Pharmaceutical combinations and their uses

Abstract

The present invention discloses a pharmaceutical combination and its use. The pharmaceutical combination comprises Compound I or a pharmaceutically acceptable salt thereof and toripalimab. The pharmaceutical combination of the present invention exhibits superior antitumor effects compared with a single drug. [Formula 1] JPEG2026500734000010.jpg38169

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese Patent Application No. 2022117029124, filed on December 28, 2022, and Chinese Patent Application No. 2023104407001, filed on April 21, 2023. This application cites the above Chinese patent applications in their entirety.

[0002] [Technical field] The present invention is in the field of medicine, and specifically relates to pharmaceutical combinations and uses thereof.

[0003] [Background technology] Currently, tumors remain a major public health problem worldwide. As our understanding of tumor biology improves, the biological characteristics of tumors, such as acquisition of signals to maintain proliferation, evasion of growth inhibitor regulation, continuous activation of replication checkpoints, reprogramming of cellular metabolism, and activation of invasion and metastasis, have gradually been analyzed. Taking these biological characteristics of tumors into consideration, traditional chemotherapy, radiation therapy, and targeted drug therapy have achieved excellent clinical therapeutic effects in the treatment of various types of tumors.

[0004] The immune checkpoint receptor 1 (PD-1) is a transmembrane protein expressed on the surface of T cells, while the ligand for PD-1, programmed death-ligand 1 (PD-L1), is expressed on the surface of tumor cells, APCs, and T cells. When PD-L1 binds to PD-1, it inhibits the downstream signaling pathway of TCR activation, thereby reducing T cell responses. Antibodies targeting these immune checkpoints, unlike conventional tumor treatments, play a role in tumor suppression by enhancing the body's own immune system. Currently, antibodies targeting PD-1 and PD-L1, such as nivolumab, atezolizumab, pembrolizumab, durvalumab, and toripalimab, have already achieved good results in immunotherapy for various malignancies.

[0005] Developed by Junshi Biosciences, toripalimab is the first monoclonal antibody drug targeting PD-1 to be approved for sale in China, and is approved for a variety of indications, including melanoma, nasopharyngeal carcinoma, urothelial carcinoma, and esophageal squamous cell carcinoma. Although toripalimab has achieved good results in the treatment of certain malignancies, its efficacy needs to be further improved.

[0006] [Summary of the Invention] The present invention aims to provide a pharmaceutical combination of Compound I and toripalimab, and uses thereof. The pharmaceutical composition of the present invention exhibits superior antitumor effects compared with the single agents.

[0007] In one aspect, the present invention provides a method for manufacturing a semiconductor device comprising: a substance X which is compound I or a pharmaceutically acceptable salt thereof; and a substance Y which is toripalimab.

[0008] [ka]

[0009] In the pharmaceutical combination, the substance X and the substance Y may be administered simultaneously or separately.

[0010] The term "administered simultaneously" means, for example, administering a "single pharmaceutical composition containing substance X" and a "single pharmaceutical composition containing substance Y" simultaneously.

[0011] The term "administered separately" refers to, for example, administering a "single pharmaceutical composition containing substance X" and a "single pharmaceutical composition containing substance Y" separately at different times, for example, administering one of the "single pharmaceutical composition containing substance X" and the "single pharmaceutical composition containing substance Y" first and the other later. The term "administered separately" may refer to administration close in time or at an interval.

[0012] Whether administered simultaneously or separately, the administration protocols (including administration route, administration frequency, dosage, administration interval, etc.) of the component X and the component Y may be the same or different, and can be adjusted as necessary by a person skilled in the art to obtain an optimal therapeutic effect.

[0013] In some embodiments, the substance X is administered orally.

[0014] In some embodiments, the substance Y is administered by injection (eg, intravenous, subcutaneous, intraperitoneal, or intramuscular injection).

[0015] In some embodiments, substance X is administered orally and substance Y is administered by injection (eg, intravenous, subcutaneous, intraperitoneal, or intramuscular).

[0016] In another aspect, the present invention provides a method for manufacturing a semiconductor device comprising: a first pharmaceutical composition comprising a substance X, which is compound I or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient; A second pharmaceutical composition comprising substance Y, which is toripalimab, and a pharmaceutical excipient. and

[0017] The first pharmaceutical composition is the sole pharmaceutical composition and the second pharmaceutical composition is the sole pharmaceutical composition.

[0018] In some embodiments, the first pharmaceutical composition is provided in the form of an oral dosage form.

[0019] In some embodiments, the second pharmaceutical composition is provided in the form of an injectable (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0020] In some embodiments, the first pharmaceutical composition is provided in the form of an oral dosage form, and the second pharmaceutical composition is provided in the form of an injectable dosage form.

[0021] In another aspect, the present invention provides a method for manufacturing a semiconductor device comprising: a first container containing the first pharmaceutical composition; a second container containing the second pharmaceutical composition described above; and a pharmaceutical combination kit comprising:

[0022] In another aspect, the present invention provides the use of a pharmaceutical combination as described herein in the manufacture of a medicament for treating cancer, The cancer is preferably colon cancer, lung cancer, cervical cancer, head and neck cancer, nasopharyngeal cancer or urothelial cancer, more preferably colon cancer.

[0023] In another aspect, the present invention provides use of substance X in the manufacture of a medicament for treating cancer, wherein substance X is compound I or a pharmaceutically acceptable salt thereof, wherein substance X is used in combination with substance Y, and substance Y is toripalimab, and the cancer is preferably colon cancer, lung cancer, cervical cancer, head and neck cancer, nasopharyngeal cancer or urothelial cancer, more preferably colon cancer; When the cancer is lung cancer, the lung cancer is preferably non-small cell lung cancer; When the cancer is head and neck cancer, the head and neck cancer is preferably head and neck squamous cell carcinoma; When the cancer is cervical cancer, the cervical cancer is preferably cervical adenocarcinoma or cervical squamous cell carcinoma.

[0024] In another aspect, the present invention provides use of substance Y, which is toripalimab, in the manufacture of a medicament for treating cancer, wherein substance Y is used in combination with substance X, which is compound I or a pharmaceutically acceptable salt thereof, and the cancer is preferably colon cancer, lung cancer, cervical cancer, head and neck cancer, nasopharyngeal cancer, or urothelial cancer, more preferably colon cancer.

[0025] When the cancer is lung cancer, the lung cancer is preferably non-small cell lung cancer.

[0026] When the cancer is head and neck cancer, the head and neck cancer is preferably head and neck squamous cell carcinoma.

[0027] When the cancer is cervical cancer, the cervical cancer is preferably cervical adenocarcinoma or cervical squamous cell carcinoma.

[0028] In another aspect, the present invention provides a method of treating cancer, comprising the step of administering to a subject (e.g., a human or a mouse) in need thereof a therapeutically effective amount of a pharmaceutical combination described herein, wherein the cancer is preferably colon cancer, lung cancer, cervical cancer, head and neck cancer, nasopharyngeal cancer or urothelial cancer, more preferably colon cancer.

[0029] When the cancer is lung cancer, the lung cancer is preferably non-small cell lung cancer.

[0030] When the cancer is head and neck cancer, the head and neck cancer is preferably head and neck squamous cell carcinoma.

[0031] When the cancer is cervical cancer, the cervical cancer is preferably cervical adenocarcinoma or cervical squamous cell carcinoma.

[0032] Administration of Substance X and Substance Y In some embodiments, the administration protocols (including route of administration, dosage, administration interval, etc.) for substance X and substance Y may be the same or different and can be adjusted as needed by one skilled in the art to obtain optimal therapeutic effects.

[0033] In some embodiments, substance X and substance Y may be administered simultaneously or separately.

[0034] In some embodiments, the substance X is administered orally.

[0035] In some embodiments, the substance Y is administered by injection (eg, intravenous, subcutaneous, intraperitoneal, or intramuscular injection).

[0036] In some embodiments, substance X is administered orally and substance Y is administered by injection (eg, intravenous, subcutaneous, intraperitoneal, or intramuscular).

[0037] In some embodiments, the administration frequency of the substance X may be QD (once a day), QOD (every other day), or BID (twice a day), preferably QD.

[0038] In some embodiments, the single dose of substance X can be administered according to the body weight of the subject, and a non-limiting example range may be 0.1 mg / kg to 1 mg / kg (referring to a single dose), for example, 0.2 mg / kg. In some embodiments, the dose of compound I is 0.2 mg / kg.

[0039] In some embodiments, the dosage of the substance X is 0.1 to 2.0 mg / dose, for example, 0.1 mg / dose, 0.2 mg / dose, 0.3 mg / dose, 0.4 mg / dose, 0.5 mg / dose, 0.6 mg / dose, 0.7 mg / dose, 0.8 mg / dose, 0.9 mg / dose, 1.0 mg / dose, 1.1 mg / dose, 1.2 mg / dose, 1.3 mg / dose, 1.4 mg / dose, 1.5 mg / dose, 1.6 mg / dose, 1.7 mg / dose, 1.8 mg / dose, 1.9 mg / dose, or 2.0 mg / dose, preferably 1.1 mg / dose.

[0040] In some embodiments, substance X is orally administered at the dosage and frequency described above, e.g., substance X is orally administered at 0.2 mg / kg QD. In some embodiments, substance X is orally administered at 1.1 mg / kg QD.

[0041] The substance Y can be administered according to the body weight of the subject, and a non-limiting example range may be 0.1 to 10 mg / kg (referring to a single dose), preferably 1 to 5 mg / kg, for example, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg, and in some embodiments, the dose of toripalimab is 1 mg / kg.

[0042] In some embodiments, the dosage of substance Y is 6 to 600 mg per dose, for example, 40 mg, 80 mg, 120 mg, 160 mg, 200 mg, 240 mg, 280 mg, 320 mg, 360 mg, 400 mg, 440 mg, 480 mg, 520 mg, 560 mg, or 600 mg, and preferably 240 mg per dose.

[0043] The administration frequency of said substance Y may be QW (once a week), BIW (twice a week), Q2W (once every two weeks) or Q3W (once every three weeks).

[0044] In some embodiments, substance Y is administered with a BIW frequency.

[0045] In some embodiments, substance Y is orally administered at the dosage and frequency described above, e.g., substance Y is injected at 1 mg / kg BIW, in some embodiments, substance Y is injected at 240 mg / dose Q3W.

[0046] When substance X and substance Y are administered separately, they can be administered consecutively according to their respective administration periods. The administration periods for substance X and substance Y may start at the same time or at different times. For example, substance X and substance Y may be administered consecutively according to their respective administration periods starting on the same day, or substance X may be administered starting on the second, third, or more days after the start of administration of substance Y, and then both substances may be administered consecutively according to their respective administration periods.

[0047] As used herein, the term "treatment" refers to therapeutic therapy. With respect to a particular disease, treatment refers to (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disease or (b) one or more biological manifestations of the disease, (3) ameliorating one or more symptoms, effects, or side effects associated with the disease or one or more symptoms, effects, or side effects associated with the disease or its treatment, or (4) reducing one or more biological manifestations of the disease or condition.

[0048] As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat a disease or condition described in this application when administered to a subject. The amount of a compound that constitutes a "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age of the subject being treated, but can be adjusted as needed by one skilled in the art.

[0049] The term "subject" as used herein refers to any animal to which or which has been administered an embodiment of the present invention, preferably a mammal, and most preferably a human. As used herein, the term "mammal" includes all mammals, including, but not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared with a compound that is relatively non-toxic and pharmaceutically acceptable, either in solution or in a suitable inert solvent. When compounds contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of a pharmaceutically acceptable base.

[0051] As used herein, the term "container" refers to any container or closure suitable for storing, transporting, dispensing and / or handling pharmaceutical products.

[0052] The term "pharmaceutical adjuvants" as used herein refers to excipients and additives used in the manufacture and formulation of pharmaceuticals, and refers to all substances contained in drug formulations except for active ingredients. For details, please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0053] The above-mentioned preferred conditions can be arbitrarily combined to obtain each preferred embodiment of the present invention, provided that this does not violate the common knowledge of the art.

[0054] The reagents and raw materials used in the present invention are commercially available.

[0055] Positive advancement effects of the present invention: The present invention provides a pharmaceutical combination of Compound I and toripalimab, which shows superior antitumor effects compared with single agents.

[0056] [Brief description of the drawing] [Figure 1] Tumor volume growth curve in mice.

[0057] [Mode for Carrying Out the Invention] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or product instructions.

[0058] Example 1: Antitumor effect of the combination of Compound I and toripalimab on subcutaneously transplanted tumors of mouse colon cancer cell CT26 1.1 Experimental conditions BALB / c-hPD1 mice, female, 6.9 weeks old (age at the time of inoculation) were provided by Jiangsu GemPharmatech Co., Ltd.

[0059] Toripalimab was provided by Shanghai Junshi Biosciences Co., Ltd.

[0060] Compound I:

[0061] [ka]

[0062] 1.2 Experimental model BALB / c-hPD1 mice were subcutaneously inoculated with CT26 cells, which were provided by Jiangsu GemPharmatech Co., Ltd.

[0063] 1.3 Cell culture Mycoplasma testing for CT26 cells was negative, and the resuscitation passage was Pn+8. Mouse colon carcinoma CT26 cells were cultured in monolayers in RPMI 1640 medium supplemented with 10% (v / v) fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C, 5% CO2, and 95% relative humidity. Depending on the cell density, they were trypsinized and passaged. Cells were digested and inoculated when in the logarithmic growth phase.

[0064] 1.4 Tumor inoculation CT26 cells in the logarithmic growth phase (inoculation passage number Pn+11) were harvested, the culture medium was removed, and the cells were washed twice with DPBS. The inoculation amount was 5 x 10 5 The cells were inoculated at 100 μL per mouse (the cell viability before and after tumor bearing was 94.31% and 91.43%, respectively).

[0065] 1.5 Group Division The tumor volume was 80.15 mm 3 When the tumor volume reached 100 mg / kg, the mice were randomly divided into groups according to the tumor volume as shown in Table 1 below. The day of grouping was defined as D0.

[0066] [Table 1]

[0067] Note: 1) The vehicle control group was physiological saline.

[0068] 2)a. The solvent used was saline.

[0069] 3)b, the medium used was 1% DMSO + 99% (1% methylcellulose).

[0070] 1.6 Administration Administration began on D0, with a volume of 10 μL / g × mouse body weight (g), and the administration protocol was as shown in Table 1. In the combined administration group, each drug was administered alone at double the drug volume without changing the drug concentration. The administration order was consistent for each administration.

[0071] 1.7 Observation In the early stages, tumors in mice were measured twice a week, and body weights were also measured twice a week. In the later stages, tumor growth was accelerated, so the observation frequency was adjusted to three times a week. After 40 days of observation, tumor growth curves (shown in Figure 1) were obtained and analyzed.

[0072] 1.8 Experimental results The tumor growth status obtained after 40 days is shown in Table 2 below.

[0073] [Table 2]

[0074] Note: "-" means no test data available.

[0075] Statistical analysis of D22 tumor volume data showed that the toripalimab group (TGI TV = 62.16%, tumor growth inhibition rate = 1 - tumor weight of experimental group / tumor weight of control group), Compound I group (TGI TV =84.57%), Toripalimab and Compound I combination group (TGI TV The tumor volume of the toripalimab and compound I combination group (TGI 1) was significantly different from that of the vehicle control group (P<0.05 or P<0.01). Statistical analysis of the D31 tumor volume data showed that the tumor volume of the toripalimab and compound I combination group (TGI 1) was significantly different from that of the vehicle control group (P<0.05 or P<0.01). TV =94.63%), toripalimab single agent group (TGI TV =24.42%), Compound I single drug group (TGI TV There was a significant difference in tumor volume between the two groups (83.37%) (P<0.05). Statistical analysis of the tumor volume data on day 40 revealed a significant difference in tumor volume between the Compound I and toripalimab combination group and the Compound I alone group (P<0.05).

[0076] In summary, the results of this experiment showed that in a subcutaneously implanted tumor model of mouse colon cancer cell CT26, toripalimab alone, compound I alone, and the combination of compound I and toripalimab all exhibited tumor-inhibitory effects compared to the control group (saline), but the combination of compound I and toripalimab exhibited superior tumor-inhibitory effects compared to toripalimab alone or compound I alone.

[0077] Example 2: Efficacy data of Compound I in combination with toripalimab for cervical adenocarcinoma in clinical trials.

[0078] Case report: Subject 1, a 69-year-old woman, was diagnosed with cervical adenocarcinoma on October 28, 2022, based on a pathology report. She provided informed consent to participate in a Phase Ib / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of the combination of Compound I and toripalimab in advanced solid tumors on November 11, 2022, and began treatment on November 18, 2022. Compound I was administered as a 0.7 mg tablet once daily. The 0.7 mg dose consisted of one 0.5 mg tablet of Compound I and two 0.1 mg tablets of Compound I. Toripalimab was administered intravenously at a dose of 240 mg every three weeks. The baseline target lesion was a confluent lymph node adjacent to the left external iliac vessel, measuring 111 mm in maximum diameter. After the combination of Compound I and toripalimab, the therapeutic effect was significant, with the tumor shrinking sustained, with a maximum tumor shrinkage rate of 17.1% and lasting for 8 cycles (21 days per cycle).

[0079] Example 3: Efficacy data of the combination of Compound I and toripalimab for head and neck squamous cell carcinoma in clinical trials.

[0080] Case report: Subject 2, a 59-year-old male, underwent a subtotal laryngectomy (upper circular) on October 28, 2020. The postoperative pathology report revealed a diagnosis of laryngeal cancer. He underwent postoperative radiation therapy from November 30, 2020, to January 21, 2021. An MRI scan confirmed recurrence on November 15, 2022. He provided informed consent to participate in a Phase Ib / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of the combination of Compound I and toripalimab in advanced solid tumors on November 17, 2022. Treatment began on November 25, 2022. Compound I was administered as a 0.7 mg tablet once daily. The 0.7 mg dose consisted of one 0.5 mg tablet of Compound I and two 0.1 mg tablets of Compound I. Toripalimab was administered intravenously at a dose of 240 mg every three weeks. The baseline target lesion was in the larynx, measuring 34 mm in maximum diameter. After the combination of Compound I and toripalimab, the treatment effect was significant, with the tumor shrinking to less than 5 mm, demonstrating a partial response and 85.3% tumor shrinkage, with the subject's partial response lasting for more than 10 cycles (21 days per cycle).

[0081] Example 4: Efficacy data of Compound I in combination with toripalimab for non-small cell lung cancer in clinical trials.

[0082] Case report: Subject 3, a 73-year-old male, was diagnosed with non-small cell lung cancer by pathological examination. Immunohistochemistry revealed high expression of PD-L1, and histogenetic testing revealed double-negative EGFR / ALK. On July 21, 2023, he provided informed consent to participate in a Phase Ib / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of the combination of Compound I and toripalimab in advanced solid tumors. After treatment, Compound I was administered as a 0.9 mg tablet once daily. The 0.9 mg dose consisted of one 0.5 mg tablet of Compound I and four 0.1 mg tablets of Compound I. Toripalimab was administered intravenously at a dose of 240 mg every three weeks. After the combination of Compound I and toripalimab, the therapeutic effect was significant, with tumor shrinkage of 48.2%, demonstrating partial response (PR, where the sum of the maximum diameters of the target lesions decreased by 30% or more and was maintained for at least 4 weeks).

[0083] Example 5: Efficacy data of Compound I in combination with toripalimab for urothelial carcinoma in clinical trials.

[0084] Case Report: Subject 4, a 71-year-old woman, was diagnosed with urothelial carcinoma of the right ureter in a pathology report from June 2023. She had previously undergone first-line gemcitabine and cisplatin combination therapy and relapsed. She provided informed consent to participate in a Phase 1b / 2 clinical trial evaluating the safety, tolerability, and preliminary efficacy of compound I in combination with toripalimab in advanced solid tumors on July 14, 2023. She began treatment on July 17, 2022. Compound I was administered as a 1.1 mg tablet once daily. The 1.1 mg dose consisted of two 0.5 mg tablets of compound I and one 0.1 mg tablet of compound I. Toripalimab was administered intravenously at a dose of 240 mg once every three weeks. Baseline target lesions included the left bladder wall and right arm, measuring a total of 81.8 mm. After the combination of Compound I and toripalimab, the therapeutic effect was significant, with sustained tumor shrinkage, the maximum tumor shrinkage was 38.9 mm, the tumor shrinkage rate was 52.4%, and PR was demonstrated, lasting for at least 6 cycles (21 days per cycle).

[0085] Example 6: Efficacy data of the combination of Compound I and toripalimab for nasopharyngeal carcinoma in clinical trials.

[0086] Case Report: Subject 5, a 54-year-old male, was diagnosed with nasopharyngeal carcinoma based on pathological findings. His cancer recurred after undergoing definitive radiation therapy in July and August 2022. He provided informed consent for participation in a Phase Ib / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of the combination of Compound I and toripalimab in advanced solid tumors on February 13, 2023, and treatment began on February 24, 2023. Compound I was administered as a 0.9 mg tablet once daily. The 0.9 mg dose included one 0.5 mg tablet of Compound I and four 0.1 mg tablets of Compound I. Toripalimab was administered intravenously at a dose of 240 mg once every three weeks. Baseline target lesions measured 26 mm in the 17th layer lymph node (left axilla) during the portal venous phase and 18 mm in the 19th layer lymph node during the portal venous phase, for a total of 44 mm. After the combination of Compound I and toripalimab, the therapeutic effect was significant, and the tumor achieved PR (partial response, where the sum of the maximum diameters of the target lesions decreased by 30% or more and lasted for at least 4 weeks), which lasted for 12 cycles (21 days per cycle). The tumor continued to shrink during treatment, with a maximum shrinkage rate of 72.7%.

[0087] Example 7: Efficacy data of the combination of Compound I and toripalimab against cervical squamous cell carcinoma in clinical trials.

[0088] Case Report: Subject 6, a 59-year-old woman, was initially diagnosed with cervical squamous cell carcinoma in March 2020 and underwent chemoradiotherapy. She provided informed consent to participate in a Phase 1b / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of Compound I in combination with toripalimab in advanced solid tumors on March 31, 2023, and began treatment on April 7, 2023. Compound I was administered as a 1.1 mg tablet once daily. The 1.1 mg dose consisted of two 0.5 mg tablets of Compound I and one 0.1 mg tablet of Compound I. Toripalimab was administered intravenously at a dose of 240 mg every three weeks. The baseline target lesion was a left cervical lymph node measuring 15 mm in maximum diameter. After the combination of Compound I and toripalimab, the therapeutic effect was significant, with the tumor shrinking sustained, up to a maximum of 10 mm, with a tumor shrinkage rate of 36.3% (PR), sustained for 8 cycles (21 days per cycle).

[0089] Example 8: Efficacy data of the combination of Compound I and toripalimab against cervical squamous cell carcinoma in clinical trials.

[0090] Case report: Subject 7, a 75-year-old woman, was diagnosed with invasive squamous cell carcinoma of the cervix on March 31, 2023. On April 4, 2023, she provided informed consent to participate in a Phase Ib / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of the combination of Compound I and toripalimab in advanced solid tumors. Treatment began on April 7, 2023. Compound I was administered as a 1.1 mg tablet once daily. The 1.1 mg dose consisted of two 0.5 mg tablets of Compound I and one 0.1 mg tablet of Compound I. Toripalimab was administered intravenously at a dose of 240 mg once every three weeks. The baseline target lesion was located in the cervix, measuring 21 mm in maximum diameter. After the combination of Compound I and toripalimab, the therapeutic effect was significant, with the tumor shrinking continuously, up to 5 mm (PR), with a tumor shrinkage rate of 76.2%, which lasted for 10 cycles (21 days per cycle).

[0091] Example 9: Efficacy data of the combination of Compound I and toripalimab against cervical squamous cell carcinoma in clinical trials.

[0092] Case Report: Subject 8, a 48-year-old woman, was diagnosed with cervical keratinizing invasive squamous cell carcinoma (KSCC) on February 8, 2022, according to a pathology report. The patient's disease had previously recurred after first-line treatment with paclitaxel and cisplatin. She provided informed consent to participate in a Phase Ib / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of compound I in combination with toripalimab in advanced solid tumors on June 2, 2023. Treatment began on June 9, 2023. Compound I was administered as a 1.1 mg tablet once daily. The 1.1 mg dose consisted of two 0.5 mg tablets of compound I and one 0.1 mg tablet of compound I. Toripalimab was administered intravenously at a dose of 240 mg every three weeks. The baseline target lesion was in the vaginal area and measured 36 mm in maximum diameter. After the combination of Compound I and toripalimab, the therapeutic effect was significant, with the tumor shrinking sustained, with a maximum tumor shrinkage rate of 36.1% (23 mm, PR) lasting for at least 8 cycles (21 days per cycle).

[0093] Example 10: Efficacy data of the combination of Compound I and toripalimab for head and neck squamous cell carcinoma in a clinical trial.

[0094] Case report: Subject 9, a 73-year-old male, was first diagnosed with right maxillary gingival squamous cell carcinoma in August 2021. In the same month, he underwent right maxillary extended resection, local extended resection of the right palate tumor, and right cervical lymph node dissection. The patient had previously received first-line treatment with karelizumab, SI-B001 (an EGFR / HER3 dual antibody), and paclitaxel, but the disease recurred due to resistance. On June 27, 2023, the patient provided informed consent to participate in a Phase 1b / II clinical trial evaluating the safety, tolerability, and preliminary efficacy of the combination of Compound I and toripalimab in advanced solid tumors. Treatment began on July 2, 2023. Compound I was administered as a 1.1 mg tablet once daily. The 1.1 mg dose consisted of two 0.5 mg tablets of Compound I and one 0.1 mg tablet of Compound I. Toripalimab was administered intravenously at a dose of 240 mg once every three weeks. The baseline target lesion was located on the right buccal surface and measured 30 mm in maximum diameter. After the combination of Compound I and toripalimab, the therapeutic effect was significant, with sustained tumor shrinkage, with a maximum tumor shrinkage rate of 100% (CR, complete remission) lasting for at least 6 cycles (21 days per cycle).

[0095] Although specific embodiments of the present invention have been described above, it is understood by those skilled in the art that these are merely examples and that various changes and modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims. [Brief explanation of the drawings]

[0096] [Figure 1] 1 shows the tumor volume increase curve of mice.

Claims

1. a substance X which is compound I or a pharmaceutically acceptable salt thereof; and substance Y is toripalimab. 【Chemistry 1】

2. (1) The substance X and the substance Y are administered simultaneously or separately; (2) the condition of orally administering the substance X; (3) the condition that the substance Y is administered by injection; The pharmaceutical combination according to claim 1, characterized in that it satisfies any one or more of the following:

3. a first pharmaceutical composition comprising a substance X, which is compound I or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient; and A second pharmaceutical composition comprising substance Y, which is toripalimab, and a pharmaceutical excipient. and a pharmaceutical combination comprising: 【Chemistry 2】

4. (1) providing the first pharmaceutical composition in the form of an oral dosage form; (2) providing the second pharmaceutical composition in the form of an injectable dosage form; The pharmaceutical combination according to claim 3, characterized in that it satisfies one or more of the following:

5. a first container containing the first pharmaceutical composition according to claim 3 or 4; and A second container containing the second pharmaceutical composition according to claim 3 or 4. and a combination pharmaceutical kit comprising:

6. Use of the pharmaceutical combination according to any one of claims 1 to 4 in the manufacture of a medicament for treating cancer.

7. 1. Use of substance X in the manufacture of a medicament for treating cancer, wherein said substance X is compound I or a pharmaceutically acceptable salt thereof, said substance X being used in combination with substance Y, and said substance Y being toripalimab. 【Transformation 3】

8. 1. Use of substance Y in the manufacture of a medicament for treating cancer, wherein said substance Y is toripalimab, and said substance Y is used in combination with substance X, wherein substance X is compound I or a pharmaceutically acceptable salt thereof. 【Chemistry 4】

9. The cancer is colon cancer, lung cancer, cervical cancer, head and neck cancer, nasopharyngeal cancer or urothelial cancer, preferably colon cancer; When the cancer is lung cancer, the lung cancer is preferably non-small cell lung cancer; When the cancer is head and neck cancer, the head and neck cancer is preferably head and neck squamous cell carcinoma; The use according to any one of claims 6 to 8, characterized in that when the cancer is cervical cancer, the cervical cancer is preferably cervical adenocarcinoma or cervical squamous cell carcinoma.

10. (1) The substance X and the substance Y are administered simultaneously or separately; (2) the condition of orally administering the substance X; (3) the condition that the substance Y is administered by injection; (4) The substance X is administered according to the body weight of the subject, and the dosage is 0.1 mg / kg to 1 mg / kg, for example, 0.2 mg / kg; (5) The dose of the substance X is 0.1 to 2.0 mg / injection, for example, 0.1 mg / injection, 0.2 mg / injection, 0.3 mg / injection, 0.4 mg / injection, 0.5 mg / injection, 0.6 mg / injection, 0.7 mg / injection, 0.8 mg / injection, 0.9 mg / injection, 1.0 mg / injection, 1.1 mg / injection, 1.2 mg / injection, 1.3 mg / injection, 1.4 mg / injection, 1.5 mg / injection, 1.6 mg / injection, 1.7 mg / injection, 1.8 mg / injection, 1.9 mg / injection or 2.0 mg / injection, preferably 1.1 mg / injection; (6) The frequency of administration of the substance X is QD, QOD, or BID, for example, QD; (7) The substance Y is administered according to the body weight of the subject, and the dosage is 0.1 mg / kg to 10 mg / kg, for example, 1 mg / kg to 5 mg / kg, for example, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg; (8) The dosage of the substance Y is 6 to 600 mg / dose, for example, 40 mg / dose, 80 mg / dose, 120 mg / dose, 160 mg / dose, 200 mg / dose, 240 mg / dose, 280 mg / dose, 320 mg / dose, 360 mg / dose, 400 mg / dose, 440 mg / dose, 480 mg / dose, 520 mg / dose, 560 mg / dose, or 600 mg / dose, preferably 240 mg / dose; (9) The administration frequency of the substance Y is QW, BIW, Q2W, or Q3W, for example, Q2W or Q3W. The use according to any one of claims 6 to 9, characterized in that one or more of the following are satisfied:

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