Use of combination of plinabulin, pembrolizumab, and docetaxel

Abstract

The present invention provides use of a combination of plinabulin, pembrolizumab, and docetaxel in preparing a drug or a kit. Specifically, the drug or the kit is applied to subjects of the following types: metastatic non-small cell lung cancer patients who have failed first-line immune checkpoint inhibitor monotherapy; and / or metastatic non-small cell lung cancer patients who have failed first-line immune checkpoint inhibitor combination chemotherapy.

Description

Use of a combination of plinabulin, pembrolizumab and docetaxel Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a use of a combination of plinabulin, pembrolizumab and docetaxel. Background Art

[0002] Immune checkpoint inhibitor (ICI)-based treatment regimens have become the standard of care for first-line treatment of metastatic epidermal growth factor receptor (EGFR) / altered lymphoma kinase (ALK) wild-type non-small cell lung cancer (NSCLC). However, disease progression is inevitable in most patients. After progression on ICI treatment, continued use of ICI monotherapy is not recommended, and chemotherapy has limited efficacy (docetaxel ORR is approximately 10%), so there is a high unmet need.

[0003] Therefore, a new therapeutic drug or regimen is urgently needed clinically to meet the treatment needs of patients who have failed first-line immune checkpoint inhibitor treatment. Summary of the Invention

[0004] To solve the above problems, the present invention provides a use of a combination of plinabulin, pembrolizumab and docetaxel.

[0005] In a first aspect of the present invention, there is provided a use of a combination of plinabulin, pembrolizumab and docetaxel in the preparation of a medicament or a kit;

[0006] And the drug or kit is administered to a subject having the following classification:

[0007] A. Patients with metastatic non-small cell lung cancer who have failed first-line immune checkpoint inhibitor monotherapy; and / or

[0008] B. Patients with metastatic non-small cell lung cancer who have failed first-line immune checkpoint inhibitor combined with chemotherapy.

[0009] In a preferred embodiment, the failure of the first-line immune checkpoint inhibitor monotherapy is the acquisition of drug resistance after the first-line immune checkpoint inhibitor monotherapy.

[0010] In a preferred embodiment, the failure of the first-line immune checkpoint inhibitor combined with chemotherapy drug treatment is the acquisition of drug resistance after the first-line immune checkpoint inhibitor combined with chemotherapy drug treatment.

[0011] In a preferred example, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.

[0012] In a preferred embodiment, the first-line immune checkpoint inhibitor is selected from the following group: PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor.

[0013] In a preferred embodiment, the first-line immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplizumab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, durvalumab, and spartalizumab.

[0014] In a preferred embodiment, the chemotherapy drug is platinum.

[0015] In a preferred embodiment, the drug is also used to prolong progression-free survival.

[0016] In a preferred embodiment, the drug is also used to improve the disease control rate.

[0017] In a preferred embodiment, the drug is also used to restore immune sensitivity.

[0018] In a second aspect of the present invention, a method of treating metastatic non-small cell lung cancer is provided, comprising administering plinabulin, pembrolizumab, and docetaxel to a subject.

[0019] In another preferred embodiment, the subject is a patient with metastatic non-small cell lung cancer who has failed first-line immune checkpoint inhibitor monotherapy.

[0020] In another preferred embodiment, the subject is a patient with metastatic non-small cell lung cancer who has failed treatment with a first-line immune checkpoint inhibitor combined with chemotherapy drugs.

[0021] In another preferred embodiment, the subject is a patient with metastatic non-small cell lung cancer who has acquired resistance after first-line immune checkpoint inhibitor monotherapy.

[0022] In another preferred embodiment, the subject is a patient with metastatic non-small cell lung cancer who has acquired drug resistance after treatment with a first-line immune checkpoint inhibitor combined with chemotherapy drugs.

[0023] In another preferred embodiment, the Plinabulin is administered at a dose of about 13.5 mg / m on day 1 of a 21-day cycle. 2 to about 30 mg / m 2 Dosage administration.

[0024] In another preferred embodiment, the pembrolizumab is administered at a dose of about 100 mg to about 600 mg on day 1 of a 21-day cycle.

[0025] In another preferred embodiment, the pembrolizumab is administered at a dose of about 100 mg to about 300 mg on day 1 of a 21-day cycle.

[0026] In another preferred embodiment, the docetaxel is administered at a dose of about 50 mg / m2 on day 1 of a 21-day cycle. 2 to about 200 mg / m2 Dosage administration.

[0027] In another preferred embodiment, the docetaxel is administered at a dose of about 50 mg / m2 on day 1 of a 21-day cycle. 2 to about 100 mg / m 2 Dosage administration.

[0028] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0029] After extensive and in-depth research, the inventors discovered for the first time that Plinabulin is a selective immunomodulatory microtubule-binding agent that promotes dendritic cell maturation and enhances anti-tumor T cell responses. This mechanism of action has been validated in in vitro and in vivo models, as well as in human trials, demonstrating its therapeutic potential for ICI-resistant patients. Based on these findings, the inventors completed the present invention.

[0030] the term

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0032] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0033] The main advantages of the present invention are:

[0034] (1) The composition for preparing a drug for treatment of the present invention is highly safe and tolerable.

[0035] (2) The composition for preparing a drug for treatment of the present invention can prolong progression-free survival and improve disease control rate.

[0036] (3) The composition for preparing a drug for treatment of the present invention can restore the immune sensitivity of the subject to which it is administered.

[0037] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are percentages by weight and parts by weight.

[0038] Example 1 Phase 2 clinical study of pembrolizumab combined with plinabulin and docetaxel in patients with metastatic non-small cell lung cancer who have failed first-line immune checkpoint inhibitor monotherapy or combination therapy

[0039] Experimental methods

[0040] This single-arm, open-label, phase 2, investigator-initiated trial will enroll patients with metastatic NSCLC who have acquired resistance to immunotherapy alone or in combination with platinum-based doublet chemotherapy. Patients will receive pembrolizumab 200 mg and docetaxel 75 mg / m2 via intravenous infusion on day 1. 2 The study is being conducted with 30 mg / m² of plinabulin (dapoxetine) and 21-day cycles of 21 days each. The primary endpoint is the objective response rate (ORR) as assessed by investigators according to RECIST 1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. The study plans to enroll 47 patients, with a formal interim analysis to be conducted when 19 patients have been enrolled.

[0041] Experimental results

[0042] As of the data lock point of January 31, 2024, a total of 19 patients were enrolled and 18 patients were evaluable. The median follow-up time was 5.9 months, the median age of the patients was 66.4 years (50-76 years), 68.4% were male and 31.6% were female. 57.9% of the patients were current or former smokers. Histology included 52.6% lung adenocarcinoma and 47.4% lung squamous cell carcinoma. The confirmed ORR was 22.2%, the DCR was 88.9% (defined as PR and SD > 4 months), the median PFS has not yet been reached (the current 6-month PFS rate is 71.1%), OS has not yet been reached (no deaths have been reported), and DoR has not yet been reached (the patient with the longest DoR was 10.5 months and is still receiving treatment).

[0043] Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 42.1% of patients. The most common grade 3 or higher TRAEs included myelosuppression (21.1%), decreased neutrophil count (10.5%), and intestinal obstruction (10.5%). Myelosuppression and decreased neutrophil count each had one grade 4 event, while all other TRAEs were grade 3. There were no treatment-related deaths.

[0044] Experimental Conclusion

[0045] In patients with metastatic non-small cell lung cancer who progressed after receiving a clinical benefit from an ICI, pembrolizumab combined with plinabulin and docetaxel prolonged PFS and improved DCR compared with historical controls of chemotherapy alone (median PFS of approximately 3.7 months, as measured by the TROPION-Lung01 study), with a tolerable safety profile. Further investigation will be conducted into the characteristics of patients who may benefit from continued ICI therapy after progression.

[0046] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. Use of a combination of plinabulin, pembrolizumab and docetaxel in the preparation of a medicament or a medicine kit; And the drug or kit is administered to a subject having the following classification: A. Patients with metastatic non-small cell lung cancer who have failed first-line immune checkpoint inhibitor monotherapy; and / or B. Patients with metastatic non-small cell lung cancer who have failed first-line immune checkpoint inhibitor combined with chemotherapy.

2. The use according to claim 1, characterized in that The failure of the first-line immune checkpoint inhibitor monotherapy is the acquisition of drug resistance after the first-line immune checkpoint inhibitor monotherapy.

3. The use according to claim 1, characterized in that The failure of the first-line immune checkpoint inhibitor combined with chemotherapy drug treatment is the acquisition of drug resistance after the first-line immune checkpoint inhibitor combined with chemotherapy drug treatment.

4. The use according to claim 1, wherein The lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.

5. The use according to claim 1, characterized in that The first-line immune checkpoint inhibitor is selected from the following group: PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor.

6. The use according to claim 1, wherein First-line immune checkpoint inhibitors were selected from the following group: pembrolizumab, nivolumab, cemiplizumab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, durvalumab, and spartalizumab.

7. The use according to claim 1, characterized in that The chemotherapy drug is platinum.

8. The use according to claim 1, characterized in that The drug is also used to prolong progression-free survival.

9. The use according to claim 1, characterized in that The drug is also used to improve disease control rates.

10. The use according to claim 1, characterized in that The medicament is also used to restore immune sensitivity.