Is KEYNOTE-394 the "icing on the cake" or "a thriving"?

In 2022, with the positive results of the international multi-center, phase III clinical study KEYNOTE-394 enrolled in 85% of Chinese patients, the indication of PD-1 immune checkpoint inhibitor pembrolizumab (commonly known as "K drug") for the treatment of advanced primary hepatocellular carcinoma (HCC) treated by previous sorafenib or oxaliplatin chemotherapy was approved
in China.

Before the approval of pembrolizumab, carrelizumab and tislelizumab in China had been approved for the second-line treatment of advanced HCC
with the results of phase II clinical studies.

KEYNOTE-394 is the first phase III clinical study
to validate the efficacy of PD-1 monoclonal antibody in the second-line treatment of advanced HCC and its survival benefits for patients.
The objective response rate of pembrolizumab was 12.
7% (1.
3% in the control group) and the 2-year overall survival (OS) rate reached 34.
3%, which was higher than that of 24.
9% in the placebo control group^[1].

However, with the rapid development of HCC system therapy and the dynamic evolution of HCC combination therapy, the significance of KEYNOTE-394 and the approval of pembrolizumab for the second-line treatment of advanced HCC is often underestimated
.

At present, a number of PD-(L)1 monoclonal antibodies (such as atezolizumab or sindilimab) combined with anti-angiogenic drug bevacizumab have been approved for first-line treatment of unresectable HCC due to their superior performance over sorafenib in phase III clinical studies ^[2-3].
In real-world clinical practice, the multi-target kinase inhibitor lenvatinib has also become a new choice
for first-line treatment of advanced HCC.
In this context, what is the significance of pembrolizumab second-line therapy for advanced HCC indicated by chemotherapy prior to sorafenib or oxaliplatin?

And KEYNOTE-394 BRINGS MORE THAN THAT
.

Traditional local treatments such as transarterial chemoembolization (TACE), hepatic arterial perfusion chemotherapy (HAIC), radiotherapy combined with PD-(L)1 and/or lenvatinib and other systemic drugs are rapidly penetrating into the clinical practice or clinical research
of middle and advanced HCC treatment.
TACE in combination with lenvatinib [⁴], HAIC [^5] or HAIC in combination with sorafenib ^[6].
First-line treatment of advanced HCC has been shown in phase III clinical studies to have higher efficacy than targeted drugs alone, bringing more significant OS benefits
.

In this context, what is the significance of PD-1 single-agent second-line therapy for clinical practice? Is KEYNOTE-394 really just another "icing on the cake" for liver cancer clinical research?

HCC surgery is an important treatment for
patients to achieve long-term survival.
In the field of liver cancer treatment in China, hepatobiliary surgery occupies a central and dominant position, which plays a huge role
in promoting the comprehensive treatment of middle and advanced HCC.

Recently, during the Merck Liver Cancer Pilot Summit Forum, this platform interviewed Professor Wang Kui, chief physician of the Department of Hepatobiliary Surgery of the Third Affiliated Hospital of Naval Military Medical University, and Professor
Wang Lu of the Department of Hepatobiliary Surgery, Fudan University Cancer Hospital, on the development trend of HCC comprehensive treatment and the significance of KEYNOTE-394 research.

Current status of comprehensive treatment of HCC in China

Professor Wang Lu

At present, the treatment of liver cancer in China is still a comprehensive treatment mode
based on surgery.
In the absence of effective systemic drugs for liver cancer before, clinical reliance is more on surgical treatment
.
For example, 20 years ago, for CNLC (Chinese liver cancer stage) stage III.
A patients with portal trunk cancer, we also chose the scheme of surgical resection, thrombus removal, clinicians often discuss how to tether, how to combine cardiac surgery, the scope of surgery is often large, but most patients experience tumor recurrence
within half a year.
Looking at it these days, we usually take a different approach
.
Portal trunk cancer thrombus and inferior vena cava cancer tethered should be treated systemically first, rather than surgery
.

Professor Wang Kui

There is no doubt that the rapid development of systemic therapeutics represented by PD-(L)1 and targeted drugs has promoted HCC combination therapy
.
Surgeons used to rely only on a knife, and interventional doctors mainly relied on implantation, but now, we have more weapons, which can be integrated into systematic drug treatment
before, during and after surgery.
But this is both an opportunity and a challenge
.

At present, in addition to pembrolizumab at home and abroad, five different PD-(L)1 drugs have been approved for first-line treatment of unresectable HCC in combination with other drugs, and four TKI-targeted drugs represented by lenvatinib have been approved for first-line or second-line treatment of unresectable HCC
.
The combination of these systemic therapies and transcatheter arterial embolization (TAE), TARE, HAIC, ablation, radiotherapy, surgical resection and other local treatments may be more than
100 varieties.
In this situation, choosing the best treatment is a huge challenge
for clinicians.

Principles of choosing a treatment regimen

Professor Wang Kui

OS benefit is the gold standard for evaluating the efficacy of oncology treatment and is the first factor
to consider when choosing a treatment option.
In addition, drug safety, tolerability, and accessibility must be considered
.

KEYNOTE-394 results demonstrate the efficacy of pembrolizumab in second-line therapy with high-level evidence-based medical evidence, so is PD-(L)1 plus bevacizumab ("A+T" and "Dada" combination") the first-line regimen still preferred for unresectable advanced HCC? If lenvatinib is first-line with pembrolizumab second-line, does it likely result in a longer OS benefit?

In clinical practice, there is no shortage of combinations such as lenvatinib combined with PD-1, but the KEYNOTE-394 study brings a high level of evidence, which brings new inspiration for us to design treatment regimens, such as the first-line use of lenvatinib or lenvatinib plus TACE/HAIC topical therapy for some patients, with second-line pembrolizumab may be a preferred regimen because it can lead to longer survival, lower side effects, and better
。

Personalized treatment regimens are the trend

Professor Wang Lu

Chinese liver cancer patients are mostly in the middle and advanced stages when they are found, but compared with patients in Europe and the United States, they are younger and have better liver function reserves, so for these patients, especially stage IIB and IIIA patients, we should set more active treatment goals, such as through local treatment methods such as TACE or HAIC combined with systematic drug treatment to achieve tumor downgrade transformation and resection, so as to strive for a longer survival
for them.

Professor Wang Kui

When we have multiple weapons in our hands, we can stage and/or personalize programs
for different groups of people and different treatment goals.

For patients with early HCC, the goal of treatment is radical cure, and the goal of cure or clinical cure can be achieved by a single means such as surgery or intervention, bringing long-term survival
to patients.
For patients with unresectable stage CNLC IIIB, systemic drug therapy to prolong survival and improve quality of life is the main treatment goal
.

For patients with large heterogeneity of CNLC IIB and IIIA, it is necessary to judge the treatment goals and decide the treatment
plan according to the characteristics of the patient, the biological characteristics of the tumor and the stage of development 。 For example, for up-to-seven mid-stage liver cancer, the tumor burden is small, TACE or TACE combined with lenvatinib may be able to effectively control, or even shrink, liver cancer, and achieve transformation resection; For liver cancers with portal trunk thrombus and a large tumor burden, the combination of FOLFOX-HAIC or sequential pembrolizumab or a combination of PD-1 and lenvatinib may result in higher objective response rates and conversion resection rates
.

While these regimens may already be widely used in current clinical practice for HCC treatment, we still need convincing high-level evidence-based medical evidence to validate the value of these regimens, as KEYNOTE-394 does for the second-line treatment of PD-1 for unresectable HCC
.

Expert profiles

Professor Wang Kui

The Third Affiliated Hospital of Naval Medical University (Oriental Hepatobiliary Surgery Hospital)

Doctor of Medicine, Professor, Chief Physician, Doctoral Supervisor

• Director of the Second Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University

• Member of the Standing Committee of the Liver Cancer Professional Committee of the Chinese Anti-Cancer Association

• Member and Secretary of General Surgery Specialty Branch of Shanghai Medical Association, leader of the Liver Surgery Group

• Member of the Standing Committee of the CSCO Interventional Radiology Committee

• Member of Oncologist Branch of Shanghai Medical Doctor Association

• Member of General Surgeon Branch of Shanghai Medical Doctor Association

• Member of the Hepatobiliary Tumor Comprehensive Treatment Committee of Shanghai Anti-Cancer Association

• Official member of the Academic Committee of the International Hepatobiliary and Pancreatic Association (IHPBA).
  

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

Professor Wang Lu

Director of the Department of Liver Surgery, Fudan University Cancer Hospital

Chief physician, professor, doctoral supervisor

• Chairman of the Hepatobiliary Tumor Comprehensive Treatment Professional Committee of Shanghai Anti-Cancer Association

• Vice Chairman of the Biliary Tract Tumor Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Colorectal Cancer Liver Metastasis Professional Committee of the Chinese Medical Doctor Association

• Vice Chairman of the Hepatic Hemangioma Professional Committee of the China Branch of the International Hepatobiliary and Pancreatic Association

• Founding member of the International Laparoscopic Society of Liver Surgery

• Member of the Standing Committee of the Metastatic Liver Cancer Professional Committee of the China Branch of the International Hepatobiliary and Pancreatic Association

• Member of the Standing Committee of the Development and Promotion Committee of Laparoscopic Hepatectomy in China

• Deputy leader of the laparoscopic surgery group of the Minimally Invasive Tumor Treatment Professional Committee of Shanghai Anti-Cancer Association

• Member of the Tumor Metastasis Professional Committee of the Chinese Anti-Cancer Association

References: (swipe up to view)

[1] Qin SK et al.
, Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study,  ASCO Gastrointestinal Cancers Symposium,  2022

[2] Ann-Lii Cheng et al.
, Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs.
sorafenib for unresectable hepatocellular carcinoma, J Hepatol.
2022 Apr; 76(4):862-873.
doi: 10.
1016/ j.
jhep.
2021.
11.
030.
Epub 2021 Dec 11

[3] Ren ZG et al.
, Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study, Lancet Oncol.
2021 Jul; 22(7):977-990.
doi: 10.
1016/S1470-2045(21)00252-7.
Epub 2021 Jun 15.

[4] Zhenwei Peng,Wenzhe Fan,Bowen Zhu et al.
Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma:A PhaseⅢ,Randomized Clinical Trial(LAUNCH)[J].
Journal of Clinical Oncology.
2022.
DOI https://doi.
org/10.
1200/JCO.
22.
00392.

[5] Ning Lyu et al.
, Arterial Chemotherapy of Oxaliplatin Plus Fluorouracil Versus Sorafenib in Advanced Hepatocellular Carcinoma: A Biomolecular Exploratory, Randomized, Phase III Trial ( FOHAIC-1); J Clin Oncol.
2022 Feb 10; 40(5):468-480.
doi: 10.
1200/JCO.
21.
01963.
Epub 2021 Dec 14.

[6] He MK，Li QJ，Zou RH，et al.
Sorafenib plus hepatic arterial infusion of oxaliplatin，fluorouracil，and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion：a randomized clinical tria [J ].
JAMA Oncol， 2019，5(7)：953-960.

Revised: Uni

Typesetting: Uni

Execution: Yuna

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