemic treatment adds a new certificate

Precise exploration has a long way to go

Expert profile

Professor Chin Lun-soo

• Chief physician, Ph.
  D.
  , PhD supervisor

• Director of Surgery, Huashan Hospital Affiliated to Fudan University/Executive Vice President of North Hospital

• Director of the Institute of Cancer Metastasesis, Fudan University

• He was awarded National Jieqing, Yangtze River Distinguished Professor, Chief of 973

• He is a member of the Surgical Branch of the Chinese Medical Association

• Former Chairman of the Precision Treatment Committee of Cancer of the Chinese Anti-Cancer Association / Honorary Chairman of the Tumor Metastasis Committee

• Vice Chairman of the Biliary Oncology Expert Committee of the Chinese Society of Clinical Oncology

• Vice President of the Gastroenterology Branch of the China Association of Research Hospitals

• President of the General Surgery Branch of the Chinese Geriatrics Association

• Member of the editorial boards of Clin Exp Metastasis, Neoplasia and other journals

• Won the second prize of the National Natural Science Award; Tan Jiazhen Life Science Award; Shanghai Science and Technology Elite; Shanghai May Day Labor Medal; Shanghai craftsmen

• Specialty: surgical treatment of hepatobiliary tumors; Prediction and prevention strategies of tumor metastasis recurrence

Question 3: What impact do the results of multiple blockbuster studies on the first-line treatment of advanced liver cancer published by ESMO in 2022 have on the clinical practice of HCC treatment in China?

Professor Qin Lunxiu

Huashan Hospital affiliated to Fudan University

The Phase III studies of LEAP-002, SHR-1210-III-310 and RATIONALE-301 first-line treatment of liver cancer were published on ESMO in the form of LBA, which attracted everyone's attention
.

LEAP-002^[1] is a double-blind, placebo-controlled phase III randomized controlled study of lenvatinib plus pabolizumab for the first-line treatment of advanced hepatocellular carcinoma with papolitinib, and it is the only study to have lenvatinib as a control group, with a blind design and a high
level of evidence.

The Phase I study KEYNOTE-524 lenvatinib in combination with pabolizumab in the treatment of advanced liver cancer yielded encouraging efficacy data, so LEAP-002 has been expected
.

It is very unfortunate that the LEAP-002 study did not achieve the preconceived statistically significant difference in efficacy, but pabolizumab combined with lenvatinib showed an improvement trend in overall survival (OS) and progression-free survival (PFS) compared to lenvatinib monotherapy
.

The median OS of control lenvalitinib monotherapy reached an unprecedented 19.
0 months in previous phase III studies, so underestimating the survival of the control group may be an important cause
of LEAP-002 "Waterloo".

In addition, LEAP-002 enrolled many patients with non-alcoholic fatty liver and hepatitis C-related HCC in the West, and HBV infected HCC patients and Asian patients (except Japan) were enrolled in a small
proportion.

Patient populations of different etiologies respond
differently to treatment.

The results of the RATIONALE-301 ^[2] study showed that the first-line treatment of irresectable HCC with tirelizumab monotherapy was not inferior to that of sorafenib, which brought about a new choice
for the first-line treatment of liver cancer compared with sorafenib.

The SHR-1310-lll-310 study^[3] showed that the combination of carrelizumab and apatinib significantly improved OS and PFS compared to sorafenib, adding a new regimen
for combination therapy.

Question 4: Is LEAP-002 a failed study? How do you see its value in clinical practice?

Professor Qin Lunxiu

Huashan Hospital affiliated to Fudan University

Although the LEAP-002 study was negative, it could not completely negate the therapeutic value
of pabolizumab plus lenvatinib.

Looking at the overall population, the combination therapy group was able to achieve objective response rates (ORR) of 26.
1% (RECIST1.
1) and 40.
8% (mRECIST), with median OS of 21.
2 months, showing encouraging efficacy in patients with advanced liver cancer, with results consistent
with our clinical experience.

From the subgroup analysis, for liver cancer patients with extrahepatic metastasis, HBV-positive, and AFP greater than 400 ng/ml, pabolizumab combined with lenvatinib has a more prominent benefit than lenvatinib monotherapy, which may be the dominant population
of this combination.

At present, how to optimize the deployment of troops in the treatment of advanced liver cancer system is still a controversial topic, and it is necessary to comprehensively consider
the purpose of treatment, patient conditions, drug research data and other aspects.

Lenvatinib-based targeted combination therapy is the preferred option, and the LEAP-002 study once again provides more evidence for the first-line treatment of lenvatinib, with growing real-world evidence that multiple combination treatments based on lenvatinib can bring better benefits
to patients with liver cancer.

Question 5: How do you see the development direction of liver cancer system treatment, and what challenges exist?

Professor Qin Lunxiu

Huashan Hospital affiliated to Fudan University

There are still many scientific problems that need to be solved in the clinical practice of liver cancer system treatment, and how to use the weapons in hand to further improve the 5-year survival rate of liver cancer patients is a common topic
that we must continue to explore.

The overall effectiveness of systemic therapy is still relatively limited, for example, the ORR of the A+T combination is 33.
2% (mRECIST) measured by the ORR of the combination regimen[^4], and the just-announced LEAP-002, and the ORR of pabolizumab combined with lenvatinib (the cola combination) is 40.
8% (mRECIST) ^[1].


In response to this problem, we need to explore some biomarkers to determine which patients can benefit
from which treatment options.

A 2021 study published by our Huashan Hospital General Surgery Team in the journal Hepatology showed that the mechanism by which lenvatinib sensitized PD-1 through the FGFR4 pathway was found in animal models and validated in clinical cohorts; For liver cancer patients with high FGFR4 and Treg, the effectiveness of lenvatinib combined with PD-1 is much higher than in patients with low FGFR4 and Treg^[5].


This also suggests that we need more basic research to explain the internal mechanisms of liver cancer and the action of each drug, to help us find accurate biomarkers to guide clinical practice
.

Multiple combination therapy modalities

The road to a cure for liver cancer

Expert profile

Professor Chen Yajin

• Director of Department of Hepatobiliary Surgery and Director of General Surgery of Sun Yat-sen Memorial Hospital, Sun Yat-sen University

• Chairman of the Hepatobiliary Pancreatic ERAS Professional Committee of the Chinese Branch of the International Hepatobiliary and Pancreatic Association

• Member of the Standing Committee of the Surgical Branch of the Chinese Medical Doctor Association

• Chairman of Hepatobiliary Surgeon Branch of Guangdong Medical Doctor Association

• He is a member of the Biliary Surgery Group of the Surgical Branch of the Chinese Medical Association

• Standing Committee Member of the Professional Committee of Biliary Surgeons of the Surgeon Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Biliary Professional Committee of the National Health Commission Capacity Building and Continuing Education Surgery

• Royal College of Surgeons Fellow (FRCS)

• Member of the Standing Committee of the International Society of Laparoscopic Liver Surgery (ILLS).
  

• He is a member of the Asia-Pacific Laparoscopic Liver Surgery Promotion Committee and the Vice Chairman of the China Branch

• Vice Chairman of the Gastrointestinal Oncology Committee of the Chinese Association of Research Hospitals

• Vice Chairman of Liver Cancer Branch of Guangdong Medical Association

• Vice Chairman of Hepatobiliary and Pancreatic Surgery Branch of Guangdong Medical Association

• Member of the Expert Committee on Quality Control of Liver Cancer at the National Cancer Center

• Deputy Editor-in-Chief of Chinese Journal of Gastrointestinal Surgery

• Editor-in-Chief of Lingnan Clinical Journal of Modern Surgery

• Laparoscopic liver resection technology won the second prize of Guangdong Provincial Science and Technology Progress Award, the third prize of Chinese medical science and technology, 2020 was awarded the "Famous Doctor of the Country - Outstanding Achievements", the winner of the 2020 Guangdong Physician Award, in 2019, 2020 and 2021, he won the Outstanding Hepatobiliary Surgeon Branch of the Guangdong Medical Doctor Association for three consecutive years, and in 2018 and 2022, he was awarded the Guangdong Top Ten Excellent Clinical Department Directors

Question 6: Liver cancer system treatment represented by immune and targeted drugs has brought many combinations and changes
to liver cancer treatment.

What kind of changes has systematic treatment brought to the surgical treatment of liver cancer in China?

Professor Chen Yajin

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

In China, surgical treatment is one of the most important treatment methods for
liver cancer treatment.

However, less than 30% of early liver cancer in China was first diagnosed, 70%-80% of liver cancer was in the middle and advanced stage when it was found, and most patients have lost the opportunity for surgical resection, or even if they can be surgically removed, but because of vascular invasion, such as with portal vein cancer emboli, the postoperative recurrence rate is very high
.

The five-year survival rate of middle and advanced liver cancer in China is less than 20%.

Systematic treatment has developed rapidly in the past two or three years, bringing unlimited possibilities to surgeons, and the concept of surgeons has also undergone a great change
.

Liver cancer treatment requires the whole process of management
with the concept of multi-dimensional combination, multi-mode sequential, and multi-disciplinary high integration.

Preoperative translational therapy for patients with unresectable liver cancer or neoadjuvant therapy and postoperative adjuvant therapy for patients with resectable liver cancer have become the focus
of current research.

For conversion therapy, a variety of combination regimens not only prolong the survival of patients with advanced liver cancer, but also greatly improve the ORR and disease control rates of liver cancer, ORR can reach 30% to 40% ^[1,3,5], more importantly, when the combination of systematic drugs is combined with local treatment methods for liver cancer, ORR can be further improved, and it is expected to improve the rate of radical surgical resection of middle and advanced liver cancer.
Let the partial unresectable liver cancer descend to obtain the opportunity for
radical surgical resection.

For resectable liver cancer, the development of systemic therapy provides more options for preoperative neoadjuvant and postoperative adjuvant therapy for high-risk patients, promising to reduce postoperative recurrence and thereby prolong patient survival
.

When choosing a perioperative systematic treatment plan, in addition to paying attention to ORR, surgeons will also pay attention to the rate of tumor progression, the time to remission, the duration of remission and the depth of remission, and whether adverse reactions affect surgery, which are very important
for the comprehensive management of the overall course of the disease.

At the international conference in the past one or two years, Chinese scholars have continuously displayed relevant preliminary research results and have been at the forefront of
the world.

Multiple small sample studies have shown the efficacy and safety of topical therapy combined with systemic therapy for the perioperative period, and it is expected that randomized controlled studies in large samples will further confirm its value
.

Question 7: What are the new developments in the combination of systemic and topical treatment of liver cancer at this ESMO conference?

Professor Chen Yajin

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

This time, ESMO has published the results of a number of systematic treatment and local treatment in liver cancer exploration, and here we share with you two representative research results, one for intermediate patients and one for translational therapy
.

The first study retrospectively explored the efficacy and safety of different TACE-based regimens in 854 patients with BCLC stage B liver cancer ^[6], and also explored the right timing
of TACE combination targeting and immunotherapy.

The results showed that among liver cancer patients receiving the TACE-based regimen, TACE combined with targeted and immune checkpoint inhibitors (TKls+ICls) therapy seemed to provide the longest PFS and OS
.

Combination therapy with "TKls+ICls" within 3 months of the first TACE surgery may be a drug strategy
for better clinical outcomes.

The second study published interim results of a study of lenvatinib plus TACE and PD-1 inhibitors versus TACE alone for the efficacy and safety of translational therapy for initially unresectable liver cancer ^[7
].

The results showed that the combination of lenvatinib and TACE and PD-1 inhibitors could increase the conversion resectable rate in patients with unresectable hepatocellular carcinoma (uHCC) and prolong the overall survival
.

The conversion resection rate in the combination therapy group was 50.
7%, while the control group TACE had a conversion resection rate of only 15.
5% (P<0.
001
).

This study supports further exploration
of lenvatinib in combination with PD-1 inhibitors and TACE in the conversion therapy of patients with initial uHCC.

Most of the currently published studies on systematic treatment and local treatment in liver cancer exploration are retrospective or small-sample prospective studies, and a number of registered phase III studies are underway, such as the LEAP-012 study of TACE combined with pabolizumab and lenvatinib for the treatment of medium-term liver cancer, etc.
It is expected that these studies will be published as soon as possible to provide higher levels of evidence
for local combination systemic therapy.

References:

[1] Richard S.
Finn, et al.
2022 ESMO.
LBA34.

[2] Masatoshi Kudo,et al.
2022 ESMO.
LBA36.

[3] S.
Qin, et al.
2022 ESMO.
LBA35.

[4] Finn RS, et al.
N Engl J Med.
2020; 14; 382(20):1894-1905.

[5] Yi C, et al.
Hepatology.
2021; 74(5):2544-2560.

[6] G.
Yuan.
ESMO 2022.
Abstract 719P.

[7] Xiao-yun Zhang, et al.
ESMO 2022.
Abstract 715P.