CN118103067A

CN118103067A - Pharmaceutical combinations of anti-PD-1 antibodies and chemotherapeutic agents and methods of use thereof

Info

Publication number: CN118103067A
Application number: CN202280061918.XA
Authority: CN
Inventors: 王岩; 马卓; 陈玉玲; 李昊宇
Original assignee: Innovent Biologics Suzhou Co Ltd
Current assignee: Innovent Biologics Suzhou Co Ltd
Priority date: 2021-09-14
Filing date: 2022-09-13
Publication date: 2024-05-28
Also published as: WO2023040804A1

Abstract

Pharmaceutical combinations comprising an anti-PD-1 antibody and a chemotherapeutic agent, and use and methods for preventing or treating tumors, especially esophageal cancer.

Description

Pharmaceutical combinations of anti-PD-1 antibodies and chemotherapeutic agents and methods of use thereof

Technical Field

The application belongs to the field of antitumor drugs, and in particular relates to a pharmaceutical composition comprising an anti-PD-1 antibody and a chemotherapeutic drug, and application and a method for preventing or treating tumors, especially esophageal cancer.

Background

With the prolongation of the average life span and the change of life behavior patterns of human beings, malignant tumors have become important diseases seriously threatening the health of human beings, and are also diseases most threatening to life. Worldwide, the incidence of esophageal cancer is 8 th and mortality is 6 th of malignant tumors, mainly in developing countries. The incidence and histological type of esophageal cancer vary greatly depending on the geographic region. The number of new-born esophageal cancers in the united states in 2017 is estimated to be 16,940, and the number of deaths is about 15,690. In the united states, the major histological type of esophageal cancer is adenocarcinoma. The 5 year survival rate of esophageal cancer is 18.4% in the united states and 12% in europe. And China is the country with the largest esophageal cancer worldwide, and the morbidity and mortality of esophageal cancer are higher than the average worldwide level. It is estimated that the number of new cancer cases in China reaches 429 ten thousand in 2015, and the incidence rate and death rate of esophageal cancer respectively occupy the 4 th and 4 th positions in all cancer death causes of 281 ten thousand and [Chen W,Zheng R,Baade PD,Zhang S,Zeng H,Bray F,et al.Cancer statistics in China,2015.CA Cancer J Clin 2016,66:115-132]. new cancer death cases are 47.8 ten thousand and 37.5 ten thousand respectively. Despite advances in the field of esophageal cancer treatment for several years, there is still a great unmet medical need.

Esophageal cancer refers to malignant tumor of esophageal epithelium origin from the hypopharynx to the esophageal-gastric junction. Esophageal cancer has two major pathological types, adenocarcinoma and squamous cell carcinoma, respectively. Squamous cell carcinoma accounts for about 90% of the total esophageal cancers in our country, and less than 30% in the united states, europe, australia and other countries.

The pattern of esophageal squamous carcinoma treatment is similar in asia and western countries. The main treatment method of early and middle stage esophageal cancer is operation, and more advanced stage esophageal cancer (accompanied by lymph node metastasis or T3-4 stage) can correspondingly receive operation after new auxiliary radiotherapy and chemotherapy or radical radiotherapy and chemotherapy. In a report of clinical data of 1510 cases of esophageal cancer patients treated by surgery in a tumor hospital in Shanxi province, the cumulative survival rates of 78%, 38% and 30% in 1, 5 and 10 years after surgery, and the median survival time of 2.68 years [ Li Guodong.1510 cases of esophageal cancer patients after surgery and prognosis influencing factor analysis, shuin academic paper, 2016]. Patients who have undergone surgery and radiotherapy after neoadjuvant treatment, and who have developed distant metastasis, typically undergo palliative chemotherapy. First-line chemotherapy regimens including cisplatin in combination with paclitaxel or 5-fluorouracil, both of which show similar efficacy in retrospective analysis in connection with esophageal squamous carcinoma treatment, median survival time is about 1 year [Liu Y,Ren Z,Yuan L,Xu S,Yao Z,Qiao L,Li K.Paclitaxel plus cisplatin vs.5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.Am J Cancer Res.2016;6:2345-2350].

Random control studies of advanced esophageal cancer are less, usually with gastric cancer, and first-line treatment is based on platinum-containing dual or triple chemotherapy. One in a randomized controlled phase 3 clinical study (REAL-2) comparing the efficacy of capecitabine and 5-fluorouracil and oxaliplatin and cisplatin in advanced first-line gastric and esophageal cancer patients 1002 patients were randomized to the treatment groups ECF (epirubicin + cisplatin + fluorouracil), ECX (epirubicin + cisplatin + capecitabine), EOF (epirubicin + oxaliplatin + fluorouracil) or EOX (epirubicin + oxaliplatin + capecitabine) at a ratio of 1:1:1, with the ratio of esophageal cancer in each treatment group being 30% -40% and the ratio of squamous cell carcinoma being about 10%. The median survival times for ECF, ECX, EOF, EOX treated groups were 9.9, 9.3 and 11.2 months, respectively, with 1 year survival rates of 37.7%, 40.8%, 40.4% and 46.8％[Liu Y,Ren Z,Yuan L,Xu S,Yao Z,Qiao L,Li K.Paclitaxel plus cisplatin vs.5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.Am J Cancer Res.2016;6:2345-2350]., respectively, in a randomized controlled phase 3 study (REAL-3) that compares EOX protocol with EOX+panitumumab, which failed to prolong survival. 275 subjects were assigned to the EOX treatment group, with 40% of esophageal cancers and 99% of adenocarcinomas. The total survival time of the EOX treated group was 11.3 months. In a phase II clinical study for studying the efficacy of docetaxel in combination with cisplatin in first-line esophageal squamous cell carcinoma, 39 subjects were enrolled, the objective remission rate was 33.33%, the disease-free progression period was 5 months, the overall survival was 8.5 months [Waddell T,Chau I,Cunningham D,Gonzalez D,Okines AFC,Wotherspoon A,et al.Epirubicin,oxaliplatin,and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer(REAL3):a randomised,open-label phase 3trial.The Lancet Oncology 2013,14:481-489.]. in a single arm phase II clinical study for assessing the efficacy of paclitaxel in combination with cisplatin, 5-fluorouracil in advanced esophageal cancer, 61 subjects were enrolled, wherein squamous cell carcinoma was 30, ORR was 48% (adenocarcinoma 48%, squamous cell carcinoma 50%), OS was 10.8 months [Ilson DH,Ajani J,Bhalla K,Forastiere A,Huang Y,Patel P,et al.Phase II trial of paclitaxel,fluorouracil,and cisplatin in patients with advanced carcinoma of the esophagus.J Clin Oncol 1998,16:1826-1834]. in a random control study for comparing cisplatin in combination with 5-fluorouracil in combination with cisplatin in combination with 5-fluorouracil, cetuximab in first-line esophageal squamous cell carcinoma, 30 subjects received cisplatin in combination with 5-fluorouracil, the objective remission rate was 13%, the disease control rate was 57%, OS was 5.5 months [Lorenzen S,Schuster T,Porschen R,Al-Batran SE,Hofheinz R,Thuss-Patience P,et al.Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus:a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie.Ann Oncol 2009,20:1667-1673.]. in a single arm study for assessing paclitaxel in first-line esophageal squamous cell carcinoma in China, the objective remission rate was 39 subjects were enrolled, and the OS was 13.5 months PF48 [Zhang X,Shen L,Li J,Li Y,Li J,Jin M.A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol 2008,31:29-33.].

Although molecular targeted drugs significantly improve prognosis for many types of solid tumors, no drug has shown clear efficacy in esophageal squamous carcinoma to date. Recent decades of cancer immunotherapy have seen rapid development, and several clinical studies have shown the efficacy of immune checkpoint inhibitors and adoptive immunotherapy in solid and hematological tumors, with preliminary efficacy data in esophageal squamous cell carcinoma.

One Pembrolizumab in a phase Ib clinical study (KEYNOTE-028) in which at least one first line system failed to treat or was intolerant of advanced esophageal cancer (PD-L1 expression greater than 1%), one Nivolumab with an ORR of 30％(95％CI,13-53)[Toshihiko Doi SAP-P,Shadia Ibrahim Jalal,Hieu Mai-Dang,Sanatan Saraf,Minori Koshiji,Ildiko Csiki,Jaafar Bennouna.Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab(MK-3475).J Clin Oncol 34,2016(suppl 4S;abstr 7)]. in a phase II clinical study in which at least one first line system failed to treat or was intolerant of advanced esophageal cancer, ORR of 17.2%, mOS of 12.1 months [Takashi Kojima HH,Kensei Yamaguchi,Shuichi Hironaka,Satoru Iwasa,Ken Kato,Takahiro Tsushima,Hirofumi Yasui,Takashi Ura,Kei Muro,Taroh Satoh,Yuichiro Doki,Atsushi Ohtsu,Yasuo Hamamoto,Yuko Kitagawa.Phase II study of nivolumab(ONO-4538/BMS-936558)in patients with esophageal cancer:Preliminary report of overall survival.J Clin Oncol 34,2016(suppl 4S;abstr TPS175)].

Disclosure of Invention

The application provides pharmaceutical combinations comprising an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof) in combination with a chemotherapeutic agent, and uses and methods for preventing or treating unresectable locally advanced, recurrent or metastatic esophageal squamous carcinoma, which methods may have superior therapeutic efficacy. In some embodiments, the pharmaceutical combination of the application comprises: (i) an anti-PD-1 antibody; (ii) platinum-based agents; and (iii) at least one selected from taxane antitumor drugs and fluoropyrimidine antitumor drugs.

As an optimal scheme, the application provides two combined treatment schemes of the anti-PD-1 antibody combined with cisplatin+taxol or cisplatin+5-fluorouracil at the same time so as to adapt to clinical treatment options of different areas and people, and the two combined treatment schemes have better treatment effects.

Specifically, the present application provides the following embodiments:

(1) Pharmaceutical combination

In one aspect, the application provides a pharmaceutical combination comprising an anti-PD-1 antibody and a chemotherapeutic agent,

An anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises HCDR1, HCDR2, HCDR3, the HCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID No. 1; HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO. 2; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO. 3; the light chain comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO. 4; LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO. 5; LCDR3 contains or consists of the amino acid sequence shown in SEQ ID NO. 6;

-KASGGTFSSYAIS(SEQ ID NO:1)；

-LIIPMFDTAGYAQKFQG(SEQ ID NO:2)；

-ARAEHSSTGTFDY(SEQ ID NO:3)；

-RASQGISSWLA(SEQ ID NO:4)；

-SAASSLQS(SEQ ID NO:5)；

-QQANHLPFT(SEQ ID NO:6)。

In one embodiment, a pharmaceutical combination is provided comprising an anti-PD-1 antibody and a chemotherapeutic agent, the anti-PD-1 antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID No. 7, a VL comprising the amino acid sequence set forth in SEQ ID No. 8; in some preferred embodiments, the anti-PD-1 antibody comprises a VH having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) homology to the amino acid sequence set forth in SEQ ID No. 7; and a VL having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) homology with the amino acid sequence shown in SEQ ID No. 8.

In one embodiment, a pharmaceutical combination is provided comprising an anti-PD-1 antibody and a chemotherapeutic agent, the anti-PD-1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID No. 9 and the light chain comprises the amino acid sequence set forth in SEQ ID No. 10; in some preferred embodiments, the anti-PD-1 antibody comprises a heavy chain having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) homology to the amino acid sequence set forth in SEQ ID No. 9, and a light chain having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) homology to the amino acid sequence set forth in SEQ ID No. 10.

In this context, the various variants of the anti-PD-1 antibodies described above retain the ability to specifically bind to the antigen PD-1.

In one embodiment, the anti-PD-1 antibody is a singeing Li Shan antibody.

In one embodiment, a pharmaceutical combination is provided comprising an anti-PD-1 antibody and a chemotherapeutic agent comprising a plurality of chemotherapeutic regimens, e.g., the chemotherapeutic agent may be: platinum-based drugs (e.g., cisplatin, carboplatin, nedaplatin, lobaplatin, oxaliplatin, cyclothioplatin); and at least one kind selected from taxane antitumor drugs (such as paclitaxel (including albumin paclitaxel, paclitaxel liposome), docetaxel, cabazitaxel) and fluoropyrimidine antitumor drugs (such as 5-fluorouracil, capecitabine, tegafur, carmofur, gemcitabine, deoxyfluorouridine, bififluracine). In some embodiments, the platinum-based drug is cisplatin, nedaplatin, oxaliplatin, or epithioplatin. In some embodiments, the taxane antineoplastic agent is paclitaxel or docetaxel. In some embodiments, the fluoropyrimidine antineoplastic agent is 5-fluorouracil, capecitabine, tegafur, deoxyfluorouridine, tegafur, or carmofur. In some embodiments, the chemotherapeutic agent comprises cisplatin, and at least one selected from paclitaxel and 5-fluorouracil. Preferably, the chemotherapeutic agent is a combination chemotherapy regimen of paclitaxel and cisplatin or a combination chemotherapy regimen of 5-fluorouracil and cisplatin.

In some embodiments, the pharmaceutical combination comprises: an anti-PD-1 antibody; platinum drugs; and at least one selected from taxane antitumor drugs and fluoropyrimidine antitumor drugs. Preferably, the pharmaceutical combination comprises: a signal di Li Shan antibody or antigen binding fragment thereof; platinum drugs; and at least one selected from taxane antitumor drugs and fluoropyrimidine antitumor drugs. Or preferably, the pharmaceutical combination comprises: an anti-PD-1 antibody; cisplatin, nedaplatin, oxaliplatin, or cyclothioplatin; and at least one selected from paclitaxel or docetaxel, 5-fluorouracil, capecitabine, tegafur, deoxyfluorouridine, tegafur, or carmofur. More preferably, the pharmaceutical combination comprises: a signal di Li Shan antibody or antigen binding fragment thereof; cisplatin, nedaplatin, oxaliplatin, or cyclothioplatin; and at least one selected from paclitaxel or docetaxel, 5-fluorouracil, capecitabine, tegafur, deoxyfluorouridine, tegafur, or carmofur.

In some embodiments, the pharmaceutical combination comprises an anti-PD-1 antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID No. 9 and a light chain comprising the amino acid sequence set forth in SEQ ID No. 10 and a chemotherapeutic agent comprising cisplatin, and at least one selected from paclitaxel and 5-fluorouracil. In some embodiments, the pharmaceutical combination comprises a signal di Li Shan antibody or antigen binding fragment thereof, cisplatin, and at least one selected from paclitaxel and 5-fluorouracil. In one embodiment, the pharmaceutical combination comprises a signal di Li Shan antibody or antigen binding fragment thereof, cisplatin, and paclitaxel. In another embodiment, the pharmaceutical composition comprises a signal-di Li Shan antibody or antigen-binding fragment thereof, cisplatin, and 5-fluorouracil.

In one embodiment, a pharmaceutical combination is provided comprising an anti-PD-1 antibody and a chemotherapeutic agent, for separate, simultaneous or sequential use. Herein, the anti-PD-1 antibody and the chemotherapeutic agent may each be packaged separately and may have conventional dosage forms in the art, such as injections, oral dosage forms (e.g., tablets, capsules, troches, powders, suspensions, etc.).

In another embodiment, a pharmaceutical combination is provided for use in the prevention or treatment of a neoplastic disease in an individual, the neoplasm being esophageal cancer, preferably esophageal squamous carcinoma, more preferably, the esophageal squamous carcinoma is unresectable, locally advanced recurrent or metastatic squamous carcinoma. In some embodiments, the composition of the pharmaceutical combination for preventing or treating a tumor is as defined above.

In some embodiments, the subject is a mammal. In a preferred embodiment, the individual is a human.

In this context, the features of the above embodiments may be combined arbitrarily, and the various technical solutions obtained thereby fall within the scope of the present application.

(2) Complete medicine box

In one embodiment, a kit is provided comprising an effective amount of an anti-PD-1 antibody, and an effective amount of a chemotherapeutic agent; preferably, a package insert is also included that is printed with instructions for using the combination of the anti-PD-1 antibody and the chemotherapeutic agent to prevent or treat cancer in an individual. Herein, the PD-1 antibody is as defined above. In some embodiments, the chemotherapeutic agent may be: platinum-based drugs (e.g., cisplatin, carboplatin, nedaplatin, lobaplatin, oxaliplatin, cyclothioplatin); and at least one kind selected from taxane antitumor drugs (such as paclitaxel (including albumin paclitaxel, paclitaxel liposome), docetaxel, cabazitaxel) and fluoropyrimidine antitumor drugs (such as 5-fluorouracil, capecitabine, tegafur, carmofur, gemcitabine, deoxyfluorouridine, bififluracine). In some embodiments, the chemotherapeutic agent may be cisplatin, and at least one combination of chemotherapy selected from paclitaxel and 5-fluorouracil, preferably paclitaxel and cisplatin combination chemotherapy or 5-fluorouracil and cisplatin combination chemotherapy.

In some embodiments, the kit comprises the above-described anti-PD-1 antibody and chemotherapeutic agent, each packaged separately. In some embodiments, the anti-PD-1 antibody and the chemotherapeutic agent are each in the form of a medicament. For example, the anti-PD-1 antibody and the chemotherapeutic agent may each be in the form of an injection or a lyophilized powder for use in formulating an injection.

(3) Application of

In one embodiment, there is provided a use of a pharmaceutical combination comprising an anti-PD-1 antibody and a chemotherapeutic agent, or a kit of parts thereof, in the manufacture of a medicament for the prevention or treatment of a neoplastic disease; preferably, the tumor is esophageal cancer, more preferably the esophageal cancer is esophageal squamous carcinoma, more preferably the esophageal squamous carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous carcinoma. Or in one embodiment, a pharmaceutical combination or kit for preventing or treating a tumor is provided, the pharmaceutical combination or kit comprising an anti-PD-1 antibody and a chemotherapeutic agent. Herein, the PD-1 antibody and chemotherapeutic agent are as defined above.

(4) Therapeutic method

In some embodiments, a method of treatment is provided comprising: administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination comprising an anti-PD-1 antibody and a chemotherapeutic agent. In some embodiments, a method of treatment is provided comprising: administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination comprising an anti-PD-1 antibody, a platinum-based drug, and at least one selected from the group consisting of a taxane-based anti-tumor drug and a fluoropyrimidine-based anti-tumor drug. In some preferred embodiments, there is provided a method of treatment comprising: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical combination comprising an anti-PD-1 antibody and a chemotherapeutic agent which is cisplatin, and at least one selected from the group consisting of paclitaxel and 5-fluorouracil; preferably, the chemotherapeutic agent is a combination of paclitaxel and cisplatin, or a combination of 5-fluorouracil and cisplatin.

In some embodiments, the anti-PD-1 antibody is administered at a single daily dose of 10mg-300mg (e.g., 20mg-250mg, 30mg-200 mg), or 1-5mg/kg (e.g., 2-4mg/kg, 3 mg/kg) or 200mg; or in some embodiments, the anti-PD-1 antibody is administered at a dose of 10mg to 300mg (e.g., 20mg to 250mg, 30mg to 200 mg), or 1 to 5mg/kg (e.g., 2 to 4mg/kg, 3 mg/kg), or 200mg during a single treatment cycle (e.g., 21 days). In some embodiments, the anti-PD-1 antibody is administered 1-2 times, preferably 1 time, in a single treatment cycle.

In some embodiments, the paclitaxel is administered at a single daily dose of 25mg to 700mg (e.g., 42.5mg to 615 mg), or 50 to 200mg/m ² (e.g., 85 to 175mg/m ²); or in some embodiments, the paclitaxel is administered in a dose of 50mg to 700mg (e.g., 85mg to 615 mg), or 100 to 200mg/m ² (e.g., 175mg/m ²) during a single treatment cycle (e.g., 21 days). In some embodiments, the paclitaxel is administered 1-4 times, preferably 1-2 times, during the 1 st treatment cycle (e.g., 21 days), and 1-2 times, preferably 1 time, during a single treatment cycle (e.g., 21 days) following the 1 st treatment cycle.

In some embodiments, the 5-fluorouracil is administered at a single daily dose of 250mg to 4200mg, preferably 300mg to 3500mg (e.g., 350mg to 3150mg, 400mg to 2800 mg), or 500 to 1200mg/m ², preferably 600 to 1000mg/m ² (e.g., 640 to 1000mg/m ²、700-900mg/m ²、800mg/m ²); or in some embodiments, the 5-fluorouracil is administered at a dose of 2500-6000mg/m ², preferably 3000-5000mg/m ² (e.g., 3200-4000mg/m ²、3500-4500mg/m ²、4000mg/m ²) during a single treatment cycle (e.g., 21 days). In some embodiments, the 5-fluorouracil is administered 1-10 times, preferably 4-6 times (e.g., 5 times) during a single treatment cycle.

In some embodiments, the cisplatin is administered at a single daily dose of 25mg to 350mg (e.g., 30mg to 315mg, 37.5mg to 262.5 mg), or 50 to 100mg/m ² (e.g., 60 to 90mg/m ², preferably 75mg/m ²); or in some embodiments, the cisplatin is administered in a dose of 25mg to 350mg (e.g., 30mg to 315mg, 37.5mg to 262.5 mg), or 50 to 100mg/m ² (e.g., 60 to 90mg/m ², preferably 75mg/m ²) during a single treatment cycle (e.g., 21 days). In some embodiments, the cisplatin is administered 1-2 times, preferably 1 time, in a single treatment cycle.

In some embodiments, the anti-PD-1 antibody is administered once on the first day of each treatment cycle (e.g., 21 days); the paclitaxel is administered once on the first day and eighth day of the first treatment cycle (e.g., 21 days) and once on the first day of each treatment cycle (e.g., 21 days) of the second and subsequent treatment cycles; the 5-fluorouracil is administered once daily for 24 hours on the first to fifth days of each treatment cycle (e.g., 21 days); the cisplatin is administered once on the first day of each treatment cycle (e.g., 21 days).

In some embodiments, the anti-PD-1 antibody is administered once on the first day of each treatment cycle (e.g., 21 days) at a dose of 20mg-250mg (e.g., 30mg-200 mg) or 3mg/kg (preferably, for individuals weighing <60kg, at a dose of 3mg/kg; and for individuals weighing > 60kg, at a dose of 200 mg);

The paclitaxel is administered once on the first day and eighth day of the first treatment cycle (e.g., 21 days) at a dose of 43.5mg-306.5mg or 87.5mg/m ² each time, and once on the first day of each treatment cycle (e.g., 21 days) of the second and subsequent treatment cycles at a dose of 87.5mg-615mg or 175mg/m ² each time;

The 5-fluorouracil is continuously administered once daily for 24 hours on the first to fifth days of each treatment cycle (for example, 21 days) at a dose of 400mg-2800mg or 800 mg/(m ². D);

The cisplatin is administered once on the first day of each treatment cycle (e.g., 21 days) at a dose of 37.5mg-262.5mg or 75mg/m ².

In one embodiment, a method of treatment is provided wherein a therapeutically effective amount of an anti-PD-1 antibody is administered in combination with a chemotherapeutic agent which is paclitaxel and cisplatin in combination with chemotherapy or 5-fluorouracil and cisplatin in combination with chemotherapy; 100-300mg or 1-5mg/kg, preferably 200mg or 3mg/kg, of the anti-PD-1 antibody, 120-200mg/m ², preferably 175mg/m ², 3000-5000mg/m ², preferably 4000mg/m ², and 60-90mg/m ², preferably 75mg/m ² of cisplatin. Herein, the "single administration" amount refers to the cumulative amount administered over a single treatment cycle.

Here, the PD-1 antibody is as defined above, and the platinum-based drug, taxane-based antitumor drug and fluoropyrimidine-based antitumor drug are as defined above as well.

In another embodiment, a method of treatment is provided wherein the anti-PD-1 antibody is administered 200mg or 3mg/kg in a single administration, the paclitaxel is administered 175mg/m ² in a single administration, the 5-fluorouracil is administered 4000mg/m ² in a single administration, and the cisplatin is administered 75mg/m ² in a single administration.

In another embodiment, a method of treatment is provided wherein the anti-PD-1 antibody is administered once every three weeks, once every cycle, on the first day of each week; the paclitaxel is administered twice in a first period, on a first day and an eighth day of each period, once in a second period and a later period, and on the first day of each period; the 5-fluorouracil is continuously administered for 24 hours per day every three weeks for the first to five days of each cycle; cisplatin is administered once every three weeks, once every cycle, and once every first day.

In another embodiment, a method of treatment is provided wherein the anti-PD-1 antibody is administered at 200mg or 3mg/kg per cycle; the paclitaxel is administered twice in a first period of 87.5mg/m ² for each administration, once in a second period and a later period, and 175mg/m ² for each administration; the 5-fluorouracil is administered at 4000mg/m ² per cycle and the cisplatin is administered at 75mg/m ² per cycle.

In another embodiment, a method of treatment is provided wherein the tumor is esophageal cancer, preferably esophageal squamous carcinoma, more preferably, the esophageal squamous carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous carcinoma.

In this context, the anti-PD-1 antibody and chemotherapeutic agent may be administered by conventional routes of administration, e.g., may be administered by oral, parenteral, etc.

Any combination of the embodiments or features of the embodiments in the above aspects is possible in this context, and the resulting solutions are also within the scope of the application.

Definition of the definition

As used herein, the term "and/or" refers to any one of the selectable items or two or more of the selectable items, i.e., it represents at least one of the selectable items.

As used herein, the terms "comprises" or "comprising," or equivalents thereof, are intended to include the recited element, integer or step, but not exclude any other element, integer or step. In this document, the terms "comprises" or "comprising" when used herein, unless otherwise indicated, also encompass the circumstance of consisting of the recited elements, integers or steps. For example, when referring to an antibody variable region "comprising" a particular sequence, it is also intended to encompass the case of an antibody variable region consisting of that particular sequence.

"Individual" includes mammals. Mammals include, but are not limited to, domesticated 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 "individual" may also be referred to herein as a "subject" or "patient".

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

As used herein, "preventing" includes inhibition of the occurrence or progression of a disease or disorder or a symptom of a particular disease or disorder. In some embodiments, individuals with a family history are candidates for prophylactic regimens. In general, the term "prevention" refers to administration of a drug prior to the occurrence of a sign or symptom, particularly in an individual at risk.

The term "effective amount" refers to the amount or dose of a formulation or composition of the application that, upon administration to a patient in a single or multiple doses, produces a desired effect in the treated patient. The effective amount can be readily determined by the attending physician as a person skilled in the art by considering a number of factors: species such as mammals; its size, age and general health; specific diseases involved; the extent or severity of the disease; response of individual patients; specific antibodies administered; mode of administration; the bioavailability characteristics of the administration formulation; a selected dosing regimen; and the use of any concomitant therapy.

"Therapeutically effective amount" means an amount effective to achieve the desired therapeutic result at the desired dosage and for the desired period of time. The therapeutically effective amount of the formulations, antibodies or antibody fragments or conjugates or compositions thereof of the present application can vary depending on a variety of factors such as the disease state, age, sex and weight of the individual and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or detrimental effect of the formulation, antibody or antibody fragment or conjugate or composition thereof is less than a therapeutically beneficial effect.

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

As used herein, unless otherwise indicated, the term "anti-PD-1 antibody" encompasses monoclonal antibodies, polyclonal antibodies, or antigen-binding fragments thereof (which fragment retains the ability of the corresponding intact antibody to specifically bind to an antigen), with anti-PD-1 monoclonal antibodies or antigen-binding fragments thereof being preferred.

As used herein, the singular term encompasses the plural term and vice versa, unless otherwise specified.

Abbreviations

Detailed Description

The present application will be described in more detail by way of examples, but it will be understood by those skilled in the art that the scope of the present application is not limited thereto.

① Test agent

Anti-PD-1 antibodies: xindi Li Shan anti-injection, xinda biopharmaceutical (Suzhou) limited, 10ml:100mg.

Placebo: mannitol, histidine, sodium citrate (dihydrate), sodium chloride, disodium edentate, polysorbate 80, citric acid (monohydrate), and water for injection.

Cisplatin: multiple dose bottling of 10mg or 20mg, manufacturer: qilu pharmaceutical Co., ltd/Intas Pharmaceuticals INDIA LIMITED/INTAS PHARMA INDIA BG is not limited.

Paclitaxel: 30mg 5mL, 150mg 25mL, manufacturer: the pharmaceutical factory Limited at the sea opening market/the Jiangsu OGmbH/EBEWE Pharma, inc. of the pharmaceutical industry of Orthoseum.

5-Fluorouracil: injection: 125mg (5 mL), 250mg (10 mL) per each, manufacturer: tianjin JinYao pharmaceutical Co., ltd/Accord Healthcare, inc./INTAS PHARMA INDIA BG is not limited.

② Subject enrollment criteria

Random, double blind, multicenter, stage III study to assess the effectiveness and safety of non-resectable, locally advanced recurrent or metastatic esophageal squamous carcinoma with treatment with first-line chemotherapy with anti-Xindi Li Shan or placebo

1) The age is more than or equal to 18 years old.

2) ECOG PS score was 0 or 1 score.

3) The subject must not be suitable for undergoing curative treatments such as curative radiotherapy and/or surgery; for the patients who receive (new) auxiliary chemotherapy/auxiliary (radiotherapy) chemotherapy/radical radiotherapy and chemotherapy in the past, the time from the last treatment to the disease recurrence is more than 6 months.

4) Can provide archiving pathological tissues or fresh pathological tissues for PD-L1 detection and can obtain detection results.

5) There is at least one measurable lesion according to RECIST version 1.1 standard.

6) Has sufficient organ and bone marrow functions.

③ Treatment regimen

Study drugs in this study were defined as the Xindi Li Shan antibody, placebo, paclitaxel, 5-fluorouracil and cisplatin. The first administration of study medication should begin on the day of randomization (cycle 1, day 1), but not 48 hours later than the day of randomization, beyond 48 hours, and the need for medication and sponsor discussion remain unaddressed. All efforts should be made to begin trial treatments on the day of random grouping. For all other study treatment cycles, such as holidays or subject failure to go to the center for other reasons of non-safety, administration may be continued for no more than one week. The specific dosages and treatment regimens are shown in table 1.

TABLE 1 dosage and treatment regimen

Remarks:

1. The Xindi Li Shan antibody/placebo should be infused prior to administration of the chemotherapeutic agent, and the Xindi Li Shan antibody/placebo is used in an amount calculated for each actual body weight when the body weight is less than 60 kg. The end of the anti/placebo infusion was at least 1 hour apart from the beginning of the infusion of the chemotherapeutic drug.

2. The first cycle using method of the paclitaxel comprises the following steps: 87.5mg/m ² IV D1, 8Q 3W, the second cycle starting with 1 st day of the cycle: 175mg/m ² IV D1Q 3W.

3. If the subject's body weight fluctuates less than 10% relative to the baseline (day of first study treatment), the baseline body weight is used to calculate body surface area from which the chemotherapeutic drug dose is calculated. Otherwise, the dosage of the chemotherapeutic medicine is calculated according to the actual weight of the day of planned administration. For ease of administration, the protocol allows for a calculated total dose per infusion of + -5% deviation.

The single cycle cumulative dose of 4.5-fluorouracil is 4000mg/m ², other clinically acceptable modes of administration may also be employed, such as 1000 mg/(m ². D) on days 1-4. A single cycle of cumulative dosing time may allow for a 20% adjustment range (i.e., 4-6 days of continuous dosing). The study was allowed to adjust the single cycle cumulative dose between 3200 and 4000mg/m ², as necessary, depending on the subject's tolerance.

④ Experimental results

Remarks:

Sin refers to the similin Li Shan antibody;

Chemo refers to a chemotherapeutic drug, specifically paclitaxel + cisplatin or cisplatin + 5-fluorouracil, and one of the chemotherapeutic drugs is clinically selected for administration.

All patents, patent applications, and other identified publications are expressly incorporated herein by reference for the purpose of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents. Moreover, any reference herein to such publications in any country is not an admission that such publications are part of the common general knowledge in the art.

Those skilled in the art will recognize that the scope of the present disclosure is not limited to the various embodiments and examples described above, but is capable of various modifications, substitutions, or rearrangements without departing from the spirit and concepts of the disclosure, which are intended to be within the scope of the disclosure.

Claims

A pharmaceutical combination comprising an anti-PD-1 antibody and a chemotherapeutic agent, the anti-PD-1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises HCDR1, HCDR2, HCDR3, the HCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID No. 1; HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO. 2; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO. 3; the light chain comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO. 4; LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO. 5; LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO. 6.
The pharmaceutical combination according to claim 1, wherein the anti-PD-1 antibody comprises a VH comprising the amino acid sequence shown in SEQ ID No. 7, a VL comprising the amino acid sequence shown in SEQ ID No. 8.
The pharmaceutical combination according to any one of claims 1-2, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID No. 9 or an amino acid sequence having at least 80% homology thereto and a light chain comprising the amino acid sequence shown in SEQ ID No. 10 or an amino acid sequence having at least 80% homology thereto.
The pharmaceutical combination according to any one of claims 1-3, wherein the chemotherapeutic agent comprises a platinum-based drug and at least one selected from the group consisting of a taxane-based anti-tumor drug and a fluoropyrimidine-based anti-tumor drug.
The pharmaceutical combination according to claim 4, wherein the platinum-based drug is cisplatin, carboplatin, nedaplatin, lobaplatin, oxaliplatin or cyclothioplatin; the taxane antitumor drug is paclitaxel, docetaxel or cabazitaxel; the fluoropyrimidine antitumor drug is 5-fluorouracil, capecitabine, tegafur, carmofur, gemcitabine, deoxyfluorouridine or bifluoride.
The pharmaceutical combination according to any one of claims 1-5, wherein the chemotherapeutic agent comprises cisplatin and at least one selected from paclitaxel and 5-fluorouracil, preferably a chemotherapeutic combination comprising paclitaxel and cisplatin or a chemotherapeutic combination of 5-fluorouracil and cisplatin.
The pharmaceutical combination according to any one of claims 1-6, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID No. 9 or an amino acid sequence having at least 80% homology thereto and a light chain comprising the amino acid sequence shown in SEQ ID No. 10 or an amino acid sequence having at least 80% homology thereto, and

The chemotherapeutic agent comprises cisplatin, and at least one selected from paclitaxel and 5-fluorouracil.
The pharmaceutical combination according to any one of claims 1-7, wherein the anti-PD-1 antibody and the chemotherapeutic agent are administered separately, simultaneously or sequentially.
The pharmaceutical combination according to any one of claims 1-8 for use in the prevention or treatment of a neoplastic disease in a subject, said tumour being an esophageal carcinoma, preferably said esophageal carcinoma is an esophageal squamous carcinoma, more preferably said esophageal squamous carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous carcinoma.
The pharmaceutical combination according to claim 9, wherein the individual is a mammal, preferably a human.
A kit comprising an effective amount of an anti-PD-1 antibody and an effective amount of a chemotherapeutic agent; preferably, further comprising a package insert printed with instructions for using the combination of the anti-PD-1 antibody and the chemotherapeutic agent to prevent or treat cancer in an individual; preferably, the chemotherapeutic drug comprises a platinum-based drug and at least one selected from taxane anti-tumor drugs and fluoropyrimidine anti-tumor drugs, and preferably, the platinum-based drug is cisplatin, carboplatin, nedaplatin, lobaplatin, oxaliplatin or cyclothioplatin; the taxane antitumor drug is paclitaxel, docetaxel or cabazitaxel; the fluoropyrimidine antitumor drug is 5-fluorouracil, capecitabine, tegafur, carmofur, gemcitabine, deoxyfluorouridine or bifluoride uracil; more preferably, the chemotherapeutic agent comprises cisplatin, and at least one selected from paclitaxel and 5-fluorouracil, or the chemotherapeutic agent is a combination of paclitaxel and cisplatin or a combination of 5-fluorouracil and cisplatin.
Use of a pharmaceutical combination according to any one of claims 1-10 or a kit of parts according to claim 11 for the manufacture of a medicament for the prevention or treatment of a neoplastic disease; preferably, the tumor is esophageal cancer, more preferably the esophageal cancer is esophageal squamous carcinoma, more preferably the esophageal squamous carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous carcinoma.
A pharmaceutical combination according to any one of claims 1 to 10 or a kit of parts according to claim 11 for use in the prevention or treatment of a tumour; preferably, the tumor is esophageal cancer, more preferably the esophageal cancer is esophageal squamous carcinoma, more preferably the esophageal squamous carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous carcinoma.
A method of preventing or treating a tumor comprising administering to the individual a therapeutically effective amount of an anti-PD-1 antibody and a therapeutically effective amount of a chemotherapeutic agent that is a combination of paclitaxel and cisplatin or a combination of 5-fluorouracil and cisplatin; 100-300mg or 1-5mg/kg of the anti-PD-1 antibody is administered in a single dose, 120-200mg/m ² of the taxol is administered in a single dose, 3000-5000mg/m ² of the 5-fluorouracil is administered in a single dose, and 60-90mg/m ² of the cisplatin is administered in a single dose.
The method of treatment according to claim 14, wherein the anti-PD-1 antibody is administered 200mg or 3mg/kg in a single dose, the paclitaxel is administered 175mg/m ² in a single dose, the 5-fluorouracil is administered 4000mg/m ² in a single dose, and the cisplatin is administered 75mg/m ² in a single dose.
The method of treatment according to claim 14 or 15, wherein the anti-PD-1 antibody is administered once every three weeks, once every cycle, on the first day of each cycle; the paclitaxel is administered twice in a first period, on a first day and an eighth day of each period, once in a second period and a later period, and on the first day of each period; the 5-fluorouracil is administered continuously 24 hours per day every three weeks, every cycle from the first to five days, and the cisplatin is administered once every three weeks, every cycle, and every first day.
The method of treatment according to any one of claims 14-16, wherein the anti-PD-1 antibody is administered at 200mg or 3mg/kg per cycle; the paclitaxel is administered twice in a first period of 87.5mg/m ² for each administration, once in a second period and a later period, and 175mg/m ² for each administration; the 5-fluorouracil is administered at 4000mg/m ² per cycle and the cisplatin is administered at 75mg/m ² per cycle.
The method of treatment according to any one of claims 14-17, wherein the tumor is esophageal cancer, preferably esophageal squamous carcinoma, more preferably the esophageal squamous carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous carcinoma.
A method of preventing or treating a tumor comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical combination comprising an anti-PD-1 antibody and a chemotherapeutic agent.
The method of claim 19, wherein the chemotherapeutic agent comprises a platinum-based drug and at least one selected from a taxane-based anti-tumor drug and a fluoropyrimidine-based anti-tumor drug; preferably, the platinum-based drug is cisplatin, carboplatin, nedaplatin, lobaplatin, oxaliplatin or cyclothioplatin; the taxane antitumor drug is paclitaxel, docetaxel or cabazitaxel; the fluoropyrimidine antitumor drug is 5-fluorouracil, capecitabine, tegafur, carmofur, gemcitabine, deoxyfluorouridine or bifluoride uracil; more preferably, the chemotherapeutic agent comprises cisplatin, and at least one selected from paclitaxel and 5-fluorouracil, or the chemotherapeutic agent is a combination of paclitaxel and cisplatin, or a combination of 5-fluorouracil and cisplatin.
The method of claim 19 or 20, wherein the anti-PD-1 antibody is administered at a single daily dose of 10mg-300mg, or 1-5mg/kg; alternatively, the anti-PD-1 antibody is administered at a dose of 10mg to 300mg, or 1 to 5mg/kg, in a single treatment cycle, preferably 1 to 2 times the anti-PD-1 antibody is administered in a single treatment cycle.
The method of claim 20 or 21, wherein the paclitaxel is administered at a single daily dose of 25mg-700mg, or 50-200mg/m ²; alternatively, the paclitaxel is administered at a dose of 50mg to 700mg, or 100 to 200mg/m ², preferably 1 to 4 times the paclitaxel is administered in the 1 st treatment cycle, and 1 to 2 times the paclitaxel is administered in the single treatment cycle following the 1 st treatment cycle.
The method of any one of claims 20-22, wherein the 5-fluorouracil is administered at a single daily dose of 250mg-4200mg, or 500-1200mg/m ²; or the 5-fluorouracil is administered at a dose of 2500-6000mg/m ² in a single treatment cycle, preferably 1-10 times in a single treatment cycle.
The method of any one of claims 20-23, wherein the cisplatin is administered at a single daily dose of 25mg-350mg, or 50-100mg/m ²; alternatively, the cisplatin may be administered in a dose of 25mg to 350mg, or 50 to 100mg/m ², in a single treatment cycle, preferably 1 to 2 times the cisplatin is administered in a single treatment cycle.
The method of any one of claims 20-24, wherein the anti-PD-1 antibody is administered once on the first day of each treatment cycle; the paclitaxel is administered once on the first day and the eighth day of the first treatment cycle, respectively, and once on the first day of each treatment cycle of the second and subsequent treatment cycles; the 5-fluorouracil is administered once daily for 24 hours on the first to fifth days of each treatment cycle; the cisplatin is administered once on the first day of each treatment cycle.
The method of any one of claims 20-25, wherein the anti-PD-1 antibody is administered once on the first day of each treatment cycle at a dose of 20mg-250mg or 3mg/kg;

The paclitaxel is administered once on the first day and the eighth day of the first treatment cycle, and the dose of each administration is 43.5mg-306.5mg or 87.5mg/m ², and once on the first day of each treatment cycle of the second treatment cycle and later, and the dose of each administration is 87.5mg-615mg or 175mg/m ²;

The 5-fluorouracil is continuously administered once daily for 24 hours on the first to fifth days of each treatment cycle, and the dosage of each administration is 400mg-2800mg or 800 mg/(m ². D);

The cisplatin is administered once on the first day of each treatment cycle at a dose of 37.5mg-262.5mg or 75mg/m ².
The method of any one of claims 21-26, wherein each of the treatment cycles is 21 days.