COMBINED PHARMACEUTICAL COMPOSITION OF C-MET KINASE INHIBITOR AND ANTI-PD-L1 ANTIBODY

Abstract

Provided are a combined pharmaceutical composition of an anti-PD-L1 antibody and a c-Met kinase inhibitor, specifically, a combined pharmaceutical composition of an anti-PD-L1 antibody and N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and the use of the combined pharmaceutical composition in the treatment of cancers, in particular, gastric cancer or liver cancer.

Claims

1. A combined pharmaceutical composition, comprising: an anti-PD-L1 antibody and a compound of formula (I) or a pharmaceutically acceptable salt thereof, ##STR00003## wherein the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 4; a heavy chain CDR2 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 5; a heavy chain CDR3 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 6; a light chain CDR1 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 10; a light chain CDR2 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 11; and a light chain CDR3 region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 12.

2. (canceled)

3. The combined pharmaceutical composition of claim 1, wherein the anti-PD-L1 antibody and the compound of formula (I) or the pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition.

4. The combined pharmaceutical composition of claim 1, wherein the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having an amino acid sequence set forth in SEQ ID NO: 1; a heavy chain CDR2 region having an amino acid sequence set forth in SEO ID NO: 2; a heavy chain CDR3 region having an amino acid sequence set forth in SEO ID NO: 3; a light chain CDR1 region having an amino acid sequence set forth in SEQ ID NO: 7; a light chain CDR2 region having an amino acid sequence set forth in SEO ID NO: 8; and a light chain CDR3 region having an amino acid sequence set forth in SEO ID NO: 9.

5. The combined pharmaceutical composition of claim 1, comprising 20 mg to 2400 mg of the anti-PD-L1 antibody.

6. The combined pharmaceutical composition of claim 1, comprising 90 mg to 180 mg of the compound of formula (I) or the pharmaceutically acceptable salt thereof.

7. A kit of pharmaceutical compositions for treating cancer, comprising (a) a first pharmaceutical composition comprising an anti-PD-L1 antibody of claim 1 as an active ingredient; and (b) a second pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.

8. A method for treating cancer, comprising: administering to a subject suffering from cancer a therapeutically effective amount of the combined pharmaceutical composition according to claim 1.

9. (canceled)

10. The method of claim 8, wherein the anti-PD-L1 antibody is continuously administered at one or more flat doses of about 20 mg to about 2400 mg.

11. The method of claim 8, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered at a dose of 90 mg to 180 mg.

12. The method of claim 8, wherein the administration is carried out by administering the compound of formula (I) or the pharmaceutically acceptable salt thereof within ±5 min of administration of the anti-PD-L1 antibody.

13. (canceled)

14. The method of claim 8, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered in combination with the hu5G11-hIgG1 antibody in 21-day treatment cycles, and the administration is done by administering by infusion 1200 mg of the hu5G11-hIgG1 antibody over a period of 60±5 min on the first day, and administering 120 mg or 150 mg of the compound of formula (I) or the pharmaceutically acceptable salt thereof once daily over 21 consecutive days.

15. (canceled)

16. The method of claim 8, wherein the cancer is liver cancer or gastric cancer.

17. The method of claim 16, wherein the liver cancer is hepatocellular carcinoma.

18. The method of claim 16, wherein the gastric cancer is gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

19. The combined pharmaceutical composition of claim 1, wherein the anti-PD-L1 antibody comprises: (1) a heavy chain variable region set forth in SEQ ID NO: 13 and a light chain variable region set forth in SEQ ID NO: 15; or (2) a heavy chain variable region set forth in SEQ ID NO: 14 and a light chain variable region set forth in SEQ ID NO: 16.

20. The combined pharmaceutical composition of claim 1, wherein the anti-PD-L1 antibody comprises: (1) a heavy chain amino acid sequence set forth in SEQ ID NO: 17 and a light chain amino acid sequence set forth in SEQ ID NO: 18; or (2) a heavy chain amino acid sequence set forth in SEQ ID NO: 19 and a light chain amino acid sequence set forth in SEQ ID NO: 20; or (3) a heavy chain amino acid sequence set forth in SEQ ID NO: 21 and a light chain amino acid sequence set forth in SEQ ID NO: 18.

21. The method of claim 10, wherein the anti-PD-L1 antibody is continuously administered at a flat dose of about 1200 mg.

22. The method of claim 10, wherein the anti-PD-L1 antibody is administered once every 21 days.

23. The method of claim 11, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered at a dose of 120 mg or 150 mg.

24. The method of claim 11, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered once daily.

Description

DETAILED DESCRIPTION

[0225] The present disclosure is further described below with reference to specific examples, which, however, are only for illustration and do not limit the scope of the present disclosure. Likewise, the present disclosure is not limited to any specific preferred embodiment described herein. It should be appreciated by those skilled in the art that equivalent substitutions or corresponding modifications made to the technical features of the present disclosure still fall within the scope of the present disclosure. Unless otherwise stated, the reagents used in the following examples are commercially available products, and the solutions can be prepared by conventional techniques in the art.

TABLE-US-00001 TABLE 1 List of abbreviations Abbreviation Chinese full name Abbreviation Chinese full name AE Adverse event ALT Alanine aminotransferase (alanine transaminase) ANOVA Analysis of variance AST Aspartate aminotransferase (aspartate transaminase) AUC Area under plasma concentration- TB Total bilirubin time curve AUCss Area under steady-state plasma DB Direct bilirubin concentration-time curve CFDA National Medical Products BUN Urea Administration CL Apparent clearance Cr Creatinine C.sub.max Maximum plasma concentration CT X-ray computed tomography observed C.sub.ss-max Steady-state peak concentration MRI Nuclear magnetic resonance C.sub.ss-min Steady-state trough concentration QTc Corrected Q-T interval C.sub.ss-av Mean steady-state plasma HBsAg Hepatitis B surface antigen concentration CTCAE Common Terminology Criteria for HBV DNA Hepatitis B Adverse Events DCR Disease control rate HCV Hepatitis C dMMR Deletion of mismatch repair gene OS Overall survival DOR Duration of response SAE Severe adverse event DLT Dose limiting toxicity SD Stable disease GCP Good clinical practice PD Disease progression HED Human equivalent dose SOP Standard operating procedure LLOQ Lower limit of quantitation TMB Tumor mutational burden MTD Maximum tolerated dose t.sub.1/2 Time required for plasma concentration to be reduced by half MSI-H Microsatellite instability-high T.sub.max Time to peak concentration observed NOAEL No observed adverse effect level TTR Time to response ORR Objective response rate V.sub.d Apparent volume of distribution PFS Progression-free survival NYHA New York Heart Disease Association ECOG PS Eastern Cooperative Oncology Group-performance status

[0226] Response Evaluation Criteria (Evaluation of Therapeutic Efficacy According to RECIST 1.1/iRECIST Evaluation Criteria)

[0227] PFS (progression-free survival): first dose to disease progression or death (whichever occurred first).

[0228] ORR (objective response rate): proportion of subjects with confirmed disease assessed as CR+PR.

[0229] DCR (disease control rate): proportion of patients whose tumors shrink or remain stable for a certain period of time, including cases of CR, PR and SD.

[0230] DoR (duration of response): for patients whose optimal response is complete or partial response, defined as the time from the first occurrence of CR or PR to disease progression or relapse or death from all causes; for subjects who achieve response and do not have disease progression or a recurrence or do not die from various causes prior to analysis, the time of the last disease assessment is counted as an end.

[0231] CR (complete response): all target lesions disappear.

[0232] PR (partial response): the total diameter of the target lesion is reduced by 30% or more.

[0233] PD (disease progression): the total diameter of the target lesion is increased by 20% or more than the minimum value of the total diameter in the research, and the absolute value of the total diameter is increased by 5 mm or more; or one or more new lesions occur.

[0234] SD (stable disease): the target lesion is reduced and does not reach the PR standard; or the target lesion is enlarged and does not reach the PD standard.

[0235] The total diameter of the target lesion is the sum of the diameters of the target lesion (including the long diameter of the lesion and the short diameter of the lymph node).

Example 1: Treatment of Liver Cancer with Combined Pharmaceutical Composition of c-Met Kinase Inhibitor and Anti-PD-L1 Antibody

[0236] 1. Inclusion criteria and treatment regimen

[0237] 1.1. Inclusion criteria

[0238] 1) Aged 18-75 years; ECOG PS score: 0-1; an expected survival time ≥3 months;

[0239] 2) Patients who have been histopathologically or cytologically diagnosed with hepatocellular carcinoma;

[0240] 3) Patients with hepatocellular carcinoma need to meet the following criteria:

[0241] (1) having not received any systemic treatment for HCC;

[0242] (2) subjects with Barcelona clinic liver cancer stage (BCLC stage) C, or subjects with stage B that are not suitable for local treatment or are refractory to local treatment, and are not suitable for treatment with radical therapy;

[0243] (3) with Child-Pugh liver function grade A;

[0244] (4) patients after local treatment (including but not limited to surgery, TACE, TAI, radiofrequency or microwave ablation, absolute alcohol injection) should be at least 4 weeks after the end of local treatment and have recovered sufficiently from treatment toxicity and/or complications to be enrolled;

[0245] 4) Central nervous system metastasis without clinical symptoms or with clinical symptoms and the disease is controlled and stable for ≥4 weeks after treatment;

[0246] 5) HBVDNA quantification must be <500 IU/mL or 2500 copies/mL, and patients in need of treatment receive anti-HBV treatment for at least 2 weeks prior to the study and are willing to receive anti-viral treatment throughout the study according to Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2019 Edition); patients with positive HCVRNA quantification must complete anti-viral treatment at least 1 month prior to the study;

[0247] 6) Having at least one measurable lesion (RECIST 1.1);

[0248] 7) Normal main organ functions meeting the following criteria:

[0249] (1) the blood routine examination criteria to be met: a) hemoglobin ≥90 g/L; b) absolute neutrophil count ≥1.5×10.sup.9/L; and c) platelet count ≥75×10.sup.9/L (no transfusion of blood or blood products, no correction using granulocyte colony-stimulating factor and drugs within 14 days);

[0250] (2) biochemical test needs to meet the following criteria: a) albumin ≥30 g/L (no transfusion of albumin or blood products within 14 days); b) ALT and AST<5.0×upper limit of normal (ULN); total bilirubin ≤2×ULN; and c) serum creatinine ≤1.5×ULN or creatinine clearance (Ccr)>50 mL/min (Cockcroft-Gault equation: Ccr=(140−age)×weight (Kg)/72×Scr (mg/dl) or Ccr=(140−age)×weight (Kg)/0.818×Scr (umol/L), calculation result×0.85 for a female);

[0251] (3) prothrombin time (PT) is prolonged by ≤3 s compared with the upper limit of normal;

[0252] 8) Radiotherapy for bone metastases accompanied by clinical symptoms must be completed at least 2 weeks prior to the study;

[0253] 9) Female subjects of childbearing age should agree to take contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study and for 6 months after the study; serum pregnancy test results should be negative within 7 days before enrollment, and the subjects must not be breastfeeding; male subjects should agree to take contraceptive measures during the study and for 6 months after the study;

[0254] 10) Voluntary participation, written informed consent and good compliance.

[0255] 1.2. Test compounds

[0256] Compound of formula (I) capsules: strength: 30 mg/capsule and 60 mg/capsule, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0257] hu5G1l-hIgG1 injection: strength: 100 mg/10 mL and 600 mg/20 mL, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0258] 1.3. Administration Regimen

[0259] Regimen A: compound of formula (I) capsules 120 mg/qd+hu5G11-hIgG1 1200 mg (the first day)

[0260] Regimen B: compound of formula (I) capsules 150 mg/qd+hu5G11-hIgG1 1200 mg (the first day)

[0261] 1.4. Administration Methods

[0262] hu5G1l-hIgG1 injection: diluted to 250 mL with 1200 mg of normal saline, the infusion time was 60±5 min, the injection was administered once every 21 days, and 21 days was counted as 1 administration cycle.

[0263] Compound of formula (I) capsules: continuously administered once daily (within ±5 min of starting infusion of hu5G11-hIgG1 injection on an empty stomach). Except in special circumstances, it was recommended to take it at a fixed time every day. 21 days was counted as an administration cycle.

[0264] 1.5. Evaluation Criteria

[0265] The main efficacy indicators were evaluated according to the RECIST1.1 criteria.

[0266] 2. Results

[0267] 2.1. Pre-Treatment Diagnosis and Treatment History

[0268] Clinical diagnosis of patient A:

[0269] (1) clinical diagnosis-primary site: hepatocellular carcinoma, moderately differentiated.

[0270] (2) TNM stage: T3bN0M0

[0271] (3) clinical stage: stage IIIB

[0272] (4) BCLC stage: stage B

[0273] Treatment history before treatment:

[0274] (1) surgery history: no

[0275] (2) history of chemotherapy and anti-tumor drug therapy: no

[0276] (3) history of radiotherapy: no

[0277] 2.2. Treatment Regimen

[0278] For patient A, the following treatment regimen, shown in regimen A, was used:

[0279] compound of formula (I) capsules 120 mg/qd+hu5G11-hIgG1 1200 mg (the first day)

[0280] 2.3. Response and Evaluation

[0281] For patient A, the response and evaluation were as follows:

[0282] screening phase (before treatment phase): target lesion: 108 mm;

[0283] 2 cycles of treatment: target lesion: 82 mm;

[0284] 4 cycles of treatment: target lesion: 75 mm;

[0285] 6 cycles of treatment: target lesion: 76 mm;

[0286] 8 cycles of treatment: target lesion: 73 mm;

[0287] 10 cycles of treatment: target lesion: 86 mm.

[0288] The best response for patient A was PR (partial response) according to the Response Evaluation Criteria.

Example 2: Treatment of Gastric Cancer with Combined Pharmaceutical Composition of c-Met Kinase Inhibitor and Anti-PD-L1 Antibody

[0289] 1. Inclusion Criteria and Treatment Regimen

[0290] 1.1. Inclusion Criteria

[0291] 1) Aged 18-75 years; ECOG PS score: 0-1; an expected survival time ≥3 months;

[0292] 2) Patients who have been histopathologically or cytologically diagnosed with gastric adenocarcinoma/gastroesophageal junction adenocarcinoma;

[0293] 3) Patients with advanced gastric adenocarcinoma/gastroesophageal junction adenocarcinoma that are not suitable for surgery and have failed first-line standard chemotherapy (no less than 2 cycles of treatment) need to meet any of the following criteria:

[0294] (1) having disease progression during the first-line treatment of the gastric cancer, or within 4 months after the end of treatment after the last administration (including maintenance monotherapy for the first-line treatment);

[0295] (2) having a recurrence or metastasis during neoadjuvant or adjuvant therapy or within 6 months after the last administration, which is considered failure of first-line systemic chemotherapy for the progressive disease;

[0296] 4) Central nervous system metastasis without clinical symptoms or with clinical symptoms and the disease is controlled and stable for ≥4 weeks after treatment;

[0297] 5) HBVDNA quantification must be <500 IU/mL or 2500 copies/mL, and patients in need of treatment receive anti-HBV treatment for at least 2 weeks prior to the study and are willing to receive anti-viral treatment throughout the study according to Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2019 Edition); patients with positive HCVRNA quantification must complete anti-viral treatment at least 1 month prior to the study;

[0298] 6) Having at least one measurable lesion (RECIST 1.1);

[0299] 7) Normal main organ functions meeting the following criteria:

[0300] (1) the blood routine examination criteria to be met: a) hemoglobin ≥90 g/L; b) absolute neutrophil count ≥1.5×10.sup.9/L; and c) platelet count ≥75×10.sup.9/L (no transfusion of blood or blood products, no correction using granulocyte colony-stimulating factor and drugs within 14 days);

[0301] (2) biochemical test needs to meet the following criteria: a) albumin ≥30 g/L (no transfusion of albumin or blood products within 14 days); b) ALT and AST<3.0×upper limit of normal (ULN); total bilirubin ≤2×ULN; and c) serum creatinine ≤1.5×ULN or creatinine clearance (Ccr)>50 mL/min (Cockcroft-Gault equation: Ccr=(140−age)×weight (Kg)/72×Scr (mg/dl) or Ccr=(140−age)×weight (Kg)/0.818×Scr (umol/L), calculation result×0.85 for a female);

[0302] (3) prothrombin time (PT) is prolonged by ≤3 s compared with the upper limit of normal;

[0303] 8) Radiotherapy for bone metastases accompanied by clinical symptoms must be completed at least 2 weeks prior to the study;

[0304] 9) Female subjects of childbearing age should agree to take contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study and for 6 months after the study; serum pregnancy test results should be negative within 7 days before enrollment, and the subjects must not be breastfeeding; male subjects should agree to take contraceptive measures during the study and for 6 months after the study;

[0305] 10) Voluntary participation, written informed consent and good compliance.

[0306] 1.2. Test Compounds

[0307] Compound of formula (I) capsules: strength: 30 mg/capsule and 60 mg/capsule, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0308] hu5G1l-hIgG1 injection: strength: 100 mg/10 mL and 600 mg/20 mL, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0309] 1.3. Administration Regimen

[0310] Regimen A: compound of formula (I) capsules 120 mg/qd+hu5G1l-hIgG1 1200 mg (the first day)

[0311] Regimen B: compound of formula (I) capsules 150 mg/qd+hu5G1l-hIgG1 1200 mg (the first day)

[0312] 1.4. Administration Methods

[0313] hu5G1l-hIgG1 injection: diluted to 250 mL with 1200 mg of normal saline, the infusion time was 60±5 min, the injection was administered once every 21 days, and 21 days was counted as 1 administration cycle.

[0314] Compound of formula (I) capsules: continuously administered once daily (within ±5 min of starting infusion of hu5G11-hIgG1 injection on an empty stomach). Except in special circumstances, it was recommended to take it at a fixed time every day. 21 days was counted as an administration cycle.

[0315] 1.5. Evaluation Criteria

[0316] The main efficacy indicators were evaluated according to the RECIST1.1 criteria.

[0317] 2. Results

[0318] 2.1. Pre-Treatment Diagnosis and Treatment History

[0319] 2.1.1. Clinical Diagnosis and Treatment History of Patient B

[0320] (1) (Gastric) adenocarcinoma, moderately-poorly differentiated, pTNM stage: pT3N3. Immunohistochemistry showed that: i. HER-2(−), Ki67 (+ about 60%), MLH1 (+), MSH2 (+), PMS2 (+), MSH6 (+), SYN (−); ii. proximal resection margin, distal resection margin, greater omentum (−); iii. lymph node showed cancer metastasis (14/18); lesser curvature tissue (−), greater curvature (2/3), region 1 tissue (−), region 3a (0/1), region 4 (2/2), region 5 (2/2), region 6 (5/5), region 7 tissue (−), region 8a (3/4), region 9 (0/1), region 12a tissue (−), and region 14v tissue (−).

[0321] (2) Radical gastrectomy was performed after the diagnosis. After radical surgery, XELOX regimen (oxaliplatin in combination with capecitabine) was used for 8 cycles of chemotherapy, followed by maintenance therapy with oxaliplatin.

[0322] 2.1.2. Clinical Diagnosis and Treatment History of Patient C

[0323] (1) Advanced gastric cancer, adenocarcinoma found in both fundus and body of stomach, hepatogastric ligament and retroperitoneal lymph node metastases and right upper arm metastases. Immunohistochemistry (fundus of stomach) showed: BRAF V600E (−), HER-2 (1+), PMS2 (+), MLH1 (+), MSH2 (+), MSH6 (+), and AFP (+). (2) Chemotherapy was performed for 8 cycles with DOS regimen (docetaxel and oxaliplatin in combination with tegafur-gimeracil-oteracil potassium) after diagnosis, followed by maintenance therapy with tegafur-gimeracil-oteracil potassium.

[0324] 2.2. Treatment Regimen [0325] For both patient B and patient C, the treatment regimen was as follows:

[0326] Regimen A: compound of formula (I) capsules 120 mg/qd+hu5G11-hIgG1 1200 mg (the first day)

[0327] 2.3. Response and Evaluation

[0328] 2.3.1. For patient B, the response and evaluation were as follows:

[0329] screening phase (before treatment phase): target lesion: 45.21 mm;

[0330] 2 cycles of treatment: target lesion: 42.79 mm;

[0331] 4 cycles of treatment: target lesion: 30.85 mm;

[0332] 6 cycles of treatment: target lesion: 30.08 mm;

[0333] 8 cycles of treatment: target lesion: 35.06 mm;

[0334] 10 cycles of treatment: target lesion: 38.13 mm.

[0335] The best response for patient B was PR (partial response) according to the Response Evaluation Criteria.

[0336] 2.3.2. For patient C, the response and evaluation were as follows:

[0337] screening phase (before treatment phase): target lesion: 18.6 mm;

[0338] 2 cycles of treatment: target lesion: 14.3 mm;

[0339] 4 cycles of treatment: target lesion: 12.0 mm;

[0340] 6 cycles of treatment: target lesion: 14.0 mm;

[0341] 8 cycles of treatment: target lesion: 14.2 mm.

[0342] The best response for patient C was PR (partial response) according to the Response Evaluation Criteria.

[0343] All technical features of the present disclosure may be combined in any way. Each feature of the present disclosure may also be replaced by other features that have the same, equivalent or similar effects. Thus, unless otherwise stated, each feature disclosed is only an example of a series of equivalent or similar features.

[0344] Furthermore, those skilled in the art can readily understand the key features of the present disclosure according to the above description. Many modifications can be made to the present invention without departing from the spirit and scope of the present disclosure so the present invention is suitable for a variety of purposes and conditions of use, and therefore such modifications are also intended to fall within the scope of the appended claim.

[0345] Herein incorporated by reference is the sequence listing filed with the USPTO as 1140-006 NATL_ST25.txt which was created on May 10, 2023, and the size is 22,406 bytes.