Immune Gemini attacked the first-line treatment of malignant pleural mesothelioma and broke the deadlock for more than ten years!

Recently, Odivo® (Navulimab injection, commonly known as O drug) combined with Yiwo® (Ipilimumab injection, commonly known as Y drug) has been approved by the National Medical Products Administration (NMPA) of China Surgically resected, newly treated adult patients with non-epithelial malignant pleural mesothelioma
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As the first and only approved dual immunotherapy in China, nivolumab combined with ipilimumab for the first-line treatment of non-epithelioid malignant pleural mesothelioma indications were submitted in November 2020 and was granted priority in the same month Evaluation qualifications
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The launch of dual immunotherapy has effectively filled the gap of new drugs without systemic treatment in this disease field for more than ten years
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Immune Gemini (Nivolumab combined with Ipilimumab) is the world's first approved immuno-oncology drug combination therapy
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Among them, ipilimumab is the world's first approved immune checkpoint inhibitor and the first and currently the only approved CTLA-4 inhibitor in China.
Nivolumab is the world's first listed PD- 1 inhibitor
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At present, nivolumab combined with ipilimumab has been approved for the first-line treatment of malignant pleural mesothelioma in many countries and regions including the United States, Japan, and the European Union.
New treatment options
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Deep dilemma: Malignant pleural mesothelioma has been treated for many years without breakthrough.
Mesothelioma is a rare and highly aggressive malignant tumor that originates in mesothelial cells.
About 3,000 cases are diagnosed in China each year.
The tumor is mainly 1,2
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Environment and genetics are considered to be risk factors for mesothelioma.
The most common risk factor is asbestos exposure.
In addition, smoking, radiation, age, sex, and rare genetic mutations are related
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Two-thirds of patients are over 65 years old, and the risk of men is about five times that of women
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Due to its relative rarity, the treatment of malignant pleural mesothelioma has not made much progress
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For resectable patients, surgical treatment is the first choice, but only a small number of patients have the opportunity to operate
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For unresectable patients, pemetrexed combined with platinum-based chemotherapy is the standard treatment in the past, but the survival benefit is not ideal2
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Although a number of clinical studies have been explored in the past 15 years, no new systemic treatment has been approved before 3
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Professor Lu Shun, chief investigator of CheckMate-743 and director of the Department of Oncology, Shanghai Jiaotong University Thoracic Hospital, said: "Malignant pleural mesothelioma is a highly aggressive and rare cancer with limited treatment options
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Its incidence is related to asbestos exposure.
Highly correlated, most patients are at an advanced stage at the time of diagnosis, and the 5-year survival rate is less than 10%2
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Among all histological types, patients with non-epithelial tissue types have a worse prognosis, and patients urgently need new treatment options to improve Therapeutic effect and prolong survival time
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"Accumulate and thin hair: Immune Gemini takes the top spot in the first-line treatment.
CheckMate-743 is a global multi-center, randomized, controlled phase III clinical study, which included 605 cases of untreated, unresectable malignancies.
Patients with pleural mesothelioma received nivolumab combined with ipilimumab (dual immunotherapy group, n=303) or pemetrexed combined with cisplatin/carboplatin (chemotherapy group, n=302) as the first-line treatment
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The primary study endpoint is overall survival (OS), and secondary study endpoints include objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) (Figure 1)
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Figure 1: CheckMate-743 study design total population: dual immune response is excellent, malignant pleural mesothelioma all-population OS benefit The results of the study show that the median OS of patients in the dual immunotherapy group in the total population at the shortest follow-up of 22 months Compared with the chemotherapy group, it was significantly improved by 4 months (18.
1 months vs.
14.
1 months; HR: 0.
74; 96.
6% CI: 0.
60, 0.
91; p=0.
002)
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The 2-year survival rate was 41% in the dual immunotherapy group and 27% in the chemotherapy group (Figure 2)
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Figure 2: OS non-epithelial patients in the total population of the CheckMate-743 study: the median OS has doubled, and the 2-year survival rate has increased to nearly 5 times! Histological type is a recognized prognostic factor for malignant pleural mesothelioma, and non-epithelial tissue types usually have a worse prognosis
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In the CheckMate-743 study, patients were stratified randomly according to histological type, and the survival of patients with non-epithelial and epithelioid pleural mesothelioma treated with dual immunotherapy were improved, which was observed in the subgroup of patients with non-epithelial tissue type The advantage is even greater
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The median OS of patients with non-epithelial tissue types in the dual immunotherapy group was extended by nearly 10 months compared with the chemotherapy group, and the risk of death was reduced by 54% (18.
1 months vs.
8.
8 months; HR: 0.
46; 95%CI: 0.
31 , 0.
68); the 2-year survival rate of the dual immunotherapy group was nearly 5 times that of the chemotherapy group (38% vs.
8%) (Figure 3)
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Figure 3: The CheckMate-743 study of non-epithelioid patients OS Professor Shun Lu said: “As the first approved systemic therapy in 15 years, nivolumab combined with ipilimumab brings two benefits to non-epithelioid patients.
The overall survival benefit times that of chemotherapy makes long-term survival of patients possible.
It is of milestone significance and is expected to become the new standard treatment for malignant pleural mesothelioma
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"Epithelioid patients: The benefits of OS have also improved, with a 2-year OS rate of 42%.
The results of the study showed that the survival of patients with epithelioid pleural mesothelioma also improved, and the median OS of patients with epithelioid tissue types in the dual immunotherapy group 18.
7 months in the chemotherapy group and 16.
5 months in the chemotherapy group (HR: 0.
86; 95%CI: 0.
69, 1.
08); the 2-year survival rates of the two groups were 42% and 33%, respectively (Figure 4)
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Figure 4: CheckMate-743 Studying OSCheckMate-743 in epithelioid patients is the first and currently the only randomized, phase III clinical study to prove that first-line dual immunotherapy compared with standard platinum-containing chemotherapy can bring survival benefits to all patients with malignant pleural mesothelioma
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Based on CheckMate-743 study In the latest release of the "Chinese Society of Clinical Oncology (CSCO) Guidelines for the Clinical Application of Immune Checkpoint Inhibitors (2021 Edition)", nivolumab combined with ipilimumab is the first-line treatment of non-epithelial and epithelial Pleural mesothelioma has become the only treatment that has received grade I (type 1 evidence) and grade II recommendations (type 2A evidence)
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Golden partner: unique combination, synergy, safe and controllable PD-1 inhibitor nivolumab The combined CTLA-4 inhibitor ipilimumab is a unique combination of two immune checkpoint inhibitors that help destroy tumor cells through potential synergistic effects 4: CTLA-4 on the surface of T cells competitively binds to antigen-presenting cells with CD28 B7 reduces the activity of T cells and cannot kill tumor cells; at the same time, the combination of PD-L1 of tumor cells and PD-1 produced by T cells also reduces the activity of T cells, so that tumor cells can avoid the killing of T cells.

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Thus, Yi horses adalimumab administering antigen-presenting cells in the early signal to activate T cells, while mAb satisfied Wu Li You avoid depletion of tumor cells to escape from immune T cells, their combination, by the balance expected to enhance T cell activity Efficacy
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In addition, some T cells activated by ipilimumab can also differentiate into memory T cells, helping to achieve long-term anti-tumor immune responses
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The CheckMate-743 study further verified the sustained survival benefits brought by this potential synergistic mechanism.
At the same time, in the treatment of pleural mesothelioma, the dose of dual immunotherapy has been continuously optimized and adjusted
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The dose of ipilimumab was adjusted from the previous 3mg/kg, Q3W to 1mg/kg, Q6W
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In the CheckMate-743 study, the double immunotherapy was consistent with the previously reported results, and no new safety signals were observed
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The incidence of treatment-related adverse events in the dual immunotherapy group was comparable to that in the chemotherapy group.
The overall incidence of treatment-related adverse events in the two groups were 80% and 82%, respectively, and the incidence of treatment-related adverse events in the two groups were 30% and 32%, respectively.
(Picture 5)
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Figure 5: CheckMate-743 research safety Professor Wu Yilong, Life Director of Guangdong Provincial People’s Hospital and Honorary Director of Guangdong Lung Cancer Institute (GLCI), said: “Nivolumab combined with ipilimumab is advanced through potential synergistic effects Patients with malignant pleural mesothelioma bring significant and long-lasting overall survival benefits, making it possible to'de- chemotherapy'
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In the CheckMate-743 study, nivolumab (3mg/kg, Q2W) combined with ipilimumab (1mg/kg, Q6W) The safety profile of the first-line treatment of malignant pleural mesothelioma is consistent with the safety of the combination therapy in previous studies of other tumor types, including the first-line dual immunotherapy for lung cancer, which achieves efficacy and safety Balance indicates that the dual immunotherapy will have the opportunity to benefit Chinese patients in different tumor types in the future
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"The future is here: the prospect of the era of dual immunotherapy can be expected.
October 2015, nivolumab combined with Iraq Pimumab has become the world's first immuno-oncology combination therapy approved by regulatory agencies.
It has been approved for 6 tumor types in more than 50 countries and regions around the world, covering lung cancer, pleural mesothelioma, melanoma, kidney cancer, and nodules.
Rectal cancer, liver cancer
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With the further disclosure of research data, the efficacy and safety of dual immunotherapy have been confirmed in more and more tumor types
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Taking lung cancer as an example, the Phase III clinical study CheckMate -9LA two-year follow-up data and CheckMate-227 four-year follow-up data announced at the just-concluded 2021 ASCO annual meeting demonstrated the use of dual immunotherapy for non-small cell lung cancer (NSCLC) The long-term survival benefits and good safety5,6
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CheckMate -9LA results showed that the two-year survival rate of patients receiving nivolumab combined with ipilimumab and two cycles of chemotherapy reached 38%, while the two-year survival rate of patients receiving chemotherapy alone was 26%
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After prolonging the follow-up time, the median OS of patients receiving dual-immune combined chemotherapy reached 15.
8 months, compared with 11 months for patients in the chemotherapy group alone
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The latest follow-up results of CheckMate -227 showed that in the main patient population (PD-L1 ≥1%) in this study, the four-year survival rate of patients in the nivolumab combined with ipilimumab treatment group reached 29%, and the chemotherapy group It is 18%
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In an exploratory analysis, for patients with PD-L1<1%, the four-year survival rate of the nivolumab combined with ipilimumab treatment group was more than twice that of the chemotherapy group (24% vs 10%)
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Dual immunotherapy provides new treatment options for domestic patients with malignant pleural mesothelioma, and also shows the potential for long-term survival benefits for patients with other tumor types
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Ms.
Chen Siyuan, General Manager of Bristol-Myers Squibb China and Hong Kong, said: “Accelerating the launch of global innovative drugs in China is Bristol-Myers Squibb’s unswerving commitment
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Following the launch of the first PD-1 inhibitor'Odivo' in China , Bristol-Myers Squibb once again brought the world's first CTLA-4 inhibitor "Yiwo" to China, and continued to change the lives of patients through science
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In the future, Bristol-Myers Squibb will continue to explore the application of immuno-oncology therapy in different tumor types, including combined immunotherapy, in order to provide patients with new treatment options
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At the same time, we will continue to explore cooperation with the Chinese government, payers and third-party institutions, and jointly improve the domestic availability of dual immunotherapy through innovative access models and diversified measures
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"With the further update of various research data, it is believed that more indications of nivolumab combined with ipilimumab will be approved.
I hope that Immune Gemini will play a greater role in the treatment of more tumor types.
To benefit more cancer patients
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References: 1.
https://gco.
iarc.
fr/today/data/factsheets/populations/160-china-fact-sheets.
pdf 2.
Chinese Medical Doctor Association Multidisciplinary Tumor Diagnosis and Treatment Specialty Committee.
Chinese Journal of Oncology, 2021, 43(4):383-394.
3.
Paul Baas, et al.
Lancet.
2021 Jan 30;397(10272):375-386.
4.
Anand Rotte.
J Exp Clin Cancer Res.
2019; 38 : 255.
5.
CheckMate -9LA.
2021 ASCO.
6.
CheckMate -227.
2021 ASCO.