Professor Qin Shukui: Pembrolizumab has been approved as a second-line treatment for advanced liver cancer, providing a new preferred drug for liver cancer patients in China

China is a country with a high incidence of primary liver cancer, with about 410,000 new liver cancer patients and about 390,000 deaths in 2020, the main type of which is hepatocellular carcinoma (^{HCC) [1].}

More than 70% of patients have reached the middle and advanced stages at the time of diagnosis, and the prognosis is poor, and it is urgent to find more effective and safe treatment ^{methods [2].}

In October 2022, based on the efficacy results of the international multicenter phase III clinical trial KEYNOTE-394, the National Medical Products Administration (NMPA) of China newly approved pembrolizumab monotherapy for the treatment of HCC patients who have previously received sorafenib or oxaliplatin-containing chemotherapy, bringing a new immunotherapy option
to the majority of liver cancer patients.

Professor Qin Shukui, the principal investigator of the KEYNOTE-394 study (international leading PI), Nanjing University of Chinese Medicine and Jinling Hospital Cancer Center, was invited to deeply interpret the design and highlights of the study, the research significance and the development direction
of liver cancer immunotherapy.

Expert profiles

Professor Qin Shukui

• Chief physician and doctoral supervisor of Cancer Center of Jinling Hospital of Nanjing University of Chinese Medicine

• Distinguished Professor of Nanjing University of Chinese Medicine and Nanjing Medical University

• Editor-in-Chief of the National Statistical Source Journal of Clinical Oncology

• Former President and Current Vice President of the Chinese Society of Clinical Oncology (CSCO).
  

• Former Chairman and Current Chairman of the Board of Supervisors of Beijing CSCO Foundation

• Expert of Hematology and Oncology Drug Advisory Committee of the State Food and Drug Administration

• Chairman of the Expert Committee on Capacity Building and Continuing Education in Oncology of the National Health Commission

• He has been engaged in clinical and scientific research in medical oncology for a long time, and is good at the diagnosis, treatment and research of hepatobiliary and pancreatic tumors

There is a high degree of heterogeneity between liver cancer in China and European and American countries, and it is urgent to find new solutions suitable for Chinese patients

Professor Qin Shukui

Jinling Hospital, Nanjing University of Chinese Medicine

As we all know, China's population accounts for only 19% of the world's population, but the number of cases and deaths of HCC is close to half of the world, seriously threatening people's health and lives
.
At the same time, compared with HCC in Europe and the United States, HCC in China has a high degree of heterogeneity, that is, there are significant differences
in the causes of pathogenesis, epidemiological characteristics, molecular biological behavior, clinical manifestations and staging, treatment strategies and methods, drugs, and survival prognosis.
For example, HCC in China is mainly related to hepatitis B virus (HBV) infection, more than 80% of HCC patients are caused by HBV infection, other reasons are water pollution (blue-green algal toxoid), aflatoxin and long-term alcohol abuse, while HCC in the West is mainly caused
by hepatitis C virus (HCV) infection and non-alcoholic fatty liver disease.

For a long time, under the severe situation of high incidence and refractory treatment of HCC, domestic clinicians and researchers have been very active
in the diagnosis and treatment and clinical research of HCC.
Under the leadership of famous experts such as Academician Wu Mengchao, Academician Tang Zhaoyou, Academician Fan Jia, Academician Dong Jiahong and Professor Shen Feng, China's liver cancer surgery has become increasingly perfect
.
In recent years, HCC system therapy has also developed rapidly, and a variety of therapeutic drugs (including oxaliplatin, molecularly targeted drugs and modern traditional Chinese medicine preparations) have been successfully developed and approved for marketing
.
With the joint efforts of experts and scholars in different disciplines, HCC multidisciplinary comprehensive diagnosis and treatment has made great progress
.
In summary, in the diagnosis, treatment and research of HCC, we must actively learn from European and American experts, but we cannot copy their experience, we must combine China's national conditions and the characteristics of HCC patients, etc.
, to develop a set of effective diagnostic and treatment methods, and in clinical research, we must also find a suitable path
.

The KEYNOTE-394 study was designed according to the characteristics of Chinese liver cancer patients, and finally achieved comprehensive and effective results

Professor Qin Shukui

Jinling Hospital, Nanjing University of Chinese Medicine

The KEYNOTE-394 study was conducted primarily in the Asia-Pacific region, with 85% of patients from China
.
Patients with HCC who progressed after systemic chemotherapy with sorafenib or oxaliplatin-containing regimens, or who were intolerant to sorafenib or oxaliplatin-containing chemotherapy, were randomized to receive pembrolizumab + best supportive care (BSC) or placebo + BSC in a 2:1 ratio; The primary endpoints were overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration to response (DoR), and safety
.

At the beginning, the KEYNOTE-394 study listened to the leading opinions of our Chinese experts, different from the KEYNOTE-240 study carried out in Europe and the United States, and later learned the lessons of the latter's failures, and comprehensively optimized and improved
the program design, statistical planning, entry criteria, test execution and quality control 。 For example, in view of the pathogenesis characteristics of HCC in the Asia-Pacific region, it emphasizes the full monitoring and strict control of underlying liver diseases (especially HBV infection); Combined with the lessons learned from previous HCC phase III studies to determine the main endpoints, combined with the requirements of the drug regulatory authorities, a single endpoint of OS was adopted to avoid PFS or ORR as the dual endpoints; In the process of research, keep pace with the times, expand the sample size from more than 300 cases to more than 400 cases later, as appropriate, to minimize the interference of follow-up treatment; Design multiple sensitivity analyses to exclude the effects of later line therapy, etc
.
The result is a unique design and strict quality control
that differs from the KEYNOTE-240 study.

Because of this, the KEYNOTE-394 study achieved the expected efficacy outcome, and pembrolizumab significantly prolonged the median OS (14.
6 months vs.
13.
0 months, HR=0.
79, P=0.
0180) in patients compared with controls, which is the longest median OS data observed in phase II and III studies of immunocheckpoint inhibitors (especially PD-1 monoclonal antibodies) in the single-agent second-line treatment of advanced HCC worldwide.
Significant survival benefit has
been shown.
The pembrolizumab group reduced the risk
of death by 21% compared with the control group.
In addition, the 2-year OS rate in the pembrolizumab group reached 34.
3%, which was higher than that of the control group of 24.
9%, that is, long-term survival was more obvious
.
For two secondary endpoints, median PFS in the pembrolizumab and control groups was 2.
6 months and 2.
3 months, respectively, significantly reducing the risk of recurrence or death by 26%, and the 2-year PFS rates were 11% and 0%, respectively; The ORRs were 12.
7% and 1.
3%,
respectively.

It should be emphasized that 66.
7% of the patients in the placebo control group received follow-up systemic antitumor therapy after tumor progression, of which 28.
1%
received PD-1/PD-L1 monoclonal antibody therapy.
Even in this setting, pembrolizumab had a significant survival benefit
compared to placebo.
The survival benefit of pembrolizumab is even more pronounced
if the effect of later line therapy on survival is excluded by sensitivity analysis.
In terms of safety, pembrolizumab was 14.
4% of treatment≥-related adverse events (TRAE) of grade 3 or higher and only 3% of grade 3 immune-related AEs.
No new safety signals
appeared.

Pembrolizumab has achieved the longest research on second-line immunomonotherapy for liver cancer, and has broad application prospects in Chinese patients

Professor Qin Shukui

Jinling Hospital, Nanjing University of Chinese Medicine

In the goal of malignant tumor treatment, living long and living well is an eternal theme
.
Before 2006, most international drug regulatory agencies decided whether drugs could be marketed based on the level of ORR, that is, "only ask about size, whether dead or alive", but in practice sometimes ORR does not translate well into OS benefits, especially in HCC treatment
.
With the development of medical science, after 2006, domestic and foreign drug regulatory agencies have taken OS as the primary basis for evaluating whether a new drug or new treatment regimen is more effective, and refer to other research endpoints
.
The KEYNOTE-394 study met the expected primary endpoint, and the median OS data of 14.
6 months in the pembrolizumab group was the best result
currently achieved for second-line HCC therapy.
At the same time, the study met all secondary endpoints, which were new options
for patients with advanced HCC that could improve ORR while having long-term survival benefits.

As mentioned above, the KEYNOTE-394 study is the world's first randomized, controlled pivotal phase III clinical trial of PD-1 monoclonal antibody monoclonal antibody monotherapy to achieve the expected efficacy in HCC therapy, which is very valuable
。 The study was led by Chinese experts to organize and optimize the design, Merck China R&D team, clinical team of each research center, research monitoring and data management team united and worked together, and received the guidance and help of NMPA and drug evaluation centers, success should be the crystallization of teamwork, which also fully reflects the level and ability
of Chinese research team in trial design, execution and quality control 。 The enrolled population in the study meets the characteristics of Asian and Chinese patients, which provides strong high-level evidence-based medical evidence for immunotherapy for HCC patients in the Asia-Pacific region, especially HBV-related HCC patients, and once again proves the difference in the efficacy and safety of immunotherapy for HCC patients in the East and the West, and provides a new basis
for the standardized diagnosis and treatment of HCC in China.

The KEYNOTE-394 study provides important clinical evidence of the efficacy of single-agent for immunotherapy for liver cancer

Professor Qin Shukui

Jinling Hospital, Nanjing University of Chinese Medicine

A META-ANALYSIS OF THE KEYNOTE-394 AND KEYNOTE-240 STUDIES TOGETHER FOUND THAT THE MEDIAN OS OF PEMBROLIZUMAB MONOTHERAPY COMPARED WITH THE CONTROL GROUP WAS SIGNIFICANTLY SUPERIOR TO THE SECOND-LINE TREATMENT OF
HCC.
At the same time, subgroup analysis showed that pembrolizumab showed significant benefits of OS, PFS, and ORR compared with controls, regardless of patient age, sex, geography, macrovascular invasion, and serum alpha-fetoprotein (AFP) levels, making pembrolizumab sufficient evidence
for second-line treatment of advanced HCC.
In the KEYNOTE-394 study, pembrolizumab demonstrated excellent efficacy and safety in Asian and Chinese patients to meet the needs of different patient populations, including patients
who could not tolerate molecularly targeted therapy and oxaliplatin-containing systemic chemotherapy.
Therefore, pembrolizumab single-agent second-line treatment of HCC has been re-included in the just-released Chinese Society of Clinical Oncology's "CSCO Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)" as IA-level evidence and recommended
as a first-level expert.
Recently, I got good news: the main paper submission of the KEYNOTE-394 study has been accepted by the American Society of Clinical Oncology (ASCO), a top international medical journal "Journal of Clinical Oncology (JCO)", and will be published
in full soon.

In 2020, the NMPA issued the "Technical Guidelines for Clinical Trials of Antitumor Drug Combination Therapy", which stated that "sufficient evidence of single-agent clinical trials should be available before carrying out combination therapy"
.
The KEYNOTE-394 study provides a reliable basis for the clinical practice and research of further immunotherapy combination therapy for HCC, and it is necessary to further explore how to synergize through the combination of immunotherapy with traditional therapies and new therapies
in the future.
At the same time, it is necessary to actively study how to control the adverse reactions related to combination therapy to ensure the safety of
long-term treatment.
In addition, at present, HCC treatment still lacks molecular biological markers, that is, very effective predictors and prognostic indicators, and relevant research needs to be actively carried out in the future to truly achieve precise and individualized treatment
.