JP7315167B2 - A therapeutic or preventive agent for skin disorders caused by anticancer drug administration - Google Patents

Description

TECHNICAL FIELD The present invention relates to therapeutic or preventive agents for skin disorders caused by administration of anticancer agents.

In recent years, as anticancer agents, molecularly targeted drugs targeting signal molecules involved in the development and proliferation of cancer have been developed and applied clinically. While the side effects of conventional anticancer drugs are reduced, multikinase inhibitors, anti-epidermal growth factor receptor (EGFR) antibody drugs, and EGFR tyrosine kinase inhibitors in particular frequently cause skin disorders as side effects (Non-Patent Document 1). Specifically, hand-foot syndrome, acne-like eruptions, dryness, paronychia, etc. appear, and pain, itching, changes in appearance, etc., significantly reduce the quality of life (QOL) of patients undergoing cancer treatment. Skin disorders such as hand-foot syndrome occur with conventional chemotherapeutic agents such as fluorouracil, pegylated liposomal doxorubicin, and capecitabine, in addition to molecular-targeted drugs (Patent Documents 1 and 2).

Hand-foot syndrome is often observed early after the initiation of treatment with a molecular-targeted drug, and is a serious side effect related to continuation of treatment (Non-Patent Document 2). Furthermore, it has been reported that a group of patients with skin disorders such as hand-foot syndrome tended to have a higher antitumor effect and a longer survival period compared to a group of patients without skin disorders. Therefore, it is important from a therapeutic point of view to maximize the antitumor effect by prolonging the administration period of molecular-targeted drugs while skillfully controlling the symptoms of skin disorders (Non-Patent Document 3).

Multi-kinase inhibitors such as sorafenib inhibit cancer cell proliferation by inhibiting multiple kinases involved in tumor cell proliferation and angiogenesis, such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), Raf, c-KIT, and FLT-3. A characteristic side effect of these drugs is hand-foot syndrome, and the symptoms are redness on the palms and soles, edema, hyperkeratosis (hyperkeratosis), paresthesia, pain, and in severe cases blisters and bleeding. However, the details of the mechanism of occurrence of hand-foot syndrome are unknown, no preventive method has been established, and there are currently only symptomatic treatments such as reducing physical irritation to the skin, exfoliating with emollients containing urea and salicylic acid, using moisturizing agents and steroids (Non-Patent Document 6).

Histopathological findings of the palms and soles of hand-foot syndrome show band-shaped necrosis of epidermal keratinocytes in the stratum spinosum to granular layer of the epidermis, and hyperkeratosis (hyperkeratosis) and parakeratosis in the stratum corneum. In addition, abnormalities in eccrine sweat glands, dilatation of capillaries, perivascular lymphocyte infiltration, etc. have been reported (Non-Patent Document 4). As a cause of hand-foot syndrome due to multikinase inhibitors, there is a theory that the onset is caused by an inhibitory reaction of c-KIT and PDGFR that are expressed in the ductal epithelium of the eccrine sweat glands of the palms and soles, and that the anti-VEGF action thins the capillaries, and the above-mentioned inhibitory reaction suppresses the proliferation of fibroblasts and endothelial cells, thereby weakening the vascular reserve function and making it easier to develop due to friction and trauma to frequently occurring sites such as the palms and soles. ).

Examples of patent documents related to therapeutic agents for hand-foot syndrome include Patent Document 1 disclosing an invention for treating or preventing hand-foot syndrome induced by fluoropyrimidine chemotherapy such as 5-FU using allopurinol, which has been used for many years in the treatment of gout, Patent Documents 2 and 3 disclosing an invention for treating or preventing hand-foot syndrome caused by anticancer drug administration using a specific anticholinergic drug, and patent documents such as hand-foot syndrome caused by molecular targeted drugs using histone deacetylase inhibitors such as phenylbutyrate. There is a patent document 4 disclosing an invention for treating skin side effects.

However, there is no literature disclosing or suggesting the use of azole antifungal drugs for treatment of skin disorders such as hand-foot syndrome.

Japanese Patent Publication No. 2009-542581 JP 2011-225553 A Patent No. 4761000 Japanese Patent Publication No. 2012-530076

Heidary et al, J Am Acad Dermatol, 58: 545-570, 2008 Lee et al, Br J Dermatol, 161: 1045-1051, 2009 Vincenzi et al, Oncologist, 15: 85-92, 2010 Lacouture et al, Ann Oncol, 19: 1955-1961, 2008 Autier et al, Arch Dermatol, 144: 886-892, 2008 Chu et al, Acta Oncol, 47: 176-186, 2008 Lammie et al, J Histochem Cytochem, 42: 1417-1425, 1994

If serious skin disorders occur as a side effect of anticancer drugs, the patient's QOL will be significantly reduced, and even if a sufficient therapeutic effect is obtained against cancer, treatment with that anticancer drug may have to be abandoned. If skin disorders can be treated and prevented, it is possible to continue anticancer drug treatment while maintaining QOL in cancer patients who have obtained favorable therapeutic effects. There is still a need for effective means for treating and preventing skin disorders caused by administration of anticancer drugs.

Accordingly, an object of the present invention is to provide effective means for treating and preventing skin disorders such as hand-foot syndrome caused as a side effect of anticancer agents.

As a result of intensive research, the inventors of the present application surprisingly found that azole antifungal drugs have the effect of restoring the viability of epidermal keratinocytes that have been reduced by treatment with anticancer drugs, and are therefore effective in the treatment and prevention of skin disorders that occur as side effects of anticancer drugs, and have completed the present invention.

That is, the present invention provides a therapeutic or prophylactic agent for hand-foot syndrome caused by administration of a multikinase inhibitor , containing an azole antifungal drug as an active ingredient.

The agent of the present invention has the effect of recovering the survival rate of epidermal keratinocytes that has decreased due to treatment with anticancer agents, and is particularly effective in treating and preventing skin disorders such as hand-foot syndrome, which is a problem with a high frequency of occurrence with molecular-targeted drugs.

This is the result of examining the cytoprotective effect of itraconazole against sorafenib-induced cytotoxicity in a monolayer culture system of normal human epidermal keratinocytes (NHEKs). (A) Results of examining the cytotoxicity of three multikinase inhibitors (sorafenib, regorafenib, lenvatinib). (B) Viability of NHEKs treated with itraconazole alone (0.1, 1, 10 μM). (C) Viability of NHEKs treated with sorafenib (7 μM) and itraconazole (0.1, 1, 10 μM). ^*** P < 0.001 (vs. vehicle (-)), ^††† P < 0.001 (vs. 7 μM sorafenib alone). This is the result of examining the cytoprotective effect of various azole antifungal drugs against sorafenib-induced cytotoxicity in a monolayer culture system of normal human epidermal keratinocytes (NHEKs). (A) Survival rate of NHEKs treated with various azole antifungal drugs (1 μM) alone. ^** P < 0.01 (vs. Vehicle), ^*** P < 0.001 (vs. Vehicle). (B) Survival rate of NHEKs treated with sorafenib (7 µM) and various azole antifungal drugs (1 µM). ^*** P < 0.001 (vs. Sorafenib (-)). ^† P < 0.05, ^†† P < 0.01, ^††† P < 0.001, ns non-significant (vs. 7 μM sorafenib alone (Vehicle)). This is the result of examining the cytoprotective effect of itraconazole against sorafenib-induced cytotoxicity using a cultured three-dimensional human epidermis model. (A) Cell viability in a cultured three-dimensional human epidermis model treated with itraconazole alone (10 μM). (B) Cell viability of a cultured three-dimensional human epidermis model treated with each concentration of sorafenib (20, 30, 40, 50 μM). ^*** P < 0.001, ^** P < 0.01 (vs. vehicle (-)). (C) Cell viability in cultured three-dimensional human epidermis models treated with sorafenib (40 μM) and itraconazole (5, 10 μM). ^*** P < 0.001 (vs. vehicle (-)), ^††† P < 0.001 (vs. 40 μM sorafenib alone).

The agent for treating or preventing skin disorders caused by administration of an anticancer agent of the present invention contains an azole antifungal agent as its active ingredient.

Azole antifungal agents are roughly classified into triazoles having a triazole ring in the molecule and imidazoles having an imidazole ring in the molecule. Known triazole antifungal agents include itraconazole, efinaconazole, fluconazole, voriconazole, ravuconazole, fosravuconazole (prodrug of ravuconazole), fosfluconazole (prodrug of fluconazole), posaconazole, and the like. Known imidazole antifungal agents include luliconazole, isoconazole, ketoconazole, clotrimazole, lanoconazole, oxiconazole, sulconazole, neticonazole, bifonazole, miconazole, and econazole. Methods for preparing these compounds are also known. The term azole antifungal agent in the present invention includes free forms of compounds including the above specific examples, pharmaceutically acceptable salts of various compounds, and solvates of various compounds and pharmaceutically acceptable salts thereof.

The azole antifungal agent used in the present invention is not particularly limited, but preferred examples include itraconazole, ketoconazole, luliconazole, efinaconazole, isoconazole, lanoconazole, sulconazole, clotrimazole, bifonazole, and at least one selected from the group consisting of pharmaceutically acceptable salts thereof; and clotrimazole, and at least one selected from the group consisting of pharmaceutically acceptable salts thereof; or itraconazole, efinaconazole, isoconazole and lanoconazole, and at least one selected from the group consisting of pharmaceutically acceptable salts thereof. Among them, itraconazole can be preferably used. However, the scope of the present invention is not limited to these.

A pharmaceutically acceptable salt can be any pharmaceutically acceptable salt such as an acid addition salt, a base addition salt, an amino acid addition salt, and the like. Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate (mesylate), benzenesulfonate, and p-toluenesulfonate (tosylate). Specific examples of base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts, and organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts, and diisopropylammonium salts. Specific examples of amino acid addition salts include addition salts of amino acids such as glycine, phenylalanine, lysine, aspartic acid and glutamic acid. Any salt can be produced by a method known in the field of chemical synthesis.

Specific examples of solvates include, but are not limited to, hydrates, ethanolates, and the like, and any solvate with a pharmaceutically acceptable solvent may be used. Compounds such as itraconazole belonging to azole antifungal drugs and solvates of salts thereof can be produced by methods known in the field of chemical synthesis.

In the present invention, the term "dermatopathy" includes various disorders that occur on the skin as side effects of anticancer agents, such as redness, erythema, edema, bleeding, pain, pruritus, inflammation, paresthesia, rash, desquamation, stratum corneum peeling, and blisters. A typical example of a skin disorder targeted by the agent of the present invention is hand-foot syndrome.

In the present invention, the term "treatment or prevention of skin disorders" includes healing, mitigation or alleviation of skin disorders that have already occurred due to administration of anticancer drugs, and suppression of the occurrence of skin disorders due to administration of anticancer drugs.

The skin disorders targeted by the present invention are skin disorders caused by administration of anticancer agents. The type of anticancer drug is not particularly limited, and includes various anticancer drugs that can cause skin damage as a side effect, including molecular targeted drugs and anticancer drugs that are not classified as molecular targeted drugs.

Typical examples of anticancer drugs that belong to molecular-targeted drugs include kinase inhibitors that target kinases such as tyrosine kinases, and antibody drugs that target molecules that are expressed in cancer cells or molecules that are highly expressed in tumors.

Kinase inhibitors include tyrosine kinase inhibitors that target tyrosine kinases such as EGFR, Her2, ALK, MET, and JAK, inhibitors that target kinases other than tyrosine kinases such as MEK and BRAF, and multi-kinase inhibitors that inhibit multiple kinases in addition to inhibitors that target these specific kinases. Specific examples of known kinase inhibitors include gefitinib (Iressa (registered trademark)), erlotinib (Tarceva (registered trademark)), imatinib (Gleevec (registered trademark)), lapatinib (Tikerb (registered trademark)), tivantinib, and the like, as tyrosine kinase inhibitors. Kinase inhibitors other than tyrosine kinases include BRAF kinase inhibitors such as Vemurafenib and Dabrafenib, and MEK inhibitors such as Trametinib. Multikinase inhibitors include sorafenib (Nexavar (registered trademark)), regorafenib (Stivarga (registered trademark)), lenvatinib (Lenvima (registered trademark)), and the like. The kinase inhibitor can be used in the form of a free form of each compound, a pharmaceutically acceptable salt of each compound, or a solvate of each compound or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts and solvates of compounds belonging to kinase inhibitors are the same as above, and can be produced by methods known in the field of chemical synthesis.

Examples of antibody drugs include cetuximab (Erbitux (registered trademark)), panitumumab (Vectibix (registered trademark)), rituximab (Rituxan (registered trademark)), alemtuzumab (Mabcampus (registered trademark)), trastuzumab (Herceptin (registered trademark)), and the like.

Examples of anticancer agents other than molecular targeted drugs include platinum agents (DNA synthesis inhibitor) such as cisplatin, carboplatin, and oxaliplatin; pyrimidine drugs (DNA synthesis inhibitor) such as fluorouracil and gemcitabine; camptothecin drugs such as irinotecan and topotecan (DNA synthesis inhibitor); epipodophyllotoxin drugs such as etoposide (DNA synthesis inhibitor); vinca alkaloid drugs such as vin (cell division inhibition); anthracycline drugs such as doxorubicin, epirubicin and pirarubicin (DNA synthesis inhibition); taxane drugs such as paclitaxel and docetaxel (apoptosis inducers);

In one aspect of the present invention, the anticancer drug is a molecularly targeted drug. Molecularly targeted drugs may be, for example, kinase inhibitors. Preferred examples of kinase inhibitors include at least one selected from the group consisting of sorafenib, regorafenib and lenvatinib, and pharmaceutically acceptable salts thereof (e.g., sorafenib tosilate, lenvatinib mesylate) and solvates (e.g., regorafenib hydrate), particularly sorafenib or a pharmaceutically acceptable salt thereof. However, the scope of the present invention is not limited to these.

Therapeutic or preventive effect on skin disorders caused by anticancer drug administration can be evaluated, for example, by using cultured skin cells such as epidermal keratinocytes, and whether or not there is an effect of recovering the cell survival rate that has decreased due to anticancer drug treatment. As described in the examples below, evaluation can be performed using monolayer cultured cells, and evaluation can also be performed using a cultured three-dimensional human epidermis model. Non-thinning of the granular layer, hypertrophy of spinous cells in the upper epidermis, and thickening of the basal layer are the histological characteristics of hand-foot syndrome (Heidary et al, J Am Acad Dermatol, 58, 545-570, 2008.). et al, Biol Pharm Bull, 40, 1530-1536, 2017.; Kazuhiro Yamamoto, Medical Pharmacology, 43, 237-244, 2017.).

Azole antifungal agents can be used as therapeutic or preventive agents for skin disorders caused by administration of anticancer agents when administered to mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, monkeys, cows, sheep, humans, etc.), particularly humans.

The administration route of the agent for treating or preventing skin disorders of the present invention is not particularly limited. It may be administered locally by coating or injection to the affected area where skin disorder has occurred, or may be administered systemically orally or parenterally. Parenteral administration routes include intravenous administration, intraarterial administration, subcutaneous administration, intramuscular administration, and intrarectal administration. Appropriate dosage forms may be prepared according to the specific route of administration. For example, ointments, creams, lotions, external liquids, gels, etc. for topical administration by application, injections for local administration by injection into the affected area, capsules (including hard capsules, soft capsules, microcapsules), tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, syrups, emulsions, suspensions, etc. for systemic administration by oral administration, and systemic administration by parenteral administration. may be prepared into dosage forms such as injections, infusions, infusions and suppositories.

Preparation of formulations in the above dosage forms can be carried out according to known manufacturing methods generally used in the pharmaceutical field. If necessary, excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers and the like that are commonly used in the field of formulations can be incorporated in the preparation. As the formulations of the known azole antifungal drugs exemplified above, formulations for topical application such as ointments, creams and liquids for external use, as well as formulations such as intravenous injections, injections and oral tablets have already been clinically used against fungal infections.

The dosage of the agent of the present invention can be appropriately selected depending on the age and weight of the patient, the condition and site of the skin disorder, the type of azole antifungal drug used, the route of administration, and the like. For example, the daily dose of the active ingredient for an adult with a body weight of about 60 kg may be about 1 μg to 100 g for local administration by application, about 0.1 μg to 1 g for oral administration, and about 0.1 μg to 1 g for systemic administration by intravenous injection. The daily dose may be administered once or divided into several doses. It may be administered daily or every few days. The administration period of the agent of the present invention may be until a certain therapeutic effect for skin disorders is obtained (until the skin disorders disappear or are reduced to a level that does not interfere with daily life), or preventive administration may be continued even after the therapeutic effects for skin disorders are obtained. After the start of administration of the anticancer agent, it may be administered prophylactically before the occurrence of skin disorder, for example, the agent of the present invention may be continuously administered over the period of administration of the anticancer agent.

The agent for treating or preventing skin disorders caused by administration of an anticancer agent of the present invention may be used in appropriate amounts or in combination with other agents in order to complement or enhance the therapeutic or preventive effect or to reduce the dosage.

EXAMPLES The present invention will be described in more detail below based on examples. However, the present invention is not limited to the following examples.

1. Cytoprotective effect of azole antifungal drugs against cytotoxicity induced by multikinase inhibitors (normal human epidermal keratinocytes; monolayer culture system)
Using a monolayer culture system of normal human epidermal keratinocytes (NHEKs) (Lonza), we investigated cytotoxicity induced by multikinase inhibitors and the effect of azole antifungal drugs on this cytotoxicity.

1-1. Cytotoxicity of multikinase inhibitors
1×10 ⁴ NHEKs/well were seeded in a 96-well microplate, multikinase inhibitors at various concentrations (1, 3, 5, 7, 10 μM) were added the next day, and cell proliferation and viability were evaluated 24 hours later using Cell counting kit-8 (Dojindo Laboratories). Sorafenib (Santa Cruz, sc-220125), regorafenib (TCI, R0142), and lenvatinib (Namiki Shoji, HY-10981) were used as multikinase inhibitors.

The results are shown in Figure 1A. Both multikinase inhibitors inhibited cell viability of NHEKs in a dose-dependent manner. Sorafenib and regorafenib had comparable cytotoxicity (<20% cell viability at 10 μM). On the other hand, lenvatinib tended to be relatively weakly cytotoxic (~60% cell viability at 10 μM).

1-2. After seeding NHEKs in the same manner as in 1-1, itraconazole (Sigma, I-6657) was added at each concentration (0.1, 1, 10 μM) the next day, and after 24 hours, cell proliferation and viability were evaluated using Cell counting kit-8. In an experiment to examine the effect of itraconazole on sorafenib-induced cytotoxicity, itraconazole was added and allowed to stand at 37°C for 30 minutes, then 7 μM sorafenib was added, and after 24 hours, cell counting kit-8 was used to evaluate cell growth and viability. Statistical processing in FIG. 1B was performed by One-way ANOVA (Dunnett's multiple comparison test), and statistical processing in FIG. 1C was performed by One-way ANOVA (Tukey's multiple comparison test).

FIG. 1B is the survival rate of NHEKs treated with itraconazole alone. No cytotoxicity was observed with itraconazole alone.

FIG. 1C shows the results of examining the effect of itraconazole on sorafenib-induced cytotoxicity. After addition of 7 μM sorafenib, cell viability of NHEKs decreased to approximately 20%. However, in the presence of itraconazole, cell viability was restored in an itraconazole dose-dependent manner. These data suggest that itraconazole has therapeutic and prophylactic effects against sorafenib-induced cutaneous cell injury.

1-3. Cytoprotective Effect of Various Azole Antifungal Agents After seeding NHEKs in the same manner as in 1-1, 1 μM of each azole antifungal agent was added the next day, and cell proliferation and viability were evaluated 24 hours later using a Cell counting kit-8. In an experiment to investigate the effect of each azole antifungal drug on sorafenib-induced cytotoxicity, the azole antifungal drug was added and allowed to stand at 37°C for 1 hour, then 7 μM sorafenib was added, and after 24 hours, cell proliferation and viability were evaluated using the Cell counting kit-8. When evaluating cell proliferation with the kit, the WST-8 reagent was added after washing the cells. The statistical processing of FIG. 2A was performed by One-way ANOVA (Dunnett's multiple comparison test), and the statistical processing of FIG. 2B was performed by One-way ANOVA (Tukey's multiple comparison test).

FIG. 2A shows the survival rate of NHEKs treated with azole antimycotics alone (average of two experiments). Although some antifungal drugs significantly increased the survival rate, none of the antifungal drugs caused single-agent cytotoxicity.

FIG. 2B shows the results of examining the effects of various azole antifungal drugs on sorafenib-induced cytotoxicity (mean value of two experiments). After addition of 7 μM sorafenib, cell viability of NHEKs decreased to approximately 20%. Azole antifungal drugs other than itraconazole were also found to have an effect of significantly recovering the cell viability or a tendency to recover the viability. These data suggest that azole antifungals other than itraconazole also have therapeutic and prophylactic effects against sorafenib-induced skin cell damage.

2. Cytoprotective effect of itraconazole against sorafenib-induced cytotoxicity (cultured three-dimensional human epidermis model; three-dimensional organ culture)
A test was performed using a cultured three-dimensional human epidermis model (EPI-200, Kurabo Industries). Three epidermal models were used for each test, and similar tests were conducted two to three times to confirm reproducibility. Statistical processing in FIG. 3B was performed by One-way ANOVA (Dunnett's multiple comparison test), and statistical processing in FIG. 3C was performed by One-way ANOVA (Tukey's multiple comparison test).

2-1. Effect of itraconazole on a cultured three-dimensional human epidermis model The epidermis model was precultured overnight at 37°C, the next day, the medium on the basal layer side of the epidermis model was replaced with a medium containing 10 µM itraconazole, cultured at 37°C for 96 hours, and then analyzed by MTT assay.

The results are shown in Figure 3A. Almost no cytotoxicity was observed with itraconazole alone.

2-2. Cytotoxicity of sorafenib on a cultured three-dimensional human epidermis model After preculturing in the same manner as in 2-1, the next day, the medium on the basal layer side of the epidermis model was replaced with a medium containing sorafenib at each concentration (20, 30, 40, 50 μM), cultured at 37°C for 96 hours, and then analyzed by MTT assay.

The results are shown in Figure 3B. Sorafenib dose-dependently decreased cell viability.

2-3. Cytotoxic effects of sorafenib and itraconazole on a cultured three-dimensional human epidermis model After pre-culturing in the same manner as in 2-1, itraconazole at each concentration (5, 10 μM) was added to the medium on the basal layer side of the epidermis model the next day, allowed to stand at 37°C for 1 hour, then replaced with a medium containing both 40 μM sorafenib and each concentration (5, 10 μM) of itraconazole, at 37°C for 96 hours. After culture, it was analyzed by MTT assay.

The results are shown in Figure 3C. After addition of 40 μM sorafenib, cell viability in the epidermal model decreased to approximately 30%. However, in the presence of itraconazole, cell viability was restored in an itraconazole dose-dependent manner. A cultured three-dimensional human epidermis model shows cytotoxicity resembling hand-foot syndrome upon sorafenib treatment. The recovery of cell viability by azole antifungal drugs confirmed in this model proves that azole antifungal drugs have therapeutic and preventive effects on skin disorders such as hand-foot syndrome caused by anticancer drug administration.

The therapeutic or preventive agent for skin disorders caused by administration of anticancer agents, which contains the azole antifungal agent of the present invention as an active ingredient, can treat or prevent skin disorders caused by administration of anticancer agents, and thus is useful in the medical field and the like.

Claims (5)

A therapeutic or prophylactic agent for hand-foot syndrome caused by administration of a multikinase inhibitor , containing an azole antifungal drug as an active ingredient. The agent according to claim 1, wherein the azole antifungal drug is at least one selected from the group consisting of itraconazole, ketoconazole, luliconazole, efinaconazole, isoconazole, lanoconazole, sulconazole, clotrimazole, bifonazole, and pharmaceutically acceptable salts thereof. 3. The agent according to claim 1, wherein said azole antifungal drug is itraconazole. The agent according to any one of claims 1 to 3 , wherein the multikinase inhibitor is at least one selected from the group consisting of sorafenib, regorafenib and lenvatinib, and pharmaceutically acceptable salts and solvates thereof. 5. The agent according to claim 4 , wherein the multikinase inhibitor is sorafenib or a pharmaceutically acceptable salt thereof.