Use of an anti-PD-1 antibody in the preparation of a drug for treating acral melanoma

Abstract

Provided is a use of an anti-PD-1 antibody and apatinib in the preparation of a drug for treating acral melanoma, the regimen has a disease control rate of 72.2% for acral melanoma and an objective disease remission rate of 22.2%. Also provided is a use of an anti-PD-1 antibody, apatinib and temozolomide in the preparation of a drug for treating melanoma.

Description

Technical Field

[0001] The present disclosure relates to the use of an anti-PD-1 antibody or an antigen-binding fragment thereof in combination with a VEGFR inhibitor in the preparation of a drug for treating acral melanoma. Background Art

[0002] Early clinical trials have shown that specific binding to anti-programmed death receptor (anti-PD-1), such as nivolumab and pembrolizumab, can significantly improve the prognosis of patients with advanced melanoma (N Engl J Med 2015; 372: 320-30 and N Engl J Med 2015; 372: 2521-32). However, most of these studies are mainly based on the efficacy data of anti-PD-1 drugs in Caucasian populations. The clinical subtypes of melanoma vary greatly among the population, and the response of anti-PD-1 drugs to different subtypes of the disease is also different.

[0003] AN Shoushtari et al. (Cancer. 2016, 122(21): 3354. doi: 10.1002 / cncr.30259) studied the efficacy of the anti-PD-1 antibody pembrolizumab on acral melanoma and mucosal melanoma. They found that the ORR in the acral melanoma group was 32% and the ORR in the mucosal melanoma group was 23%, which were comparable to the data from early clinical studies.

[0004] T. Maeda et al. (Br J Dermatol. 2018 Nov 17. doi: 10.1111 / bjd.17434) reported the clinical research data of nivolumab in Asian patients with different clinical subtypes of melanoma (such as acral melanoma, mucosal melanoma and cutaneous melanoma). Among 68 patients, the ORR was 29.4%, of which 2 patients had complete response, 18 patients had partial response, 11 patients had stable disease, and 37 patients had progressive disease. In the three subtypes, the ORR of the cutaneous melanoma group was 42.9%, the ORR of the mucosal melanoma group was 20.7%, and the ORR of the acral melanoma group was 18.8%. Further subdivided into metastatic and non-metastatic, the ORR of the cutaneous melanoma group was 41.7%, the ORR of the mucosal melanoma group was 17.6%, and the ORR of the acral melanoma group was only 7.7%. Regardless of whether the metastatic disease was subdivided, the acral melanoma group showed a poor ORR (7.7% Vs 17.6% Vs 41.7%). Therefore, there are still many uncertainties in the use of PD-1 antibody alone for the treatment of acral melanoma.

[0005] The combined use of more than one anti-tumor drug with different but interrelated targets can give full play to the advantages of each component, which can not only enhance the anti-tumor activity of a single drug but also reduce drug toxicity. It is a widely accepted anti-tumor therapy.

[0006] Apatinib is the world's first oral anti-angiogenic drug for advanced gastric cancer. It is highly selective for VEGFR-2 and has strong anti-angiogenic effects. In a multicenter, randomized, double-blind, placebo-controlled Phase III trial of apatinib as a second-line treatment for patients with metastatic gastric / gastroesophageal junction cancer, the results showed that compared with placebo, apatinib alone can prolong the median overall survival by 1.8 months and the median progression-free survival by 0.8 months, and the adverse events are controllable. The structural formula of apatinib is shown in formula (I).

[0007]

[0008] Currently, there are several PD-1 antibodies and VEGFR inhibitors (such as sunitinib, sorafenib, etc.) in clinical phase II / III, with indications for malignant liver cancer (sorafenib combined with PD-1 antibodies) and metastatic renal cell carcinoma (sunitinib combined with PD-1 antibodies). Preliminary results show that the combination of the two drugs is better than single drugs, but the combination of PD-1 antibodies and VEGF inhibitors has many uncertainties and deserves further study. At the same time, there are no reports on the combination of VEGFR inhibitors and PD-1 antibodies for the treatment of acral melanoma. On the other hand, whether the combination of PD-1 antibodies, VEGF inhibitors and alkylating agents such as temozolomide can achieve a better combination of drug efficacy is also uncertain and deserves further study. Summary of the invention

[0009] The present disclosure provides a use of an anti-PD-1 antibody and a VEGFR inhibitor in combination in the preparation of a medicament for treating acral melanoma (melanoma).

[0010] PD-1 antibodies are known. In some optional embodiments, the anti-PD-1 antibody or its antigen-binding fragment is selected from: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolizumab, CA-170, MEDI-0680, JS-001, TSR-042, Cemiplimab, Camrelizumab, Pembrolizumab, Toripalimab, Sintilimab, Tislelizumab, LZM-009, AK-103 and Nivolumab.

[0011] In some embodiments, the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

[0012] The heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.

[0013] name sequence serial number HCDR1 SYMMS SEQ ID NO: 1 HCDR2 TISGGGANTYYPDSVKG SEQ ID NO: 2 HCDR3 QLYYFDY SEQ ID NO: 3 LCDR1 LASQTIGTWLT SEQ ID NO: 4 LCDR2 TATSLAD SEQ ID NO: 5 LCDR3 QQVYSIPWT SEQ ID NO: 6

[0014] In an optional embodiment, the PD-1 antibody is a humanized antibody.

[0015] In some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0016] Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3 and IgG4. "Isotype" refers to the Ab species or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene. In some optional embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in the present application comprises a heavy chain constant region of a human IgG1, IgG2, IgG3 or IgG4 isotype, preferably a heavy chain constant region of an IgG1 or IgG4 isotype.

[0017] In other optional embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of κ or λ.

[0018] In some embodiments, the PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region as shown in SEQ ID NO: 10 or a variant thereof, wherein the variant preferably has an amino acid change of 0-10 in the light chain variable region sequence as shown in SEQ ID NO: 10, and more preferably an amino acid change of A43S; and a heavy chain variable region as shown in SEQ ID NO: 9 or a variant thereof, wherein the variant preferably has an amino acid change of 0-10 in the heavy chain variable region sequence as shown in SEQ ID NO: 9, and more preferably an amino acid change of G44R.

[0019] The variable region sequences of the heavy and light chains of the aforementioned PD-1 antibody or its antigen-binding fragment are as follows:

[0020] Heavy chain variable region

[0021]

[0022] Light chain variable region

[0023]

[0024] In an optional embodiment, the humanized antibody light chain sequence is a sequence as shown in SEQ ID NO: 8 or a variant thereof; the variant preferably has 0-10 amino acid changes in the light chain variable region; more preferably, an amino acid change of A43S. The humanized antibody heavy chain sequence is a sequence as shown in SEQ ID NO: 7 or a variant thereof; the variant preferably has 0-10 amino acid changes in the heavy chain variable region; more preferably, an amino acid change of G44R.

[0025] In some embodiments, the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO:8, and the heavy chain sequence is the sequence shown in SEQ ID NO:7.

[0026] The sequences of the heavy and light chains of the humanized antibody are as follows:

[0027] Heavy chain

[0028]

[0029]

[0030] Light chain

[0031]

[0032] Antibody Common Name CAS Number References Camrelizumab 1798286-48-2 WO2017054646 Nivolumab 946414-94-4 WO2006121168 Pembrolizumab 1374853-91-4 WO2008156712 Cemiplimab 1801342-60-8 WO2015112800 Toripalimab 1924598-82-2 WO2014206107 Sintilimab 2072873-06-2 WO2017024465 Tislelizumab 1858168-59-8 WO2015035606

[0033] On the other hand, in some embodiments, the VEGFR inhibitor is a VEGFR-2 inhibitor.

[0034] In some embodiments, the VEGFR inhibitor is selected from apatinib, anlotinib, tafitinib, famitinib, sorafenib or a pharmaceutically acceptable salt thereof, preferably apatinib or a pharmaceutically acceptable salt thereof.

[0035] The pharmaceutically acceptable salts disclosed herein are selected from methanesulfonate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, citrate, benzenesulfonate, benzoate, naphthysulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate. In some embodiments, the pharmaceutically acceptable salt of apatinib is selected from methanesulfonate. In some embodiments, the pharmaceutically acceptable salt of anlotinib is selected from hydrochloric acid. The combined anti-PD-1 antibody and VEGFR inhibitor disclosed herein have a synergistic pharmacodynamic effect.

[0036] Further, the patient in the present disclosure is selected from recurrent, unresectable or metastatic.

[0037] In some embodiments, the recurrence is a post-operative recurrence.

[0038] In an alternative embodiment, the patient is selected from patients with recurrent disease after surgery.

[0039] In alternative embodiments, the patient is selected from those who cannot undergo surgical resection.

[0040] On the other hand, the aforementioned anti-PD-1 antibody and VEGFR inhibitor regimen further comprises an alkylating agent.

[0041] In some embodiments, the use further comprises temozolomide or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof administered to a human subject (dosed according to patient weight) is selected from 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg / kg, 3.4 mg / kg, 3.6 mg / kg, 3.8 mg / kg, 4.0 mg / kg, 4.2 mg / kg , 4.4mg / kg, 4.6mg / kg, 4.8mg / kg, 5.0mg / kg, 5.2mg / kg, 5.4mg / kg, 5.6mg / kg, 5.8mg / kg, 6.0mg / kg, 6.2mg / kg, 6.4mg / kg, 6.6mg / kg, 6.8mg / kg, 7.0mg / kg, 7.2mg / kg, 7.4mg / kg, 7.6mg / kg, 7.8mg / kg, 8.0mg / kg, 8.2mg / kg, 8.4mg / kg, 8.6mg / kg, 8.8mg / kg, 9.0mg / kg, 9.2mg / kg, 9.4mg / kg, 9.6mg / kg, 9.8mg / kg, 10.0mg / kg or any value between any two values, preferably 3mg / kg.

[0043] In another embodiment, the PD-1 antibody or antigen-binding fragment thereof is administered to human subjects at a dose of 1 to 600 mg, preferably 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg, 2.4 mg, 2.6 mg, 2.8 mg, 3.0 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4.0 mg, 4.2 mg, 4.4 mg, 4.6 mg. g, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg , 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245m g, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320 mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 39 5mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 4 70mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg or any value between any two values, preferably 200mg.

[0044] The anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0045] In some embodiments, the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure administered to human subjects is 50-600 mg / once every 2-3 weeks, more preferably 200 mg / once every 2-3 weeks.

[0046] In other embodiments, the dosage of the VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in human subjects is selected from 0.1-500 mg, which can be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 20 0mg, 225mg, 250mg, 275mg, 300mg, 375mg, 400mg, 500mg, more preferably 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg, 125mg, 150mg, 175mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg or any value between any two values, preferably 250mg or 375mg.

[0047] For the purposes disclosed herein, the dosing frequency of the VEGFR inhibitor, such as apatinib, is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once a day for three days a week, once a day for four days a week, and once a day for five days a week.

[0048] In some embodiments, the dosage of the PD-1 antibody or its antigen-binding fragment administered to human subjects is selected from 60 to 600 mg, intravenous infusion, once every one to three weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate administered to human subjects is selected from 250 mg to 500 mg, oral, once every one to two days.

[0049] In some embodiments, the PD-1 antibody or its antigen-binding fragment is administered to human subjects at a dosage selected from 1-5 mg / kg, intravenous infusion, once every one to three weeks; the VEGFR inhibitor such as apatinib mesylate is administered to human subjects at a dosage selected from 250 mg to 500 mg, orally, once every one to two days.

[0050] In some embodiments, the dosage of the PD-1 antibody or its antigen-binding fragment in human subjects is selected from 200 mg, intravenous infusion, once every two weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate in human subjects is selected from 250 mg, oral, once a day.

[0051] In some embodiments, the dosage of the PD-1 antibody or its antigen-binding fragment administered to human subjects is selected from 3 mg / kg, intravenous infusion, once every two weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate administered to human subjects is selected from 250 mg, oral, once a day.

[0052] In some embodiments, the dosage of the PD-1 antibody or its antigen-binding fragment in human subjects is selected from 200 mg, intravenous infusion, once every two weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate in human subjects is selected from 375 mg, oral, once a day.

[0053] Furthermore, the VEGFR inhibitor disclosed in the present invention is taken after meals, for example, within 30 minutes after a meal.

[0054] On the other hand, in another embodiment, the alkylating agent such as temozolomide is administered to a human subject at a dose (administered by body surface area) selected from 50 mg / m 2 ~300 mg / m 2 , including 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg g, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg or any value between any two values, preferably 150 mg / m 2 or 200 mg / m 2 .

[0055] The alkylating agents disclosed herein, such as temozolomide, are administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0056] In some embodiments, the alkylating agent, such as temozolomide, is administered to a human subject at a dose selected from 150 mg / m 2 or 200 mg / m 2 , oral, once a day.

[0057] In some embodiments, the alkylating agent, such as temozolomide, is administered to a human subject at a dose selected from 150 mg / m 2 or 200 mg / m 2 , orally, once a day, for 5 days.

[0058] In some embodiments, the alkylating agent, such as temozolomide, is administered to a human subject at a dose selected from 150 mg / m 2 or 200 mg / m 2 , taken orally, once a day for 5 days, followed by a 23-day break.

[0059] In other embodiments, the dosage of the PD-1 antibody or antigen-binding fragment thereof in human subjects is selected from 60 to 600 mg, intravenous infusion, once every one to three weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate in human subjects is selected from 250 mg to 500 mg, oral, once every one to two days; the dosage of the alkylating agent such as temozolomide in human subjects is selected from 150 mg / m 2 or 200 mg / m 2 , oral, once a day.

[0060] In other embodiments, the dosage of the PD-1 antibody or its antigen-binding fragment in human subjects is selected from 200 mg, intravenous infusion, once every two weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate in human subjects is selected from 250 mg, oral, once a day; the dosage of the alkylating agent such as temozolomide in human subjects is selected from 200 mg / m 2 , orally, once a day, for 5 days.

[0061] Another aspect of the present disclosure further provides a use of an anti-PD-1 antibody, a VEGFR inhibitor and temozolomide or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating melanoma.

[0062] In some embodiments, the dosage of the PD-1 antibody or antigen-binding fragment thereof in human subjects is selected from 60 to 600 mg; the dosage of the VEGFR inhibitor such as apatinib mesylate in human subjects is selected from 0.1 mg to 500 mg; the dosage of the alkylating agent such as temozolomide in human subjects is selected from 50 mg / m 2 Up to 200 mg / m2 .

[0063] In other embodiments, the dosage of the PD-1 antibody or its antigen-binding fragment in human subjects is selected from 60 to 600 mg, intravenous infusion, once every one to three weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate in human subjects is selected from 0.1 to 500 mg, oral, once every one to two days; the dosage of the alkylating agent such as temozolomide in human subjects is selected from 50 mg / m 2 Up to 200 mg / m 2 , oral, once a day.

[0064] In other embodiments, the dosage of the PD-1 antibody or its antigen-binding fragment in human subjects is selected from 200 mg, intravenous infusion, once every two weeks; the dosage of the VEGFR inhibitor such as apatinib mesylate in human subjects is selected from 250 mg, oral, once a day; the dosage of the alkylating agent such as temozolomide in human subjects is selected from 200 mg / m 2 , orally, once a day, for 5 days.

[0065] The present disclosure also provides a use of an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating mucosal melanoma (mucosal melanoma), further comprising an alkylating agent, wherein the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.

[0066] The present disclosure provides the above-mentioned anti-PD-1 antibody combined with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a treatment for preparing a drug for treating acral melanoma, and further comprises an alkylating agent, and the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.

[0067] The present disclosure also provides an anti-PD-1 antibody for treating melanoma (such as acral melanoma), wherein the anti-PD-1 antibody is administered in combination with a VEGFR inhibitor. In some embodiments, an alkylating agent is also included, and the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.

[0068] In addition, the present disclosure also provides a VEGFR inhibitor for treating melanoma (such as acral melanoma), wherein the VEGFR inhibitor is administered in combination with an anti-PD-1 antibody. In some embodiments, an alkylating agent is also included, and the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.

[0069] The present disclosure also provides an alkylation inhibitor such as temozolomide or a pharmaceutically acceptable salt thereof for treating melanoma (such as acral melanoma), wherein the alkylation inhibitor is administered in combination with an anti-PD-1 antibody and a VEGFR inhibitor. The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. In some embodiments, the adverse drug reaction is selected from the group consisting of anti-PD-1 antibodies or VEGFR inhibitors such as apatinib or a pharmaceutically acceptable salt thereof.

[0070] On the other hand, the present disclosure provides the above-mentioned anti-PD-1 antibody, VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in combination with temozolomide or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. In some embodiments, the adverse drug reaction is selected from the group consisting of anti-PD-1 antibody-induced or VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, or temozolomide or a pharmaceutically acceptable salt thereof.

[0071] The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a drug for reducing the dosage of the anti-PD-1 antibody alone and / or the dosage of the VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof.

[0072] The present disclosure provides a method for treating acral melanoma, comprising administering to a patient an effective amount of the above-mentioned anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and further administering to the patient an effective dose of an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof.

[0073] The present disclosure also provides a combination for treating acral melanoma. In some embodiments, the combination contains an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof. In other embodiments, the aforementioned combination further comprises an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof.

[0074] On the other hand, the present disclosure also provides a combination for treating melanoma, comprising an anti-PD-1 antibody, a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof. The combination contains an effective dose of an anti-PD-1 antibody, a VEGFR inhibitor or an alkylating agent. In some embodiments, the melanoma includes a mucosal melanoma or an acral melanoma.

[0075] The present disclosure also provides a method for reducing the dosage of an anti-PD-1 antibody alone and / or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, comprising administering the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof to a patient, and further administering an effective dose of an alkylating agent to the patient, wherein the alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, when used in combination with PD-1, the dosage of the VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof is 10% to 100% of its single-administered dosage, preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5%. In some embodiments, when used in combination with PD-1, the dosage of the alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof is 10% to 100% of its single-administered dosage, preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5%.

[0077] In some embodiments, when used in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, the dose of the anti-PD-1 antibody is 10% to 100%, preferably 10% to 50%, of the dose of the anti-PD-1 antibody alone. In some embodiments, when used in combination with a VEGFR inhibitor, the dose of the alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof is 10% to 100%, preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5% ​​of the dose of the alkylating agent alone.

[0078] In the embodiments of the present disclosure, when the PD-1 antibody is used in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof or / and an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof, the adverse drug reactions mediated by the anti-PD-1 antibody and / or immunity can be reduced; preferably, the adverse reactions are selected from vascular-related adverse reactions, glandular dysfunction, skin adverse reactions, respiratory system adverse reactions, liver-related adverse reactions, endocrine-related adverse reactions, digestive system adverse reactions, kidney-related adverse reactions, fatigue, and fever; the preferred vascular-related adverse reactions are selected from hemangioma, vasculitis, lymphangioma, and the glandular dysfunction is selected from hypothyroidism, hypoparathyroidism, pancreatic dysfunction, and the like. The adverse reactions are selected from the group consisting of pruritus, urticaria, rash, and toxic epidermal necrolysis; the adverse reactions of the respiratory system are selected from the group consisting of pneumonia, bronchitis, chronic obstructive pulmonary disease, and pulmonary fibrosis; the adverse reactions of the liver are selected from the group consisting of hepatitis and abnormal liver function; the adverse reactions of the endocrine system are selected from the group consisting of type I diabetes, type II diabetes, and hypoglycemia; the adverse reactions of the kidney are selected from the group consisting of nephritis and renal failure; the adverse reactions of the digestive system are selected from the group consisting of diarrhea, nausea, vomiting, enteritis, and constipation; more preferably, the adverse reactions of the drugs are selected from the group consisting of hemangioma, hypothyroidism, hypoparathyroidism, pruritus, pneumonia, hepatitis, abnormal liver function, type I diabetes, nephritis, and renal failure.

[0079] The present disclosure also provides a drug combination, which contains a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or an antigen-binding fragment thereof, and further includes an alkylating agent, wherein the alkylating agent is selected from temozolomide or a pharmaceutically acceptable salt thereof.

[0080] In the disclosed embodiments, the PD-1 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody needs to be formulated into an injectable form before injection. A particularly preferred injectable form of the PD-1 antibody is an injection solution or a lyophilized powder injection, which comprises a PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffer may be selected from one or more of acetate, citrate, succinate, and phosphate. The stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, and maltose. The surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, preferably the polyoxyethylene sorbitan fatty acid esters are polysorbate 20, 40, 60 or 80, most preferably polysorbate 20. The most preferred injectable form of the PD-1 antibody comprises a PD-1 antibody, an acetate buffer, trehalose, and polysorbate 20.

[0081] The combination regimen disclosed herein may optionally further comprise other components, including but not limited to other anti-tumor drugs and the like.

[0082] Unless otherwise explained, the terms in this disclosure have the following meanings:

[0083] The disclosure of "combination" is a mode of administration, which refers to the administration of at least one dose of VEGFR inhibitors such as apatinib or a pharmaceutically acceptable salt thereof and at least one dose of PD-1 antibody or an antigen-binding fragment thereof within a certain time limit, wherein both substances show pharmacological effects. The time limit may be within a dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. VEGFR inhibitors such as apatinib or a pharmaceutically acceptable salt thereof and PD-1 antibody or an antigen-binding fragment thereof may be administered simultaneously or sequentially. This period includes treatments in which VEGFR inhibitors such as apatinib or a pharmaceutically acceptable salt thereof and PD-1 antibody or an antigen-binding fragment thereof are administered by the same route of administration or different routes of administration. The combined administration mode described in the present application is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration. In other embodiments, the disclosure of "combination" refers to the administration of three different types of drugs such as VEGFR inhibitors, PD-1 antibodies, and alkylating agents such as temozolomide within a certain time limit, and the time limit is as described above.

[0084] As used herein, an "effective amount" or "effective dose" includes an amount sufficient to improve or prevent the symptoms or symptoms of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0085] The term "humanized antibody", also known as CDR-grafted antibody, refers to an antibody produced by transplanting mouse CDR sequences into human antibody variable region frameworks, i.e., different types of human germline antibody framework sequences. The strong antibody variable antibody response induced by chimeric antibodies due to carrying a large amount of mouse protein components can be overcome. Such framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references. For example, germline DNA sequences of human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk / vbase), and in Kabat, EA et al., 1991 Sequences of Proteins of Immunological Interest, 5th edition. In a preferred embodiment of the present application, the CDR sequence of the PD-1 humanized antibody is selected from SEQ ID NO: 1, 2, 3, 4, 5, 6.

[0086] The term "antigen-binding fragment" refers to a Fab fragment, a Fab' fragment, a F(ab')2 fragment, and an Fv fragment sFv fragment that binds to human PD-1, which has antigen-binding activity; and comprises one or more CDR regions selected from SEQ ID NO: 1 to SEQ ID NO: 6 of the antibody described in the present application. The Fv fragment contains the variable region of the heavy chain and the variable region of the light chain of the antibody, but has no constant region, and is the smallest antibody fragment with all antigen-binding sites. Generally, the Fv antibody also contains a polypeptide linker between the VH and VL domains, and is capable of forming the structure required for antigen binding. Two antibody variable regions can also be connected into a polypeptide chain using different connectors, which is called a single-chain antibody or single-chain Fv (sFv). The term "binding to PD-1" in the present application refers to the ability to interact with human PD-1. The term "antigen binding site" in the present application refers to a discontinuous three-dimensional site on the antigen that is recognized by the antibody or antigen-binding fragment of the present application.

[0087] Progression-free survival (PFS): The time from randomization to the first documented objective tumor progression or death from any cause, whichever occurs first.

[0088] Overall survival (OS) refers to the period from randomization to death from any cause. For subjects who are still alive at the last follow-up, their OS is counted as data loss based on the last follow-up time. For subjects who are lost to follow-up, their OS is counted as data loss based on the last confirmed survival time before loss of follow-up. OS with data loss is defined as the time from randomization to censoring.

[0089] Objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain level and remain shrinking for a certain period of time, including cases of CR and PR. The solid tumor response evaluation criteria (RECIST 1.1 standard) are used to assess the objective response of tumors. Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to the RECIST 1.1 standard.

[0090] The disease control rate (DCR) refers to the percentage of confirmed complete remission, partial remission and stable disease (≥8 weeks) among patients who can be evaluated for efficacy.

[0091] Complete remission (CR): All target lesions disappear and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm.

[0092] Partial response (PR): The sum of target lesion diameters decreased by at least 30% compared with the baseline level.

[0093] Disease progression (PD): The minimum value of the sum of all target lesion diameters measured during the entire experimental study is used as a reference, and the relative increase in the sum of diameters is at least 20% (if the baseline measurement value is the smallest, the baseline value is used as a reference); in addition, the absolute value of the sum of diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0094] Stable disease (SD): The target lesion has neither decreased to the level of PR nor increased to the level of PD, but is somewhere in between. The minimum value of the sum of diameters can be used as a reference for research. DETAILED DESCRIPTION

[0095] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0096] Example 1: Study on the treatment of acral melanoma with anti-PD-1 antibody combined with apatinib mesylate

[0097] Compound A: PD-1 antibody was prepared according to the method in patent application WO2017054646A, and the sequences of its heavy and light chains are as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in the present disclosure. 200 mg / bottle, prepared into 20 mg / ml for use.

[0098] Compound B: Apatinib mesylate, can be prepared according to the method in patent application WO2010031266A1.

[0099] Inclusion criteria: (1) Patients with postoperative recurrence, unresectable or metastatic acral melanoma confirmed by pathological histology; (2) 3. Patients who had not received any systemic anti-tumor drug treatment in the past

[0100] Dosage:

[0101] PD-1 antibody: fixed dose of 200 mg, intravenous infusion (no prophylactic medication required), or for subjects with baseline body weight <50 kg, 3 mg / kg, once every 2 weeks, 4 weeks per cycle;

[0102] Apatinib: 250 mg / tablet, orally, once a day, one tablet at a time, after meals.

[0103] in conclusion:

[0104] A total of 20 subjects were enrolled, and among the 18 subjects who could be evaluated, the sum of the target lesion diameters of 4 patients decreased by at least 30% compared with the baseline level, 9 subjects showed stable disease (SD), and 5 patients showed progressive disease. The overall disease control rate was 72.2%, the disease remission rate was 22.2%, and the disease remission rate of single-agent PD-1 was 15%, which significantly improved the safety and efficacy of patients' medication.

[0105] Example 2: Study on the treatment of acral melanoma with anti-PD-1 antibody combined with apatinib mesylate

[0106] Compound A: PD-1 antibody was prepared according to the method in patent application WO2017054646A, and the sequences of its heavy and light chains are as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in the present disclosure. 200 mg / bottle, prepared into 20 mg / ml for use.

[0107] Compound B: Apatinib mesylate, can be prepared according to the method in patent application WO2010031266A1.

[0108] Compound C: Temozolomide, Temozolomide for injection (powder injection, Shanghai Hengrui) or Temozolomide capsules (Merck)

[0109] Inclusion criteria: (1) Patients with recurrent, unresectable or metastatic melanoma (including acral melanoma) confirmed by pathological histology; (2) 3. No previous treatment with any systemic anti-tumor drugs.

[0110] Dosage:

[0111] PD-1 antibody: fixed dose of 200 mg, intravenous infusion (no prophylactic medication required), or for subjects with baseline body weight <50 kg, 3 mg / kg, once every 2 weeks, 4 weeks per cycle;

[0112] Apatinib: 250 mg / tablet, oral, once a day, one tablet at a time, after meals, one cycle for 28 days;

[0113] Temozolomide: 200 mg / m 2 , orally or intravenously, once a day, for 5 consecutive days, with a cycle of 28 days.

[0114] in conclusion:

[0115] Among the 23 evaluable subjects, all target lesions disappeared in one patient, no new lesions appeared, and tumor markers were normal (CR), the sum of the diameters of target lesions in 11 patients decreased by at least 30% (PR) compared with the baseline level, 10 patients showed stable disease (SD), and 1 patient was out of the group. The disease control rate was 96.65% (22 cases) and the objective response rate was 52.17% (12 cases). Compared with other treatments, such as two drugs (ORR 22.2%, DCR 72.2%) or single-agent PD-1 (15%), it has obvious advantages. Sequence Listing <110> Jiangsu Hengrui Medicine Co., Ltd. Suzhou Shengdia Biopharmaceutical Co., Ltd. <120> Use of an anti-PD-1 antibody in the preparation of a drug for treating acral melanoma <160> 10 <170> SIPOSequenceListing 1.0 <210> 1 <211> 5 <212> PRT <213> Rat (Mus musculus) <400> 1 Ser Tyr Met Me Ser 1 5 <210> 2 <211> 17 <212> PRT <213> Rat (Mus musculus) <400> 2 Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <210> 3 <211> 7 <212> PRT <213> Rat (Mus musculus) <400> 3 Gln Leu Tyr Tyr Phe Asp Tyr 1 5 <210> 4 <211> 11 <212> PRT <213> Rat (Mus musculus) <400> 4 Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Thr 1 5 10 <210> 5 <211> 7 <212> PRT <213> Rat (Mus musculus) <400> 5 Thr Ala Thr Ser Leu Ala Asp 1 5 <210> 6 <211> 9 <212> PRT <213> Rat (Mus musculus) <400> 6 Gln Gln Val Tyr Ser Ile Pro Trp Thr 1 5 <210> 7 <211> 443 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <222> (1)..(443) <223> Heavy chain sequence <400> 7 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 340 345 350 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 <210> 8 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <222> (1)..(214) <223> Light chain sequence <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 9 <211> 116 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <222> (1)..(116) <223> Heavy chain variable region <400> 9 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser Ser 115 <210> 10 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <222> (1)..(10) <223> Light chain variable region <400> 10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105

Claims

1. Use of an anti-PD-1 antibody or an antigen-binding fragment thereof and a VEGFR inhibitor in combination with temozolomide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating acral melanoma; wherein: The VEGFR inhibitor is selected from apatinib or a pharmaceutically acceptable salt thereof, the light chain variable region of the anti-PD-1 antibody or its antigen-binding fragment comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively, and the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively.

2. The use according to claim 1, wherein the PD-1 antibody is selected from a humanized antibody or an antigen-binding fragment thereof.

3. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype.

4. The use according to claim 3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1 or IgG4 isotype.

5. The use according to claim 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of κ or λ.

6. The use according to claim 2, wherein the light chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8 or a variant thereof; the heavy chain variable region sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof.

7. The use according to claim 6, wherein the variant has 0-10 amino acid changes in the light chain variable region.

8. The use according to claim 6, wherein the variant is an amino acid change of A43S.

9. The use according to claim 6, wherein the variant has 0-10 amino acid changes in the heavy chain variable region.

10. The use according to claim 6, wherein the variant is an amino acid change of G44R.

11. The use according to claim 2, wherein the PD-1 antibody or antigen-binding fragment thereof comprises a light chain as shown in SEQ ID NO: 8, and a heavy chain as shown in SEQ ID NO:

7.

12. The use according to claim 1, wherein the acral melanoma is selected from recurrent, unresectable or metastatic.

13. The use according to claim 12, wherein the recurrent acral melanoma is selected from recurrent melanoma after surgery.

14. The use according to claim 1, wherein the dosage of the PD-1 antibody or antigen-binding fragment thereof is selected from 1-10 mg / kg.

15. The use according to claim 1, wherein the dosage of the PD-1 antibody or antigen-binding fragment thereof is selected from 3 mg / kg.

16. The use according to claim 1, wherein the dosage of the PD-1 antibody or antigen-binding fragment thereof is selected from 50-600 mg.

17. The use according to claim 1, wherein the dosage of the PD-1 antibody or antigen-binding fragment thereof is selected from 200 mg.

18. The use according to claim 1, wherein the dosage of the VEGFR inhibitor is selected from 0.1-500 mg.

19. The use according to claim 1, wherein the dose of the VEGFR inhibitor is selected from 250 mg or 375 mg.

20. The use according to claim 1, wherein the temozolomide dose is selected from 50 mg / m 2 ~300 mg / m 2 .

21. The use according to claim 1, wherein the temozolomide dose is selected from 150 mg / m 2 or 200 mg / m 2 .

22. The use of claim 1, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of methanesulfonate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, citrate, benzenesulfonate, benzoate, naphthylate, lactate, malate, hydrochloride, hydrobromide, sulfate and phosphate.

23. A drug combination comprising an effective therapeutic amount of a PD-1 antibody or an antigen-binding fragment thereof and apatinib or a pharmaceutically acceptable salt thereof, further comprising an alkylating agent, wherein the alkylating agent is temozolomide or a pharmaceutically acceptable salt thereof, and the anti-PD-1 antibody or an antigen-binding fragment thereof is as described in claim 1.

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