COMBINATION DRUG FOR TREATING KIDNEY CANCER

Abstract

The present invention relates to the field of biomedicines. Disclosed is a combination drug for treating kidney cancer, comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. The present invention also provides use of the combination drug in the preparation of drugs for treating kidney cancer.

Claims

1. A pharmaceutical combination for use in treating kidney cancer, comprising: an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical combination comprises the anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, (3.5-29):1, (3.5-14.5):1, or (7-14.5):1.

2. The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination comprises: a pharmaceutical composition of the anti-PD-L1 antibody, and a pharmaceutical composition of anlotinib or the pharmaceutically acceptable salt thereof.

3-14. (canceled)

15. The pharmaceutical combination according to claim 2, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a solution for injection; the pharmaceutical composition of anlotinib or the pharmaceutically acceptable salt thereof is an oral solid formulation.

16-25. (canceled)

26. A kit for use in treating kidney cancer, comprising: an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, wherein the anti-PD-L1 antibody is contained in a first compartment, and anlotinib or the pharmaceutically acceptable salt thereof is contained in a second compartment.

27. The kit according to claim 26, wherein the kit is suitable for administration within a single treatment cycle and comprises a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody and a pharmaceutical composition comprising 84-168 mg of anlotinib.

28. (canceled)

29. The pharmaceutical combination according to claim 1, wherein the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 4; a heavy chain CDR2 region selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 5; a heavy chain CDR3 region selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 6; a light chain CDR1 region selected from the group consisting of SEQ ID NO: 7 and SEQ ID NO: 10; a light chain CDR2 region selected from the group consisting of SEQ ID NO: 8 and SEQ ID NO: 11; and a light chain CDR3 region selected from the group consisting of SEQ ID NO: 9 and SEQ ID NO: 12.

30. The pharmaceutical combination according to 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 SEQ ID NO: 2; a heavy chain CDR3 region having an amino acid sequence set forth in SEQ 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 SEQ ID NO: 8; and a light chain CDR3 region having an amino acid sequence set forth in SEQ ID NO: 9.

31. The pharmaceutical combination according to claim 1, wherein the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 13 or SEQ ID NO: 14; and a light chain variable region having at least 80% homology to an amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16.

32. The pharmaceutical combination according to claim 1, wherein the anti-PD-L1 antibody comprises: a heavy chain variable region selected from the group consisting of heavy chain variable regions of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 and hu5G11-hIgG4 humanized antibodies; and a light chain variable region selected from the group consisting of light chain variable regions of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 and hu5G11-hIgG4 humanized antibodies.

33. A method for treating kidney cancer, comprising administering to a patient in need an effective amount of a pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

34. The method according to claim 33, wherein the pharmaceutical combination comprises the anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, (3.5-29):1, (3.5-14.5):1, or (7-14.5):1.

35. The method according to claim 33, wherein the anti-PD-L1 antibody is administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

36. The method according to claim 33, wherein one treatment cycle comprises 21 days; the PD-L1 antibody is administered on the first day of each treatment cycle, and anlotinib or the pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each cycle.

37. The method according to claim 36, wherein 1200 mg of the PD-L1 antibody is administered on the first day of each treatment cycle, and 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or the pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each treatment cycle.

38. The method according to claim 33, wherein the kidney cancer is advanced kidney cancer; the kidney cancer is clear cell renal cell carcinoma or non-clear cell renal cell carcinoma; the kidney cancer is clear cell renal cell carcinoma, or a renal cell carcinoma dominated by clear cell components; a patient with the kidney cancer is a low-risk kidney cancer patient, or a medium-risk kidney cancer patient, or a high-risk kidney cancer patient; the kidney cancer is treatment-naive renal cell carcinoma; the kidney cancer is treatment-naive advanced renal cell carcinoma; or the kidney cancer is a kidney cancer that has not been subjected to systemic prior treatment.

39. The method according to claim 38, wherein the prior treatment includes surgical treatment, radiotherapy, or medication.

40. The method according to claim 33, wherein the anti-PD-L1 antibody and anlotinib or the pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and are administered simultaneously, sequentially or at intervals.

41. The method according to claim 33, wherein the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 4; a heavy chain CDR2 region selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 5; a heavy chain CDR3 region selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 6; a light chain CDR1 region selected from the group consisting of SEQ ID NO: 7 and SEQ ID NO: 10; a light chain CDR2 region selected from the group consisting of SEQ ID NO: 8 and SEQ ID NO: 11; and a light chain CDR3 region selected from the group consisting of SEQ ID NO: 9 and SEQ ID NO: 12.

42. The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle and comprises a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody provided in multiple-dose form or in a single-dose form.

43. The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle and comprises a pharmaceutical composition comprising 84-168 mg of anlotinib; or wherein the pharmaceutical combination comprises a pharmaceutical composition comprising 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or the pharmaceutically acceptable salt thereof in a unit dose.

Description

DETAILED DESCRIPTION

[0120] For clarity, the present application is further described with the following examples, which are, however, not intended to limit the scope of the present application. All reagents used herein are commercially available and can be used without further purification. In the examples, the anti-PD-L1 antibody was prepared as described in WO2016022630, and after affinity chromatography, an eluate containing the antibody was obtained by conventional antibody purification methods.

Example 1. Clinical Trial of Kidney Cancer

[0121] Kidney cancer subjects that met the criteria were given anti-PD-L1 antibody injections and anlotinib hydrochloride capsules. Response evaluation was performed once every 6 weeks (42 days). Subjects with disease control and tolerable adverse effects could be continuously medicated until clinical benefits were lost, until the toxicity was intolerable, until PD was given by response evaluation, or until the investigator deemed further medication inappropriate, whichever occurred first. Then the study ended.

[0122] 1.1 Primary Inclusion Criteria:

[0123] 1) Histopathologically confirmed clear cell renal cell carcinoma, including advanced renal cell carcinoma dominated by clear cell components;

[0124] 2) Have not been subjected to systemic medication for locally advanced/metastatic diseases (those who failed previous cytokine therapy/were drug resistant were enrolled);

[0125] 3) Non-surgically resectable locally advanced/metastatic diseases, and having at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1); and

[0126] 4) Age: 18-80 years old (calculated based on the date of signing the consent form); male or female; ECOG score: 0-1; expected survival>3 months.

[0127] 1.2 Test Drug

[0128] Anti-PD-L1 antibody hu5G11-hIgG1 injection: 1200 mg of the anti-PD-L1 antibody injection was diluted to 250 mL with normal saline, and the infusion time was 60±10 min (from the beginning of the infusion of the anti-PD-L1 antibody injection until the end of the infusion of the anti-PD-L1 antibody injection and the completion of flushing the tube with normal saline (20 mL recommended)). The anti-PD-L1 antibody injection was administered on the first day, and once every 21 days—that is, 21 days were counted as a treatment cycle. (i.e., anti-PD-L1 antibody injection: 1200 mg, d1/q3w) strength: 600 mg/20 mL. Anlotinib hydrochloride capsule (anlotinib dihydrochloride as active ingredient): once daily (orally taken before breakfast), 1 capsule (10 mg) each time. The oral administration was performed for 2 consecutive weeks and interrupted for 1 week—that is, 21 days were counted as a treatment cycle, and the drug was administered on days 1-14 of each cycle. Except in special circumstances, it was recommended to take it at a fixed time every day. (i.e., anlotinib hydrochloride capsule: 10 mg/qd, d1-14/q3w)

[0129] The investigator could adjust the dose of the anlotinib hydrochloride capsule, e.g., to 12 mg, 10 mg or 8 mg, according to the disease condition, safety and other aspects.

[0130] 1.3 Evaluation Criteria

[0131] Safety evaluation: the NCI-CTCAE 5.0 criteria were adopted.

[0132] Response evaluation: the RECIST 1.1 criteria and the iRECIST criteria were adopted.

[0133] 1.4 Endpoints

[0134] Primary Endpoint

[0135] Effectiveness indicator: progression-free survival (PFS) given by the Independent Review Committee's (IRC) evaluation.

[0136] Secondary Endpoints

[0137] Effectiveness indicators: progression-free survival (PFS), overall survival (OS), objective response rate (ORR=complete response (CR)+partial response (PR)), disease control rate (DCR=CR+PR+stable disease (SD)), duration of response (DOR), 12-month progression-free survival rate, 12-month and 24-month overall survival rates, and quality of life score, given by the investigator's evaluation; and immune-related effectiveness indicators (such as iPFS).

[0138] Safety indicators: incidence and severity of adverse events (AEs), laboratory test value abnormalities and serious adverse events (SAEs).

[0139] Biomarker: the correlation of PD-L1 expression with response.

[0140] Immunogenicity of anti-PD-L1 antibody injection: anti-drug antibody (ADA) positive rate, and so on.

[0141] 1.5 Response

[0142] Preliminary studies showed that subjects could benefit from the treatment and achieve significant response. Up to the day the data were acquired, in this study of using anlotinib hydrochloride in combination with the anti-PD-L1 antibody to treat renal cell carcinoma (anlotinib hydrochloride capsules were administered to the subjects at a dose of 12 mg/qd, d1-14/q3w), 34 subjects in the test group (anlotinib hydrochloride combined with anti-PD-L1 antibody group) had completed at least 2 cycles of treatment, and some of them had completed 10 cycles of treatment; according to the statistics by best response, 16 patients (16/34) had achieved stable disease, and 17 patients (17/34) had achieved partial response, as detailed in Table 1, in which the patients were classified according to the IMDC criteria into low-risk patients, medium-risk patients, and high-risk patients.

TABLE-US-00003 TABLE 1 Summary of best response after completion of at least 2 cycles of treatment (N = 34) Number of subjects (ratio) Low-risk Medium-risk High-risk Total of Response patients patients patients patients CR 0/12 0/16 0/6 0/34 (0.00%) (0.00%) (0.00%) (0.00%) PR 7/12 8/16 2/6 17/34 (58.33%) (50.00%) (33.33%) (50.00%) SD 5/12 8/16 3/6 16/34 (41.67%) (50.00%) (50.00%) (47.06%) PD 0/12 0/16 1*/6 1*/34 (0.00%) (0.00%) (16.67%) (2.94%) ORR 7/12 8/16 2/6 17/34 (58.33%) (50.00%) (33.33%) (50.00%) DCR 12/12 16/16 5/6 33/34 (100.00%) (100.00%) (83.33%) (97.06%) *The response evaluated as iUPD (the iRECIST criteria), further response evaluation was required.

[0143] In addition, the results show that the combination treatment regimen produced a quick response in the treatment of kidney cancer; as shown in Table 2, after 2 cycles of treatment, the results of response evaluation showed that in the test group, 25 patients (25/34) had stable disease and 8 patients (8/34) had partial response: the objective response rate (ORR) was up to 23.53% and the disease control rate (DCR) up to 97.06%.

TABLE-US-00004 TABLE 2 Summary of response in first tumor evaluation (2 cycles of treatment completed) (N = 34) Number of subjects (ratio) Low-risk Medium-risk High-risk Total of Response patients patients patients patients CR 0/12 0/16 0/6 0/34 (0.00%) (0.00%) (0.00%) (0.00%) PR 2/12 6/16 0/6 8/34 (16.67%) (37.50%) (0.00%) (23.53%) SD 10/12 10/16 5/6 25/34 (83.33%) (62.50%) (83.33%) (73.53%) PD 0/12 0/16 1*/6 1734 (0.00%) (0.00%) (16.67%) (2.94%) ORR 2/12 6/16 0/6 8/34 (16.67%) (37.50%) (0.00%) (23.53%) DCR 12/12 16/16 5/6 33/34 (100.00%) (100.00%) (83.33%) (97.06%) *The response evaluated as iUPD (the iRECIST criteria), further response evaluation was required.