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    Home > Medical News > Latest Medical News > Second-line indications for liver cancer: What is the efficacy of domestic PD-1 when drug O is withdrawn and drug K is approved?

    Second-line indications for liver cancer: What is the efficacy of domestic PD-1 when drug O is withdrawn and drug K is approved?

    • Last Update: 2021-07-30
    • Source: Internet
    • Author: User
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    Author: Xiao Guang

    On July 23, Bristol-Myers Squibb (BMS) announced that after consultation with the FDA, it would voluntarily withdraw Opdivo (nivolumab, commonly known as O drug) in the U.
    S.
    market for single-drug use that had previously received sorafenib ( Sorafenib) is an indication for hepatocellular carcinoma (HCC) patients

    .

    BMS's decision is based on the meeting of the Oncology Drug Advisory Committee in April this year and subsequent discussions with the FDA
    .

    Drug O encounters Waterloo, drug K gets accelerated approval

    Drug O encounters Waterloo, drug K gets accelerated approval

    Drug O was first approved for the second-line treatment of HCC under the FDA's accelerated approval plan in September 2017, and is the first immunotherapy drug approved for HCC
    .

    The accelerated approval is based on data from the Phase I/II CheckMate-040 trial
    .
    This is a multicenter, open label, dose escalation and expansion study

    .
    A total of 262 patients with advanced HCC with or without HCV or HBV infection were enrolled.
    The results showed that the objective response rate (ORR) was 15%-20%, and the disease control rate (DCR) was 58%-64%

    .
    Further follow-up results showed that for patients who did not receive sorafenib treatment, the median overall survival (OS) of O-drug second-line treatment reached 15.
    6 months

    .
    In view of this, the FDA approved O drugs for the second-line treatment of HCC

    .

    However, in the confirmatory clinical trial CheckMate-459, according to the pre-specified analysis, O drug and sorafenib first-line treatment of liver cancer, although the ORR data consistent with the previous accelerated approval was achieved, the primary endpoint of OS did not reach the statistics.
    Learn meaning

    .
    Based on this, the FDA Oncology Advisory Committee opposed the continued accelerated approval of O drugs with a 5:4 vote

    .

    CheckMate 459 Primary Endpoint OS Achieved Negative Results (Source: 2019 ESMO)

    CheckMate 459's PFS has a negative result (Source: 2019 ESMO)

    It is worth noting that the second-line liver cancer PD-1-Merck’s Keytruda (pembrolizumab, pembrolizumab, commonly known as K drug) compared with placebo for the second-line treatment of advanced HCC Phase III study KEYNOTE-240 results released: This study did not achieve the established statistically significant OS and progression-free survival (PFS) benefits
    .

    The median OS of the K drug group and the placebo group were 13.
    9 months vs 10.
    6 months, respectively; the median PFS were 3.
    0 months vs 2.
    8 months, and the ORR was 16.
    9% vs 2.
    2%, respectively

    .
    Although negative results were also obtained in OS and PFS, the FDA's Oncology Drug Advisory Committee approved the accelerated approval of the second-line indication of K drug for liver cancer with a result of 8:0

    .

    The OS results of KEYNOTE-240 did not meet statistical assumptions (Source: Reference 2)

    Domestic PD-1 helps immunotherapy for liver cancer

    Domestic PD-1 helps immunotherapy for liver cancer

    Drug O is the world's first and China's first PD-1 inhibitor approved for marketing
    .
    In 2014, O drug obtained accelerated approval from the FDA in the United States, and in 2018 it was approved for marketing in China

    .
    However, in the subsequent confirmatory trials for HCC indications, the previously expected primary endpoint of OS could not be reached

    .
    After four years of painstaking efforts, the outcome was not ideal

    .

    Part of the reason for the failure of Drug O may be the principle of immune checkpoint inhibitors: it takes time to adjust and mobilize the immune balance in the body, and the body functions of patients with advanced liver cancer enter the downward channel, which makes many patients unable to maintain the normal immune system in the body.
    Disease progression occurs after the change, which explains to a certain extent the result that OS has not reached statistical significance

    .

    After the O drug second-line liver cancer indication is withdrawn, the K drug can continue to be used for the treatment of second-line hepatocellular carcinoma in the United States, but it has not yet been approved in China
    .
    So far, Chinese patients currently have only two single-drug immune drugs that can be used for second-line liver cancer, and both are domestic drugs.
    The following is a brief introduction

    .

    Carrelizumab

    In 2020, the humanized PD-1 monoclonal antibody developed by Hengrui Medicine-Carrelizumab (trade name: Erica) was approved by NMPA for the second-line treatment of HCC, becoming the first approved treatment in China PD-1 inhibitor for liver cancer
    .

    This approval is mainly based on the results of a national multi-center phase II clinical study of carrelizumab in the treatment of advanced hepatocellular carcinoma in China that has failed previous systemic treatments
    .
    This is also the world's first and largest clinical study of immune checkpoint inhibitors for liver cancer patients in China

    .
    The research was co-led by Professor Qin Shukui from the General Hospital of the Eastern Theater Command of the People's Liberation Army and Professor Ren Zhenggang from Zhongshan Hospital of Fudan University

    .
    A total of 220 patients were enrolled in the study.
    The results showed that the ORR of all patients was 14.
    7%; the median OS was 13.
    8 months, and the 6-month and 12-month OS rates of all patients were 74.
    4% and 55.
    9%, respectively; disease progression Patients who continue to use carrelizumab can still benefit

    .

    Since the advent of carrelizumab, it has been widely recognized in the oncology field at home and abroad
    .
    Due to its excellent efficacy and safety, the treatment plan of karelizumab combined with apatinib was included in the 2019 version of the national liver cancer diagnosis and treatment standard.
    In 2020, karelizumab was included in the CSCO lung cancer, liver cancer, and esophageal cancer , Recommendations in the clinical diagnosis and treatment guidelines for lymphoma

    .

    Tilelizumab

    In June of this year, NMPA formally approved the second domestic PD-1 tislelizumab (trade name: Beizean) as a single drug for HCC patients who have undergone at least one systemic treatment
    .
    Tilelizumab is a humanized lgG4 anti-PD-1 monoclonal antibody developed by BeiGene

    .
    This approval is based on the results of a study called RATIONALE 208

    .

    This is a single-arm, multi-center, open-ended, phase II study conducted globally
    .
    The study included a total of 249 HCC patients who had received at least one systemic treatment in the past.
    The results showed that the median PFS of the patients was 2.
    7 months, and the median OS was 13.
    2 months, which is comparable to the previous published data of international similar drugs

    .
    At the same time, the study found that nearly 80% of patients with objective remission can continue to remission for more than one year, suggesting that once the patient population has an effect, it is not easy to resist drug resistance, and the anti-tumor effect is stable and long-lasting

    .
    In addition, in this study, 3 patients achieved complete remission (CR), giving us the hope that liver cancer will be "cured"

    .

    Liver cancer is one of the most "Chinese characteristics" malignant tumors
    .
    According to statistics, more than 300,000 people die from liver cancer in China every year, accounting for about half of the global liver cancer deaths

    .
    Different from European and American countries, the occurrence of liver cancer in China is closely related to chronic hepatitis B virus infection, and most patients are in the middle and late stages when they are first diagnosed

    .
    Therefore, clinical research on liver cancer based on patients in China is particularly important

    .
    It is the most urgent clinical need to provide new and more effective treatments for the vast number of liver cancer patients in China, and it is also the responsibility of national pharmaceutical companies

    .

    PD-1/PD-L1 immunosuppressants have been the hottest topic in the anti-cancer field in recent years
    .
    Such drugs benefit a wide range of super survivors and may bring clinical cures, and have attracted the attention of cancer patients

    .
    Among domestic drugs, carrelizumab and tislelizumab are at the forefront of domestic liver cancer immune drugs, and the future is promising

    .
    We also look forward to more therapeutic drugs/programs coming out in the future to benefit more liver cancer patients

    .

    Reference

    1.
    Bruno Sangro, Chiun Hsu, Yoon-Koo Kang, et al.
    CheckMate 040: Efficacy, Hepatic Safety, and Biomarkers of Nivolumab + Ipilimumab Combination Therapy in Patients with Advanced Hepatocellular Carcinoma.
    AASLD 2019 Abstract: 0200.

    2.
    Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: Updated data from the randomized, phase III KEYNOTE-240 study.
    2021ASCO GI, abs268.

    3.
    Qin S, Ren Z, Meng Z, et al.
    Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, randomised, open-label, parallel-group, phase 2 trial.
    Lancet Oncol.
    Feb 26,2020.

    4.
    Results from a global Phase 2 study of tislelizumab, an investigational PD-1 antibody, in patients with unresectable hepatocellular carcinoma.

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