CN109481687B - Combination of a CDK4/6 inhibitor in combination with a HER2 inhibitor for the treatment of gastric cancer - Google Patents

Combination of a CDK4/6 inhibitor in combination with a HER2 inhibitor for the treatment of gastric cancer Download PDF

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CN109481687B
CN109481687B CN201811338449.3A CN201811338449A CN109481687B CN 109481687 B CN109481687 B CN 109481687B CN 201811338449 A CN201811338449 A CN 201811338449A CN 109481687 B CN109481687 B CN 109481687B
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gastric cancer
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CN109481687A (en
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沈琳
高静
龚继芳
李健
张小田
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Jiangsu Hengrui Medicine Co Ltd
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Beijing Institute for Cancer Research
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Abstract

The present invention discloses a combination of a CDK4/6 inhibitor in combination with a HER2 inhibitor for the treatment of gastric cancer. The invention claims the use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used for treating HER2 positive and drug resistant gastric cancer patients. In the past history of clinical research on gastric cancer, patients who have first-line treatment drug resistance have little benefit no matter what kind of drug/scheme is used, the treatment combination provided by the invention can achieve such good benefit effect, the fact is rare, the treatment combination is provided by the inventor of the invention for the first time based on the result of preclinical research, and clinical research is carried out on the patients to prove that the treatment combination is a milestone type major breakthrough in the field of gastric cancer.

Description

Combination of a CDK4/6 inhibitor in combination with a HER2 inhibitor for the treatment of gastric cancer
Technical Field
The present invention relates to a combination of a CDK4/6 inhibitor in combination with a HER2 inhibitor for the treatment of gastric cancer.
Background
Asia is the highest incidence area of gastric cancer in the world, and new onset patients in China account for 47% of the world every year. The latest statistical data of Chinese tumor registration show that the incidence and death rate of gastric cancer are three highest in national malignant tumors, and the health of Chinese people is seriously harmed. About 80% of Chinese gastric cancer patients have late stage disease diagnosis (distant metastasis or local progressive stage), lose operative radical treatment chance or have high postoperative recurrence and metastasis rate, and the drug therapy is the main treatment means for patients with late stage. Chemotherapy has been the cornerstone of gastric cancer drug therapy for the past decades, but the limited benefit to patients and the high toxicity have led gastric cancer therapy research to enter the bottleneck, the 5-year survival rate of late-stage gastric cancer patients wanders to 20-30%, and the median overall survival period hardly exceeds 12 months.
At present, tumor targeted therapy is a hot point of treatment, the successful application of anti-HER 2 molecular targeted drug trastuzumab breaks through the bottleneck of gastric cancer chemotherapy, the total life cycle of HER2 positive patients is prolonged to about 16 months, the progress is a milestone, and HER2 is the only and clear 'star' therapeutic target in the field of gastric cancer. Worldwide and China gastric cancer diagnosis and treatment guidelines clearly indicate that HER2 positive patients preferentially recommend trastuzumab in combination with chemotherapy as a first-line treatment regimen. In gastric cancer, the proportion of HER2 positive patients is about 12-15%, and of HER2 positive patients, only about 50% of patients can benefit significantly from trastuzumab-targeted therapy, and these significantly benefited patients develop resistance (secondary resistance) at 8-9 months post-treatment for the majority of patients over the course of drug treatment, and a significant proportion of patients are resistant to primary drugs. Clinically, the restraint is not reasonable for the first-line drug-resistant gastric cancer patients, the subsequent two-line or three-line treatment strategies are mostly selected based on the experience of clinicians, and even if some patients can benefit from the subsequent two-line or three-line treatment, the benefits are very little. Therefore, the search for post-drug resistance treatment strategies is becoming a major concern.
It is known that drug resistance is a main reason for failure of drug therapy, and the high heterogeneity and complex tumor microenvironment of gastric cancer cells cause complex drug resistance mechanism, so far, the drug resistance mechanism of the gastric cancer field including chemotherapeutic drugs and targeted drugs is not clear.
Disclosure of Invention
It is an object of the present invention to provide a combination of a CDK4/6 inhibitor in combination with a HER2 inhibitor for the treatment of gastric cancer.
The invention claims the use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used for treating HER2 positive gastric cancer patients.
The invention also claims the use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used for treating HER2 positive and drug resistant gastric cancer patients.
The invention also claims the use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used for treating gastric cancer patients who are HER2 positive and resistant to HER2 inhibitors.
The invention also claims the use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used for treating gastric cancer patients.
In any of the above applications, the active ingredients of the composition are CDK4/6 inhibitor and HER2 inhibitor.
In any of the above applications, the ingredients of the two ingredients may specifically be: CDK4/6 inhibitor 100mg X21: HER2 inhibitor 400mg × 28.
The invention also claims a composition whose active ingredients are a CDK4/6 inhibitor and a HER2 inhibitor; the composition is used for treating HER2 positive gastric cancer patients.
The invention also claims a composition whose active ingredients are a CDK4/6 inhibitor and a HER2 inhibitor; the composition is used for treating HER2 positive and drug resistant gastric cancer patients.
The invention also claims a composition whose active ingredients are a CDK4/6 inhibitor and a HER2 inhibitor; the composition is used for treating gastric cancer patients who are HER2 positive and resistant to HER2 inhibitors.
The invention also claims a composition whose active ingredients are a CDK4/6 inhibitor and a HER2 inhibitor; the composition is used for treating gastric cancer patients.
In any of the above compositions, the ingredients of the two ingredients may specifically be: CDK4/6 inhibitor 100mg X21: HER2 inhibitor 400mg × 28.
Each dosing cycle was 28 days. The specific medication method of each medication cycle comprises the following steps: 100mg CDK4/6 inhibitor, orally administered once daily for 3 weeks; HER2 inhibitor 400mg, orally administered once daily for 4 weeks.
Any of the CDK4/6 inhibitors described above may specifically be SHR6390, but may also be others.
Any one of the HER2 inhibitors described above may specifically be pirfenib, but may also be others.
Any one of the above gastric cancer patients may specifically be a patient who has metastasis after a radical gastric cancer treatment, for example, a patient who has liver metastasis after a radical gastric cancer treatment.
The gastric cancer patient can be a patient with multiple metastasis when the gastric cancer is diagnosed, such as a patient with multiple lymph node metastasis or peritoneal metastasis.
In the past history of clinical research on gastric cancer, patients who have first-line treatment drug resistance have little benefit no matter what kind of drug/scheme is used, the treatment combination provided by the invention can achieve such good benefit effect, the fact is rare, the treatment combination is provided by the inventor of the invention for the first time based on the result of preclinical research, and clinical research is carried out on the patients to prove that the treatment combination is a milestone type major breakthrough in the field of gastric cancer.
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Figure 1 is an identification of a HER2 inhibitor secondary drug resistant gastric cancer PDX model.
FIG. 2 is a graphical representation of the pathomorphological identity of PDX tissues before and after drug resistance.
FIG. 3 is a western blot method for detecting expression changes of several key molecules in cell cycle before and after drug resistance.
FIG. 4 shows the tumor growth curve (A) of the drug-resistant PDX model after single or combined drug administration, and the western blot method for detecting the expression changes (B) of several key molecules in the cell cycle before and after drug administration.
FIG. 5 is a comparison of imaging results before and after administration of a drug to a patient.
FIG. 6 is a comparison of the results of blood tumor markers (CEA, CA199, CA72.4) before and after administration to a patient.
FIG. 7 shows the results of pre-and post-administration imaging of the patient for two-drug administration.
FIG. 8 is a comparison of the results of blood tumor markers (CEA, CA199, CA72.4) before and after two-use.
Detailed Description
The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. The experimental procedures in the following examples are conventional unless otherwise specified. The experimental materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified. In the quantitative experiments in the following examples, three replicates were set up and the results averaged. The mice in the examples were NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice. In the examples, the CDK4/6 inhibitor was SHR6390 (heliotropin), and in the examples, the HER2 inhibitor was pirtinib (heliotropin). The patients were all volunteers with informed consent.
EXAMPLE 1 presentation of CDK4/6 inhibitor in combination with HER2 inhibitor therapeutic combination
Reliable exploration of drug-resistant post-treatment strategies must be successful depending on transformation studies, and "preclinical study-guided clinical trial development" is the only way, on the basis of which the inventors of the present invention have designed and developed chain-based studies.
The most important premise for the research of a drug resistance mechanism is that the optimal preclinical drug resistance model is provided, and the drug resistance model screened based on the traditional cell line is greatly different from the tumor characteristics of patients and is no longer the optimal choice for drug resistance research.
The inventor of the invention constructs a large-scale mouse subcutaneous transplanted tumor (PDX) model based on tumor tissues of a patient by using real-time endoscopic biopsy trace late gastric cancer tissues in the early stage, establishes a PDX tissue bank, and confirms the high consistency of the PDX tissues and the tumor characteristics of the patient, wherein the PDX model becomes an optimal model for preclinical research and also provides an optimal platform for constructing a drug-resistant PDX model. The PDX tissue bank consists of PDX tissue derived from tumor tissue from a plurality of patients, each PDX tissue prepared by the method of: the patient tumor tissue was inoculated subcutaneously into mice until the tumor volume was as large as about 150-200mm3Size, tumor tissue was taken and frozen.
The inventor selects a HER2 positive PDX model sensitive to a HER2 inhibitor from a PDX model library established by the inventor, simulates patient administration by adopting a long-term intermittent induction method for about 8 months, and constructs a HER2 inhibitor drug-resistant PDX model.
The construction process of the HER2 inhibitor sensitive PDX model and the HER2 inhibitor drug-resistant PDX model is as follows (pirtinib is a HER2 inhibitor): recovering PDX tissue from the PDX tissue bank, inoculating to the subcutaneous tissue of the mouse, and waiting for the tumor volume to be about 150-3Size (for about 1 month)Beginning administration of pirfenib for about 3 months (gavage, once daily, single dose of 20mg/kg), the tumor exhibits resistance to 20mg/kg of pirfenib; tumor tissue was isolated and re-inoculated into new mice until the tumor volume reached about 150-200mm3Size (for about 1 month), beginning administration of pirtinib for about 3 months (gavage, once daily, single dose of 40mg/kg), the tumor showed complete resistance to 40mg/kg of pirtinib. C019 represents a mouse subcutaneously inoculated with resuscitated PDX tissue for 1 month, S019 represents a mouse administered with pirtinib at a single dose of 20mg/kg for 2 weeks, and R019 represents a mouse administered with pirtinib at a single dose of 40mg/kg for 3 months.
Method of resistance test: the inhibitor group was given pirtinib (gavage, once daily, single dose of 40mg/kg), the control group was given an equal volume of saline, and tumor volume was measured every 3 days. The results of drug sensitivity for the C019 and R019 models are shown in fig. 1 (mean value of 5 mice per group). C019 is highly sensitive to pirfenib, and the tumor inhibition rate of the pirfenib is more than 100%. R019 shows high resistance to pirfenib.
The HE staining was performed on PDX tissues of C019, S019 and R019, and the results are shown in FIG. 2. The PDX tissues remain pathomorphologically consistent over long drug induction.
The method comprises the steps of performing transcriptome sequencing on PDX tissues before and after drug resistance (C019 PDX tissue, S019 PDX tissue and R019 PDX tissue), performing signal path enrichment analysis on a sequencing result, finding that abnormal regulation and enrichment of a cell cycle in the tissues after drug resistance are most remarkable compared with the tissues before drug resistance, verifying the tissues before and after drug resistance by using western blot, and finding that the expression level of key molecules (cyclin D1, CDK4/6, pRb and the like) participating in cell cycle regulation is remarkably increased in the tissues after drug resistance (figure 3), particularly the downstream effector Rb phosphorylation of CDK4/6 and cyclin D1 is remarkably increased. Therefore, the inventor speculates that the cyclinD1-CDK4/6 pathway abnormality may be involved in gastric cancer HER2 targeted therapy resistance, and the hypothesis is verified in a drug-resistant PDX model by combining CDK4/6 inhibitor or becoming a post-drug-resistant treatment strategy.
The PDX model for resistance to HER2 inhibitor (R019 mice, 5 mice per group) was administered in groups:
first group (vehicle control group): the normal saline is given by intragastric administration (oral administration) once a day, the volume of a single time is 100 mu l, and the administration lasts for 3 weeks;
second group (HER2 inhibitor group): the pirfenib is administered by intragastric (oral) administration once a day, the volume of a single dose is 100 mu l, the dose of the single dose is '40 mg/kg', and the administration lasts for 3 weeks;
third group (CDK4/6 inhibitor group): SHR6390 was administered intragastrically (orally) once daily in a single dose of 100 μ l, "SHR 6390100 mg/kg" for 3 weeks;
fourth panel (CDK4/6 inhibitor in combination with HER2 inhibitor panel): once daily gavage (oral) was given pyrroltinib and SHR6390 in a single bolus volume of 100 μ l, and in single doses of "pyrroltinib 40 mg/kg" and "SHR 6390100 mg/kg", for 3 weeks.
Tumor volume was measured every 3 days and the results are shown in figure 4A, with CDK4/6 inhibitor in combination with HER2 inhibitor having significant synergistic tumor suppression.
In-depth mechanism research proves that after combined administration, the expression of key molecules (cyclin D1, CDK4/6, pRb and the like) involved in the cell cycle in tissues is reduced, particularly pRb is remarkably reduced, and cells are arrested in the G1 phase to play a tumor inhibition role (figure 4B).
EXAMPLE 2 therapeutic efficacy of CDK4/6 inhibitor in combination with HER2 inhibitor in gastric cancer patients
First, the course of disease and the treatment condition of patient one
The first patient: sun, woman
The gastric poorly differentiated adenocarcinoma is confirmed to be diagnosed in 2017 in 2 months; post-operative pathological staging pT4N1M0 (stage III), immunohistochemistry for HER2 positive (3 +); oxaliplatin in combination with fluorouracil chemotherapy was performed 3 months in 2017 after surgery.
The liver metastasis is found by reexamination in 8 months in 2017, and the patient is subjected to multi-line treatment of paclitaxel combined with platinum (disease progression), irinotecan combined with fluorouracil and apatinib (disease progression), docetaxel combined with fluorouracil (disease progression) and paclitaxel liposome (disease progression) in sequence by considering the disease progression, and the disease progression is found by reexamination in 7 months in 2018, so that the disease still progresses rapidly after the patient receives the multi-line treatment. For such patients, the general prognosis is poor.
Clinical study of 8-month enrolled inventors in 2018. 2018.8.6-2018.9.2, cycle 1 medication is given for 28 days, with the specific medications: 100mg CDK4/6 inhibitor, orally administered once daily for 3 weeks; HER2 inhibitor 400mg, orally administered once daily for 4 weeks. 2018.9.4 to 2018.9.8 human granulocyte stimulating factor was administered at 150 μ g, qd leukogenic therapy due to myelosuppression. 2018.9.10-2018.10.7 are given cycle 2 drug therapy for 28 days, as specified for cycle 1. 2018.10.8 PET-CT and conventional CT review were performed to evaluate PR (partial response). FIG. 5A shows the PET-CT results before and after treatment, FIG. 5B shows the CT results before and after treatment, the PET-CT examination before treatment shows the results within 1 week before administration, and the CT examination before treatment shows the results of 2018.7.21. After 2 cycles of treatment, the lesion of the patients is particularly obviously reduced, and the tumor markers CEA, CA199 and CA72.4 are respectively reduced to 26.97ng/ml, 86.1U/ml and 7.92U/ml from 122.2ng/ml, 1871U/ml and 23.54U/ml before the grouping (figure 6, in each group of results, the left side is before treatment and the right side is after treatment). The patient started cycle 3 at 2018.10.10, with the same dose as before, and followed by follow-up treatment follow-up.
The results show that patients have completed 2 cycles (around 2 months) of treatment and evaluated pr (partial response), the lesions are significantly reduced, and the benefit from treatment is evident.
Disease course and treatment condition of patient II
The second patient: yang, woman
In 2016, the middle-low differentiated adenocarcinoma of the antrum of the stomach is confirmed and radical gastric cancer resection is performed. Postoperative pathology: middle-low differentiation adenocarcinoma of the lesser curvature of the distal antrum, pathological stage after operation: pT3N3b, immunohistochemistry showed HER2 positive (3 +).
Right inguinal lymph node metastasis was found in 2 months in 2016, and oxaliplatin in combination with capecitabine chemotherapy (progression of disease), RC48-ADC therapy (progression of disease), irinotecan in combination with trastuzumab (progression of disease) were given in succession for multiple lines of treatment.
2018 patients enrolled in the clinical study of the inventors at 9 months. Cycle 1 dosing was given during periods 2018.9.11-2018.10.8 for 28 days, with specific dosing being: 100mg CDK4/6 inhibitor, orally administered once daily for 3 weeks; HER2 inhibitor 400mg, orally administered once daily for 4 weeks. Cycle 2 drug treatment was given at 2018.10.9-2018.11.5 for 28 days, with the same dosing as cycle 1. 2018.11.7 for enhanced CT review, the reduction in SD was assessed (stable disease, approximately 20% reduction in tumor). Fig. 7 is the pre-and post-treatment CT results, fig. 7A is the pre-treatment CT result (2018.9.9), and fig. 7B is the post-treatment CT result. After 2 cycles of treatment, the lesions of the patients were particularly obviously reduced, and the tumor markers CEA, CA199 and CA72.4 were also respectively reduced from 5.49ng/ml, 250.1U/ml and 78.46U/ml before the treatment to 1.92ng/ml, 14.32U/ml and 12.74U/ml (FIG. 8, in each group of results, the left side is before the treatment and the right side is after the treatment). The patient started cycle 3 at 2018.11.6, with the same dose as before, and followed by follow-up treatment follow-up.
The results indicate that the patients have completed 2 cycles of treatment and evaluated a reduction in SD, with significant reduction in lesions and significant benefit from treatment.

Claims (1)

  1. Use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used to treat HER2 positive gastric cancer patients; the CDK4/6 inhibitor is SHR 6390; the HER2 inhibitor is pyrroltinib.
    2. Use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used to treat HER2 positive and drug resistant gastric cancer patients; the CDK4/6 inhibitor is SHR 6390; the HER2 inhibitor is pyrroltinib.
    3. Use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used for treating HER2 positive and HER2 inhibitor resistant gastric cancer patients; the CDK4/6 inhibitor is SHR 6390; the HER2 inhibitor is pyrroltinib.
    4. Use of a CDK4/6 inhibitor and a HER2 inhibitor in the preparation of a composition; the composition is used for treating gastric cancer patients; the CDK4/6 inhibitor is SHR 6390; the HER2 inhibitor is pyrroltinib.
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CN110840892A (en) * 2018-08-21 2020-02-28 江苏恒瑞医药股份有限公司 Use of a tyrosine kinase inhibitor in combination with a CDK4/6 inhibitor for the preparation of a medicament for the prevention or treatment of a neoplastic disease

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WO2015134674A1 (en) * 2014-03-04 2015-09-11 The Regents Of The University Of California Biomarkers of response to cyclin d-cdk4/6 targeted therapies in cancer

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CN110840892A (en) * 2018-08-21 2020-02-28 江苏恒瑞医药股份有限公司 Use of a tyrosine kinase inhibitor in combination with a CDK4/6 inhibitor for the preparation of a medicament for the prevention or treatment of a neoplastic disease

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