TW202337897A - Pharmaceutical combinations of anti-pd-1 antibody and anti-vegf-a antibody and method of use thereof - Google Patents

Abstract

The present application directs to a pharmaceutical combination comprising an anti-PD-1 antibody and one or more chemotherapeutic agents, and the pharmaceutical combination may further comprise an anti-VEGF-A antibody. The present application also directs to the use and method of using the pharmaceutical combination to prevent or treat cancer.

Description

Drug combinations of anti-PD-1 antibodies and anti-VEGF-A antibodies and methods of use

The present invention discloses a pharmaceutical combination comprising an anti-PD-1 antibody and one or more chemotherapeutic agents. The pharmaceutical combination may further comprise an anti-VEGF-A antibody, and the pharmaceutical combination is used to prevent or treat cancer. The invention also discloses uses and methods of using the composition product to prevent or treat cancer.

With the extension of average human life span and changes in lifestyle behaviors, malignant tumors have become an important disease that seriously threatens human health and is also the disease that poses the greatest threat to human life. According to data released by the National Cancer Center in February 2017, there are 4.29 million new cancer cases and 2.81 million cancer deaths in China every year, which is equivalent to 12,000 people suffering from cancer and 7,500 people dying from cancer every day. As my country's population ages further, the incidence and mortality of cancer will continue to rise. Among all causes of cancer death, lung cancer (25.2%) ranks first, followed by liver cancer (14.4%), gastric cancer (14.3%) and esophageal cancer (9.3%). These four types of cancer have poor prognosis and account for all cancer deaths. 63.2% (2017 China Cancer Registration Annual Report. National Cancer Center, Bureau of Disease Control and Prevention, Ministry of Health, 2017).

Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of all lung cancer cases, and approximately 70% of NSCLC patients have locally advanced or metastatic disease that is not suitable for surgical resection at the time of diagnosis. Patients with advanced driver gene-positive NSCLC can use corresponding targeted therapy. The positive rate of EGFR gene mutations in Asian people and Chinese lung adenocarcinoma patients is 48.5% (Gou LY, Wu YL. Prevalence of driver mutations in non-small-cell lung cancers in the People's Republic of China. Lung Cancer Target Therapy , 2014 ). Tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, or icotinib) are recommended as first-line treatments for patients with EGFR-mutated advanced NSCLC. If the disease progresses after treatment with first- and second-generation TKIs, if there is a T790M mutation, third-generation TKIs (osimertinib, etc.) can be used for treatment. If the T790M mutation is negative or progresses after osimertinib treatment, platinum-containing doublet chemotherapy is recommended as a systemic treatment option (Chinese Society of Clinical Oncology (CSCO) Primary Lung Cancer Diagnosis and Treatment Guidelines 2018 Edition) ^{Error! Reference source not found.} . For such patients, the efficacy still needs to be further improved (Mok TSK1, Kim SW1, Wu YL et al, Gefitinib Plus Chemotherapy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer Resistant to First-Line Gefitinib (IMPRESS ): Overall Survival and Biomarker Analyses. J Clin Oncol. 2017 Dec 20;35(36):4027-4034) ^{Error! Reference source not found.} , there is an urgent clinical need for new treatment options. The 35th Annual Meeting of the European Society for Medical Oncology (ESMO) released the results of a meta-analysis of bevacizumab combined with platinum chemotherapy in the first-line treatment of advanced non-squamous NSCLC. It has been confirmed that bevacizumab-based chemotherapy can achieve significant survival benefit, prolong response time and expected safety in patients with advanced non-squamous NSCLC. Sun Yat-sen University has confirmed that bevacizumab combined with chemotherapy can treat patients with EGFR-TKI resistance. Efficacy and Safety Study of Bevacizumab Plus Chemotherapy in EGFR-TKI Resistant Non-Squamous Non-Small Cell Lung Cancer. ClinicalTrials.gov , NCT02139579, 2014), the results are not known yet, and further research is needed on immunotherapy for such patients. The immunotherapy combined group provides an alternative treatment method that may improve such patients.

The invention discloses a pharmaceutical combination comprising an anti-PD-1 antibody and one or more chemotherapeutic agents. Preferably, the invention also discloses a pharmaceutical combination comprising an anti-PD-1 antibody, an anti-VEGF-A antibody and one or more chemotherapeutic agents. Drug combination, in addition, the present invention also discloses the use of the drug combination, and the method of using the drug combination to treat lung cancer, such as the treatment of non-small cell lung cancer, especially the treatment of locally advanced or metastatic EGFR mutations that have failed EGFR-TKI treatment Non-squamous non-small cell lung cancer.

The present invention also provides a drug administration method, which method includes a combined treatment period and a maintenance treatment period. The drug administration method can be used to treat lung cancer, such as non-small cell lung cancer, especially in localized EGFR mutated areas where EGFR-TKI treatment fails. Advanced or metastatic non-squamous non-small cell lung cancer.

Detailed description of the invention

1) Definition of terms

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which they belong. For the purposes of the present invention, the following terms are defined below.

As used herein, the term "and/or" means any one of the options or two or more of the options

As used herein, the term "comprises" or "includes" means the inclusion of the stated element, integer or step, but does not exclude any other element, integer or step. When the term "comprises" or "includes" is used herein, combinations of the stated elements, integers, or steps are also encompassed unless otherwise indicated. For example, when reference is made to an antibody variable region that "comprises" a particular sequence, it is also intended to encompass antibody variable regions that consist of that particular sequence.

"Individual" includes mammals. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., , mice and rats). In some embodiments, the individual is a human, including a child, adolescent, or adult.

The term "administration in combination" refers to the administration of two or more therapeutic agents to treat a disease as described herein. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, for example, as a single composition having a fixed ratio of the active ingredients. Alternatively, such administration involves co-administration of the individual active ingredients in multiple or separate containers (eg tablets, capsules, powders and liquids). Powders and/or liquids can be reconstituted or diluted to the desired dosage prior to administration. Additionally, such administration includes administering each type of therapeutic agent at approximately the same time or at different times in a sequential manner. In either case, the treatment regimen will provide for the beneficial effects of the drug combination in treating the disorder or condition described herein.

As used herein, "treating" means slowing, interrupting, retarding, alleviating, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.

As used herein, "prevention" includes the inhibition of the onset or progression of a disease or condition or symptoms of a particular disease or condition. In some embodiments, individuals with a family history of the disease are candidates for preventive regimens. Generally, the term "prevention" refers to the administration of a drug before signs or symptoms occur, especially in an individual at risk.

The term "effective amount" refers to an amount or dose of a formulation or composition of the present invention that produces the desired effect in a treated patient when administered to the patient in single or multiple doses. The effective amount can be readily determined by the attending physician, who is one of ordinary skill in the art, by considering factors such as: the species of the mammal; its size, age and general health; the specific disease involved; the extent of the disease; or severity; individual patient response; specific antibody administered; mode of administration; bioavailability characteristics of the administered formulation; selected dosing regimen; and use of any concomitant therapy.

As used herein, the term "pharmaceutical composition" refers to a composition containing at least one active ingredient or a plurality of active ingredients suitable for administration to an animal, preferably a mammal, including humans.

The term "about" when used in connection with a numerical value is meant to encompass a range of numerical values having a lower limit that is 10% less than the specified numerical value and an upper limit that is 10% greater than the specified numerical value.

The purpose of the term "superiority margin" is to show that the drug under study is more effective than the control drug (active drug or placebo control), to infer clinically meaningful superiority, and to determine the clinically acceptable The boundary value is called the superiority boundary value.

abbreviation

2) Drug combination

The present invention provides a pharmaceutical combination comprising an anti-PD-1 antibody and one or more chemotherapeutic agents.

In a preferred embodiment, the present invention provides a pharmaceutical combination including an anti-PD-1 antibody, an anti-VEGF-A antibody and one or more chemotherapeutic agents.

In one embodiment, the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises HCDR1, HCDR2, HCDR3 and the light chain comprises LCDR1, LCDR2, LCDR3, wherein,

HCDR1 contains or consists of the amino acid shown in SEQ ID NO: 1 (KASGGTFSSYAIS);

HCDR2 contains or consists of the amino acid shown in SEQ ID NO: 2 (LIIPMFDTAGYAQKFQG);

HCDR3 contains or consists of the amino acid shown in SEQ ID NO: 3 (ARAEHSSTGTFDY);

LCDR1 contains or consists of the amino acid shown in SEQ ID NO: 4 (RASQGISSWLA);

LCDR2 contains or consists of the amino acid shown in SEQ ID NO: 5 (SAASSLQS);

LCDR3 contains or consists of the amino acid shown in SEQ ID NO: 6 (QQANHLPFT).

In one embodiment, the anti-PD-1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence shown in SEQ ID NO: 7, or comprises An amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 7, or is determined by SEQ ID NO. : Composed of 7; the VL contains the amino acid sequence shown in SEQ ID NO: 8, or contains at least 90%, 91%, 92%, 93%, 94%, 95%, 96% of the same amino acid sequence as SEQ ID NO: 8 , an amino acid sequence with 97%, 98% or 99% identity, or consisting of SEQ ID NO: 8.

SEQ ID NO:7:

SEQ ID NO:8:

In one embodiment, the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 9, or has an amino acid sequence that is at least 90% identical to SEQ ID NO: 9. An amino acid sequence that is 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical, or consists of SEQ ID NO: 9; the light chain comprises SEQ ID NO : The amino acid sequence shown in 10, or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with SEQ ID NO: 10 The specific amino acid sequence may consist of SEQ ID NO: 10.

SEQ ID NO:9:

SEQ ID NO: 10:

In one embodiment, the anti-VEGF-A antibody is bevacizumab.

In one embodiment, the one or more chemotherapeutic agents are pemetrexed, platinum-based drugs. In a preferred embodiment, the platinum is cisplatin.

In one embodiment, the dosage of the anti-PD-1 antibody in the pharmaceutical combination is 50-500 mg, preferably 50 mg, 60 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, more preferably 200mg.

In one embodiment, the dosage of anti-VEGF-A antibody in the pharmaceutical combination is 1-20 mg/kg, preferably 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 12mg/kg, 14mg/kg, 15mg/kg, 16mg/kg, 18mg/kg, 20mg/kg, preferably 15mg/kg; or anti-VEGF- The dose of A antibody is 60-1200mg, preferably 60mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg, 480mg, 540mg, 600mg, 720mg, 840mg, 900mg, 960mg, 1080mg, 1200mg, and more preferably 900mg.

In one embodiment, the dosage of pemetrexed in the medicine is 200-600 mg/m ² , such as 200 mg/m ² , 300 mg/m ² , 400 mg/m ² , 450 mg/m ² , 500 mg/m ² , or any conventional dosage in the art.

In one embodiment, the dose of cisplatin in the drug is 50-100, such as 50 mg/m ² , 60 mg/m ² , 70 mg/m ² , 75 mg/m ² , 80 mg/m ² , or any of the prior art of conventional dosage.

In one embodiment, the pharmaceutical combination is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six weeks, preferably once every three weeks.

In one embodiment, intravenous administration of the pharmaceutical combination is provided.

In one embodiment, the anti-PD-1 antibody, anti-VEGF-A antibody, and chemotherapeutic agent included in the pharmaceutical combination can be administered simultaneously, separately, or sequentially.

In one embodiment, an anti-PD-1 antibody, an anti-VEGF-A antibody, and a chemotherapeutic agent are administered sequentially. Preferably, the anti-PD-1 antibody is administered first, then the anti-VEGF-A antibody is administered, and then the Use chemotherapeutic agents. It is better to administer the anti-PD-1 antibody first, then apply the anti-VEGF-A antibody 0.5-24 hours later (preferably, apply the anti-VEGF-A antibody for 30-60 minutes), and then apply the chemotherapeutic agent 0.5-24 hours later.

3) Complete medicine box

In one embodiment, the invention provides a kit comprising an effective amount of an anti-PD-1 antibody and an effective amount of a chemotherapeutic agent. In a preferred embodiment, the kit provided by the present invention also contains an effective amount of anti-VEGF-A antibody.

In one embodiment, the individual active ingredients of the kit are stored in separate containers.

In one embodiment, the anti-PD-1 antibody in the kit includes HCDR1, HCDR2, HCDR3 shown in SEQ ID NO: 1, 2, 3 and LCDR1, LCDR2 shown in SEQ ID NO: 4, 5, 6 , LCDR3.

In one embodiment, the anti-PD-1 antibody in the kit includes the VH set forth in SEQ ID NO:7 and the VL set forth in SEQ ID NO:8.

In one embodiment, the anti-PD-1 antibody in the kit includes the heavy chain set forth in SEQ ID NO: 9 and the light chain set forth in SEQ ID NO: 10.

In one embodiment, the kit of parts includes 50 mg, 60 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg of anti-PD-1 antibody.

In one embodiment, the anti-VEGF-A antibody in the kit is bevacizumab.

In one embodiment, the kit of parts includes 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 600 mg, 720 mg, 840 mg, 900 mg, 960 mg, 1080 mg or 1200 mg of anti-VEGF-A antibody.

In one embodiment, the chemotherapeutic agents in the kit are preferably pemetrexed and cisplatin.

In one embodiment, the dose of pemetrexed in the kit is 200-600 mg/m ² , such as 200 mg/m ² , 300 mg/m ² , 400 mg/m ² , 450 mg/m ² , 500 mg/m ² , or any conventional dosage in the art.

In one embodiment, the dose of cisplatin in the kit is 50-100, such as 50 mg/m ² , 60 mg/m ² , 70 mg/m ² , 75 mg/m ² , 80 mg/m ² , or any existing Conventional dosage in technology.

In one embodiment, the kit further includes a package insert bearing printed instructions for the use of a combination of an anti-PD-1 antibody and an anti-VEGF-A antibody to prevent or treat cancer in an individual.

4) Treatment methods

In one embodiment, the invention provides a method of preventing or treating tumors in a subject, comprising administering to the subject a pharmaceutical combination or kit of the invention.

In one embodiment, the treatment method includes 2 administration phases:

(i) Phase I, sequentially administering to the subject an anti-PD-1 antibody, an anti-VEGF-A antibody, and a chemotherapeutic agent; or sequentially administering to the subject an anti-PD-1 antibody and a chemotherapeutic agent, and

(ii) In the second stage, the subject is administered anti-PD-1 antibody, anti-VEGF-A antibody and chemotherapeutic agent in sequence; or the subject is administered anti-PD-1 antibody and chemotherapeutic agent in sequence.

In one embodiment, the treatment method includes 2 administration phases:

(i) In the first phase, subjects are administered anti-PD-1 antibodies, anti-VEGF-A antibodies, pemetrexed and platinum drugs in sequence; or subjects are administered anti-PD-1 antibodies, pemetrexed in sequence plugs and platinum drugs, and

(ii) In the second phase, the subject is administered anti-PD-1 antibody, anti-VEGF-A antibody and pemetrexed sequentially; or the subject is administered anti-PD-1 antibody and pemetrexed sequentially.

In one embodiment, the platinum drug is cisplatin.

In one embodiment, the first phase is a combination treatment phase, and the second phase is a maintenance treatment phase.

In a preferred embodiment, the treatment method includes:

(i) the first phase of combination treatment period, in which subjects are sequentially administered anti-PD-1 antibody, anti-VEGF-A antibody, pemetrexed, and platinum-based drugs, and

(ii) In the second maintenance treatment period, subjects were administered anti-PD-1 antibody, anti-VEGF-A antibody and pemetrexed sequentially.

In one embodiment, the platinum drug is cisplatin.

In a specific embodiment, the single dose of the anti-VEGF-A antibody is 15 mg/kg, the single dose of the anti-PD-1 antibody is 200 mg, and the single dose of pemetrexed is 500 mg. /m ² , the single dose of cisplatin is 75 mg/m ² .

In another embodiment, the combination treatment period includes 4 cycles, wherein every three weeks is a treatment cycle, and the doses are administered sequentially on the first day of each cycle.

In one embodiment, the subject receives up to 4 cycles of cisplatin

In one embodiment, other pharmaceutical ingredients, such as anti-PD-1 antibodies, anti-VEGF-A antibodies, and pemetrexed, are administered continuously.

In one embodiment, all subjects are treated for up to 24 months.

In one embodiment, the tumor is lung cancer, preferably, the lung cancer is non-small cell lung cancer, and more preferably, the non-small cell lung cancer has failed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment EGFR-mutated locally advanced or metastatic non-squamous non-small cell lung cancer.

In one embodiment, the treatment method provided by the invention achieves the following benefits:

(a) The progression-free survival (PFS) of the subject is improved, for example, compared with the chemotherapy treatment group using pemetrexed and cisplatin, the progression-free survival is significantly improved;

(b) The objective response rate (ORR) of the subject is improved, such as significantly improved progression-free survival compared with the chemotherapy treatment group using pemetrexed and cisplatin;

(c) The subject's duration of response (DOR) is improved, such as significantly improved progression-free survival relative to the chemotherapy treatment group with pemetrexed and cisplatin.

5)Use

In one embodiment, the present invention provides the use of the above pharmaceutical combination or kit for treating tumors.

In another embodiment, the present invention provides the use of the above pharmaceutical combination or kit in the preparation of drugs for preventing or treating tumors.

In one embodiment, the tumor is lung cancer, preferably, the lung cancer is non-small cell lung cancer, and more preferably, the non-small cell lung cancer has failed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment EGFR-mutated locally advanced or metastatic non-squamous non-small cell lung cancer.

In one embodiment, the pharmaceutical combination or kit of the present invention can achieve the following benefits:

(a) The progression-free survival (PFS) of the subject is improved, for example, compared with the chemotherapy treatment group using pemetrexed and cisplatin, the progression-free survival is significantly improved;

(b) The objective response rate (ORR) of the subject is improved, such as significantly improved progression-free survival compared with the chemotherapy treatment group using pemetrexed and cisplatin;

(c) The subject's duration of response (DOR) is improved, such as significantly improved progression-free survival relative to the chemotherapy treatment group with pemetrexed and cisplatin.

Example 1

受試藥物

Test drug

Anti-PD-1 antibody, sintilimab injection, Innovent Biologics (Suzhou) Co., Ltd., specification: 10ml: 100mg.

Anti-VEGF-A antibody, bevacizumab injection, manufacturer: Innovent Biologics (Suzhou) Co., Ltd. Specifications: 4ml: 100mg.

Pemetrexed: 500mg/bottle

Cisplatin: 10 mg or 20 mg multi-dose vials

Placebo 1: Sodium citrate (dihydrate): 5.88mg/ml

Sodium chloride: 2.92mg/ml

Histine: 3.73mg/ml

Mannitol: 30.06mg/ml

Disodium edetate: 0.0075mg/ml

Polysorbate 80: 0.2mg/ml

Citric acid (monohydrate): appropriate amount, adjust pH to 6.0

Placebo 2: Sodium acetate: 1.64mg/ml

Sorbitol: 50mg/ml

Polysorbate 80 Polysorbate 80: 2mg/ml

Glacial acetic acid: adjust pH to 5.2

入組標準

Inclusion criteria

1) Sign the written informed consent;

18歲且

75歲的男性或女性； 2)Age

18 years old and

Male or female over 75 years old;

3) According to the 8th edition of the TNM staging of lung cancer by the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer Classification, locally advanced or metastatic disease (IIIB, IIIC or IV) that is inoperable and cannot be treated with radical concurrent chemoradiotherapy and is confirmed by histology or cytology stage) non-squamous NSCLC;

4) The presence of EGFR mutation is confirmed by tumor histology, cytology or hematology before EGFR-TKI treatment;

5) After EGFR-TKI treatment failure (based on RECIST V1.1, disease progression confirmed by imaging), any one of the following requirements is met:

a) Previously received 1st or 2nd generation EGFR-TKI (such as: icotinib, gefitinib, erlotinib, afatinib or other 1st or 2nd generation EGFR-TKIs already marketed in China EGFR-TKI) treatment and failure requires histological confirmation of negative EGFR20 exon T790M mutation;

b) Previously received treatment with 1st or 2nd generation EGFR-TKI (such as icotinib, gefitinib, erlotinib, afatinib), and histology or Hematology confirmed the presence of EGFR exon 20 T790M mutation positivity, subsequent treatment with third-generation EGFR-TKI (such as osimertinib or other third-generation EGFR-TKI already marketed in China) and failure; (if the first There is no T790M test result after failure of first- or second-generation EGFR-TKI treatment, and the disease must progress after taking the third-generation EGFR-TKI for more than 6 months; if treatment with first- or second-generation EGFR-TKI There is no T790M test result after failure. If the disease progresses after taking the 3rd generation EGFR-TKI in the clinical development stage, it is still effective to switch to the marketed 3rd generation EGFR-TKI. The latter must meet the requirements for disease progression after the latter's treatment time exceeds 6 months) ;

c) Previously received third-generation EGFR-TKI (such as osimertinib or other third-generation EGFR-TKI already marketed in China) treatment when first diagnosed with EGFR-mutated NSCLC and failed;

6) There must be at least one measurable lesion as a target lesion (according to RECIST V1.1). Measurable lesions located within the previous radiation field or after local treatment can also be selected as target lesions if progression is confirmed;

7) Eastern Cooperative Oncology Group performance status score (ECOG PS) is 0 to 1 points;

3個月； 8) Estimated survival time

3 months;

9) Laboratory results at the time of screening must meet the following requirements (no blood components, cell growth factors, and other intravenous or subcutaneous corrective treatment drugs are allowed to be administered within the first 14 days of obtaining laboratory test results):

1.5×10⁹/L，血小板計數(PLT)

100×10⁹/L，血紅蛋白(HGB)

90g/L(7日內無輸血或無促紅細胞生成素依賴性)； a) Blood routine: absolute neutrophil count (ANC)

1.5×10 ⁹ /L, platelet count (PLT)

100×10 ⁹ /L, hemoglobin (HGB)

90g/L (no blood transfusion or erythropoietin dependence within 7 days);

1.5倍正常值上限(ULN)；不存在肝轉移受試者其丙胺酸胺基轉移酶(ALT)和天門冬胺酸胺基轉移酶(AST)

2.5倍ULN，肝轉移受試者其ALT和AST

5倍ULN； b) Liver function: total bilirubin (TBIL)

1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in subjects without liver metastases

2.5 times ULN, ALT and AST in subjects with liver metastasis

5 times ULN;

1.5倍ULN或Cr清除率

60mL/min(Cockcroft-Gault公式)，且尿常規檢測結果顯示尿蛋白(UPRO)<2+或24小時尿蛋白定量<1g； c) Renal function: Serum creatinine (Cr)

1.5 times ULN or Cr clearance rate

60mL/min (Cockcroft-Gault formula), and routine urine test results show urine protein (UPRO) <2+ or 24-hour urine protein quantification <1g;

1.5倍ULN，且部分促凝血酶原時間(PTT)或活化部分凝血活酶時間(APTT)

1.5倍ULN； d) International normalized ratio (INR) within 7 days before study treatment

1.5 times ULN and partial prothrombin time (PTT) or activated partial thromboplastin time (APTT)

1.5 times ULN;

10) For female subjects of childbearing age, the urine or serum pregnancy test should be negative within 3 days before receiving the first study drug administration (Cycle 1, Day 1). If a urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is required;

治療方案

treatment plan

This study is an evaluation of sintilimab ± bevacizumab in combination with pemetrexed and cisplatin in patients with EGFR mutations who have failed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. A randomized, double-blind, multicenter phase III clinical study of efficacy and safety in patients with locally advanced or metastatic non-squamous non-small cell lung cancer (ORIENT-31).

This study plans to enroll 630 patients with EGFR-mutated stage IIIB, IIIC and IV non-squamous NSCLC who failed EGFR-TKI treatment. Patients with locally advanced or metastatic non-squamous non-small cell lung cancer who have failed EGFR-TKI treatment in the past will be randomly assigned to trial group A in a 1:1:1 ratio in the first phase after signing informed consent. (sintilimab + bevacizumab + pemetrexed + cisplatin) or experimental group B (sintilimab + placebo 2 + pemetrexed + cisplatin) or control group C (placebo agent 1 + placebo 2 + pemetrexed + cisplatin); in the second phase, they were randomly assigned to trial group A (sintilimab + bevacizumab + pemetrexed) in a ratio of 2:2:1 Trexed + cisplatin) or experimental group B (sintilimab + placebo 2 + pemetrexed + cisplatin) or control group C (placebo 1 + placebo 2 + pemetrexed + cisplatin) . Stratification factors included: sex (male or female) and brain metastasis (presence or absence). The treatment of each group in this study is divided into a combination treatment period and a maintenance treatment period, as follows:

First stage:

Experimental group A (N=160):

Combination treatment period: sintilimab 200 mg + bevacizumab + pemetrexed + cisplatin, Q3W*4,

Maintenance treatment period: sintilimab 200mg + bevacizumab + pemetrexed, Q3W*4

Experimental group B (N=160):

Combination treatment period: sintilimab 200mg + placebo 2 + pemetrexed + cisplatin, Q3W*4

Maintenance treatment period: sintilimab 200mg + placebo 2 + pemetrexed, Q3W*4

Control group C (N=160):

Combination treatment period: placebo 1 + placebo 2 + pemetrexed + cisplatin, Q3W*4

Maintenance treatment period: placebo 1 + placebo 2 + pemetrexed, Q3W*4

Second stage:

Experimental group A (N=60):

Combination treatment period: sintilimab 200 mg + bevacizumab + pemetrexed + cisplatin, Q3W*4

Maintenance treatment period: sintilimab 200mg + bevacizumab + pemetrexed, Q3W*4

Experimental group B (N=60):

Combination treatment period: sintilimab 200mg + placebo 2 + pemetrexed + cisplatin, Q3W*4

Maintenance treatment period: sintilimab 200mg + placebo 2 + pemetrexed, Q3W*4

Control group C (N=30):

Combination treatment period: placebo 1 + placebo 2 + pemetrexed + cisplatin, Q3W*4

Maintenance treatment period: placebo 1 + placebo 2 + pemetrexed, Q3W*4

The specific treatment options are shown in the table below:

試驗結果

Test results

At the first interim analysis, the median follow-up time was 9.8 months.

Second interim analysis, median follow-up time: 13.1 months.

The trial results showed that in the intention-to-treat (ITT) population, based on the independent imaging review committee (IRRC) assessment, the sintilimab injection and bevacizumab injection combined with chemotherapy group (trial group A), sintilimab injection and The median progression-free survival (PFS) (95% CI) of the monoclonal antibody injection combined with chemotherapy group (test group B) and chemotherapy group (control group C) was 6.9 months (6.0, 9.3) and 5.6 months (95% CI), respectively. 4.7,6.9), 4.3 months (4.1,5.4). Compared with control group C, experimental group A achieved a significant and clinically significant PFS extension (HR=0.464, 95% CI: 0.337, 0.639; P<0.0001), reaching the preset superiority margin; experimental group B compared with control group The PFS of Group C reached superiority in the second interim analysis (HR=0.718, 95% CI: 0.549, 0.941; P=0.0155), so sintilimab injection combined with chemotherapy was added with bevacizumab. Anti-injection has a clinically significant PFS benefit, which is better than the chemotherapy combination of pemetrexed and cisplatin, and also shows a better benefit trend than the three-drug combination of sintilimab and chemotherapy. |[Zhou Xi (Xi]] In addition, the key secondary efficacy endpoints objective response rate (ORR) and duration of response (DOR) of experimental group A compared with control group C were improved. The results of PFS, ORR, and DOR evaluated by the investigators It is consistent with the IRRC assessment conclusion.

TW202337897A_111144252_SEQL.xml

Claims (17)

A pharmaceutical combination comprising (1) an anti-PD-1 antibody, and (2) one or more chemotherapeutic agents, wherein the anti-PD-1 antibody includes a heavy chain and a light chain, wherein the heavy chain includes HCDR1, HCDR2, HCDR3 , the HCDR1 includes or consists of the amino acid shown in SEQ ID NO: 1; HCDR2 includes or consists of the amino acid shown in SEQ ID NO: 2; HCDR3 includes the amino group shown in SEQ ID NO: 3 Acid or consisting of; the light chain includes LCDR1, LCDR2, LCDR3, the LCDR1 includes or consists of the amino acid shown in SEQ ID NO: 4; LCDR2 includes the amino acid shown in SEQ ID NO: 5 or consists of Its composition; LCDR3 contains or consists of the amino acid shown in SEQ ID NO: 6. The drug combination according to claim 1, wherein the anti-PD-1 antibody comprises VH and VL, wherein the VH comprises the amino acid sequence shown in SEQ ID NO: 7, or has at least 90 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence or consisting of SEQ ID NO: 7, the VL contains SEQ ID NO : The amino acid sequence shown in 8, or having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with SEQ ID NO: 8 A specific amino acid sequence, or consisting of SEQ ID NO: 8. The drug combination as described in claim 1 or 2, wherein the anti-PD-1 antibody includes a heavy chain and a light chain, wherein the heavy chain includes the amino acid sequence shown in SEQ ID NO: 9, or includes the same amino acid sequence as SEQ ID NO. :9 An amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity, or consisting of SEQ ID NO: 9, The light chain contains the amino acid sequence shown in SEQ ID NO: 10, or contains at least 90%, 91%, 92%, 93%, 9%, 95%, 96%, 97% of the amino acid sequence shown in SEQ ID NO: 10 , an amino acid sequence with 98% or 99% identity or consisting of SEQ ID NO: 10. The pharmaceutical combination according to any one of claims 1 to 3, further comprising anti-VEGF- A Antibodies. The drug combination according to any one of claims 1 to 4, wherein the anti-VEGF-A antibody is bevacizumab. The drug combination according to any one of claims 1 to 5, wherein the chemotherapeutic agent is pemetrexed and a platinum drug, and preferably, the platinum is cisplatin. The drug combination according to any one of claims 1 to 6, wherein the anti-VEGF-A antibody dose is selected from 1-20 mg/kg, preferably 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg /kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 12mg/kg, 14mg/kg, 15mg/kg, 16mg/kg, 18mg/kg, 20mg/kg, preferably 15mg /kg; or the anti-VEGF-A antibody dose is selected from 60-1200mg, preferably 60mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg, 480mg, 540mg, 600mg, 720mg, 840mg, 900mg, 960mg, 1080mg, 1200mg, Better 900mg: The anti-PD-1 antibody dose is selected from 50-500mg, preferably 50mg, 60mg, 70mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, preferably 200mg. The pharmaceutical combination as described in any one of claims 1 to 7, wherein the pharmaceutical combination is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six weeks, more preferably Preferably, the drug combination is administered once every three weeks, for example by intravenous injection of the antibody. The pharmaceutical combination according to any one of claims 1 to 8, wherein the anti-VEGF-A antibody, the anti-PD-1 antibody and one or more chemotherapeutic agents are administered simultaneously, separately or sequentially, and the ratio is greater than It is best to administer the medicines in sequence. The pharmaceutical combination according to any one of claims 1 to 9, wherein the sequential administration is to administer an anti-PD-1 antibody first, then an anti-VEGF-A antibody, and then a chemotherapeutic agent; preferably, the anti-PD-1 antibody is administered first, and then the anti-VEGF-A antibody is administered. Apply anti-VEGF-A antibody 0.5-24 hours after PD-1 antibody. It is better to use anti-VEGF-A antibody. The body time is 30 to 60 minutes; the chemotherapeutic agent is administered 0.5 to 24 hours after the anti-VEGF-A antibody is administered. A complete kit, which includes the drug combination as described in any one of claims 1 to 10, which includes an effective amount of anti-PD-1 antibody, an effective amount of chemotherapeutic agent (preferably pemetrexed, cisplatin ), preferably also includes an effective amount of an anti-VEGF-A antibody; preferably, also includes a package insert printed with information about the use of a combination of an anti-PD-1 antibody and an anti-VEGF-A antibody for prevention or treatment in an individual Cancer fact sheet. A complete kit as described in claim 11, including 50 mg, 60 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300, 350, 400 mg, 450 mg or 500 mg of anti-PD-1 antibody and 60 mg, 120 mg, 180 mg, 240 mg , 300mg, 360mg, 420mg, 480mg, 540mg, 600mg, 720mg, 840mg, 900mg, 960mg, 1080mg or 1200mg anti-VEGF-A antibody. The use of a pharmaceutical combination as described in any one of claims 1 to 10 or a complete kit as described in claim 11 or 12 in the preparation of drugs for preventing or treating tumors; preferably, the tumor is lung cancer, Preferably, the lung cancer is non-small cell lung cancer, and more preferably, the non-small cell lung cancer is locally advanced or metastatic non-squamous cell carcinoma with EGFR mutation that has failed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. Non-small cell lung cancer. A method of treating tumors in a subject, comprising administering to the subject a pharmaceutical combination as described in any one of claims 1 to 10 or a kit as described in claim 11 or 12, wherein the following steps are performed Administration: (i) In the first phase, subjects are given anti-PD-1 antibody, anti-VEGF-A antibody, pemetrexed and platinum drugs (preferably cisplatin) in sequence; or subjects are given anti-PD- 1 Antibodies, pemetrexed and platinum drugs (preferably cisplatin), (ii) In the second stage, the subject is administered anti-PD-1 antibody, anti-VEGF-A antibody and pemetrexed in sequence; or the subject is administered anti-PD-1 antibody and pemetrexed in sequence, Preferably, (i) The first phase is the combination treatment phase, in which subjects are given anti-PD-1 antibodies, anti-VEGF-A antibodies, pemetrexed and platinum drugs (preferably cisplatin) in sequence, and (ii) The second phase is maintained as the maintenance treatment period, in which subjects are given anti-PD-1 antibody, anti-VEGF-A antibody and pemetrexed in sequence. The treatment method as described in claim 14, wherein the single dose of the anti-VEGF-A antibody is 15 mg/kg, the single dose of the anti-PD-1 antibody is 200 mg, and the single dose of pemetrexed is 15 mg/kg. The drug dose is 500 mg/m ² and the single dose of cisplatin is 75 mg/m ² . The treatment method as described in claim 14 or 15, wherein the combined treatment period includes 4 cycles, wherein every three weeks is a treatment cycle, and is administered sequentially on the first day of each cycle, wherein a maximum of 4 cycles of cisplatin are administered. Platinum and other drugs were administered continuously during the treatment period, which was continued for a maximum of 24 months in all subjects. The treatment method as described in any one of claims 14 to 16, wherein the tumor is lung cancer. Preferably, the lung cancer is non-small cell lung cancer. More preferably, the non-small cell lung cancer is transepidermal growth factor receptor casein. Locally advanced or metastatic non-squamous non-small cell lung cancer with EGFR mutations that have failed treatment with amino acid kinase inhibitors (EGFR-TKIs).