Use of combination of pyrido[2,3-d]pyrimidin-2(1H)-one derivative in preventing or treating tumor disease

Abstract

The use of a combination of a pyrido[2,3-d]pyrimidin-2(1H)-one derivative and an anti-PD-1 or anti-PD-L1 antibody and / or a chemotherapeutic drug in the preparation of a drug for preventing or treating a tumor disease.

Description

Use of pyrido[2,3-d]pyrimidin-2(1H)-one derivatives in combination with immunosuppressants or / and chemotherapeutic drugs for the prevention or treatment of tumor diseases TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and relates to the use of pyrido[2,3-d]pyrimidin-2(1H)-one derivatives in combination with immunosuppressants or / and chemotherapeutic drugs for the prevention or treatment of tumor diseases. BACKGROUND

[0002] Lung cancer is one of the major health problems worldwide, with more than 2 million new lung cancer patients each year, half of which occur in the Asian region. The main risk factors for lung cancer include smoking, ionizing radiation, chronic lung disease, and family history. Between 1990 and 2022, due to advances in detection methods and treatment methods, the incidence and mortality rates of lung cancer in the United States have shown a downward trend, while the number of new lung cancer cases in China has continued to rise. Lung cancer is the cancer with the highest incidence and mortality in China, with 871,000 new cases in 2022 and 767,000 deaths. Lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC accounting for 80-85%. NSCLC subtypes are further divided into lung adenocarcinoma (accounting for 55-60% of Chinese patients), lung squamous cell carcinoma (accounting for 28.02%), and large cell carcinoma (accounting for 0.45%), etc. Driver gene mutations often occur in lung adenocarcinoma, with the highest frequencies of EGFR and KRAS mutations in the Chinese population, at 39.0% and 8.0%, respectively. The mutation frequencies of other driver genes such as ALK, ROS1, BRAF, RET, and HER2 are 2.4-5.5%, 7.4-10.3%, 0.6-1.1%, 0.6%-1.5%, and 1.7-4.3%, respectively. Compared to American patients, EGFR mutations are more common in Chinese patients, while KRAS G12C, the most common KRAS mutation in NSCLC, has an incidence of 3-4.6% in Chinese patients, but an incidence of 13.6% in Western populations. Currently, there are corresponding drugs approved for first-line treatment targeting multiple driver gene mutations, but for KRAS mutant patients, the Chinese Society of Clinical Oncology (CSCO), the National Comprehensive Cancer Network (NCCN), and other guidelines recommend that the standard first-line therapy be chemotherapy ± immunotherapy, but the benefits are limited. Therefore, exploring more optimal treatment options to benefit more KRAS mutant tumor patients is a hot and difficult topic in current clinical research.

[0003] KRAS gene encodes KRAS protein, which is a guanine nucleotide-binding protein with GTPase activity. KRAS protein is composed of a central G domain that hydrolyzes GTP and is highly conserved, and a C-terminal hypervariable region (HVR). In cells, KRAS is in an inactive state when it binds to guanosine diphosphate (GDP), and in an activated state when it binds to guanosine triphosphate (GTP). KRAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) in this conversion process. KRAS plays a pivotal role in cell signal regulation. Activation of KRAS leads to activation of downstream RAS-RAF-MEK-ERK, PI3K-AKT-mTOR or RALGEF-RAL axis signaling pathways, thereby regulating cell growth, metabolism, differentiation, and cell cycle processes. When KRAS mutates, it damages the activity of GAPase and the intrinsic GTPase activity, which blocks the GTP hydrolysis process, allowing KRAS to remain in an activated state bound to GTP and continuously activating downstream signaling pathways, thereby inducing tumor occurrence. Studies have found that KRAS mutations can also down-regulate the expression of major histocompatibility complex I (MHC I) in tumor cells, up-regulate the expression of PD-L1, recruit myeloid-derived suppressor cells (MDSCs), and inhibit the killing activity of T cells, ultimately leading to tumor immune escape. In mice with normal immune function, KRAS G12C inhibitor AMG510 treatment can lead to a pro-inflammatory microenvironment, promoting the infiltration of CD8 + T cells, macrophages, and dendritic cells, and the combination of AMG510 and immunosuppressive agents produces a lasting antitumor effect.

[0004] The combination of chemotherapy and immunotherapy is the most widely used treatment for patients with driver gene-negative NSCLC in clinical practice. Based on the results of the IMpower130 study, the treatment of PD-L1 monoclonal antibody atezolizumab combined with pemetrexed plus platinum can improve the PFS and OS of patients with driver gene-negative NSCLC compared with traditional chemotherapy regimens, and is superior to simple chemotherapy for patients in each subgroup, including those with negative PD-L1 expression. Based on this study, the atezolizumab combined chemotherapy treatment regimen has been approved for the first-line treatment of driver gene-negative non-squamous NSCLC that cannot be surgically resected. On the basis of the safety and tolerability of the subjects, the addition of KRAS G12C inhibitor treatment to the chemotherapy and immunotherapy regimen can further kill tumor cells from different mechanisms, and may amplify the clinical benefits of the subjects.

[0005] In combination with the above preclinical and clinical research results, it is suggested that KRAS G12C inhibitor combined with immunotherapy ± chemotherapy can improve the therapeutic effect, and the combination therapy can better kill tumor cells, and also has a lasting antitumor effect, and the combination administration can make more KRAS G12C mutant NSCLC patients benefit. SUMMARY

[0006] The present application provides a use of a KRAS G12C inhibitor combined with an anti-PD-1 or anti-PD-L1 antibody in the preparation of a drug for treating a tumor disease.

[0007] In certain embodiments of the present application, the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1H)-one, M-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1H)-one, P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)- one, 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6- chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)- one, or a pharmaceutically acceptable salt thereof.

[0008] In certain embodiments of the present application, the pharmaceutically acceptable salt of the above-mentioned compound is selected from hydrochloride, sulfate, hydrobromide, phosphate, benzenesulfonate, cinnamate, tartrate, oxalate, succinate, fumarate, methanesulfonate, p-toluenesulfonate, isethionate or camphorate; preferably hydrochloride, sulfate, methanesulfonate, p-toluenesulfonate or isethionate; more preferably isethionate.

[0009] In certain embodiments of the present application, the KRAS G12C inhibitor is selected from the hydroxyethanesulfonate salt of P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0010] In certain embodiments of the present application, the anti-PD-1 antibody is selected from Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab or Serplulimab;

[0011] In certain embodiments of the present application, the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, Sugemalimab, Envafolimab or Adebrelimab; preferably Adebrelimab.

[0012] In certain embodiments of the present application, one or more chemotherapeutic drugs are further combined;

[0013] The chemotherapeutic drug is selected from one or more of cyclophosphamide, daunorubicin, doxorubicin, mitoxantrone, methotrexate, vincristine, vindesine, etoposide, teniposide, dexamethasone, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, gemcitabine or pemetrexed;

[0014] Preferably, one or more of cisplatin, carboplatin or pemetrexed are further combined.

[0015] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the single dose is in the range of 10-50 mg / kg; preferably 10-30 mg / kg; more preferably 10-20 mg / kg. An exemplary dose is selected from 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg.

[0016] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the frequency of administration is once a week, twice a week, or once in three weeks; preferably once in three weeks.

[0017] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the frequency of administration is once a week, twice a week, or once in three weeks; preferably once in three weeks.

[0018] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the frequency of administration is once a week, twice a week, or once in three weeks; preferably once in three weeks.

[0019] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the frequency of administration is once a week, twice a week, or once in three weeks; preferably once in three weeks.

[0020] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the frequency of administration is once a week, twice a week, or once in three weeks; preferably once in three weeks.

[0021] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the single administration dose is in the range of 500-1500 mg; preferably 600-1200 mg; and exemplary doses are selected from 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, or 1500 mg.

[0022] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the administration frequency is once a week, once in two weeks, or once in three weeks; preferably once in three weeks.

[0023] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and is administered by intravenous injection once in three weeks, with a single administration dose of 600-1200 mg.

[0024] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the single administration dose is in the range of 500-1500 mg; preferably 600-1200 mg; and exemplary doses are selected from 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, or 1500 mg.

[0025] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and the administration frequency is once a week, once in two weeks, or once in three weeks; preferably once in three weeks.

[0026] In certain embodiments of the application, the anti-PD-1 or anti-PD-L1 antibody is selected from atezolizumab, and is administered by intravenous injection once in three weeks, with a single administration dose of 600-1200 mg.

[0027] The application also provides a use of a KRAS G12C inhibitor in combination with one or more chemotherapeutic drugs in treating a tumor disease;

[0028] wherein the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, M-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((S)-4-acryloyl-2- methylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof;

[0029] Preferably, the pharmaceutically acceptable salt of the compound is selected from a hydrochloride, a sulfate, a hydrobromide, a phosphate, a benzenesulfonate, a cinnamate, a tartrate, an oxalate, a succinate, a fumarate, a methanesulfonate, a p-toluenesulfonate, a hydroxyethanesulfonate or a camphorate; preferably a hydrochloride, a sulfate, a methanesulfonate, a p-toluenesulfonate or a hydroxyethanesulfonate; more preferably a hydroxyethanesulfonate;

[0030] More preferably, the KRAS G12C inhibitor is selected from a hydroxyethanesulfonate salt of P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)- one;

[0031] The chemotherapeutic drug is selected from one or more of cyclophosphamide, daunorubicin, doxorubicin, mitoxantrone, methotrexate, vincristine, vindesine, etoposide, teniposide, dexamethasone, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, gemcitabine or pemetrexed; preferably from one or more of cisplatin, carboplatin or pemetrexed.

[0032] In certain embodiments of the application, cisplatin is combined, wherein the single dose of cisplatin ranges from 10 to 100 mg / m 2 ; preferably from 20 to 80 mg / m 2 ; more preferably from 35 to 75 mg / m 2 ; exemplary doses are selected from 10 mg / m 2 , 15 mg / m 2 , 20 mg / m 2 , 25 mg / m 2 , 30 mg / m 2 , 35 mg / m 2 , 36 mg / m 2 , 37 mg / m 2 , 38 mg / m 2 , 39 mg / m 2 , 40 mg / m 2 , 41 mg / m 2 , 42 mg / m 2 , 43 mg / m 2 , 44 mg / m 2 , 45 mg / m 2 , 46 mg / m 2 , 47 mg / m 2 , 48 mg / m 2 , 49 mg / m 2 , 50 mg / m 2 , 51 mg / m 2 , 52 mg / m 2 , 53 mg / m 2 , 54 mg / m 2 , 55 mg / m 2 , 56 mg / m 2 , 57 mg / m 2 , 58 mg / m 2 , 59 mg / m 2 , 60 mg / m 2 , 61 mg / m 2 , 62 mg / m 2 , 63 mg / m 2 , 64 mg / m 2 , 65 mg / m 2 , 66 mg / m 2, 67 mg / m 2 , 68 mg / m 2 , 69 mg / m 2 , 70 mg / m 2 , 71 mg / m 2 , 72 mg / m 2 , 73 mg / m 2 , 74 mg / m 2 , 75 mg / m 2 or 80 mg / m 2 .

[0033] The cisplatin is administered once a week, twice a week or three times a week; preferably three times a week;

[0034] Preferably, the cisplatin is administered intravenously three times a week at a dose ranging from 20 to 80 mg / m 2 ; more preferably, the cisplatin is administered once a day at a dose ranging from 35 to 75 mg / m 2 .

[0035] or / and, in combination with carboplatin, wherein the carboplatin is administered at a dose ranging from AUC=1 to AUC=6; preferably AUC=2 to AUC=5; exemplary doses are selected from AUC=1, AUC=1.5, AUC=2, AUC=2.25, AUC=2.5, AUC=2.75, AUC=3, AUC=3.25, AUC=3.5, AUC=3.75, AUC=4, AUC=4.25, AUC=4.5, AUC=4.75, AUC=5, AUC=5.5 or AUC=6;

[0036] The carboplatin is administered once a week, twice a week or three times a week; preferably three times a week;

[0037] Preferably, the carboplatin is administered intravenously three times a week at a dose ranging from AUC=2 to AUC=5;

[0038] or / and, in combination with pemetrexed, wherein the pemetrexed is administered at a dose ranging from 100 to 1000 mg / m 2 ; preferably 200 to 500 mg / m 2 ; exemplary doses are selected from 100 mg / m 2 , 150 mg / m 2 , 200 mg / m 2 , 250 mg / m 2 , 275 mg / m 2 , 300 mg / m 2 , 325 mg / m 2 , 350 mg / m 2 , 375 mg / m 2, 400 mg / m 2 , 425 mg / m 2 , 450 mg / m 2 , 475 mg / m 2 , 500 mg / m 2 , 550 mg / m 2 , 600 mg / m 2 , 650 mg / m 2 , 700 mg / m 2 , 750 mg / m 2 , 800 mg / m 2 , 850 mg / m 2 , 900 mg / m 2 , 950 mg / m 2 , or 1000 mg / m 2 .

[0039] The frequency of administration of the pemetrexed is once a week, once in two weeks or once in three weeks; preferably once in three weeks;

[0040] Preferably, the pemetrexed is administered intravenously once in three weeks at a dose of 200-500 mg / m 2 .

[0041] In certain embodiments of the application, the single dose of the KRAS G12C inhibitor ranges from 200-1200 mg; preferably from 200-800 mg; more preferably 200 mg, 400 mg or 800 mg; exemplary doses are selected from 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg or 1200 mg.

[0042] The KRAS G12C inhibitor of the present application can be administered in the form of a free base or a salt, but the dosage is calculated in the form of a free base unless otherwise specified.

[0043] In some embodiments of the present application, the KRAS G12C inhibitor is administered once a day, twice a day or three times a day; preferably once a day.

[0044] In some embodiments of the present application, the KRAS G12C inhibitor is administered orally once a day, and the single administration dosage is 200-800 mg; preferably, the KRAS G12C inhibitor is administered orally once a day, and the single administration dosage is 200 mg, 400 mg or 800 mg.

[0045] In some embodiments of the present application, the KRAS G12C inhibitor is administered simultaneously, concurrently, independently or sequentially with an anti-PD-1 or anti-PD-L1 antibody or / and a chemotherapeutic drug.

[0046] The administration route of the combination described in the present application is selected from oral administration, parenteral administration, transdermal administration, the parenteral administration including but not limited to intravenous injection, subcutaneous injection, intramuscular injection, preferably oral administration or intravenous injection.

[0047] In the regimen of the present application, the combination optionally further comprises other components, which include but are not limited to other drugs for treating tumor diseases.

[0048] The present application also provides a combination preparation comprising (a) a KRAS G12C inhibitor and at least one of the following components:

[0049] (b) one or more chemotherapeutic drugs;

[0050] (c) one or more anti-PD-1 or anti-PD-L1 antibodies;

[0051] Preferably, the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, M-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((S)-4-acryloyl-2- methylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof, more preferably the hydroxyethylsulfate salt of P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;

[0052] the anti-PD-1 antibody is selected from Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, or Serplulimab;

[0053] the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, Sugemalimab, Envafolimab or Adebrelimab; preferably Adebrelimab;

[0054] the chemotherapeutic drug is selected from one or more of cyclophosphamide, daunorubicin, doxorubicin, mitoxantrone, methotrexate, vincristine, vindesine, etoposide, teniposide, dexamethasone, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, gemcitabine or pemetrexed; preferably one or more of cisplatin, carboplatin or pemetrexed;

[0055] the combination further comprises one or more pharmaceutically acceptable carriers, excipients or diluents.

[0056] The present application also provides a pharmaceutical composition comprising (a) a KRAS G12C inhibitor and at least one of the following:

[0057] (b) one or more chemotherapeutic drugs;

[0058] (c) one or more anti-PD-1 or anti-PD-L1 antibodies;

[0059] Preferably, the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, M-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((S)-4-acryloyl-2- methylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof, more preferably the hydroxyethylsulfate salt of P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;

[0060] the anti-PD-1 antibody is selected from Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, or Serplulimab;

[0061] the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, Sugemalimab, Envafolimab or Adebrelimab; preferably Adebrelimab;

[0062] the chemotherapeutic agent is selected from one or more of cyclophosphamide, daunorubicin, doxorubicin, mitoxantrone, methotrexate, vincristine, vindesine, etoposide, teniposide, dexamethasone, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, gemcitabine or pemetrexed; preferably one or more of cisplatin, carboplatin or pemetrexed;

[0063] When the combination is in the form of a pharmaceutical composition, it further comprises one or more pharmaceutically acceptable carriers, excipients or diluents.

[0064] In certain embodiments of the present application, the pharmaceutical composition can be prepared in any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays.

[0065] In certain embodiments of the present application, the combination preparation or pharmaceutical composition can be used for the prevention or treatment of a tumor disease.

[0066] The present application also provides a method for preventing or treating a tumor disease, comprising administering to a patient comprising administering an effective dose of (a) one KRAS G12C inhibitor and at least one of the following components:

[0067] (b) one or more chemotherapeutic agents;

[0068] (c) one or more anti-PD-1 or anti-PD-L1 antibodies;

[0069] Preferably, the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, M-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((S)-4-acryloyl-2- methylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof, more preferably the hydroxyethylsulfate salt of P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;

[0070] the anti-PD-1 antibody is selected from Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, or Serplulimab;

[0071] the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, Sugemalimab, Envafolimab or Adebrelimab; preferably Adebrelimab;

[0072] the chemotherapeutic drug is selected from one or more of cyclophosphamide, daunorubicin, doxorubicin, mitoxantrone, methotrexate, vincristine, vindesine, etoposide, teniposide, dexamethasone, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, gemcitabine or pemetrexed; preferably one or more of cisplatin, carboplatin or pemetrexed.

[0073] The present application also provides a method for preventing or treating a tumor disease, comprising a) administering to a patient an effective dose of a KRAS G12C inhibitor, an anti-PD-1 or anti-PD-L1 antibody, pemetrexed, carboplatin or / and cisplatin for 4-6 cycles of standard treatment, and b) administering to the patient an effective dose of a KRAS G12C inhibitor, an anti-PD-1 or anti-PD-L1 antibody and pemetrexed for maintenance treatment after the standard treatment; the KRAS G12C inhibitor and the anti-PD-1 or anti-PD-L1 antibody are as described above.

[0074] the administration cycle is selected from 4 weeks, 3 weeks, 2 weeks, 1 week or 24 hours; preferably 3 weeks;

[0075] The present application also provides a pharmaceutical kit for use in a medicament for treating a tumor disease, wherein the compositions of the KRAS G12C inhibitor, the anti-PD-1 or anti-PD-L1 antibody or / and one or more chemotherapeutic drugs described in the present application are packaged.

[0076] The present application combines the administration of a KRAS G12C inhibitor, an anti-PD-1 or anti-PD-L1 antibody or / and one or more chemotherapeutic drugs, thereby enhancing the use in a medicament for treating a tumor disease and improving the therapeutic effect.

[0077] The tumor disease described in the present application is selected from leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumor, breast cancer, lung cancer or colorectal cancer; preferably lung cancer.

[0078] The lung cancer described in the present application is selected from non-small cell lung cancer, preferably KRAS G12C mutant non-small cell lung cancer.

[0079] The term "in combination" as used herein refers to a mode of administration in which at least one dose of a KRAS G12C inhibitor and at least one dose of an anti-PD-1 or anti-PD-L1 antibody or / and at least one dose of a chemotherapeutic drug are administered within a certain time period, wherein both substances show a pharmacological effect. The time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. The KRAS G12C inhibitor and the anti-PD-1 or anti-PD-L1 antibody or / and the chemotherapeutic drug can be administered simultaneously or sequentially. This time period includes treatments in which the KRAS G12C inhibitor and the anti-PD-1 or anti-PD-L1 antibody or / and the chemotherapeutic drug are administered via the same or different routes of administration.

[0080] The term "effective amount" refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; or / and relieve to some extent one or more of the symptoms associated with the disorder. To the extent the drug can prevent development of or arrest further development of malignant cells, it can be cytostatic or / and cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the duration of survival, duration of progression free survival (PFS), the response rates (RR), duration of response or / and quality of life. DETAILED DESCRIPTION

[0081] The application will be explained in more detail with reference to the examples, which are only used to illustrate the technical solutions of the application, and do not limit the essence and scope of the application.

[0082] Example 1. Evaluation of the in vivo inhibitory effect of drug A combination therapy on human non-small cell lung cancer cell line NCI-H358 subcutaneous xenograft tumor in PBMC humanized NCG mice

[0083] 1.1 Experimental materials

[0084] Drug A: hydroxyethylsulfate salt of P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, prepared using the method in WO2020239077, drug preparation uses 0.5% HPMC;

[0085] Drug B: Adagrasib, purchased from Suzhou Shengdiya Biomedicine Co., Ltd;

[0086] Drug C: Cisplatin, from Jiangsu Haosen Pharmaceutical Group Co., Ltd.

[0087] Drug D: Pemetrexed disodium, from Jiangsu Haosen Pharmaceutical Group Co., Ltd.

[0088] Human non-small cell lung cancer NCI-H358 cells were cultured in vitro in monolayer, and the culture conditions were RPMI 1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin, and cultured in a 37°C 5% CO2 incubator. The cells were passaged by routine digestion with trypsin-EDTA twice or three times a week. When the cell saturation was 80%-90% and the number reached the required amount, the cells were collected, counted, and inoculated.

[0089] PBMC: purchased from Zhejiang Free Trade Zone Maishun Biotechnology Co., Ltd.

[0090] NCG mice, female, body weight 17-19 g, purchased from Jiangsu Jizhuangkang Biotechnology Co., Ltd.

[0091] 1.2 Experimental method

[0092] 0.1 mL of PBMC cell suspension (containing 5 x 10 6 cells) was injected into the NCG mice through the tail vein.

[0093] After 8 days of PBMC cell inoculation, 0.1 mL (6 x 10 6 NCI-H358 cells were inoculated subcutaneously on the right side of each mouse. On the 13th day after cell inoculation, the average tumor volume reached 150 mm 3 After cell inoculation, the mice were grouped and administered, and the day of administration was defined as day 0 (PG-D0). The mice were administered p.o (drug A) or i.p (drugs B, C and D) once a day (QD, drug A) or twice a week (BIW, drug B) or once a week (QW, drugs C and D); the administration volume was 10 mL / kg; the solvent group was given the same volume of "solvent" (0.5% HPMC or Saline); the specific administration dose and administration schedule are shown in Table 2-1. The tumor volume was measured, the mice were weighed, and the data were recorded.

[0094] The experimental index was to investigate the effect of the drug on tumor growth, and the specific index was T / C% or tumor inhibition rate TGI (%).

[0095] The tumor diameter was measured with a vernier caliper, and the tumor volume (V) was calculated according to the formula:

[0096] V = 1 / 2 x a x b 2 where a and b represent the long diameter and short diameter of the tumor, respectively.

[0097] T / C(%) = (T-T i ) / (C-C i ) x 100, wherein T and C are the tumor volumes of the dosing group and the control group at the end of the experiment, T i and C i are the tumor volumes of the dosing group and the control group at the beginning of the experiment.

[0098] Tumor inhibition rate (TGI) (%) = 100 - T / C (%).

[0099] When the tumor regresses, the tumor inhibition rate (TGI) (%) = 100 - (T-T i ) / T i x 100.

[0100] If the tumor shrinks compared to the initial volume, i.e., T < T i or C < C i , it is defined as partial tumor regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR).

[0101] At the end of the experiment, when the endpoint is reached or the average tumor volume reaches 2,000 mm 3 , the mice are euthanized, and the tumors are dissected and photographed.

[0102] The experimental data are analyzed and plotted using GraphPad Prism 9.1.2. Based on the tumor volume data at different time points in each group, statistical analysis is performed using Dunnett's multiple comparisons test in Two-way ANOVA to evaluate the differences between groups. Dunnett's multiple comparisons test in One-way ANOVA is used for analysis of differences in tumor volume between groups. t-test is used for analysis of differences in tumor volume between two groups. p < 0.05 is defined as statistically significant difference.

[0103] Table 1. Dosing regimen of drug A combined with drug B in NCI-H358 model

[0104] 1.3 Experimental conclusion:

[0105] In the KRAS G12C human non-small cell lung cancer xenograft PBMC humanized mouse model, the tumor inhibition effect of drug A combined with drug B is better than that of drug A single agent and drug B single agent, the tumor inhibition effect of drug A combined with drug C and drug D is better than that of drug C and drug D, the tumor inhibition effect of drug A combined with drug B and drug C and drug D is better than that of drug B combined with drug C and drug D, and the combined drug animals are well tolerated.

[0106] Example 2. Ib phase clinical study of safety, tolerability, efficacy and pharmacokinetics of drug A combination therapy in patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)

[0107] This is a multicenter, open-label, Ib phase clinical study to evaluate the safety, tolerability, efficacy and PK characteristics of drug A in combination with immunotherapy or / and chemotherapy in subjects with KRAS G12C-mutated advanced solid tumors.

[0108] 2.1 Study design

[0109] This study is conducted in subjects with KRAS G12C-mutated locally advanced or metastatic NSCLC. The study is conducted in the following cohorts:

[0110] • Drug A in combination with immunotherapy cohort:

[0111] Arm A: Drug A is administered at 200 mg (QD) until disease progression or other criteria for discontinuation of study treatment are met (except for treatment after disease progression); atezolizumab is administered at 20 mg / kg (Q3W) until disease progression or administration for 2 years (subjects who continue treatment after disease progression also need to discontinue atezolizumab for 2 years), with a cycle of every three weeks throughout the study.

[0112] Arm B: Drug A is administered at 400 mg (QD) until disease progression or other criteria for discontinuation of study treatment are met (except for treatment after disease progression); atezolizumab is administered at 20 mg / kg (Q3W) until disease progression or administration for 2 years (subjects who continue treatment after disease progression also need to discontinue atezolizumab for 2 years), with a cycle of every three weeks throughout the study.

[0113] • Drug A in combination with immunotherapy + chemotherapy cohort:

[0114] After completion of the interim analysis of ARM A / ARM B, the safe and effective dose of drug A evaluated by SRC meeting is selected to conduct Cohort C1 (safety lead-in phase) study.

[0115] Cohort C1: Drug A + atezolizumab (20 mg / kg) + pemetrexed (500 mg / m 2 ) + carboplatin (AUC = 5) or cisplatin (75 mg / m 2), every 3 weeks for a cycle, and after 4-6 cycles, switch to Drug A + Adagrasyl (20 mg / kg) + Pemetrexed (500 mg / m 2 ) for maintenance therapy until disease progression (except for post-progression treatment) or other criteria for discontinuation of study treatment are met. Among them, when the treatment of Adagrasyl is more than 2 years, the administration of Adagrasyl needs to be stopped (the treatment of Adagrasyl for subjects who continue to be treated after disease progression for 2 years also needs to be stopped), and the administration of Drug A and Pemetrexed is not limited by 2 years (i.e., continuous administration until the criteria for termination of treatment are met, and Drug A allows post-progression treatment)

[0116] Cohort C2: maintenance therapy of Drug A + Adagrasyl (20 mg / kg) + Pemetrexed (500 mg / m 2 ) until disease progression (except for post-progression treatment) or other criteria for discontinuation of study treatment are met. Among them, when the treatment of Adagrasyl is more than 2 years, the administration of Adagrasyl needs to be stopped (the treatment of Adagrasyl for subjects who continue to be treated after disease progression for 2 years also needs to be stopped), and the administration of Drug A and Pemetrexed is not limited by 2 years (i.e., continuous administration until the criteria for termination of treatment are met, and Drug A allows post-progression treatment).

[0117] · Drug A combined with chemotherapy cohort:

[0118] Cohort D: Drug A combined with platinum-containing doublet chemotherapy for locally advanced or metastatic non-squamous NSCLC subjects who are positive for KRAS G12C mutation and have not been treated systemically.

[0119] 2.2 Sample size determination

[0120] About 80-340 subjects will be enrolled in this study, and about 60-120 subjects will be enrolled in the combined Adagrasyl cohort ARM A / B cohort in this study; about 10 subjects will be enrolled in the safety observation phase of the combined Adagrasyl + chemotherapy cohort, and after confirming safety, 1-2 effective doses may be selected for subsequent enrollment, about 30-100 subjects not fixed;

[0121] The safety observation phase of the combined chemotherapy cohort plans to enroll 10 subjects, and after confirming safety, 1-2 effective doses may be selected for subsequent enrollment of about 30-100 subjects not fixed.

[0122] Based on the accumulation of clinical trial data, preclinical efficacy, and research progress of similar drugs, the study population may be adjusted.

[0123] 2.2.1 Subject inclusion criteria:

[0124] A subject must meet all the following criteria to be enrolled in this study:

[0125] 1. Male or female, 18 years of age or older (≥ 18 years of age).

[0126] 2. Subjects have at least 1 target lesion according to RECIST 1.1. The requirements for target lesions are: measurable lesions that have not been irradiated or that have clearly progressed following local therapy, and the longest diameter at baseline is ≥ 10 mm (if it is a lymph node, the requirement is that the maximum short diameter is ≥ 15 mm).

[0127] a) Subjects in Cohort C2 who have received 4-6 prior lines of standard treatment are not restricted in comparison to subjects who have not received prior standard treatment.

[0128] 3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1 and no deterioration within 2 weeks prior to first dose.

[0129] 4. Patients with locally advanced (Stage III B / IIIC), metastatic or recurrent (Stage IV) NSCLC that is unresectable, who are not candidates for definitive concurrent chemoradiation, and who have histological / cytological pathology-confirmed NSCLC. (Subjects in Cohorts C1, C2, and D must have pathology-confirmed non-squamous NSCLC)

[0130] 5. Subjects must provide a tumor tissue sample (at least 5 unstained tumor tissue slides or 1 block of formalin-fixed, paraffin-embedded tumor tissue. A recent tumor biopsy is recommended; if not available, a previously archived tumor tissue is acceptable) for confirmation of tumor tissue as KRAS G12C-mutated by the central laboratory.

[0131] 6. Subjects must provide a tumor tissue sample (at least 5 unstained tumor tissue slides or 1 block of formalin-fixed, paraffin-embedded tumor tissue. If a tumor tissue block has already been provided for KRAS G12C mutation testing, it need not be repeated. A recent tumor biopsy is recommended; if not available, a previously archived tumor tissue is acceptable) for testing of tumor cell PD-L1 status by the central laboratory.

[0132] 7. Subjects have not received prior systemic anti-tumor therapy for advanced / metastatic NSCLC; chemotherapy or / and radiotherapy is allowed as part of neoadjuvant / adjuvant therapy unless the subject has experienced disease recurrence / progression at least 6 months after the last treatment. (Subjects in Cohort C2 are not restricted.)

[0133] 8. Minimum expected survival of greater than 12 weeks.

[0134] 9. Female subjects of childbearing potential are willing to take suitable precautions against pregnancy (refer to Appendix XIV) and should not be breast-feeding from the time of signing the informed consent until 6 months after the last dose. Male subjects are willing to use a barrier method of birth control (i.e. condom) from the time of signing the informed consent until 6 months after the last dose.

[0135] 10. Female subjects have a negative serum pregnancy test result within 7 days prior to the first dose or meet one of the following criteria to demonstrate no risk of pregnancy:

[0136] a) Postmenopausal defined as age > 60 years and amenorrhea for at least 12 months after cessation of all exogenous hormonal replacement therapy;

[0137] b) Women less than 60 years of age are considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal therapy with levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the laboratory postmenopausal reference range;

[0138] c) Have undergone irreversible surgical sterilization including hysterectomy, bilateral oophorectomy or bilateral tubal ligation, but not bilateral tubal occlusion.

[0139] 11. Willing to participate in the clinical trial, understand the study procedures and are able to sign the informed consent form in writing prior to any protocol-related procedures.

[0140] 12. Subjects are willing and able to comply with the protocol-specified procedures to complete the corresponding visits, treatments and other study procedures.

[0141] * For subjects in each cohort, enrollment is allowed as soon as the central laboratory confirms the eligibility of the biopsy, without waiting for the PD-L1 level.

[0142] 2.2.2 Subject-specific inclusion criteria:

[0143] In addition to the above general inclusion criteria, subjects must also meet all criteria for the specific cohort for which enrollment is planned.

[0144] Cohort C2

[0145] 1. Subjects have stable disease (SD, PR, CR compared to the tumor assessment before receiving standard treatment) after 4-6 cycles of standard treatment (platinum + pemetrexed + anti-PD-1 / anti-PD-L1 mAb treatment) and are still in the stable disease state at the time of screening. Subjects have not received other systemic anti-tumor therapy before the current systemic anti-tumor therapy, and the last treatment is less than 6 weeks from signing the informed consent.

[0146] a) Chemotherapy or / and radiotherapy is allowed as part of neoadjuvant / adjuvant therapy, and treatment has ended at least 6 months before the diagnosis of advanced or metastatic disease.

[0147] 2.2.3 Exclusion Criteria for Subjects

[0148] Subjects who meet any of the following exclusion criteria are not eligible for enrollment into this study:

[0149] 1. Received or is currently undergoing the following treatments:

[0150] a) Previously treated or is currently being treated with a KRAS G12C inhibitor.

[0151] b) Received cytotoxic chemotherapy drugs, traditional Chinese medicine treatment for antitumor indications (the drug list is detailed in Appendix Four), or other antitumor drugs (such as small molecule targeted therapy, etc.) within 14 days before the first administration of study treatment; or received experimental drugs, large molecule drugs with antitumor effects (such as monoclonal antibodies, antibody drug conjugates, or bispecific antibodies, etc.) within 28 days before the first administration of study treatment; or needs to continue receiving these drugs during the study period.

[0152] c) Received local radiotherapy within 2 weeks before the first administration of study treatment; received more than 30% of bone marrow irradiation (detailed in Appendix Six) or received extensive radiotherapy within 4 weeks before the first administration of study treatment.

[0153] d) There is pleural effusion / abdominal effusion that needs clinical intervention (patients who do not need to drain effusion or have been stable for more than 2 weeks after draining effusion can be enrolled); or there is pericardial effusion (small amount of pericardial effusion that has been stable for more than 2 weeks is allowed to enroll). If antitumor drugs are used locally (such as thoracic perfusion) during drainage, the subject must also meet the requirement of being washed out for at least 5 drug half-lives or 21 days (whichever is shorter) before the first administration of study treatment.

[0154] e) Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks before the first administration of study treatment. The definition of major surgery refers to level 3 and level 4 surgeries as specified in the Medical Technology Clinical Application Management Measures in Appendix Eight.

[0155] f) Brain metastasis (unless asymptomatic, stable for more than 4 weeks before the first administration, does not require steroid treatment at least 2 weeks before the first administration, and there is no significant clinical significance edema around the tumor lesion on imaging); patients who have progressed due to brain metastasis during the last treatment before screening or after treatment without treatment; subjects with meningeal metastasis or brainstem metastasis; subjects with spinal cord compression (discovered by radiological examination, whether symptomatic or not); only CNS lesions can be used as target lesions according to RECIST v1.1 criteria.

[0156] g) Within 7 days prior to the first dose of study drug, use of strong inhibitors or strong inducers of CYP3A4 or CYP2C8, strong inhibitors or strong inducers of P-gp / BCRP, or drugs or foods that are sensitive substrates of CYP3A4 or CYP2C8, or P-gp / BCRP; or the need for continued treatment with these drugs during the study (list of drugs in Appendix IV).

[0157] h) Ongoing treatment with drugs known to prolong the QT interval or predispose to torsades de pointes; or the need for continued treatment with these drugs during the study (list of drugs and washout times in Appendix IV).

[0158] 2. Presence of prior treatment with toxicity (except alopecia and residual neurotoxicity) of > Grade 2 by the Common Terminology Criteria for Adverse Events (CTCAE version 5.0).

[0159] 3. Known to carry EGFR sensitive mutations, ALK fusion mutations, ROS-1 fusion mutations, RET fusion mutations, MET exon skipping mutations, BRAF V600 mutation positive and mutations in KRAS other than G12C.

[0160] 4. History of other primary solid tumors, except:

[0161] a) A solid tumor that has been completely resected with no evidence of active disease for > 5 years prior to study entry and with very low risk of recurrence;

[0162] b) Non-melanoma skin cancer or lentigo maligna that has been adequately treated and is without evidence of disease recurrence;

[0163] c) Carcinoma in situ, such as cervical carcinoma in situ, that has been adequately treated and is without evidence of disease recurrence;

[0164] d) Non-metastatic prostate cancer with definitive treatment.

[0165] 5. Inadequate bone marrow reserve or liver and kidney organ function, reaching any of the following laboratory limits (without correction treatment within 1 week prior to the laboratory blood draw):

[0166] a) Neutrophil count < 1.5 x 109 / L;

[0167] b) Platelet count < 90 x 109 / L;

[0168] c) Hemoglobin < 90 g / L;

[0169] d) Total bilirubin > 1.5 x upper limit of normal (ULN); if there is a clear Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases, total bilirubin > 3.0 x ULN.

[0170] e) alanine aminotransferase (ALT) or / and aspartate aminotransferase (AST) > 2.5 x ULN; if liver metastases are present, then ALT or / and AST > 5.0 x ULN;

[0171] f) creatinine > 1.5 x ULN and creatinine clearance < 50 mL / min (calculated by Cockcroft-Gault formula in Appendix IX); creatinine clearance needs to be confirmed only if creatinine > 1.5 x ULN;

[0172] g) international normalized ratio (INR) > 1.5 and partial activated thromboplastin time (APTT) > 1.5 x ULN;

[0173] h) serum albumin (ALB) < 28 g / L.

[0174] 6. During the Screening Period, any of the following cardiac test criteria:

[0175] a) mean QT interval corrected for Fridericia (QTcF) > 470 msec on electrocardiogram (ECG) test at rest, Fridericia formula in Appendix VII;

[0176] b) resting ECG suggestive of any clinically significant investigator judged important rhythm, conduction or ECG morphologic abnormalities (e.g., complete left bundle branch block, 3° atrioventricular block, 2° atrioventricular block, and PR interval > 250 msec, etc.);

[0177] c) presence of any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, refractory hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death of a first degree relative under 40 years of age or any concomitant medication that prolongs the QT interval;

[0178] d) left ventricular ejection fraction (LVEF) < 50%.

[0179] 7. Have a serious, uncontrolled or active cardiovascular or cerebrovascular disease, including but not limited to:

[0180] a) myocardial infarction (MI) within 6 months prior to first dose of study drug;

[0181] b) unstable angina within 6 months prior to first dose;

[0182] c) congestive heart failure (CHF) within 6 months prior to first dose;

[0183] d) cerebrovascular accident (excluding lacunar infarcts) or transient ischemic attack within 6 months prior to first dose;

[0184] e) a history of atrial arrhythmias of clinical importance (determined by the investigator);

[0185] f) a history of ventricular arrhythmias of clinical importance (determined by the investigator), or any ventricular arrhythmia occurring during the screening period.

[0186] 8. Diabetic ketoacidosis or hyperglycemic hyperosmolar state within 6 months prior to first dose.

[0187] 9. Severe or poorly controlled hypertension, including: history of hypertensive crisis, hypertensive encephalopathy.

[0188] 10. Major bleeding symptoms of clinical significance, such as gastrointestinal bleeding, gastric ulcer bleeding, gross hematuria, or presence of vasculitis, within 4 weeks prior to first dose.

[0189] 11. Severe arterial or venous thromboembolic events, such as deep vein thrombosis, pulmonary embolism, etc. (except for implantable venous access ports, catheter-related thrombosis, or superficial venous thrombosis, which are not considered “severe” thromboembolisms), within 3 months prior to first dose.

[0190] 12. Severe infection within 4 weeks prior to first dose, including but not limited to complications of infection treated with >2 weeks of intravenous antibiotics, bacteremia, severe pneumonia, etc.; active infection treated with therapeutic intravenous antibiotics within 2 weeks or oral antibiotics within 1 week prior to first dose. Subjects receiving or having received prophylactic antibiotic therapy (e.g., for prevention of urinary tract infections) can be enrolled.

[0191] 13. Received continuous glucocorticoid therapy for more than 30 days within 30 days prior to first dose, or required long-term (>30 days) treatment with glucocorticoids (equivalent to >10 mg prednisone / day) (except for subjects requiring long-term inhaled glucocorticoids for asthma and topical glucocorticoid medications for skin), or have other acquired, congenital immunodeficiency disorders, or have a history of organ transplantation or hematopoietic stem cell transplantation.

[0192] 14. Presence of an active infectious disease, such as active hepatitis B (defined as positive screening test for hepatitis B surface antigen [HBsAg] with detectable HBV-DNA of >500 IU / mL) or hepatitis C (defined as positive screening test for hepatitis C virus antibody [HCV-Ab] with positive HCV-RNA). Subjects with chronic HBV infection must be receiving antiviral therapy and monitored for HBV-DNA during the study.

[0193] 15. Known tuberculosis (evidence of active tuberculosis infection within 1 year), syphilis (positive for both Treponema pallidum specific and non-specific antibodies), or human immunodeficiency virus (HIV) infection (positive for anti-HIV antibodies). Infectious diseases other than hepatitis B and C are not actively screened during the screening period.

[0194] 16. Presence of clinically significant gastrointestinal dysfunction that can affect drug intake, transport, or absorption, such as inability to take oral medications, uncontrollable nausea or vomiting, extensive history of gastrointestinal resection, uncontrolled recurrent diarrhea, uncontrolled gastric disease requiring long-term use of proton pump inhibitor acid-suppressive drugs, Crohn's disease, ulcerative colitis, etc.

[0195] 17. Presence of hepatic encephalopathy, hepatorenal syndrome, or ≥ Child-Pugh B cirrhosis.

[0196] 18. Presence of other moderate to severe pulmonary disease (including interstitial lung disease, radiation pneumonitis or drug-related pneumonitis requiring steroid treatment, etc.) that can interfere with the detection or management of drug-related pulmonary toxicity, or history of such disease.

[0197] 19. History of severe neurologic or psychiatric disorders, including epilepsy, dementia, or major depression, etc. that interfere with assessment.

[0198] 20. Subjects with active or history of autoimmune diseases that can potentially relapse (such as systemic lupus erythematosus, inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis, vasculitis, glomerulitis, etc.), or subjects at high risk (patients with solid organ transplants). However, subjects with the following diseases are allowed to enroll: 1) Type I diabetes mellitus patients who are stable on a fixed dose of insulin; 2) autoimmune hypothyroidism who only require hormone replacement therapy; 3) skin diseases (such as eczema, rash covering < 10% of body surface, psoriasis without ophthalmologic symptoms, etc.) that do not require systemic treatment.

[0199] 21. Female subjects who are pregnant, lactating, or planning to become pregnant during the study.

[0200] 22. Subjects who, in the opinion of the investigator, are likely to be non-compliant with the procedures and requirements of the study.

[0201] 23. Subjects who, in the opinion of the investigator, have any condition that poses a safety risk to the subject or that would interfere with the assessment of the study.

[0202] 2.2.4 Subject-specific exclusion criteria:

[0203] In addition to the general exclusion criteria above, subjects are not eligible for enrollment if they meet any of the exclusion criteria for the specific cohort:

[0204] Arm A / B:

[0205] 1. Prior use of anti-PD-1 (L1) therapy or therapy against another stimulatory or co-inhibitory T cell receptor (e.g. CTLA-4, OX-40, CD137).

[0206] 2. Subjects who have been vaccinated or will be vaccinated with a live vaccine or an anti-tumor vaccine or other immunostimulatory anti-tumor therapy within 28 days prior to first dose (Note: Injections with inactivated virus vaccines against seasonal influenza are allowed within 4 weeks prior to first dose; however, attenuated live influenza vaccines are not allowed).

[0207] 3. Subjects with a history of hypersensitivity or contraindication to any of the active or inactive ingredients of Drug A and Adjuvants or to drugs with a similar chemical structure or in the same class.

[0208] 4. Subjects who have received systemic immunosuppressive medications within 2 weeks prior to dosing.

[0209] Cohort C1:

[0210] 1. Subjects with NSCLC of other histological types, including mixed NSCLC with squamous and glandular components with squamous component predominant, NSCLC with small cell lung cancer component

[0211] 2. Prior use of anti-PD-1 (L1) therapy or therapy against another stimulatory or co-inhibitory T cell receptor (e.g. CTLA-4, OX-40, CD137).

[0212] 3. Subjects who have been vaccinated or will be vaccinated with a live vaccine or an anti-tumor vaccine or other immunostimulatory anti-tumor therapy within 28 days prior to first dose (Note: Injections with inactivated virus vaccines against seasonal influenza are allowed within 4 weeks prior to first dose; however, attenuated live influenza vaccines are not allowed).

[0213] 4. Subjects with a history of hypersensitivity, adverse reactions or contraindication to any of the active or inactive ingredients of Drug A, Adjuvants, Pemetrexed, Carboplatin or Cisplatin, including but not limited to Adjuvants allergy, Pemetrexed allergy, Carboplatin allergy, Cisplatin allergy, dextrose or mannitol allergy, etc., or to drugs with a similar chemical structure or in the same class.

[0214] 5. Subjects with a history of hypersensitivity, adverse reactions or contraindication to ancillary drugs used during chemotherapy or immunotherapy (e.g. dexamethasone, vitamin B12, folic acid).

[0215] 6. Received systemic immunosuppressive medications within 2 weeks prior to dosing.

[0216] Cohort C2:

[0217] 1. Subjects with NSCLC of other histological types, including mixed NSCLC with squamous component predominant in squamous gland mixed carcinoma, NSCLC with small cell lung cancer component

[0218] 2. Subjects who have received anti-PD-1 (L1) therapy or therapy against another stimulatory or co-inhibitory T cell receptor (e.g. CTLA-4, OX-40, CD137) in the neoadjuvant / adjuvant setting.

[0219] 3. Subjects who have been vaccinated or will be vaccinated with live vaccines or anti-tumor vaccines or other immunostimulatory anti-tumor therapies within 28 days prior to first dose (Note: Injections with inactivated virus vaccines against seasonal influenza are allowed within 4 weeks prior to first dose; however, attenuated live influenza vaccines are not allowed.)

[0220] 4. Subjects with hypersensitivity, adverse reactions or contraindications to any active or inactive ingredients of Drug A, Adaveltumab, Pemetrexed or drugs with similar chemical structure or in the same class, including but not limited to Adaveltumab allergy, Pemetrexed allergy, etc.

[0221] 5. Subjects with hypersensitivity, adverse reactions or contraindications to adjuvant drugs used during chemotherapy or immunotherapy (e.g. dexamethasone, vitamin B12, folic acid).

[0222] 6. Subjects who have received maintenance therapy in the NSCLC systemic anti-tumor treatment regimen.

[0223] 7. Received systemic immunosuppressive medications within 2 weeks prior to dosing.

[0224] Cohort D:

[0225] 1. Subjects with NSCLC of other histological types, including mixed NSCLC with squamous component predominant in squamous gland mixed carcinoma, NSCLC with small cell lung cancer component.

[0226] 2. Subjects with hypersensitivity, adverse reactions or contraindications to any active or inactive ingredients of Drug A, Pemetrexed, Carboplatin or Cisplatin or other drugs that can be applied in this study, or drugs with similar chemical structure or in the same class, including but not limited to Pemetrexed allergy, Carboplatin allergy, Cisplatin allergy, dextrose or mannitol allergy, etc.

[0227] 3. Subjects who have had hypersensitivity, adverse reactions, or contraindications to adjuvant drugs used during chemotherapy (such as dexamethasone, vitamin B12, folic acid) in the past.

[0228] 2.3 Study Medication

[0229] 2.3.1 Study Drug Information

[0230] Drug A

[0231] • Dosage form: tablet

[0232] • Strength: 200 mg (calculated as C 31 H 32 Cl2FN7O2S)

[0233] • Route of administration: oral

[0234] • Shelf life: 24 months

[0235] • Storage condition: sealed, stored below 30°C

[0236] The study drugs used in this trial are provided by Jiangsu Haosen Pharmaceutical Group Co., Ltd.

[0237] Adalimumab

[0238] • Trade name: HUMIRA®

[0239] • Generic name: Adalimumab for injection

[0240] • Strength: 600 mg (12 ml) / bottle

[0241] • Route of administration: intravenous drip

[0242] • Dosage and usage: 20 mg / kg per dose, intravenous drip, one cycle every 21 days, administered on the first day of each cycle. The required drug is drawn from the Adalimumab injection, slowly injected at one time into the infusion bag containing 0.9% sodium chloride injection or 5% glucose injection, and the infusion bag is gently turned over to mix the drug solution evenly. The drug concentration after dilution in the infusion bag is in the range of 0.5 mg / ml to 9 mg / ml. The infusion device with 0.2 μm or 0.22 μm online filter is used for administration. Once diluted, the product should be used immediately. If it cannot be used immediately, the diluted solution should be stored at room temperature for no more than 4 hours (including the room temperature storage in the infusion bag and the duration of infusion); stored at 2-8°C for no more than 24 hours (calculated from the start of dilution). If the drug solution is stored under refrigerated conditions after dilution, it should be restored to room temperature before use. In any case, do not freeze the product.

[0243] Storage Condition: Store at 2-8℃, protect from light. Do not freeze.

[0244] Manufacturer: Suzhou Shengdiya Biomedicine Co., Ltd.

[0245] Pemetrexed for Injection (Alimta)

[0246] Generic Name: Pemetrexed for Injection

[0247] Trade Name: Alimta

[0248] Chemical Name: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium

[0249] Molecular Formula: C 20 H 19 N5Na2O6

[0250] Molecular Weight: 471.37

[0251] Characteristics: The product is a white or light yellow loose mass or powder.

[0252] Storage: Protect from light, store in airtight container at 30℃ or below

[0253] Dosage and Administration: The dosage is 500 mg / m 2 , intravenous infusion, one cycle every 21 days, on the first day of each cycle. If the subject's body weight increases or decreases by ≥10%, the dosage should be calculated based on the new body surface area.

[0254] Manufacturer: Jiangsu Haosen Pharmaceutical Group Co., Ltd.

[0255] Cisplatin Injection (Nuxin)

[0256] Generic Name: Cisplatin Injection

[0257] Trade Name: Nuxin

[0258] Chemical Name: (cis) diamminedichloroplatinum

[0259] Molecular Formula: CL2H6N2Pt

[0260] Molecular Weight: 300.05

[0261] Characteristics: The product is a light yellow-green to light yellow to slightly sticky clear liquid.

[0262] Storage: Store in airtight container, protect from light

[0263] Dosage and Administration: The dosage is 75 mg / m 2Calvert formula: Total amount of carboplatin (mg) per dose = set AUC (mg / mL / min) x [Ccr (mL / min) + 25], set AUC (mg / mL / min) = 5, intravenous infusion. Ccr is calculated according to Cockroft-Gault formula in Appendix F. Each 21 days is a cycle, and the drug is given on the first day of each cycle. If the weight of the subject increases or decreases by ≥10%, the dose should be calculated according to the new body surface area.

[0264] Manufacturer: Jiangsu Huaosen Pharmaceutical Group Co., Ltd.

[0265] Carboplatin injection

[0266] Generic name: Carboplatin injection

[0267] Trade name: Paraplatin

[0268] Chemical name: Carboplatin

[0269] Molecular formula: C6H 12 N2O4Pt

[0270] Molecular weight: 371.3

[0271] Characteristics: Carboplatin for injection is a white or white-like lyophilized loose block or powder

[0272] Storage: Store in the shade, in a cool place (not more than 20°C)

[0273] Dosage and administration: Calvert formula: Total amount of carboplatin (mg) per dose = set AUC (mg / mL / min) x [Ccr (mL / min) + 25], set AUC (mg / mL / min) = 5, intravenous infusion. Ccr is calculated according to Cockroft-Gault formula in Appendix F. Each 21 days is a cycle, and the drug is given on the first day of each cycle. If the weight of the subject increases or decreases by ≥10%, the dose should be calculated according to the new body surface area.

[0274] Manufacturer: Qilu Pharmaceutical Co., Ltd.

[0275] 2.3.2 Dosing regimen

[0276] Drug A tablets:

[0277] The time of taking the medicine should be as consistent as possible every day, and the drug should be taken at an interval of 24 hours under the QD administration mode. If the subject does not take the medicine at the time point according to the study plan, if the over-the-window time does not exceed half of the specified drug administration interval, the subject can take the medicine again; if the over-the-window time exceeds half of the specified drug administration interval, the subject cannot take the medicine again, and should take the next dose of medicine at the next planned time of taking the medicine. The subject should fast for 2 hours before taking the medicine and for 2 hours after taking the medicine.

[0278] Adalimumab:

[0279] Adcertis should be administered as a fixed 20 mg / kg intravenous infusion over 30 to 60 minutes (not to exceed 2 hours including the flushing period) on Day 1 of each cycle. At the end of the infusion, the line should be flushed with sufficient volume of either normal saline or 5% dextrose solution.

[0280] When Adcertis is administered in combination with chemotherapy, Adcertis should be administered first as an intravenous infusion, followed by chemotherapy at least 30 minutes later.

[0281] Chemotherapy administration:

[0282] Subjects receive 4 to 6 cycles of standard first-line chemotherapy regimen of cisplatin or carboplatin in combination with pemetrexed. The investigator selects the regimen based on the subject's physical condition and tolerance. Pemetrexed in combination with cisplatin regimen: pemetrexed 500 mg / m 2 intravenous infusion + cisplatin 75 mg / m 2 intravenous infusion, administered on Day 1 of each cycle, every 21 days as a cycle; pemetrexed in combination with carboplatin regimen: pemetrexed 500 mg / m 2 intravenous infusion + carboplatin AUC = 5 intravenous infusion, administered on Day 1 of each cycle, every 21 days as a cycle; if the subject cannot tolerate cisplatin for safety reasons, cisplatin can be replaced by carboplatin, with a total of 4 to 6 cycles of chemotherapy maintained. After 4 to 6 cycles of platinum doublet chemotherapy, the subject continues to receive maintenance therapy with pemetrexed 500 mg / m 2 intravenous infusion, administered on Day 1 of each cycle, every 21 days as a cycle, until disease progression or other criteria for treatment discontinuation are met.

[0283] It is recommended that cisplatin be administered as an intravenous infusion over more than two hours, and that the infusion of cisplatin be administered approximately 30 minutes after the administration of pemetrexed is completed. Hydration regimens should be administered to the patient before and / or after cisplatin treatment.

[0284] In addition, the subject should take the following medications before and after chemotherapy:

[0285] ① Folic acid and vitamin supplementation: To reduce toxicity, subjects receiving pemetrexed treatment must be instructed to take a low-dose folic acid preparation or a folic acid-containing multivitamin orally daily. Folic acid must be taken orally once daily for at least 5 days during the 7 days preceding the first pemetrexed dose, and throughout the treatment course and for 21 days after the last pemetrexed dose. Subjects must also receive an intramuscular injection of vitamin B12 within 7 days preceding the first pemetrexed dose, followed by injections every 3 cycles. Subsequent vitamin B12 injections can be scheduled on the same day as pemetrexed. The folic acid dosage ranges from 350 to 1000 μg / day, with a commonly used dose of 400 μg / day; the vitamin B12 dose is 1000 μg / dose. Subjects may also receive other approved pretreatments or concomitant medications with pemetrexed. Specific dosing times and dosages are at the investigator's discretion.

[0286] ② Corticosteroid supplementation: Pre-administration of dexamethasone (or similar drugs) can reduce the incidence and severity of skin reactions. It is recommended to administer dexamethasone 4 mg orally twice daily, one day before, on, and one day after pemetrexed administration, or follow local clinical practice. If dexamethasone is not used, it can be replaced with an equivalent dose of dexamethasone 4 mg twice daily. Specific dosing times and dosages are subject to investigator's judgment.

[0287] The dosing regimens for each cohort are shown in Table 2.

[0288] Table 1 Recommended Dosing Regimen *If a medication is discontinued for any reason during treatment, other medications may continue to be used.

[0289] 2.4 Dosage Adjustment

[0290] 2.4.1 Dosage adjustment of drug A

[0291] Dosage adjustments for drug A are categorized into temporary discontinuation, dose reduction, and permanent discontinuation. For adverse events determined by the investigator to be related to investigational drug A, recommended toxicity management principles are shown in Table 3.

[0292] If the researcher determines that the adverse event is likely or definitely unrelated to drug A, but the subject is temporarily unable to use drug A for various reasons, the researcher may, at their discretion and with the consent of the sponsor, suspend or resume the administration of drug A.

[0293] Table 3. Recommended toxicity management principles for adverse events related to drug A.

[0294] Note: If several AEs occur simultaneously, the dose should be adjusted according to the most serious AE; supportive treatment should be given as needed according to local practice / guidelines during the suspension of study treatment; after dose reduction, the previous dose level should not be returned to; if the subject has been reduced to the lowest dose (up to 2 dose levels of dose reduction) and still cannot tolerate, it is recommended to terminate the treatment; subjects who terminate study treatment should be observed until toxicity is resolved; suspension of dosing does not affect the planned tumor evaluations.

[0295] For subjects who do not meet the dose adjustment requirements of this section but the investigator decides not to suspend treatment or suspend treatment, adjust dose, permanently terminate study treatment based on benefit / risk considerations, can be discussed with the sponsor and agreed by the sponsor.

[0296] Suspension of dosing:

[0297] The suspension of dosing of Drug A should not exceed 21 days to ensure the subject receives the intended drug exposure. If the suspension exceeds the above criteria, the subject will end study dosing unless the investigator and sponsor agree to continue dosing after discussion (e.g. non-infectious pneumonia requires recovery for 28 days, non-drug related toxicity causes suspension of drug for more than 21 days and no disease progression, etc.).

[0298] Dose reduction:

[0299] The dose adjustment plan for Drug A is referenced in Table 4. The allowed dose reduction is the safe and effective dose that has been validated in the dose escalation phase (200 mg QD, 400 mg QD, 800 mg QD), up to 2 dose levels (if needed) of dose reduction of study drug is allowed. If the subject still cannot tolerate after receiving 2 dose levels of Drug A dose reduction or has been reduced to the 200 mg QD dose group and still cannot tolerate, the dosing will be terminated. Subjects who are judged to permanently discontinue by the dose adjustment principle are not allowed to receive any dose of Drug A.

[0300] Table 4 Dose adjustment plan for Drug A tablets

[0301] Permanent discontinuation:

[0302] Subjects who meet the protocol-specified criteria for treatment discontinuation are not allowed to receive any dose of Drug A. During combination therapy, if Drug A is discontinued due to any reason during the treatment, the other drugs are allowed to continue to be used.

[0303] 2.4.2 Dose adjustment of Ademotumab

[0304] Dose modifications for adagrasylumab are categorized as dose interruption, dose delay, and permanent discontinuation. No dose reduction is performed for adagrasylumab. The recommended toxicity management principles for investigator-assessed adagrasylumab study drug-related adverse events are shown in Table 5.

[0305] Table 5. Recommended toxicity management principles for adagrasylumab-related adverse events *Adverse reaction severity is based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0).

[0306] Dose interruption:

[0307] If a patient has a Grade 2 infusion reaction / hypersensitivity reaction to adagrasylumab during infusion or an adverse event that cannot be determined to be unrelated to adagrasylumab, the infusion rate should be reduced or the infusion of adagrasylumab should be interrupted. When the symptoms have resolved, the administration of adagrasylumab can be considered and closely observed. If the reaction recurs, the injection of adagrasylumab should be immediately discontinued and the administration of adagrasylumab in this cycle should not be resumed.

[0308] Dose reduction:

[0309] No dose modification is performed for adagrasylumab in the clinical study phase.

[0310] Dose delay:

[0311] A delay in the administration of adagrasylumab due to immune-related toxicity is allowed for up to 12 weeks. If the pause exceeds the above criteria, the subject ends the administration of adagrasylumab in this study, unless the investigator and the sponsor agree to continue the administration after discussion.

[0312] Permanent discontinuation:

[0313] A subject who meets the protocol-specified criteria for permanent discontinuation is not allowed to receive further administration of adagrasylumab. During combination therapy, if adagrasylumab is discontinued during treatment for any reason, the use of other drugs is allowed to continue.

[0314] 2.4.3 Dose adjustment of chemotherapy drugs

[0315] Dose modifications for chemotherapy drugs are categorized as interruption of dosing, delay of dosing, dose reduction, and permanent discontinuation. The following provides dose modification guidelines for chemotherapy. If an adverse event is only associated with one of the drugs, only that drug needs to be modified. For adverse events not listed in the following tables that are associated with pemetrexed, cisplatin, and carboplatin, the Investigator should refer to the prescribing information (if available) or the center's standard of care for appropriate treatment of the subject. If the Investigator assesses that the risk-benefit ratio for the subject is such that the modification according to the table cannot be made, the dose modification can be made according to local clinical practice.

[0316] The time window for each dose of chemotherapy is calculated from the date of the previous dose. The following criteria must be met prior to each cycle of chemotherapy to administer treatment: absolute neutrophil count > 1.5 x 10 9 / L (1500 / mm 3 ), platelet count > 75 x 10 9 / L (100,000 / mm 3 ), Ccr > 45 mL / min, total bilirubin < 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times the upper limit of normal. If these criteria are met, it is recommended that chemotherapy be initiated within 3 days; if these criteria are not met, the dose should be delayed. If the criteria are met within 3 weeks, it is recommended that the next cycle of treatment be initiated within 3 days, with a maximum delay of 3 weeks. If the delay exceeds 21 days, the patient should be discontinued from chemotherapy. For some patients, the Investigator may decide to initiate chemotherapy or chemotherapy is extended beyond 21 days without meeting the criteria for initiation of chemotherapy based on benefit / risk considerations, and should be agreed upon with the Sponsor.

[0317] During the combination therapy, every effort should be made to ensure that all intravenous infusions are administered on the same day of Cycle 1. If it is found that administration cannot be performed on the same day as specified in the protocol, the Investigator should agree with the Sponsor. For subjects in Cohort C1 and Cohort C2, when the delay in administration due to adecatumumab exceeds 21 days, to maintain the efficacy of the subject, the chemotherapy of the current cycle can be administered alone, and the administration of adecatumumab can be re-evaluated in the next administration cycle.

[0318] 2.4.3.1 Dose Modification for Pemetrexed in Combination with Cisplatin Regimen

[0319] Table 6 / 7 / 8 provides recommendations for dose modifications of chemotherapy drugs in the event of hematologic or non-hematologic toxicities during pemetrexed in combination with cisplatin chemotherapy.

[0320] (1) Hematologic Toxicities

[0321] If the patient experiences a hematologic toxicity (decrease in absolute neutrophil count, decrease in platelet count) as shown in Table 6, treatment with pemetrexed in combination with cisplatin should be withheld. If the patient recovers to baseline levels or slightly below baseline levels (absolute neutrophil count > 1.5 x 10 9 / L, platelet count > 75 x 10 9 / L) within 21 days of the delay in dosing, treatment should be resumed according to the requirements of Table 6. If the patient exceeds 21 days, the patient will be discontinued from treatment. If the patient requires a dose reduction due to both a decrease in absolute neutrophil and platelet counts, the patient will receive the lower dose.

[0322] Table 6. Dose adjustments for pemetrexed and cisplatin due to hematologic toxicity

[0323] (2) Non-hematologic toxicity

[0324] If the patient experiences a non-hematologic toxicity (excluding neurotoxicity) of Grade > 3, treatment with pemetrexed in combination with cisplatin should be withheld. The maximum duration of delay in treatment is 21 days, during which time the toxicity should decrease to CTCAE Grade < 1 or baseline. Once the above criteria are met and the criteria for resuming treatment are met, treatment should be resumed according to the requirements of Table 7.

[0325] Table 7. Dose adjustments for pemetrexed and cisplatin due to non-hematologic toxicity *Excluding neurotoxicity

[0326] (3) Neurotoxicity

[0327] If the patient experiences a neurotoxicity of Grade < 2, treatment does not need to be delayed and the dose of pemetrexed and cisplatin should be adjusted according to Table 8. If the patient experiences a neurotoxicity of Grade 3 or 4, treatment with pemetrexed in combination with cisplatin should be discontinued.

[0328] Table 8. Dose adjustments for pemetrexed and cisplatin due to neurotoxicity

[0329] 2.4.3.2 Dose adjustments for pemetrexed in combination with carboplatin

[0330] Tables 9 / 10 / 11 are recommendations for dose adjustments for the chemotherapy drugs if the patient experiences a hematologic or non-hematologic toxicity during treatment with pemetrexed in combination with carboplatin.

[0331] (1) Hematologic toxicity

[0332] If the patient experiences a hematologic toxicity (decrease in absolute neutrophil count, decrease in platelet count) as shown in Table 9, treatment with pemetrexed in combination with carboplatin should be withheld. If the patient recovers to baseline levels or slightly below baseline levels (absolute neutrophil count > 1.5 x 10 9 / L, platelet count ≥75×10 9 If the blood glucose level is low ( / L), chemotherapy should begin according to the requirements in Table 9. Chemotherapy will be discontinued once 21 days have elapsed. If a patient requires a dose reduction due to both a decrease in absolute neutrophil and platelet count, a lower dose will be administered.

[0333] Table 9 Dosage Adjustments for Pemetrexed and Carboplatin Due to Hematologic Toxicity

[0334] (2) Nephrotoxicity

[0335] If the patient's Ccr is below 60 mL / min, the medication should be adjusted according to Table 10.

[0336] Table 10 Dosage Adjustment of Carboplatin Due to Nephrotoxicity

[0337] Patients with a Ccr rate below 60 mL / min have an increased risk of severe myelosuppression. The dosage recommendations above apply to the initial course of treatment. Subsequent dose adjustments should be made based on the patient's degree of myelosuppression and tolerability.

[0338] (3) Non-hematologic toxicity

[0339] If a patient experiences a grade ≥3 non-hematologic toxicity (excluding nephrotoxicity), pemetrexed combined with carboplatin therapy should be discontinued. The maximum delay in chemotherapy is 21 days, during which time the toxicity should decrease to CTCAE grade 1 or baseline. Once the above conditions are met and the criteria for initiating chemotherapy are satisfied, treatment should be started according to the requirements in Table 11.

[0340] Table 11 Dosage Adjustments for Pemetrexed and Carboplatin Due to Non-Hematologic Toxicity

[0341] 2.4.3.3 Dosage Adjustment of Pemetrexed Maintenance Regimen

[0342] Tables 12 / 13 / 14 provide recommendations for dose adjustments of chemotherapy drugs when patients experience hematologic or non-hematologic toxicity during pemetrexed monotherapy maintenance therapy.

[0343] (1) Hematological toxicity

[0344] If a patient develops hematologic toxicities as shown in Table 12 (decreased absolute neutrophil count, decreased platelet count), chemotherapy should be suspended. If the patient recovers to baseline levels or slightly below baseline levels (absolute neutrophil count ≥1.5 × 10⁻⁶) within 21 days of delayed administration, chemotherapy should be discontinued. 9 / L, platelet count ≥75×10 9If the patient experiences a Grade 3 or 4 non-hematologic toxicity (excluding neurotoxicity) that does not resolve to Grade 0 or 1 within 21 days of the onset of the toxicity, the patient should be removed from the study. If the patient experiences a Grade 3 or 4 non-hematologic toxicity (excluding neurotoxicity) that resolves to Grade 0 or 1 within 21 days of the onset of the toxicity, the patient should be removed from the study if the toxicity recurs.

[0345] Table 12 Dose Modification of Pemetrexed Due to Hematologic Toxicity

[0346] (2) Non-Hematologic Toxicity

[0347] If the patient experiences a Grade >3 non-hematologic toxicity (excluding neurotoxicity), chemotherapy should be withheld. The maximum duration of chemotherapy delay is 21 days during which time the toxicity should resolve to CTCAE Grade <1 or baseline. Once the above criteria are met and the criteria for starting chemotherapy are met, treatment should be resumed according to the requirements in Table 13.

[0348] Table 13 Dose Modification of Pemetrexed Due to Non-Hematologic Toxicity *Excluding neurotoxicity

[0349] (3) Neurotoxicity

[0350] If the patient experiences a Grade <2 neurotoxicity, treatment should not be delayed and the dose of pemetrexed should be adjusted according to Table 14; if a Grade 3 or 4 neurotoxicity occurs, chemotherapy should be discontinued.

[0351] Table 14 Dose Modification of Pemetrexed Due to Neurotoxicity

[0352] Dose Interruptions for Chemotherapy:

[0353] If the patient experiences a severe hypersensitivity / infusion reaction to pemetrexed or cisplatin or carboplatin or develops an adverse event that cannot be judged to be related to the study drug during the infusion, the infusion should be stopped immediately and the adverse event should be documented.

[0354] Termination of Treatment for Chemotherapy:

[0355] If the patient experiences any Grade 3 or 4 hematologic or non-hematologic toxicity after a second dose reduction, chemotherapy should be discontinued. If a Grade 3 or 4 neurotoxicity occurs during pemetrexed plus cisplatin or pemetrexed plus carboplatin or pemetrexed monotherapy, chemotherapy should be discontinued immediately.

[0356] The longest delay period for chemotherapy drugs during chemotherapy is 21 days. If a subject receiving doublet chemotherapy has not recovered to the standard for dosing after 21 days of delay, the subject can receive single agent chemotherapy at the discretion of the investigator that the subject can tolerate, and the other chemotherapy drug will be judged to have discontinued dosing. Once discontinuation of dosing of one chemotherapy drug occurs during chemotherapy, the subject will not receive treatment with that chemotherapy drug in subsequent dosing. If the investigator judges that the subject cannot tolerate either chemotherapy drug, the subject will discontinue dosing of any chemotherapy drug.

[0357] During combination therapy, if one chemotherapy drug is discontinued due to any reason during treatment, the other chemotherapy drug and the study drug are allowed to continue.

[0358] 2.5 Study Evaluations

[0359] 2.5.1 Safety Evaluation Criteria

[0360] Safety of the drug will be evaluated with reference to the CTCAE version 5.0 published by the U.S. Department of Health and Human Services / National Institutes of Health / National Cancer Institute. Adverse events will be classified as definitely related, possibly related, possibly unrelated, definitely unrelated, and indeterminate with respect to the study drug.

[0361] 2.5.2 Efficacy Evaluation Criteria

[0362] Efficacy evaluation of this study will be performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. RECIST 1.1 criteria will be used to assess the response of each subject to antitumor therapy and to calculate ORR, DoR, DCR, and PFS when the investigator performs tumor assessments. At the baseline period, chest enhanced CT (mandatory), abdominal enhanced CT (mandatory), head enhanced MRI / CT (mandatory), bone scan (mandatory), and CT examination or MRI scan of other relevant lesion sites must be performed within 28 days before the start of study treatment. In this study, CT examination with intravenous administration of contrast agent is the preferred method. MRI should be used when CT is not feasible or medically contraindicated. For the assessment of brain lesions, enhanced MRI is the preferred method. The slice thickness of CT scan should be ≤ 5 mm. Chest enhanced CT, abdominal enhanced CT, head enhanced MRI / enhanced CT can use the results of examination within 28 days before the first dosing, and bone scan can use the results of examination within 3 months before the first dosing, which are not subject to the time of knowledge limitation. If there is PET-CT examination (slice thickness should be ≤ 5 mm) within 3 months before the first dosing, the bone scan examination that needs to be performed is not mandatory. If a suspicious metastatic lesion is found by bone scan or PET-CT, the bone metastatic lesion must be confirmed by CT, MRI, or X-ray, and the confirmed lesion can be recorded as a non-target lesion. Ideally, it should be performed as close to the start of study treatment as possible. Additional imaging examinations can be performed based on the signs or / and symptoms of individual subjects.

[0363] Starting after the initiation of treatment, chest enhanced CT (mandatory), abdominal enhanced CT (including upper and lower abdomen and pelvis, mandatory), baseline confirmed metastatic positive sites (mandatory), and imaging of other metastatic sites of interest will be performed every 6 weeks (± 7 days) through Week 54, and then every 12 weeks (± 7 days) thereafter until objective disease progression as defined by RECIST 1.1 or withdrawal from the trial.

[0364] If a subject has a brain lesion or metastatic lesion in other sites at the screening visit, then at each subsequent visit, the subject will undergo tumor assessment of the corresponding site (brain metastatic lesion: head enhanced MRI; bone metastatic lesion: X-ray, enhanced CT, or enhanced MRI); for sites without metastasis at baseline (e.g., no brain metastasis or bone metastasis), subsequent visit assessment is not mandatory, at the discretion of the investigator. For subjects with bone metastasis, bone scan is an optional item, at the discretion of the investigator.

[0365] The same method (CT / MRI) used for the baseline assessment should be used at each follow-up assessment unless there is a medical contraindication or force majeure (e.g., the study center updates the examination instrument or contrast agent uniformly). If a subject cannot undergo enhanced CT examination due to reasons such as allergy to CT contrast agent during the treatment period and follow-up period, plain CT examination can be used instead; if a subject cannot undergo enhanced MRI examination due to reasons such as allergy to MRI contrast agent, plain MRI examination can be used instead. Tumor assessment should be performed as much as possible according to the study plan. If the subject's assessment exceeds the planned time window, and the disease has not progressed, the subsequent assessment should be performed as much as possible according to the previously planned visit time while continuing to receive study treatment. If any other site is suspected of having a tumor, the suspected site should also undergo the corresponding imaging examination. Subjects who are evaluated as CR or PR for the first time need to be confirmed at least 4 weeks later, and this confirmation does not affect the subsequent planned assessment.

[0366] When the investigator has doubts about whether disease progression has occurred, especially for the response of NTLs or the identification of new lesions, it is recommended to continue treatment until re-evaluation according to the study plan, or re-evaluation can be performed in advance if there are clinical indications. If disease progression is confirmed at the time of re-evaluation, the date of the previous examination should be taken as the date of progression.

[0367] When non-target lesion progression occurs, the overall deterioration of the non-target lesions must have reached the degree that treatment must be terminated, even if the target lesion is in SD or PR. The general increase in size of one or more non-target lesions is often not enough to meet the progression criteria. Therefore, it is relatively rare for the overall tumor progression to be defined only by the changes in non-target lesions when the target lesion is in stable disease or partial remission.

[0368] At each visit, the assessment of tumor objective response will be classified as CR, PR, SD, and PD according to RECIST 1.1 criteria. The assessment of target lesion progression should be compared with the minimum sum of the diameters of all target lesions during the entire course of treatment, and an increase to the criteria is PD. In the absence of disease progression, the assessment of tumor response (CR and PR) and disease stabilization (SD) should be compared with the baseline lesions.

[0369] 2.5.3 Adverse Events

[0370] 2.5.3.1 Grading Criteria for Adverse Events

[0371] All events will be graded according to the grading criteria in the National Cancer Institute’s CTCAE version 5.0. For other adverse events not listed in the CTCAE grading criteria, the adverse events will be graded using the recommendations for clinical description of adverse event severity in the CTCAE version 5.0. The reference criteria are shown in Table 15.

[0372] Table 15 Clinical Description of Adverse Event Severity (Grade 1 to 5)

[0373] 2.5.3.2 Assessment of Causality between Adverse Events and Trial Drug

[0374] The investigator will assess the causality between the study drug and each AE. According to the criteria for judging the causality between drug and adverse events, the correlation between adverse events and the use of trial drug will be classified into five levels: definitely related, probably related, possibly unrelated, definitely unrelated, and unable to determine. The correlation judged as definitely related, probably related, and unable to determine will be considered as adverse events related to the drug. The criteria for judging the relationship between adverse events and trial drug are shown in Table 16.

[0375] Table 16 Criteria for Judging the Relationship between Adverse Events and Trial Drug

[0376] 2.5.4 Serious Adverse Events

[0377] 2.5.4.1 Definition of Serious Adverse Events

[0378] A serious adverse event is judged when the adverse event meets any one or more of the following criteria:

[0379] • Results in death

[0380] • Is immediately life-threatening (an immediate risk of dying, not a hypothetical concern that death might occur in the future)

[0381] • Results in persistent or significant disability (incapacitated, bedridden, or on the verge of death) * • Requires inpatient hospitalization or prolongation of existing hospitalization

[0382] • Results in permanent or significant disability / incapacity

[0383] • Results in congenital anomalies or birth defects

[0384] • Other medically important events: which, if untreated, could have resulted in the conditions listed above.

[0385] The following are not considered "hospitalization" for SAE reporting:

[0386] • Rehabilitation facility

[0387] • Nursing home

[0388] • Routine emergency room admission

[0389] • Same-day surgery (e.g., outpatient / same-day / non- bedridden surgery)

[0390] • Admission for a pre-existing illness without occurrence of a new adverse event or worsening of the pre-existing illness

[0391] • Hospitalization for administrative reasons (e.g., routine annual physical)

[0392] • Hospitalization as specified in the protocol during the clinical trial

[0393] • Elective hospitalization not related to worsening of an adverse event (e.g., elective cosmetic surgery)

[0394] • Admission to hospital solely for blood product use

[0395] • Social reasons (e.g., insurance reimbursement)

[0396] 2.5.4.2 Suspected and Unexpected Serious Adverse Reactions (SUSAR)

[0397] All events judged to be definitely related, probably related, or unrelated, to the study drug are considered to be drug-related serious adverse events. If the nature and severity of the clinical presentation of a drug-related serious adverse event exceeds the safety reference information in the Investigator Brochure, it will be reported as a SUSAR for expedited reporting.

[0398] 2.5.4.3 Reporting of Death Cases

[0399] All deaths occurring after the first dose of study drug and up to 90 days after the last dose of study drug should be reported as follows:

[0400] • Death related to disease progression should be recorded in the eCRF but should not be reported as an SAE during the study.

[0401] • If not death due to clear progression of the disease under study, the AE leading to death should be reported as an SAE to the Sponsor within 24 hours of the investigator's knowledge. If applicable, the report should include an assessment of disease progression, the primary cause of death, and other possible causes of death.

[0402] • Death of unknown cause should be reported as an SAE to the Sponsor within 24 hours of the investigator's knowledge of the death, but every effort should be made to determine and provide the Sponsor with the cause of death. Autopsy can be helpful in assessing the cause of death. If an autopsy is performed, a copy of the autopsy results should be reported to the Sponsor within 24 hours of the results.

[0403] Deaths occurring after the end of the 90-day safety follow-up should be reported as follows:

[0404] • Only death-related events related to the study drug are collected, and the investigator should report to the Sponsor as an SAE within 24 hours of knowledge. The report should include an assessment of disease progression, the primary cause of death, and other possible causes of death.

[0405] 2.6 Study Results

[0406] In the study cohort of Drug A in combination with immunotherapy:

[0407] 1) In terms of efficacy, the study data as of 2025-3-1 showed that in 2 patients receiving Drug A and Adjuvants, the confirmed objective response rate (cORR) was 100% (2 / 2), the disease control rate (DCR) was 100% (2 / 2), and the median progression-free survival (PFS) had not been reached.

[0408] 2) In terms of safety, the study data as of 2025-3-1 showed that in 2 patients receiving Drug A and Adjuvants, the incidence of adverse events (TEAEs) and treatment-related adverse events (TRAEs) during treatment was 100% (2 / 2), the incidence of treatment-related adverse events of grade 3 or higher was 50% (1 / 2), and no serious adverse events occurred.

[0409] In the study cohort of Drug A in combination with immunotherapy plus chemotherapy:

[0410] 1) Efficacy: As of March 1, 2025, the study data showed that among the 10 patients who received Drug A, Adagrasib, and chemotherapy, the unconfirmed objective response rate (uORR) was 60% (6 / 10), and the disease control rate (DCR) was 100% (10 / 10). The median progression-free survival (PFS) had not yet been reached.

[0411] 2) Safety: As of March 1, 2025, the study data showed that among the 11 patients who received Drug A, Adagrasib, and chemotherapy, the incidence of treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) was 100% (11 / 11), and the incidence of grade 3 or higher TRAEs was 63.6% (7 / 11). No serious adverse events occurred.

[0412] 2.7 Study Conclusion

[0413] The potential benefits of the KRAS G12C inhibitor Drug A combination therapy (including combination immunotherapy / chemotherapy) regimen for the treatment of KRAS G12C mutant advanced tumors outweigh the risks, and it can meet the current clinical needs of such tumor patients, thereby improving the treatment effect, prolonging the survival, and improving the quality of life of such tumor populations.

Claims

1. Use of a KRAS G12C inhibitor in combination with an anti-PD-1 or anti-PD-L1 antibody in the treatment of a neoplastic disease, wherein the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1H)-one, M-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1H)-one, P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)- one, 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6- chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)- one, or a pharmaceutically acceptable salt thereof; Preferably, the pharmaceutically acceptable salt of the compound is selected from a hydrochloride, a sulfate, a hydrobromide, a phosphate, a benzenesulfonate, a cinnamate, a tartrate, an oxalate, a succinate, a fumarate, a methanesulfonate, a p-toluenesulfonate, a hydroxyethanesulfonate or a camphorate; preferably a hydrochloride, a sulfate, a methanesulfonate, a p-toluenesulfonate or a hydroxyethanesulfonate; more preferably a hydroxyethanesulfonate; More preferably, the KRAS G12C inhibitor is selected from a hydroxyethanesulfonate salt of P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1H)-one. the anti-PD-1 antibody is selected from Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab or Serplulimab; the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, Sugemalimab, Envafolimab or Adebrelimab; preferably Adebrelimab.

2. Use according to claim 1, characterized in that, further combined with one or more chemotherapy drugs; the chemotherapy drug is selected from one or more of cyclophosphamide, daunorubicin, doxorubicin, mitoxantrone, methotrexate, vincristine, vindesine, etoposide, teniposide, dexamethasone, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, gemcitabine or pemetrexed; preferably, further combined with one or more of cisplatin, carboplatin or pemetrexed.

3. Use according to claim 1 or 2, characterized in that, the anti-PD-1 or anti-PD-L1 antibody is selected from Adebrelimab, with a single administration dose ranging from 10 to 50 mg / kg; preferably 10 to 30 mg / kg; more preferably 10 to 20 mg / kg; the administration frequency is once a week, once every two weeks or once every three weeks; preferably once every three weeks; preferably, Adebrelimab is administered by intravenous injection once every three weeks, with a single administration dose of 10 to 30 mg / kg; more preferably, the anti-PD-1 or anti-PD-L1 antibody is administered by intravenous injection once every three weeks, with a single administration dose of 10 to 20 mg / kg. or, selected from Envafolimab, with a single administration dose ranging from 100 to 500 mg; preferably 100 to 300 mg; the administration frequency is once a week, once every two weeks or once every three weeks; preferably once every three weeks; preferably, Envafolimab is administered by subcutaneous injection once every three weeks, with a single administration dose of 100 to 300 mg; or, selected from Sugemalimab, with a single administration dose ranging from 500 to 1500 mg; preferably 600 to 1200 mg; the administration frequency is once a week, once every two weeks or once every three weeks; preferably once every three weeks; preferably, Sugemalimab is administered by intravenous injection once every three weeks, with a single administration dose of 600 to 1200 mg; or selected from Atezolizumab, with a single administration dose ranging from 500 to 1500 mg; preferably 600 to 1200 mg; the administration frequency is once a week, once every two weeks or once every three weeks; preferably once every three weeks; preferably, Atezolizumab is administered by intravenous injection once every three weeks, with a single administration dose of 600 to 1200 mg.

4. Use of a KRAS G12C inhibitor in combination with one or more chemotherapeutic agents for the treatment of a neoplastic disease, wherein the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3- d]pyrimidin-2(1 H)-one, M-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3- chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3- d]pyrimidin-2(1 H)-one, P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3- chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3- d]pyrimidin-2(1 H)-one, 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-fluoro-7-(2- fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3- d]pyrimidin-2(1 H)-one, 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1 H)-one, 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1 H)- one, or a pharmaceutically acceptable salt thereof; Preferably, the pharmaceutically acceptable salt of the compound is selected from a hydrochloride, a sulfate, a hydrobromide, a phosphate, a benzenesulfonate, a cinnamate, a tartrate, an oxalate, a succinate, a fumarate, a methanesulfonate, a p-toluenesulfonate, a hydroxyethanesulfonate or a camphorate; preferably a hydrochloride, a sulfate, a methanesulfonate, a p-toluenesulfonate or a hydroxyethanesulfonate; more preferably a hydroxyethanesulfonate; More preferably, the KRAS G12C inhibitor is selected from a hydroxyethanesulfonate salt of P-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2- fluorophenyl)-6-chloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2(1 H)-one; the chemotherapeutic agent is selected from one or more of cyclophosphamide, daunorubicin, doxorubicin, mitoxantrone, methotrexate, vincristine, vindesine, etoposide, teniposide, dexamethasone, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, gemcitabine or pemetrexed; Preferably, one or more of cisplatin, carboplatin or pemetrexed is selected.

5. Use according to claims 2 to 4, characterized in that, in combination with cisplatin, in a single dose ranging from 10 to 100 mg / m 2 ; preferably from 20 to 80 mg / m 2 ; more preferably from 35 to 75 mg / m 2 ; Cisplatin is administered once a week, once in two weeks or once in three weeks; preferably once in three weeks; Preferably, cisplatin is administered intravenously every three weeks at a dose of 20 to 80 mg / m 2 ; more preferably, cisplatin is administered once a day at a dose of 35 to 75 mg / m 2 ; or / and, in combination with carboplatin, wherein the single administration dose of carboplatin ranges from AUC=1 to 7; preferably AUC=5 to 7; more preferably AUC=5 Carboplatin is administered once a week, once in two weeks or once in three weeks; preferably once in three weeks; Preferably, carboplatin is administered intravenously once in three weeks with a dose calculated as AUC=2 to 5; or / and in combination with pemetrexed, wherein the single administration dose of pemetrexed ranges from 100 to 1000 mg / m 2 ; preferably from 200 to 500 mg / m 2 ; Pemetrexed is administered once a week, once in two weeks or once in three weeks; preferably once in three weeks; Preferably, the pemetrexed is administered intravenously once every three weeks at a dose of 200 to 500 mg / m 2 .

6. Use according to any one of claims 1 to 5, characterized in that, The single administration dose of KRAS G12C inhibitor ranges from 200 to 1200 mg; preferably from 200 to 800 mg; more preferably 200, 400 or 800 mg; The administration frequency of KRAS G12C inhibitor is once a day, twice a day or three times a day; preferably once a day. Preferably, KRAS G12C inhibitor is administered orally once a day with a single administration dose of 200 to 800 mg; preferably once a day with a single administration dose of 200, 400 or 800 mg.

7. Use according to any one of claims 1 to 6, characterized in that, KRAS G12C inhibitor is applied simultaneously, concurrently, independently or sequentially with anti-PD-1 or anti-PD-L1 antibody or / and chemotherapeutic drug.

8. A pharmaceutical composition, characterized by, KRAS G12C inhibitor is applied simultaneously, concurrently, independently or sequentially with anti-PD-1 or anti-PD-L1 antibody or / and chemotherapeutic drug. KRAS G12C inhibitor is applied simultaneously, concurrently, independently or sequentially with anti-PD-1 or anti-PD-L1 antibody or / and chemotherapeutic drug. KRAS G12C inhibitor is applied simultaneously, concurrently, independently or sequentially with anti-PD-1 or anti-PD-L1 antibody or / and chemotherapeutic drug. Preferably, the KRAS G12C inhibitor is selected from 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, M-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((S)-4-acryloyl-2- methylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof, more preferably the hydroxyethylsulfate salt of P-4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(6-amino-3-chloro-2-fluorophenyl)-6-chloro-1-(2-isopropyl-4- (methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; the anti-PD-1 antibody is selected from Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, or Serplulimab; the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, Sugemalimab, Envafolimab or Adebrelimab; preferably Adebrelimab; the chemotherapeutic drug is selected from one or more of Cyclophosphamide, Daunorubicin, Doxorubicin, Mitoxantrone, Methotrexate, Vincristine, Vinblastine, Etoposide, Teniposide, Dexamethasone, Cisplatin, Carboplatin, Oxaliplatin, Paclitaxel, Docetaxel, Gemcitabine or Pemetrexed; preferably one or more of Cisplatin, Carboplatin or Pemetrexed; when the combination is a pharmaceutical composition, further comprising one or more pharmaceutically acceptable carriers, excipients or diluents.

9. Use according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the prevention or treatment of a neoplastic disease, wherein, the oncological disease is selected from Leukemia, Neuroblastoma, Melanoma, Esophageal cancer, Head and neck tumor, Breast cancer, Lung cancer or Colorectal cancer; preferably Lung cancer.

10. The use or pharmaceutical composition according to claim 9, for the manufacture of a medicament for the prevention or treatment of a neoplastic disease, wherein, the Lung cancer is selected from Non-Small Cell Lung Cancer, preferably KRAS G12C-mutated Non-Small Cell Lung Cancer. the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, Sugemalimab, Envafolimab or Adebrelimab; preferably Adebrelimab; the chemotherapeutic drug is selected from one or more of Cyclophosphamide, Daunorubicin, Doxorubicin, Mitoxantrone, Methotrexate, Vincristine, Vinblastine, Etoposide, Teniposide, Dexamethasone, Cisplatin, Carboplatin, Oxaliplatin, Paclitaxel, Docetaxel, Gemcitabine or Pemetrexed; preferably one or more of Cisplatin, Carboplatin or Pemetrexed; when the combination is a pharmaceutical composition, further comprising one or more pharmaceutically acceptable carriers, excipients or diluents. the oncological disease is selected from Leukemia, Neuroblastoma, Melanoma, Esophageal cancer, Head and neck tumor, Breast cancer, Lung cancer or Colorectal cancer; preferably Lung cancer. the Lung cancer is selected from Non-Small Cell Lung Cancer, preferably KRAS G12C-mutated Non-Small Cell Lung Cancer.

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