CN109806393B - Application of anti-PD-1 antibody, pemetrexed and platinum drugs in combined treatment of non-small cell lung cancer - Google Patents
Application of anti-PD-1 antibody, pemetrexed and platinum drugs in combined treatment of non-small cell lung cancer Download PDFInfo
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- CN109806393B CN109806393B CN201811362630.8A CN201811362630A CN109806393B CN 109806393 B CN109806393 B CN 109806393B CN 201811362630 A CN201811362630 A CN 201811362630A CN 109806393 B CN109806393 B CN 109806393B
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Abstract
The invention relates to application of an anti-PD-1 antibody in combination with pemetrexed and platinum drugs in preparation of drugs for treating non-small cell lung cancer. Specifically, the invention relates to an application of an anti-PD-1 antibody combined with pemetrexed and carboplatin in preparation of a medicament for treating non-small cell lung cancer, wherein the anti-PD-1 antibody combined with pemetrexed and carboplatin shows a good anti-tumor curative effect compared with pemetrexed and carboplatin.
Description
Technical Field
Use of an anti-PD-1 antibody or an antigen-binding fragment thereof, pemetrexed and a platinum drug in combination for the preparation of a medicament for the treatment of non-small cell lung cancer.
Background
Worldwide, lung cancer has become a leading cause of cancer death. In china, lung cancer is the leading cause of cancer incidence and mortality. Despite the recent generations of cytotoxic drugs and targeted therapies that have been introduced over the last 20 years, the survival prognosis for patients with advanced lung cancer, particularly those without known driver mutant genes, remains poor, and advanced or metastatic lung cancer remains a fatal disease with an unmet medical need.
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, with approximately 75% of NSCLC patients being found in the middle and advanced stages with a very low 5-year survival rate. There is still a great clinical need to select an appropriate systemic treatment for patients with advanced or metastatic NSCLC. NSCLC can be further classified as squamous cell carcinoma and non-squamous cell carcinoma. Non-squamous cell carcinomas include adenocarcinomas, large cell carcinomas and other subtypes of cell carcinoma. . Non-squamous cell carcinoma patients are further classified according to the presence or absence of a driver mutant gene (EGFR mutation or ALK gene rearrangement). For advanced NSCLC patients with wild-type EGFR/ALK genes, a platinum-containing dual-drug systemic treatment regimen based on platinum-based drugs is usually employed. Drugs that have been approved for the treatment of advanced/metastatic non-small cell lung cancer include platinum drugs (e.g., cisplatin, carboplatin), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), vinorelbine, vinblastine, etoposide, pemetrexed, gemcitabine, and the like. Using a combination of these drugs, a 1-year survival rate of 30% to 40% can be achieved, superior to single drug.
The PD-1 inhibitor is a new tumor immunotherapy medicament which is currently spotlighted, and currently, a plurality of pharmaceutical companies across countries develop monoclonal antibodies aiming at PD-1/PD-L1 signal pathways, the anti-PD-1 antibody provided by the invention and WO2017054646A disclose the sequence and the preparation method of the antibody, the anti-PD-1 antibody is in Clinical stage III and has good safety, and reported Clinical research results show that the anti-PD-1 antibody has certain anti-tumor effect ([ J ]. Journal of Clinical Oncology 35(2017): e15572-e 15572).
Currently, clinical research on the application of PD-1 combined chemotherapeutic drugs in the treatment of non-small cell lung cancer is under development, clinical benefit and safety are preliminarily proved, but large-scale clinical tests are further proved, and combined treatment schemes are further optimized to further improve clinical benefit and safety, so that the treatment field still needs to further explore suitable anti-PD-1 antibodies and chemotherapeutic drugs for combined treatment of non-small cell lung cancer.
Disclosure of Invention
The invention provides an application of an anti-PD-1 antibody and pemetrexed plus platinum drug in preparation of a drug for treating non-small cell lung cancer, wherein a light chain variable region of the PD-1 antibody or an antigen binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6 respectively; the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively; wherein the platinum-based drug is selected from the group consisting of: carboplatin, cisplatin, oxaliplatin, Nedaplatin (Nedaplatin), lobaplatin (lobaplatin), satraplatin (satraplatin), cycloplatin (cycloplatin), Miboplatin (Miboplatin), Enloplatin, Iproplatin, Dicycloplatin, with carboplatin and cisplatin being preferred.
The invention provides an application of an anti-PD-1 antibody and pemetrexed plus carboplatin in preparing a medicament for treating non-small cell lung cancer, wherein a light chain variable region of the PD-1 antibody or an antigen binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6 respectively; the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively.
The invention also provides an application of the anti-PD-1 antibody in preparing a medicament for treating non-small cell lung cancer, wherein the light chain variable region of the PD-1 antibody or an antigen binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6 respectively; the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2, and SEQ ID NO 3, respectively.
Wherein, the CDR sequences are shown in the following table:
| name (R) | Sequence of | Number of |
| HCDR1 | SYMMS | SEQID NO：1 |
| HCDR2 | TISGGGANTYYPDSVKG | SEQID NO：2 |
| HCDR3 | QLYYFDY | SEQID NO：3 |
| LCDR1 | LASQTIGTWLT | SEQID NO：4 |
| LCDR2 | TATSLAD | SEQID NO：5 |
| LCDR3 | QQVYSIPWT | SEQID NO：6 |
Preferably, the anti-PD-1 antibody or an antigen-binding fragment thereof is an anti-PD-1 humanized antibody.
Preferably, the humanized antibody light chain variable region sequence is the sequence shown in SEQ ID NO. 10 or a variant thereof; the variant preferably has 0-10 amino acid changes in the light chain variable region; more preferably the amino acid change of A43S. The humanized antibody heavy chain variable region sequence is shown as SEQ ID NO. 9 or the variant thereof; the variant preferably has 0-10 amino acid changes in the heavy chain variable region; more preferably a change in the amino acid of G44R.
The variable region sequences of the heavy and light chains of the humanized antibody are shown as follows:
heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS
SEQID NO：9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO：10
Preferably, the humanized antibody light chain sequence is 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 a 43S. The humanized antibody heavy chain sequence is shown as 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 a change in the amino acid of G44R.
In a preferred embodiment of the invention, the humanized antibody light chain sequence is as shown in SEQ ID NO. 8 and the heavy chain sequence is as shown in SEQ ID NO. 7.
The sequences of the heavy and light chains of the humanized antibodies are shown below:
heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQID NO：7
Light chains
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO：8
In a preferred embodiment of the invention, the non-small cell lung cancer is advanced or metastatic non-squamous cell lung carcinoma.
In a preferred embodiment of the invention, the non-small cell lung cancer is selected from EGFR/ALK gene wild-type advanced or metastatic non-squamous cell lung cancer.
In a preferred embodiment of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose selected from the group consisting of 1-10mg/kg, preferably 1mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg, and most preferably 3 mg/kg.
In a preferred embodiment of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose selected from the group consisting of 50-600mg, preferably from 60mg, 100mg, 200mg, 400mg, 600mg, most preferably 200 mg.
In a preferred embodiment of the invention, the pemetrexed dose is selected from 200-700mg/m 2 Preferably 200mg/m 2 、300mg/m 2 、400mg/m 2 、500mg/m 2 、600mg/m 2 、700mg/m 2 Most preferably 500mg/m 2 。
In a preferred embodiment of the invention, the dose of carboplatin administered is selected from the group consisting of 1-10mg/ml/min, preferably from 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/min, 7mg/ml/min, 8mg/ml/min, most preferably 5mg/ml/min, calculated as the area under the curve (AUC).
In a preferred embodiment of the invention, the carboplatin dose is selected from 200-400mg/m 2 Once every three to four weeks, preferably 200mg/m 2 、300mg/m 2 、400mg/m 2 。
In a preferred embodiment of the invention, the carboplatin dose is selected from 50mg/m 2 Once daily.
In the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once a week, once a three weeks, once a month, preferably once a three weeks.
In the present invention, wherein the pemetrexed is administered once a week, once every two weeks, once every three weeks, once a month, preferably once every three weeks.
In the present invention, wherein the administration frequency of carboplatin is once a week, once every two weeks, once every three weeks, once a month, preferably once every three weeks.
In the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof, pemetrexed, and carboplatin are administered in combination for the treatment of non-small cell lung cancer in the order of administration of the anti-PD-1 antibody, pemetrexed, and carboplatin.
In a preferred embodiment of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once three weeks, pemetrexed once three weeks, carboplatin once three weeks, in a combined order of administration: the drug treatments were given sequentially on day 1 of each cycle, first by intravenous drip of anti-PD-1 antibody, then by intravenous drip of pemetrexed, and then by intravenous drip of carboplatin.
In the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof, pemetrexed, and carboplatin are used in combination for the treatment of non-small cell lung cancer, and the three can be administered in the same administration cycle or in different administration cycles. The treatment period may be 1 week, 2 weeks, 3 weeks (21 days), 3-4 weeks (21-28 days), 4 weeks (28 days), preferably the treatment period is 3 weeks.
In the present invention, after the combination treatment with the anti-PD-1 antibody, pemetrexed and carboplatin has been continued for 4-6 weeks, maintenance treatment with the anti-PD-1 antibody and pemetrexed can be selected.
In the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof can also be used in combination with other platinum-based dual-drug platinum-containing chemotherapeutic regimens. For example PD-1 antibody + pemetrexed + cisplatin, PD-1 antibody + paclitaxel + carboplatin, PD-1 antibody + paclitaxel + cisplatin, PD-1 antibody + gemcitabine + cisplatin, PD-1 antibody + docetaxel + cisplatin, PD-1+ vinorelbine + cisplatin.
In a preferred embodiment of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered by injection, such as subcutaneous or intravenous injection, the anti-PD-1 antibody or antigen-binding fragment thereof being formulated in an injectable form prior to injection. A particularly preferred injectable form of the anti-PD-1 antibody or antigen-binding fragment thereof is an injection solution or a lyophilized powder injection comprising the anti-PD-1 antibody or antigen-binding fragment thereof, a buffer, a stabilizer, and optionally further comprising a surfactant. The buffer can be one or more selected from acetate, citrate, succinate and phosphate. The stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, maltose. The surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80, most preferably polysorbate 20. The most preferred injectable form of the anti-PD-1 antibody or antigen-binding fragment thereof comprises the anti-PD-1 antibody or antigen-binding fragment thereof, acetate buffer, trehalose, and polysorbate 20.
In the present invention, the term "combination" is an administration mode including the respective cases of administering the three drugs sequentially, or simultaneously, and the term "simultaneously" herein means that the anti-PD-1 antibody or an antigen-binding fragment thereof, pemetrexed, and carboplatin are administered in the same administration cycle, for example, three drugs are administered within 1 week, 2 weeks, 3 weeks, and 4 weeks. By "sequential" administration, it is meant that the anti-PD-1 antibody or antigen-binding fragment thereof, pemetrexed, and carboplatin are administered separately over different dosing cycles. These administration modes are all the combination administration described in the present invention.
The administration route of the combination of the present invention is selected from oral administration, parenteral administration, transdermal administration, and the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.
Also provided in the present invention is a method of treatment comprising administering to a patient an effective amount of the aforementioned anti-PD-1 antibody or antigen-binding fragment thereof, pemetrexed, and carboplatin.
The invention also provides a pharmaceutical kit, or a pharmaceutical pack, comprising an effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof, pemetrexed and carboplatin as described above.
The invention also provides a pharmaceutical composition comprising an effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof, pemetrexed, and carboplatin as described above, in combination with one or more pharmaceutically acceptable excipients, diluents, or carriers.
Detailed Description
Term of
In order that the invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless clearly defined otherwise herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "humanized antibody", also known as CDR-grafted antibody (CDR-grafted antibody), refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework, i.e., a different type of human germline antibody framework sequence. Can overcome the strong antibody variable antibody reaction induced by the chimeric antibody because of carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. Germline DNA Sequences of genes such as the human heavy and light chain variable regions can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/VBase), as well as in Kabat, E.A. et al, 1991Sequences of Proteins of Immunological Interest, 5 th edition. In a preferred embodiment of the invention, the CDR sequences of the mouse humanized antibody of PD-1 are selected from SEQ ID NO 1, 2, 3, 4, 5, 6.
The term "antigen-binding fragment" refers to Fab fragments, Fab 'fragments, F (ab') 2 fragments, and Fv fragments sFv fragments that bind to human PD-1, which have antigen-binding activity; comprising one or more CDR regions of an antibody of the invention selected from SEQ ID NO 1 to SEQ ID NO 6. The Fv fragment contains the variable regions of the antibody heavy and light chains, but lacks the constant region, and has the smallest antibody fragment with the entire antigen-binding site. Generally, Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the structures required for antigen binding. Two antibody variable regions can also be joined into a single polypeptide chain using different linkers, known as single chain antibodies (scFv) or single chain fv (sFv). The term "binds to PD-1" in the context of the present invention means capable of interacting with human PD-1. The term "antigen binding site" of the present invention refers to a three-dimensional spatial site that is not antigenically contiguous and is recognized by an antibody or antigen binding fragment of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Example 1
1. Test antibodies and compounds
The sequences of heavy and light chains of the anti-PD-1 antibody are shown as SEQ ID NO:7 and SEQ ID NO: 8. 200 mg/piece, 20mg/ml is prepared for standby.
Pemetrexed was purchased from Jiangsu Hawson pharmaceutical group, Inc., and carboplatin was purchased from Qilu pharmaceutical Co.
2. Criteria for Subjects in groups
(1) Histologically or cytologically diagnosed as advanced or metastatic non-squamous cell lung cancer (NSCLC).
(2) Systemic drug treatment for advanced/metastatic NSCLC was not received.
(3) EGFR mutations and ALK ectopy were negative.
(4) ECOG score 0-1.
3. Method of administration
anti-PD-1 antibody: three weeks each is a dosing cycle, with 200mg of anti-PD-1 antibody administered to the patient on the first day of the cycle, by intravenous drip, for about 20-60 minutes. The administration is allowed to be delayed for a maximum of 12 weeks, calculated from the last administration time, otherwise the treatment is terminated.
Pemetrexed for injection: every three weeks is a dosing cycle, the first day of each cycle is 500mg/m administered to the patient 2 Pemetrexed, intravenous drip, over 10 minutes. The administration is allowed to be delayed for up to 9 weeks, calculated from the time of last administration, otherwise the treatment is terminated.
Carboplatin for injection: three weeks each were a dosing cycle, with AUC 5 carboplatin administered to the patient on the first day of the cycle, intravenously instilled over 30 minutes. The administration is allowed to be delayed for up to 9 weeks, calculated from the time of last administration, otherwise the treatment is terminated.
The sequence of combined administration: the drug treatments were administered sequentially on day 1 of each cycle, with intravenous drip of anti-PD-1 antibody administered at least 30min later, followed by intravenous drip of pemetrexed and at least 30min later, followed by intravenous drip of carboplatin. The time window for administration may be ± 3 days, but within 72h prior to each administration, the subject must complete a test that includes various clinical needs to assess the tolerability of continued administration.
Test groups: the combination therapy of anti-PD-1 antibody + pemetrexed + carboplatin may last for 4-6 cycles, after which the maintenance therapy of anti-PD-1 antibody + pemetrexed may be selected.
Control group: the pemetrexed + carboplatin combination treatment may last for 4-6 cycles, after which single drug maintenance therapy of pemetrexed may be selected.
4. Results of clinical trials
By 11/14 days 2017, 121 patients were enrolled, of which 66 patients had at least one post-treatment tumor assessment. In the test group, 14 patients were partially relieved, 21 patients were stable, and 2 patients developed progressive disease. The Disease Control Rate (DCR) was 94.6% and the Objective Remission Rate (ORR) was 37.8%. In the control group, 10 patients had partially relieved disease, 21 patients had stable disease, and 5 patients had progressive disease. The Disease Control Rate (DCR) was 86.1% and the Objective Remission Rate (ORR) was 27.8%. The results of the preliminary analysis of the objective remission rate show that the anti-PD-1 antibody combined with the platinum-containing dual-drug chemotherapy regimen shows a good anti-tumor effect compared to the platinum-containing dual-drug chemotherapy regimen. With the increase of the data of patients in the group, the ORR of the test group is greatly improved. The incidence of adverse events was substantially equivalent in the test group and the control group.
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Claims (21)
1. The application of the anti-PD-1 antibody in combination with pemetrexed and platinum drugs in preparation of drugs for treating non-small cell lung cancer is characterized in that the light chain sequence of the anti-PD-1 antibody is a sequence shown as SEQ ID NO. 8, and the heavy chain sequence is a sequence shown as SEQ ID NO. 7.
2. Use according to claim 1, wherein the platinum-based drug is selected from: carboplatin, cisplatin, oxaliplatin, Nedaplatin, lobaplatin, satraplatin, cycloplatin, Miboplatin, Enloplatin, Iproplatin, Dicycloplatin.
3. The use according to claim 1, wherein the non-small cell lung cancer is advanced or metastatic non-squamous cell lung cancer.
4. The use according to claim 3, wherein the non-small cell lung cancer is selected from EGFR/ALK gene wild-type advanced or metastatic non-squamous cell lung cancer.
5. Use according to claim 3, wherein the platinum-based drug is selected from: carboplatin and cisplatin.
6. The use according to claim 4, wherein the platinum-based drug is selected from the group consisting of: carboplatin, cisplatin.
7. The use according to any one of claims 1 to 6, wherein the anti-PD-1 antibody dose is selected from 1 to 10 mg/kg.
8. The use of claim 7, wherein the anti-PD-1 antibody is administered in an amount selected from the group consisting of 1mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, and 10 mg/kg.
9. The use according to any one of claims 1 to 6, wherein the anti-PD-1 antibody dose is selected from the group consisting of 50 to 600 mg.
10. The use of claim 9, wherein the anti-PD-1 antibody is administered in an amount selected from the group consisting of 60mg, 100mg, 200mg, 400mg, and 600 mg.
11. The use as claimed in any one of claims 1 to 6 wherein the pemetrexed dose is selected from 200-700mg/m 2 。
12. The use according to claim 11, wherein the pemetrexed dose is selected from 200mg/m 2 、300mg/m 2 、400mg/m 2 、500mg/m 2 、600mg/m 2 、700mg/m 2 。
13. The use of claim 2, 5 or 6 wherein the dose of carboplatin administered is selected from 1 to 10mg/ml/min as calculated as area under the curve (AUC).
14. The use according to claim 13, wherein the dose of carboplatin administered is selected from the group consisting of 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/min, 7mg/ml/min, 8mg/ml/min, calculated as area under the curve (AUC).
15. The use as claimed in claim 2, 5 or 6 wherein the carboplatin dose is selected from 200-400mg/m 2 Once every three to four weeks.
16. The use according to claim 15, wherein the carboplatin dose is selected from 200mg/m 2 、300mg/m 2 、400mg/m 2 Once every three to four weeks.
17. The use according to claim 2, 5 or 6, wherein the carboplatin dose is selected from 50mg/m 2 Once daily.
18. A pharmaceutical pack for the treatment of non-small cell lung cancer comprising an effective amount of the anti-PD-1 antibody of any one of claims 1-17, pemetrexed and carboplatin.
19. A pharmaceutical composition for the treatment of non-small cell lung cancer comprising an effective amount of an anti-PD-1 antibody according to any one of claims 1-17, pemetrexed and carboplatin together with one or more pharmaceutically acceptable excipients, diluents or carriers.
20. The pharmaceutical package of claim 18 or the pharmaceutical composition of claim 19, wherein the non-small cell lung cancer is advanced or metastatic non-squamous cell lung cancer.
21. The pharmaceutical package of claim 18 or the pharmaceutical composition of claim 19, wherein the non-small cell lung cancer is EGFR/ALK gene wild-type advanced or metastatic non-squamous cell lung cancer.
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| MX2023002278A (en) * | 2020-08-28 | 2023-03-10 | Shanghai Junshi Biosciences Co Ltd | Use of an anti-pd-1 antibody and a cytotoxic anticancer drug in treatment of non-small cell lung cancer. |
| CN115227812A (en) * | 2021-04-22 | 2022-10-25 | 上海君实生物医药科技股份有限公司 | Use of anti-PD-1 antibody in combination with first-line chemotherapy for treating advanced NSCLC |
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