Method for treating non-small cell lung cancer using Anti-PD-1 and VEGF bispecific antibody

Abstract

Provided is a method for treating cancer by means of administering to an individual a certain dose of an anti-PD-1 and VEGF bispecific antibody, or in combination with other drugs. The method has significant effectiveness and safety. Also provided are a composition and use related thereto.

Description

Treatment of non-small cell lung cancer with anti-PD-1 and VEGF bispecific antibodies Technical Field

[0001] This invention relates to the field of biomedicine, and more specifically to a method for treating cancer using anti-PD-1 and VEGF bispecific antibodies. Background Technology

[0002] Bispecific antibodies, due to their unique mechanism of action and multi-targeting capabilities, are becoming an important direction in cancer treatment and other disease fields. In 2024, Akeso Biopharma Co., Ltd.'s ivonescimab injection (trade name: Idafang) was approved for marketing in China. The approved indication is for the treatment of patients with EGFR gene mutation-positive locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in combination with pemetrexed and carboplatin. As a pioneer of anti-PD-1 and VEGF bispecific antibodies, the launch of this bispecific antibody provides new treatment options for NSCLC patients. Meanwhile, at the 2024 World Conference on Lung Cancer (WCLC) in September 2024, Akeso Biopharma disclosed clinical data from the HARMONi-2 study (AK112-303). HARMONi-2 (NCT05499390) was a randomized, double-blind phase III study designed to compare the efficacy of evoxisinumab and pembrolizumab as first-line treatment for PD-L1-positive aNSCLC patients. Data showed that evoxisinumab (20 mg / kg, Q3W) was significantly superior to pembrolizumab (200 mg, Q3W) in progression-free survival (PFS), with a significantly lower hazard ratio (HR) than expected. As the first head-to-head phase III study comparing an anti-PD-1 and VEGF bispecific antibody with a PD-1 antibody, this demonstrated a comparative advantage in aNSCLC. Compared with pembrolizumab, a PD-1 drug, the anti-PD-1 and VEGF bispecific antibody evoxisin had a higher objective response rate (ORR, 50.0% vs. 38.5%) and disease control rate (DCR, 89.9% vs. 70.5%).

[0003] WO2024141027A1 discloses a novel anti-PD-1 and VEGF bispecific antibody. By linking a VHH-form nanobody to a PD-1 antibody, a structurally stable bispecific antibody that can be highly enriched in the tumor region and has significant inhibitory effects on melanoma and colon cancer is obtained.

[0004] A recent report from the International Agency for Research on Cancer (IARC), a branch of the World Health Organization, shows that approximately 20 million new cancer cases and 9.7 million cancer deaths occurred globally in 2022. Lung cancer accounted for the largest share of these figures: 2.5 million new lung cancer cases and 1.8 million deaths. Lung cancer has two main subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), accounting for 15% and 85% of all lung cancer cases, respectively. Currently, the main treatments for NSCLC are surgery, radiotherapy, and chemotherapy. Although the availability of evoxisumab has provided a new treatment option for NSCLC patients, not all lung cancer patients experience clinical benefit in terms of objective response rates, and there is room for further improvement in both treatment efficacy and safety. Therefore, there remains a significant unmet clinical need in the first-line, second-line, and post-second-line treatment of lung cancer. Summary of the Invention

[0005] This invention relates to a method for treating cancer with anti-PD-1 and VEGF bispecific antibodies. This method has significant efficacy and safety, and can provide more possibilities for prolonging disease progression, improving quality of life, and treating the disease for first-line, second-line, and post-second-line lung cancer patients of different types.

[0006] In some embodiments, the method comprises administering an effective amount of a liquid formulation of anti-PD-1 and VEGF bispecific antibodies to an individual having said cancer.

[0007] In some embodiments, the anti-PD-1 and VEGF bispecific antibody comprises: (a) a first binding domain that specifically binds to PD-1, and (b) a second binding domain that specifically binds to VEGF.

[0008] In some embodiments, the first binding domain that specifically binds to PD-1 is an anti-PD-1 antibody or its antigen-binding fragment; the second binding domain that specifically binds to VEGF is VHH.

[0009] In some embodiments, the second binding domain that specifically binds to VEGF comprises the CDR1 amino acid sequence as shown in SEQ ID NO: 1, the CDR2 amino acid sequence as shown in SEQ ID NO: 2, and the CDR3 amino acid sequence as shown in SEQ ID NO: 3.

[0010] In some embodiments, the second binding domain that specifically binds to VEGF contains an amino acid sequence as shown in SEQ ID NO: 4.

[0011] In some implementations, the first binding domain that specifically binds to PD-1 includes a heavy chain variable region (VH) and / or a light chain variable region (VL).

[0012] In some embodiments, the VH of the first binding domain that specifically binds to PD-1 comprises the HCDR1 amino acid sequence as shown in SEQ ID NO: 5, the HCDR2 amino acid sequence as shown in SEQ ID NO: 6, and the HCDR3 amino acid sequence as shown in SEQ ID NO: 7.

[0013] In some embodiments, the VH of the first binding domain that specifically binds to PD-1 comprises an amino acid sequence as shown in SEQ ID NO: 8.

[0014] In some embodiments, the VL of the first binding domain that specifically binds to PD-1 comprises the LCDR1 amino acid sequence as shown in SEQ ID NO: 9, the LCDR2 amino acid sequence as shown in SEQ ID NO: 10, and the LCDR3 amino acid sequence as shown in SEQ ID NO: 11.

[0015] In some embodiments, the VL of the first binding domain that specifically binds to PD-1 comprises an amino acid sequence as shown in SEQ ID NO: 12.

[0016] In some embodiments, the anti-PD-1 and VEGF bispecific antibody comprises a heavy chain (HC) and / or a light chain (LC).

[0017] In some embodiments, the anti-PD-1 and VEGF bispecific antibody comprises a heavy chain containing an amino acid sequence as shown in SEQ ID NO: 13.

[0018] In some embodiments, the anti-PD-1 and VEGF bispecific antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO: 14. Table 1. Sequence Number Corresponding Amino Acid Sequence List

[0019] In some implementations, the cancer is lung cancer.

[0020] In some implementations, the lung cancer is non-small cell lung cancer (NSCLC).

[0021] In some implementations, the NSCLC is a scaly NSCLC.

[0022] In some implementations, the NSCLC is a non-scaly NSCLC.

[0023] In some implementations, the NSCLC is PD-L1 negative NSCLC; preferably, the PD-L1 negative status is TPS < 1%.

[0024] In some implementations, the NSCLC is PD-L1 positive NSCLC; preferably, the PD-L1 positivity is TPS ≥ 1%.

[0025] In some implementations, the NSCLC has brain metastases.

[0026] In some implementations, the NSCLC does not have brain metastases.

[0027] In some implementations, the NSCLC is driver gene-negative NSCLC.

[0028] In some implementations, the NSCLC is driver gene-positive NSCLC.

[0029] In some implementations, the NSCLC is an NSCLC with an EGFR-sensitive mutation.

[0030] In some implementations, the NSCLC is an NSCLC that is positive for other driver genes (other than EGFR-sensitive mutations).

[0031] Preferably, the other driver genes are ALK, RET, ROS1, BRAF, NTRK, MET 14, KRAS, or HER2.

[0032] In some implementations, the NSCLC is NSCLC that has not undergone systemic treatment.

[0033] In some implementations, the NSCLC is NSCLC following EGFR-TKI (Tyrosine kinase inhibitor) treatment.

[0034] In some implementations, the NSCLC is NSCLC following first-line TKI treatment.

[0035] Preferably, the NSCLC is locally advanced NSCLC; more preferably, the NSCLC is inoperable locally advanced NSCLC; even more preferably, the locally advanced stage is stage IIIB or IIIC.

[0036] Preferably, the NSCLC is a metastatic NSCLC; more preferably, the NSCLC is an NSCLC classified as IV in the TNM staging.

[0037] Preferably, the cancer is driver gene-negative squamous NSCLC that has not undergone systemic treatment.

[0038] Preferably, the cancer is driver gene-negative, untreated non-squamous NSCLC.

[0039] Preferably, the cancer is driver gene negative, PD-L1 positive, and untreated NSCLC.

[0040] Preferably, the cancer is EGFR-sensitive mutation, and is non-squamous NSCLC after EGFR-TKI treatment.

[0041] Preferably, the cancer is non-squamous NSCLC that is positive for other driver genes (except for EGFR-sensitive mutations) and has undergone first-line TKI treatment.

[0042] Preferably, the EGFR-TKI includes, but is not limited to, erlotinib, gefitinib, afatinib, osimertinib, almonertinib, dacomitinib, lazertinib, eriocitnib, icotinib, olmutinib, mobocertinib, canertinib, lapatinib, brigatinib, or capmatinib.

[0043] Preferably, the first-line TKI includes but is not limited to crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, selpercatinib, pralsetinib, entrectinib, repotrectinib, sitravatinib, furmonertin ib, vemurafenib, dabrafenib, encorafenib, larotrectinib, selitrectinib, capmatinib, tepotinib, sotorasib, adagrasib, lapatinib, neratinib, tucatinib, sunitinib, pazopanib, sorafenib, axitinib, regorafenib, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, trametinib, cobimetinib, binimetinib, midostaurin, gilteriti nib, quizartinib, lenvatinib, cabozantinib, vandetanib, regorafenib, ibrutinib, acalabrutinib, zanubrutinib, ripretinib, avapritinib, mobocertinib, or canertinib.

[0044] In some implementations, the individual is given an intravenous infusion of a liquid formulation containing both anti-PD1 and VEGF bispecific antibodies.

[0045] In some embodiments, the dosage of the anti-PD1 and VEGF bispecific antibody in a single administration to the individual ranges from 1 mg / kg to 100 mg / kg (including but not limited to: 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 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, ...). 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 31mg / kg, 32mg / kg, 33mg / kg, 3 4mg / kg, 35mg / kg, 36mg / kg, 37mg / kg, 38mg / kg, 39mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 60mg / kg, 70mg / kg, 80mg / kg, 90mg / kg and 100mg / kg).

[0046] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-50 mg / kg, 10 mg / kg-50 mg / kg, 15 mg / kg-50 mg / kg, 20 mg / kg-50 mg / kg, 25 mg / kg-50 mg / kg, 30 mg / kg-50 mg / kg, 35 mg / kg-50 mg / kg, 40 mg / kg-50 mg / kg, and 45 mg / kg-50 mg / kg.

[0047] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-45 mg / kg, 10 mg / kg-45 mg / kg, 15 mg / kg-45 mg / kg, 20 mg / kg-45 mg / kg, 25 mg / kg-45 mg / kg, 30 mg / kg-45 mg / kg, 35 mg / kg-45 mg / kg, and 40 mg / kg-45 mg / kg.

[0048] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-40 mg / kg, 10 mg / kg-40 mg / kg, 15 mg / kg-40 mg / kg, 20 mg / kg-40 mg / kg, 25 mg / kg-40 mg / kg, 30 mg / kg-40 mg / kg, and 35 mg / kg-40 mg / kg.

[0049] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-35 mg / kg, 10 mg / kg-35 mg / kg, 15 mg / kg-35 mg / kg, 20 mg / kg-35 mg / kg, 25 mg / kg-35 mg / kg and 30 mg / kg-35 mg / kg.

[0050] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-30 mg / kg, 10 mg / kg-30 mg / kg, 15 mg / kg-30 mg / kg, 20 mg / kg-30 mg / kg and 25 mg / kg-30 mg / kg.

[0051] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-25 mg / kg, 10 mg / kg-25 mg / kg, 15 mg / kg-25 mg / kg and 20 mg / kg-25 mg / kg.

[0052] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-20 mg / kg, 10 mg / kg-20 mg / kg and 15 mg / kg-20 mg / kg.

[0053] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg-15 mg / kg and 10 mg / kg-15 mg / kg.

[0054] Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation of the anti-PD1 and VEGF bispecific antibody administered to the individual in a single dose is selected from 5 mg / kg to 10 mg / kg.

[0055] Preferably, the amount of anti-PD1 and VEGF bispecific antibody in the liquid formulation administered to the individual in a single dose is 10 mg / kg.

[0056] Preferably, the amount of anti-PD1 and VEGF bispecific antibody in the liquid formulation administered to the individual in a single dose is 20 mg / kg.

[0057] In some embodiments, the anti-PD1 and VEGF bispecific antibody liquid formulation is administered alone or in combination with one, two, or three of paclitaxel, carboplatin, and pemetrexed.

[0058] In some implementations, the method also includes combination therapy.

[0059] In some embodiments, the individual is given an intravenous infusion of a liquid formulation of anti-PD1 and VEGF bispecific antibodies, and / or paclitaxel, and / or carboplatin, and / or pemetrexed disodium for injection.

[0060] Preferably, the individual is intravenously infused with a liquid formulation of anti-PD1 and VEGF bispecific antibodies, paclitaxel injection, and carboplatin injection.

[0061] Preferably, the individual is intravenously infused with a liquid formulation of anti-PD1 and VEGF bispecific antibodies, pemetrexed disodium for injection, and carboplatin injection.

[0062] In some implementations, the dose range for a single administration of paclitaxel to the individual is 100 mg / m². 2 -300mg / m 2 (Including but not limited to: 100mg / m²) 2 125mg / m 2 150mg / m 2 175mg / m 2 200mg / m 2 225mg / m 2 250mg / m 2 275mg / m 2 and 300mg / m 2 ).

[0063] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -300mg / m 2 125mg / m 2 -300mg / m 2 150mg / m 2 -300mg / m 2175mg / m 2 -300mg / m 2 200mg / m 2 -300mg / m 2 225mg / m 2 -300mg / m 2 250mg / m 2 -300mg / m 2 and 275mg / m 2 -300mg / m 2 .

[0064] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -275mg / m 2 125mg / m 2 -275mg / m 2 150mg / m 2 -275mg / m 2 175mg / m 2 -275mg / m 2 200mg / m 2 -275mg / m 2 225mg / m 2 -275mg / m 2 and 250mg / m 2 -275mg / m 2 .

[0065] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -250mg / m 2 125mg / m 2 -250mg / m 2 150mg / m 2 -250mg / m 2 175mg / m 2 -250mg / m 2 200mg / m 2 -250mg / m 2 and 225mg / m 2 -250mg / m 2 .

[0066] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -225mg / m 2 125mg / m 2 -225mg / m 2 150mg / m2 -225mg / m 2 175mg / m 2 -225mg / m 2 and 200mg / m 2 -225mg / m 2 .

[0067] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -200mg / m 2 125mg / m 2 -200mg / m 2 150mg / m 2 -200mg / m 2 and 175mg / m 2 -200mg / m 2 .

[0068] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -175mg / m 2 125mg / m 2 -175mg / m 2 and 150mg / m 2 -175mg / m 2 .

[0069] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -150mg / m 2 and 125mg / m 2 -150mg / m 2 .

[0070] Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -125mg / m 2 .

[0071] Preferably, the dose of paclitaxel administered to the individual in a single dose is 175 mg / m². 2 .

[0072] In some embodiments, the dose range for a single administration of injectable pemetrexed disodium to the individual is 100 mg / m². 2 -1000mg / m 2 (Including but not limited to: 100mg / m²) 2 200mg / m 2 300mg / m 2 400mg / m 2 500mg / m2 600mg / m 2 700mg / m 2 800mg / m 2 900mg / m 2 and 1000mg / m 2 ).

[0073] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -1000mg / m 2 200mg / m 2 -1000mg / m 2 300mg / m 2 -1000mg / m 2 400mg / m 2 -1000mg / m 2 500mg / m 2 -1000mg / m 2 600mg / m 2 -1000mg / m 2 700mg / m 2 -1000mg / m 2 800mg / m 2 -1000mg / m 2 and 900mg / m 2 -1000mg / m 2 .

[0074] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -900mg / m 2 200mg / m 2 -900mg / m 2 300mg / m 2 -900mg / m 2 400mg / m 2 -900mg / m 2 500mg / m 2 -900mg / m 2 600mg / m 2 -900mg / m 2 700mg / m 2 -900mg / m 2 and 800mg / m 2 -900mg / m 2 .

[0075] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -800mg / m 2 200mg / m 2 -800mg / m 2 300mg / m 2 -800mg / m 2 400mg / m 2 -800mg / m 2 500mg / m 2 -800mg / m 2 600mg / m 2 -800mg / m 2 and 700mg / m 2 -800mg / m 2 .

[0076] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -700mg / m 2 200mg / m 2 -700mg / m 2 300mg / m 2 -700mg / m 2 400mg / m 2 -700mg / m 2 500mg / m 2 -700mg / m 2 and 600mg / m 2 -700mg / m 2 .

[0077] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -600mg / m 2 200mg / m 2 -600mg / m 2 300mg / m 2 -600mg / m 2 400mg / m 2 -600mg / m 2 and 500mg / m 2 -600mg / m 2 .

[0078] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -500mg / m 2 200mg / m2 -500mg / m 2 300mg / m 2 -500mg / m 2 and 400mg / m 2 -500mg / m 2 .

[0079] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -400mg / m 2 200mg / m 2 -400mg / m 2 and 300mg / m 2 -400mg / m 2 .

[0080] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -300mg / m 2 and 200mg / m 2 -300mg / m 2 .

[0081] Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -200mg / m 2 .

[0082] Preferably, the dose of pemetrexed disodium for injection administered to the individual in a single dose is 500 mg / m². 2 .

[0083] In some implementations, the dose range of a single administration of carboplatin injection to the individual is AUC = 1-10 (including but not limited to: AUC = 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10).

[0084] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-10, 2-10, 3-10, 4-10, 5-10, 6-10, 7-10, 8-10 and 9-10.

[0085] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9 and 8-9.

[0086] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, and 7-8.

[0087] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-7, 2-7, 3-7, 4-7, 5-7, and 6-7.

[0088] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-6, 2-6, 3-6, 4-6, and 5-6.

[0089] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-5, 2-5, 3-5, and 4-5.

[0090] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-4, 2-4, and 3-4.

[0091] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-3 and 2-3.

[0092] Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-2.

[0093] Preferably, the dose of carboplatin injection administered to the individual in a single administration is AUC = 5.

[0094] In some embodiments, the liquid formulation of the anti-PD1 and VEGF bispecific antibody is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, it is administered once every 3 weeks.

[0095] In some implementations, paclitaxel is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, it is administered once every 3 weeks.

[0096] In some embodiments, the dosing frequency of pemetrexed disodium for injection is once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the dosing frequency is once every 3 weeks.

[0097] In some embodiments, carboplatin injection is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, it is administered once every 3 weeks.

[0098] In some implementations, carboplatin injection is administered for a maximum of 3, 4, or 5 cycles; preferably, it is administered for a maximum of 4 cycles.

[0099] This invention relates to a method for treating driver gene-negative, untreated squamous NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, paclitaxel injection, and carboplatin injection, wherein the dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, administered once every 3 weeks, and the dosage of the paclitaxel injection is 175 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0100] This invention relates to a method for treating driver gene-negative, untreated squamous NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, paclitaxel injection, and carboplatin injection. The dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, administered once every 3 weeks; the dosage of the paclitaxel injection is 175 mg / m², administered once every 3 weeks; and the dosage of the carboplatin injection is AUC=5, administered once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0101] This invention relates to a method for treating driver gene-negative, untreated non-squamous NSCLC, comprising intravenous infusion of an anti-PD-1 and VEGF bispecific antibody liquid formulation, pemetrexed disodium for injection, and carboplatin injection into an individual. The dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, administered once every 3 weeks, and the dosage of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0102] This invention relates to a method for treating driver gene-negative, untreated non-squamous NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection. The dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, administered once every 3 weeks; the dosage of the pemetrexed disodium for injection is 500 mg / m², administered once every 3 weeks; and the dosage of the carboplatin injection is AUC=5, administered once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0103] This invention relates to a method for treating NSCLC that is driver gene negative, has PD-L1 expression TPS ≥ 1%, and has not received systemic treatment. The method comprises intravenously infusing an anti-PD-1 and VEGF bispecific antibody liquid formulation into an individual at a dose of 10 mg / kg, and at a frequency of once every 3 weeks. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0104] This invention relates to a method for treating NSCLC that is driver gene negative, has PD-L1 expression TPS ≥ 1%, and has not received systemic treatment. The method comprises intravenously infusing a liquid formulation of an anti-PD-1 and VEGF bispecific antibody into an individual at a dose of 20 mg / kg, and at a frequency of once every 3 weeks. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0105] This invention relates to a method for treating non-squamous NSCLC with EGFR-sensitive mutations following EGFR-TKI treatment. The method comprises intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection. The dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, administered once every 3 weeks. The dosage of the pemetrexed disodium for injection is 500 mg / kg. 2The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0106] This invention relates to a method for treating non-squamous NSCLC with EGFR-sensitive mutations following EGFR-TKI treatment. The method comprises intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection. The dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, administered once every 3 weeks. The dosage of the pemetrexed disodium for injection is 500 mg / m², administered once every 3 weeks. The dosage of the carboplatin injection is AUC=5, administered once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0107] This invention relates to a method for treating non-squamous NSCLC with other driver gene positivity (excluding EGFR-sensitive mutations) after first-line TKI therapy. The method comprises intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection. The dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, administered once every 3 weeks. The dosage of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0108] This invention relates to a method for treating non-squamous NSCLC with other driver gene positivity (excluding EGFR-sensitive mutations) after first-line TKI treatment. The method comprises intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection. The dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, administered once every 3 weeks. The dosage of the pemetrexed disodium for injection is 500 mg / m², administered once every 3 weeks. The dosage of the carboplatin injection is AUC=5, administered once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

[0109] All references cited in this article, including patents, patent applications, and various publications, are incorporated in their entirety by reference, as if each reference were individually and specifically cited and presented in its entirety in this article.

[0110] The references and inclusions of patent documents in this article are for convenience only and do not reflect any opinion on the validity, patentability, and / or enforceability of such patent documents.

[0111] All headings and subheadings used herein are for convenience only and should not be construed as limiting the invention in any way.

[0112] The use of any and all examples or exemplary wording provided herein (e.g., such as) is intended only to better illustrate the invention and not to limit the scope of the invention, unless otherwise stated. Nothing in the specification should be construed as indicating that any unclaimed element is essential to the practice of the invention.

[0113] This invention includes all modifications and equivalents to the subject matter set forth in the appended claims, where permitted by applicable law. Definitions

[0114] Unless otherwise specifically stated otherwise, the practice of this invention will take place using conventional methods of virology, immunology, microbiology, molecular biology, and recombinant DNA techniques within the scope of the art, or in the same sense as commonly understood by one of ordinary skill in the art to which this invention pertains. Many of these are described below for illustrative purposes, and such techniques are well described in the literature.

[0115] As used herein, unless otherwise specified, the singular forms “a / an” and “the” include plural referents.

[0116] The term "antibody" refers to any antigen-binding molecule containing at least one (e.g., one, two, three, four, five, or six) complementarity-determining regions (CDRs) (such as any one of the three CDRs of an immunoglobulin light chain or any one of the three CDRs of an immunoglobulin heavy chain) and capable of specifically binding to an antigen. Non-limiting examples of antibodies include: monoclonal antibodies, polyclonal antibodies, bispecific antibodies, multispecific antibodies, VHH, single-chain antibodies, chimeric antibodies, humanized antibodies, and humanized antibodies, etc. The term "antibody" as used herein includes both naturally occurring and non-naturally occurring antibodies. Generally, naturally occurring antibodies (also called immunoglobulins) consist of two classes of polypeptide chains: a light chain and a heavy chain. The non-limiting antibody disclosed in this invention can be a complete tetraimmunoglobulin chain antibody composed of two heavy chains and two light chains. The heavy chain of an antibody can be any isoform, including IgM, IgG, IgE, IgA, or IgD, or subisoforms, including IgG1, IgG2, IgG2a, IgG2b, IgG3, IgG4, IgE1, IgE2, etc. The light chain can be a kappa light chain or a lambda light chain. Each heavy chain contains a variable domain (or variable region, VH) and a constant domain (or constant region, CH), which are linked together by disulfide bonds within the constant domain. Each light chain contains a variable domain (or variable region, VL) and a constant domain (or constant region, CL), which are each linked to one heavy chain by a disulfide bond. The variable region of each light chain is aligned with the variable region of the heavy chain it binds to. Both the light and heavy chain variable regions contain three hypervariable regions sandwiched between more conserved framework regions (FRs). These hypervariable regions, also known as complementarity-determining regions (CDRs), constitute the primary antigen-binding surface of the antibody. Determining the antibody's critical DNA sequence (CDR) by analyzing its amino acid sequence is a well-known method. Many common CDR definitions exist, including but not limited to IMGT, KABAT, CHOTHIA, ABM, and CONTACT. In some embodiments, the antibody described in this invention may be a VHH or a protein containing a VHH that has antigen-binding capabilities. In some embodiments, the antibody may contain a constant region or Fc region of a human antibody. The heavy chain constant region or Fc region may be derived from IgM, IgG, IgE, IgA, or IgD or their subisotypes, such as, but not limited to, IgG1, IgG2, IgG3, and IgG4. The light chain constant region may be derived from the kappa light chain or the lambda light chain. The term "antibody" also includes derivatives, such as adjustments, conversions, additions, or reductions in structural / functional fragments, like antibody-drug conjugates.

[0117] The term "antigen-binding fragment" refers to one or more protein domains (e.g., formed by amino acids of a single polypeptide, or by amino acids of two or more polypeptides (e.g., the same or different polypeptides)) capable of specifically binding to one or more of the same or different antigens (e.g., tumor antigens). In some examples, antigen-binding fragments can bind to antigens or epitopes with specificity and affinity similar to naturally occurring antibodies. In some embodiments, the antigen-binding fragment may be an antibody or a fragment thereof. The antigen-binding fragment comprises a portion of an antibody, preferably the antigen-binding region and / or variable region of the antibody. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab′, F(ab′)2, and Fv fragments. In some embodiments, the antigen-binding fragment may be VHH. In some embodiments, the antigen-binding fragment may include other optional structures. The antigen-binding fragments described herein are non-limiting examples, and other examples of antigen-binding fragments are known in the art.

[0118] The term "CDR" (complementarity-determining region) is used to refer to a hypervariable region. Unless otherwise specified, the CDRs involved in this invention are defined using the KABAT system, and the immunoglobulin residues involved in this invention are numbered using the Kabat index. The method of defining CDRs using the KABAT system and the method of numbering amino acid residues using the KABAT index are well known to those skilled in the art, and can be annotated and analyzed using tools available at, for example, the URL "http: / / www.abysis.org / abysis / sequence_input / key_annotation / key_annotation.cgi".

[0119] The term "specificity" refers to an antigen-binding protein or antibody that selectively recognizes a specific epitope of an antigen. For example, natural antibodies are monospecific. As used herein, the terms "bispecific" or "multispecific" indicate that an antigen-binding protein or antibody has two or more antigen-binding sites, at least two of which bind to different antigens or different epitopes of the same antigen. The terms "bispecific binding molecule" and "multispecific binding molecule" refer to molecules that specifically bind to two or more antigens and contain two or more antigen-binding domains. The antigen-binding domains may each be independently an antibody fragment (e.g., scFv, Fab, nanobodies), a ligand and fragment thereof, a receptor and fragment thereof, or a non-antibody-derived conjugate (e.g., fibronectin, Fynomer, DARPin).

[0120] “VHH” (variable domain of heavy chain of heavy-chain antibody) can also be called “heavy chain single domain antibody”, “single domain antibody (sdAb)”, “VHH domain”, “VHH structural domain”, “VHH antibody”, “VHH antibody fragment”, nanobody, “Nanobody”, and “Nanobody structural domain”, etc., and these names are used interchangeably. VHH originally came from the antigen-binding immunoglobulin variable domain of “heavy-chain antibody” (hcAb, i.e. “antibody lacking light chain”) (C. Hamers-Casterman, T. Atarhouch, et al. Naturally occurring antibodies devoid of light chains. Nature, June 3, 1993, Vol. 363, pp. 446-448). The term "VHH domain" distinguishes this type of variable domain from the heavy chain variable domain (VH or VH domain) present in conventional antibodies composed of two light chains and two heavy chains (hereinafter referred to as conventional antibodies), and the light chain variable domain (VL or VL domain) present in conventional antibodies. The VHH domain specifically binds to epitopes without the need for other antigen-binding domains (unlike the VH or VL domains in conventional antibodies, where the VL domain and VH domain are combined to recognize epitopes). The VHH domain is an antigen recognition unit formed by a single immunoglobulin domain.

[0121] The term "driver gene" refers to a key gene that undergoes functional variations (including but not limited to point mutations, insertions / deletions, gene rearrangements, or amplifications) and continuously activates specific signaling pathways, directly or indirectly promoting tumor occurrence, development, survival, proliferation, invasion, or metastasis at the molecular and cellular levels, thereby conferring a selective growth advantage to tumor cells. Variations in these genes form the molecular biological basis of tumorigenesis and maintenance. These gene alterations include, but are not limited to, base substitutions, insertions, deletions, splicing abnormalities, gene fusions, copy number increases, or gene amplifications, as well as other genetic or epigenetic alterations leading to abnormal activation or dysregulation of protein function. Currently, a series of important driver genes have been identified in lung adenocarcinoma, the most common including EGFR, ALK, ROS1, KRAS, BRAF, MET, RET, NTRK, and HER2.

[0122] "Driver gene positivity" refers to the confirmation, through molecular detection methods, of at least one known, clinically significant driver gene mutation in a patient's tumor tissue or other samples. This gene alteration is identified as having oncogenic function or playing a driving role in the occurrence or progression of lung cancer, and this status constitutes direct scientific evidence for the use of corresponding targeted drug therapy. The term "driver gene positivity" is not limited to a specific gene type or alteration form, but includes, but is not limited to, activating mutations, gain-of-function mutations, pathogenic gene fusions, functional splicing site mutations, and biologically significant gene amplifications or copy number changes, such as EGFR mutations or exon deletions, ALK rearrangements or fusions, ROS1 rearrangements or fusions, BRAF V600 site mutations or V600E mutations, RET rearrangements or fusions, MET14 exon skipping mutations, NTRK1 / 2 / 3 rearrangements, HER2 mutations, and KRAS mutations.

[0123] "Driver gene negative" means that no known driver gene alterations (or those labeled as oncogenic / targetable) were found within the scope of the testing performed. "Negative" does not mean "no mutations"—tumors may still contain a large number of transient mutations or rare alterations that have not yet been identified / labeled as drivers.

[0124] The term "administration" refers to the administration of a composition (e.g., a protein molecule or a formulation comprising a protein molecule as described herein) to a subject or system. Administration to animal subjects (e.g., to humans) can be performed via any suitable route. For example, in some embodiments, administration can be via bronchial (including bronchial infusion), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous administration. Formulations can be prepared in a manner suitable for systemic or topical / topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or those prepared for percutaneous, mucosal, or oral administration. Formulations will generally include diluents and, in some cases, adjuvants, buffers, preservatives, etc.

[0125] The term "treatment" refers to a clinical intervention designed to alter the natural course of an individual or cell in a clinicopathological process. Desired therapeutic effects include slowing disease progression, improving or alleviating disease states, and mitigating or improving prognosis. For example, reducing or eliminating one or more symptoms associated with the disease or condition being treated (such as cancer, inflammation, or an autoimmune disease).

[0126] The term "effective amount" refers to an amount or dose sufficient to produce a beneficial or intended effect, including preventing, slowing, delaying, or inhibiting the progression of a disease (such as cancer). In the case of cancer, the effective amounts of VHH, bispecific antibodies, multispecific antigen-binding constructs, pharmaceutical compositions, and immunoconjugates provided in this application may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slowly to a certain extent and preferably prevent) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slowly to a certain extent and preferably prevent) the metastasis of tumor cancer cells; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent. As understood in the clinical setting, an effective amount of a drug, compound, or pharmaceutical composition may or may not be combined with another drug, compound, or pharmaceutical composition. Therefore, an "effective amount" may be considered in the context of administration of one or more therapeutic agents, and if combined with one or more other agents, it may be considered that an effective amount of a single agent can achieve or realize the desired result.

[0127] The terms “individual,” “subject,” and “patient” used herein are used interchangeably throughout the specification and are used to describe animals (human or non-human) to which they are treated by the method according to the invention. Mammals are preferred, including but not limited to humans, cattle, horses, felines, canines, rodents, or primates. In some embodiments, humans are preferred.

[0128] The term “and / or” refers to a specific disclosure of each of two particular features or components, whether or not the other is included. The term “and / or” as used in phrases such as “A and / or B” herein is intended to include: A and B, A or B, A (alone), B (alone). Similarly, the term “and / or” as used in phrases such as “A, B and / or C” is intended to cover the following aspects: A and B and C, A or B or C, A or B, A or C, B or C, A and B, A and C, B and C, A (alone), B (alone), C (alone).

[0129] The term "cycle" refers to the time it takes to complete one treatment cycle. Chemotherapy cycles are typically 21 days (3 weeks) long, some are 14 days (2 weeks) or 28 days (4 weeks) long, and a few are 42 days (6 weeks) long, depending on the patient's condition, the drugs used, and the treatment regimen. A chemotherapy cycle is calculated from the first day of chemotherapy drug injection until the 14th, 21st, 28th, or 42nd day (depending on the dosing regimen). It is generally understood that if one dose of the drug is administered every X weeks, then X weeks is the length of one cycle. For example, one cycle in this article usually refers to 3 weeks (21 days), but in different contexts, it can also refer to 1 week (7 days), 2 weeks (14 days), or 4 weeks (28 days).

[0130] The term "dosage" refers to the amount of active ingredient in a drug formulation received by a patient. For example, a dosage of 20 mg / kg for a liquid formulation of anti-PD-1 and VEGF bispecific antibodies means that the weight of anti-PD-1 and VEGF bispecific antibodies injected per kilogram of the patient's body weight is 20 mg. For a 60 kg patient, the total injected dose would contain a total weight of 1200 mg of anti-PD-1 and VEGF bispecific antibodies. Detailed Implementation

[0131] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Example 1: Preparation of anti-PD-1 and VEGF bispecific antibody PV#10 liquid formulation (injection)

[0132] The anti-PD-1 and VEGF bispecific antibody PV#10 was expressed in CHO-K1 cells. The heavy chain amino acid sequence of PV#10 is shown in SEQ ID NO: 13 of this application, and the light chain amino acid sequence is shown in SEQ ID NO: 14 of this application. After obtaining purified anti-PD-1 and VEGF bispecific antibody PV#10, a liquid formulation was prepared, with an antibody concentration of 50 mg / ml for injection. Example 2: Phase I clinical study evaluating the efficacy and safety of anti-PD-1 and VEGF bispecific antibody PV#10 injection as monotherapy in patients with locally advanced or metastatic malignant solid tumors.

[0133] This study is a multicenter, open-label phase I clinical trial aimed at dose escalation and expansion of PV#10 injection monotherapy in advanced malignant solid tumors. The study aims to evaluate the safety, tolerability, maximum tolerated dose / maximum administered dose, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, RP2D (phase II recommended dose), and preliminary antitumor efficacy of the monotherapy.

[0134] As of May 30, 2025, the results of the Phase I monotherapy dose escalation and expansion studies are summarized below.

[0135] A total of 80 subjects received PV#10 injection monotherapy, including 14 subjects in the escalation phase (1 mg / kg, 3 mg / kg, 10 mg / kg, 20 mg / kg or 30 mg / kg, Q2W) and 66 subjects in the expansion phase (10 mg / kg, 20 mg / kg or 30 mg / kg, Q2W; and 20 mg / kg, Q3W). As of May 30, 2025, the dose escalation phase was completed without any DLT events.

[0136] In the 20 mg / kg Q3W dose group (n=38), 35 subjects (92.1%) experienced treatment-related adverse events (TRAEs), 10 (26.3%) experienced grade ≥3 TRAEs, 7 (18.4%) experienced serious TRAEs, 3 (7.9%) experienced TRAEs leading to permanent discontinuation, and 13 (34.2%) experienced immune-related adverse events (irAEs). Most TRAEs were grade 1-2.

[0137] In summary, most adverse events that occurred during the study were grade 1-2 in severity. It is estimated that the PV#10 injection at a dose range of 20 mg / kg Q3W is well tolerated and has manageable safety in subjects with advanced tumors.

[0138] Among the 38 subjects with malignant solid tumors who received PV#10 injection 20 mg / kg Q3W, the median age was 61.0 years, 76.3% of the subjects were male, 100% had a baseline ECOG score ≥1, 30 (78.9%) had non-small cell lung cancer, 3 (7.9%) had PD-L1 TPS <1%, the median number of prior treatments was 1.0 (Q1-Q3: 1.0-2.0), 4 (10.5%) had received prior anti-PD-1 / PD-L1 therapy, and 5 (13.2%) had received prior anti-VEGF therapy.

[0139] A total of 27 NSCLC patients received PV#10 injection 20 mg / kg Q3W and underwent at least one post-baseline tumor assessment. The best overall response outcome was: PR in 11 patients (40.7%), SD in 14 patients (51.9%), and PD in 2 patients (7.4%). The ORR was 40.7% (11 / 27; 95% CI: 22.4, 61.2), and the DCR was 92.6% (95% CI: 75.7, 99.1). Among them, 19 were treatment-naïve NSCLC patients, and the best overall response outcome was: PR in 8 patients (42.1%), SD in 11 patients (57.9%). The ORR was 42.1% (8 / 19; 95% CI: 20.3, 66.5), and the DCR was 100% (95% CI: 82.4, 100).

[0140] As of June 27, 2025, updated efficacy data: 21 treatment-naïve NSCLC patients received PV#10 injection monotherapy at 20 mg / kg every 3 weeks, with ORR and DCR of 52.4% (95% CI: 29.8, 74.3) and 100% (95% CI: 83.9, 100.0), respectively.

[0141] Preliminary results suggest that PV#10 injection 20mg / kg Q3W monotherapy has good antitumor activity in advanced NSCLC. Example 3: A multi-cohort, open-label, multicenter phase Ib clinical study evaluating the efficacy and safety of anti-PD-1 and VEGF bispecific antibody PV#10 injection monotherapy or combination therapy for locally advanced or metastatic non-small cell lung cancer. 1. Study Objectives

[0142] Main research objective: To evaluate the efficacy of PV#10 injection, an anti-PD-1 and VEGF bispecific antibody, as monotherapy or in combination therapy for locally advanced or metastatic non-small cell lung cancer.

[0143] Secondary study objectives: • To evaluate the safety of PV#10 injection (anti-PD-1 and VEGF bispecific antibody) as monotherapy or in combination therapy for locally advanced or metastatic non-small cell lung cancer. • To evaluate the pharmacokinetic characteristics of PV#10 injection (anti-PD-1 and VEGF bispecific antibody) as monotherapy or in combination therapy for locally advanced or metastatic non-small cell lung cancer. • To evaluate the immunogenicity of PV#10 injection (anti-PD-1 and VEGF bispecific antibody).

[0144] Exploratory Study Objectives: • To explore biomarkers that predict the efficacy of the anti-PD-1 and VEGF bispecific antibody PV#10 injection. 2. Study Endpoints

[0145] Primary endpoint: • Objective response rate (ORR)

[0146] Secondary endpoints: • Disease control rate (DCR) • Duration of response (DOR) • Progression-free survival (PFS) • Overall survival (OS) • Incidence and severity of adverse events / serious adverse events (rated based on NCI CTCAE V5.0) • Vital signs, physical examination, ECOG performance status score, 12-lead electrocardiogram, laboratory tests • Pharmacokinetic characteristics of anti-PD-1 and VEGF bispecific antibody PV#10 injection • Incidence of anti-PD-1 and VEGF bispecific antibody PV#10 injection anti-adverse antibody (ADA)

[0147] Exploratory endpoints: • Correlation between biomarkers and the antitumor efficacy of drugs 3. Study population

[0148] Patients with inoperable locally advanced or metastatic non-small cell lung cancer. 4. Study Design

[0149] This study is a multi-cohort, open-label, multicenter clinical trial aimed at exploring the safety, efficacy, and pharmacokinetic characteristics of PV#10 injection, an anti-PD-1 and VEGF bispecific antibody, as monotherapy or in combination therapy for patients with unresectable locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer (NSCLC).

[0150] This study is a multi-cohort study with a total of 5 cohorts. Cohorts 1-3 are planned to enroll patients who have not received systemic therapy, while cohorts 4-5 are planned to enroll patients who have received prior first-line tyrosine kinase inhibitor (TKI) therapy. The disease characteristics of each cohort are as follows: Table 2. Study Design and Cohort Characteristics

[0151] The study first screened and enrolled participants in cohorts 1 and 2. Participants who met the inclusion and exclusion criteria after the screening period were randomly assigned 1:1 to receive either PV#10 (anti-PD-1 and VEGF bispecific antibody) injection at 10 mg / kg or 20 mg / kg in combination with chemotherapy. Cohort 1 received PV#10 injection in combination with paclitaxel and carboplatin; cohort 2 received PV#10 injection in combination with pemetrexed and carboplatin. To further evaluate the efficacy and safety of PV#10 injection in combination with chemotherapy, at least 30 additional participants could be enrolled at the selected dose level (10 mg / kg or 20 mg / kg) in each cohort.

[0152] Cohorts 3 through 5 were non-randomized. Cohort 3 received monotherapy with the anti-PD-1 and VEGF bispecific antibody PV#10 injection; Cohorts 4 and 5 received PV#10 injection in combination with pemetrexed and carboplatin.

[0153] Subjects receive the study treatment until disease progression, intolerable toxicity, voluntary withdrawal, death, or termination of the study by the sponsor.

[0154] Imaging progression during the study was assessed according to RECIST 1.1 criteria. Tumor assessment of measurable target lesions was performed according to RECIST 1.1, starting from the date of first administration of the study drug. Tumor imaging assessments were performed every 6 weeks (±7 days) during subsequent treatment phases up to week 48, and then every 12 weeks (±14 days). Tumor assessment time points were not affected by dose adjustments or interruptions. The study continued until imaging-confirmed disease progression, initiation of new anti-tumor therapy, withdrawal of informed consent, death, loss to follow-up, or fulfillment of other study termination criteria (whichever occurs first).

[0155] The safety of participants will be closely monitored throughout the study, adverse events will be collected and appropriate symptomatic treatment will be provided, and concomitant medications will be recorded. The study will conduct exploratory evaluations of pharmacokinetics and pharmacodynamics. After treatment, all participants will be followed up every 3 months (±14 days) until death, loss to follow-up, withdrawal of informed consent, or termination of the study by the sponsor. 5. Investigational Drug, Dosage, and Administration Method Table 3. Investigational Drug, Dosage, and Administration Design 6. Planned number of participants

[0156] The plan is to enroll 30-60 cases in each cohort, for a total of approximately 150-300 cases. 7. Inclusion Criteria

[0157] Subjects must meet all of the following criteria to be enrolled:

[0158] General requirements: 1. Voluntary participation in the study and signing of an informed consent form; 2. Willingness and ability to comply with the trial and follow-up procedures; 3. Male or female, aged 18–80 years; 4. Expected survival ≥ 3 months; 5. ECOG performance status score of 0 or 1.

[0159] Disease Characteristics: 6. Cohorts 1 through 5 require patients with histopathologically or cytologically confirmed unresectable locally advanced or metastatic NSCLC (stages IIIB / IIIC / IV according to the UICC / AJCC 8th edition lung cancer staging). Locally advanced NSCLC must be defined as tumors that are deemed inoperable or radiotherapy-inoperable by the investigator. 7. Cohort 1: Patients with histopathologically or cytologically confirmed squamous NSCLC who have not received systemic therapy at the current stage of locally advanced or metastatic disease (patients who have undergone radical surgery or radiotherapy are eligible if recurrence or metastasis occurs more than 6 months after the completion of neoadjuvant / adjuvant or concurrent / sequential therapy). 8. Cohort 2: Patients with histopathologically or cytologically confirmed non-squamous NSCLC who have not received systemic therapy at the current stage of locally advanced or metastatic disease (patients who have undergone radical surgery or radiotherapy are eligible if recurrence or metastasis occurs more than 6 months after the completion of neoadjuvant / adjuvant or concurrent / sequential therapy). 9. Cohort 3: NSCLC patients with known driver gene negativity and PD-L1 positive expression, defined as a tumor cell positive percentage (TPS) ≥1%; and who have not received systemic therapy at the current locally advanced or metastatic stage (for patients who have undergone radical surgery or radiotherapy, they can be enrolled if recurrence or metastasis occurs more than 6 months after the completion of neoadjuvant / adjuvant or concurrent / sequential therapy); 10. Cohort 4: Non-squamous NSCLC patients with histopathological or cytological confirmation, known EGFR-sensitive mutations, and who have previously received EGFR-TKI therapy and failed; 11. Cohort 5: Non-squamous NSCLC patients with histopathological or cytological confirmation, known driver gene positivity other than EGFR-sensitive mutations, and who have previously received approved TKI therapy and failed; 12. All participants in all cohorts must provide a report on the detection of driver genes (at least EGFR and ALK) based on tissue samples that meets the requirements of this study. If the report does not meet the requirements of this study or cannot be provided, a tumor tissue sample from when or after a diagnosis of locally advanced or metastatic tumor must be provided, archived within three years, prepared from paraffin blocks or freshly obtained, with 8 unstained FFPE pathological sections (preferably recently obtained tumor tissue samples) for driver gene detection (if the number of sections is insufficient, the number of sections may be reduced with the sponsor's consent); Participants in cohort 3 must provide a report on the detection of PD-L1 expression levels based on tissue samples that meets the requirements of this study before enrollment; All participants in all cohorts must provide a tumor tissue sample from when or after a diagnosis of locally advanced or metastatic tumor, archived within three years, prepared from paraffin blocks or freshly obtained, with at least 7 unstained FFPE pathological sections (preferably recently obtained tumor tissue samples) for CD8+ T cell and PD-L1 expression level detection; 13. Have at least one measurable lesion according to RECISTv1.1 criteria;

[0160] Organ Function and Contraception Requirements 14. Sufficient cardiac, bone marrow, liver, kidney, and coagulation functions should meet the following standards (normal values ​​are based on clinical trial center standards): • Cardiac function: Left ventricular ejection fraction ≥50%; QT interval calculated according to the Fridricia method (QTcF), males <470ms, females <480ms (corrected using the Fridricia formula); • No platelet or red blood cell transfusions within 14 days prior to the complete blood count, and no use of thrombopoietin (TPO), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), or interleukin-11 (IL-11) for correction; Bone marrow function: Hemoglobin ≥9g / dL; Absolute neutrophil count (ANC) ≥1.5×10⁻⁶. 9 / L; Platelets ≥100×10 9 / L; • Within 7 days prior to study administration, liver function: serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (≤ 2.5 × ULN for patients with liver metastases); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases); albumin (ALB) ≥ 30 g / L; • Within 7 days prior to study administration, renal function: serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) calculated according to the Cockcroft-Gault formula ≥ 50 mL / min; urinalysis results showing urine protein <++; for subjects with baseline urine strip test showing urine protein ≥++, a 24-hour urine sample should be collected, and the protein content in the urine within 24 hours should be < 1 g (if both testing methods are used, the value obtained from the 24-hour urine sample will be used for eligibility); • Within 7 days prior to study dosing, coagulation function should be: activated partial thromboplastin time (APTT) ≤ 1.5 × ULN, international normalized ratio (INR) ≤ 1.5 × ULN (INR for subjects receiving anticoagulation therapy should be in the range of 2-3); 15. Female subjects should be surgically sterilized or postmenopausal patients. Women of reproductive age must agree to use at least one medically approved method of contraception (such as intrauterine device, birth control pills, or condoms) during and for 6 months after the study treatment period. A negative blood pregnancy test must be obtained within 7 days prior to study enrollment, or a false-positive blood pregnancy test excluded by the investigator; and the subject must be a non-lactating woman. Male subjects should agree to use at least one medically approved method of contraception during and for 6 months after the study treatment period. 8. Statistical Analysis

[0161] The datasets for analysis include: • Full analysis set (FAS): Based on the principles of intention-to-treat (ITT) analysis, this set includes all enrolled subjects who received at least one treatment with the study drug. • Response-evaluable set (RES): Includes all enrolled subjects who received at least one treatment with the study drug and at least one post-baseline tumor assessment. • Safety analysis set (SS): Includes all enrolled subjects who received at least one treatment with the study drug. • Pharmacokinetics analysis set (PKS): Includes all enrolled subjects who received at least one treatment with the anti-PD-1 and VEGF bispecific antibody PV#10 injection, with at least one effective post-dosage concentration data point during the trial, and without any significant protocol deviations or violations affecting pharmacokinetic evaluation. • The Antidrug antibody set (ADAS) includes all subjects who have received at least one dose of the study drug and have evaluable ADA data, with no significant protocol deviations / violations or events deemed to significantly affect ADA characteristics.

[0162] General principle: All statistical analyses adopt... Completed with version 9.4 or later. Unless otherwise specified, continuous data are primarily described using mean, standard deviation, median, Q1, Q3, maximum, and minimum values; categorical data are described using frequency and percentage.

[0163] Efficacy analysis will be conducted based on the FAS set. ORR and DCR will be summarized according to RECIST v1.1. Two-sided 95% confidence intervals (CIs) for ORR and DCR will also be provided based on the Clopper-Pearson (exact) method. Furthermore, waterfall plots will be drawn by cohort and by subject based on the percentage change in total target lesion diameter relative to baseline to observe the optimal trend of change in total target lesion diameter. Spider plots will be drawn by cohort and visit time point for the percentage change in IRC and investigator-assessed total target lesion diameter relative to baseline to reflect the trend of change in total target lesion diameter. For time-event endpoints (i.e., PFS, DoR, and OS), the Kaplan-Meier method will be used for estimation, yielding survival function estimates for each cohort and survival times and two-sided 95% CIs (based on log-log transformation) corresponding to the 25th, 50th (median), and 75th percentiles. In addition, the Kaplan-Meier method will be used to calculate the survival probability at different time points, and the corresponding 95% CIs will be calculated based on the Greenwood formula. Kaplan-Meier curves will be plotted.

[0164] Safety analysis included the number and incidence of TEAEs, treatment-related adverse events, serious adverse events, and treatment-related serious adverse events, categorized by cohort. Cross-analysis tables of relative baseline changes and clinical significance were provided for vital signs, physical examinations, laboratory tests, and 12-lead electrocardiograms, while cross-analysis tables of relevant baseline changes were provided for ECOG.

[0165] PK analysis listed serum concentrations by different dose groups and planned sampling time points, and summarized them using descriptive statistics, including number of cases, arithmetic mean, geometric mean, standard deviation, coefficient of variation, median, maximum, and minimum. Individual and mean serum concentration-time curves were plotted for each dosing regimen.

[0166] Immunogenicity analysis will be a descriptive analysis of immunogenicity results, including but not limited to analyzing the number and proportion of subjects positive for anti-drug antibodies (ADA) by dose group and planned sampling time point. Where applicable, the impact of immunogenicity on the pharmacokinetic (PK), efficacy, or safety of the investigational drug will be evaluated. 9. Data

[0167] 9.1 Clinical study data on the first-line treatment of advanced squamous NSCLC with anti-PD-1 and VEGF bispecific antibody PV#10 injection in combination with carboplatin and paclitaxel.

[0168] Study cohort 1 enrolled patients with driver gene-negative, systemically untreated squamous NSCLC. Selected patients were randomly assigned 1:1 to receive either PV#10 injection 10 mg / kg, Q3W, in combination with carboplatin and paclitaxel, or PV#10 injection 20 mg / kg, Q3W, in combination with carboplatin and paclitaxel.

[0169] The research results up to October 17, 2025 are summarized below.

[0170] A total of 61 subjects received PV#10 injection in combination with carboplatin and paclitaxel. There were 30 subjects in the PV#10 injection 10 mg / kg dose group and 31 subjects in the PV#10 injection 20 mg / kg dose group. Detailed subject information is shown in Table 4. Table 4. Subject Information

[0171] Of the 58 patients, at least one post-baseline tumor assessment was performed, and 100% of the patients showed tumor shrinkage at the first tumor assessment. According to the data in Tables 5 and 6, the ORR and cORR (confirmed objective response rate) trends were similar between the PV#10 injection 10 mg / kg group and the PV#10 injection 20 mg / kg group, with the 10 mg / kg group showing slightly better efficacy data.

[0172] Stratified analysis showed that in the TPS < 1% group, the 10 mg / kg group had relatively better efficacy data; in the TPS ≥ 1% group, the 20 mg / kg group had slightly better efficacy data. Table 5. Efficacy Data Table 6. Efficacy Data

[0173] The safety profiles of the PV#10 injection 10 mg / kg group and the PV#10 injection 20 mg / kg group were comparable. The safety profile of PV#10 injection combined with carboplatin and paclitaxel was manageable in patients with advanced NSCLC. Specific data are shown in Table 7. Table 7. Safety Data

[0174] The above data demonstrate that PV#10 injection, at doses of 10 mg / kg or 20 mg / kg, and in combination with carboplatin and paclitaxel, exhibits excellent tumor shrinkage and manageable safety in driver gene-negative advanced squamous NSCLC in patients who have not received systemic therapy, regardless of whether the tumor is PD-L1 positive or negative.

[0175] The research results up to December 22, 2025 are summarized below.

[0176] A total of 61 subjects received PV#10 injection in combination with carboplatin and paclitaxel. There were 30 subjects in the PV#10 injection 10 mg / kg dose group and 31 subjects in the PV#10 injection 20 mg / kg dose group. Detailed subject information is shown in Table 8. Table 8. Subject Information

[0177] Of the 58 patients, at least one post-baseline tumor assessment was performed, and 100% of patients showed tumor shrinkage at the first tumor assessment. According to the ORR, cORR (confirmed objective response rate), and DCR (disease control rate) data in Tables 9 and 10, both the PV#10 injection 10 mg / kg group and the PV#10 injection 20 mg / kg group demonstrated excellent efficacy. Overall, the efficacy data for the 10 mg / kg group were relatively superior.

[0178] Stratified analysis showed that in the TPS < 1% group, the 10 mg / kg group had relatively better efficacy data; in the TPS ≥ 1% group, the 20 mg / kg group had relatively better efficacy data. Table 9. Efficacy Data

[0179] The current median follow-up time is 6 months, and 37 of the 39 responders (94.9%) are still receiving treatment. Median duration of response (mDoR) and median progression-free survival (mPFS) are not yet mature. Table 10. Efficacy data.

[0180] The PV#10 injection at both the 10 mg / kg and 20 mg / kg dose groups showed good safety profiles, with the 10 mg / kg group exhibiting even better safety data. The safety profile of PV#10 injection combined with carboplatin and paclitaxel was manageable in patients with advanced NSCLC. Specific data are shown in Table 11. Table 11. Safety Data

[0181] The above data demonstrate that PV#10 injection, at doses of 10 mg / kg or 20 mg / kg, and in combination with carboplatin and paclitaxel, exhibits excellent tumor shrinkage and manageable safety in driver gene-negative advanced squamous NSCLC in patients who have not received systemic therapy, regardless of whether the tumor is PD-L1 positive or negative.

[0182] 9.2 Clinical data on the first-line treatment of advanced non-squamous NSCLC with anti-PD-1 and VEGF bispecific antibody PV#10 injection in combination with carboplatin and pemetrexed.

[0183] Cohort 2 of the study enrolled non-squamous NSCLC subjects who were driver gene negative and had not received systemic treatment. Eligible subjects were randomly assigned 1:1 to receive either PV#10 injection 10 mg / kg, Q3W, in combination with carboplatin and pemetrexed or PV#10 injection 20 mg / kg, Q3W, in combination with carboplatin and pemetrexed.

[0184] The research results up to October 17, 2025 are summarized below.

[0185] A total of 60 subjects received PV#10 injection in combination with carboplatin and pemetrexed. There were 30 subjects in the PV#10 injection 10 mg / kg dose group and 30 subjects in the PV#10 injection 20 mg / kg dose group. Detailed subject information is shown in Table 12. Table 12. Subject Information

[0186] Of the 57 patients, at least one post-baseline tumor assessment was performed, and 98% of patients showed tumor shrinkage at the initial assessment. According to the data in Tables 13 and 14, both the PV#10 injection 10 mg / kg group and the PV#10 injection 20 mg / kg group demonstrated excellent efficacy. Overall, the efficacy data for the 10 mg / kg group were relatively superior.

[0187] Stratified analysis showed that in the TPS < 1% group, the 10 mg / kg group had significantly better efficacy data; in the TPS ≥ 1% group, the 10 mg / kg group had relatively better efficacy data. Table 13. Efficacy Data Table 14. Efficacy Data

[0188] The safety profiles of the PV#10 injection 10 mg / kg group and the PV#10 injection 20 mg / kg group were comparable. The safety profile of PV#10 injection in combination with carboplatin and pemetrexed was manageable in patients with driver gene-negative advanced NSCLC. Specific data are shown in Table 15. Table 15. Safety Data

[0189] The above data demonstrate that PV#10 injection at doses of 10 mg / kg or 20 mg / kg, in combination with carboplatin and pemetrexed, has excellent therapeutic efficacy and manageable safety in driver gene-negative advanced non-squamous NSCLC that has not undergone systemic treatment.

[0190] The research results up to December 22, 2025 are summarized below.

[0191] A total of 60 subjects received PV#10 injection in combination with carboplatin and pemetrexed. There were 30 subjects in the PV#10 injection 10 mg / kg dose group and 30 subjects in the PV#10 injection 20 mg / kg dose group. Detailed subject information is shown in Table 16. Table 16. Subject Information

[0192] Of the 57 patients, at least one post-baseline tumor assessment was performed, and 98% of patients showed tumor shrinkage at the first assessment. According to the ORR, cORR (confirmed objective response rate), and DCR (disease control rate) data in Tables 17 and 18, both the PV#10 injection 10 mg / kg group and the PV#10 injection 20 mg / kg group demonstrated excellent efficacy. Overall, the efficacy data for the 10 mg / kg group were significantly superior.

[0193] Stratified analysis showed that in the TPS < 1% group, the 10 mg / kg group had significantly better efficacy data; in the TPS ≥ 1% group, the 10 mg / kg group had relatively better efficacy data. Table 17. Efficacy Data

[0194] The current median follow-up time is 6 months, and 29 of the 29 responders (100%) are still receiving treatment. Median duration of response (mDoR) and median progression-free survival (mPFS) are not yet mature. Table 18. Efficacy data.

[0195] The PV#10 injection at 10 mg / kg and 20 mg / kg doses showed good safety profiles, with the 10 mg / kg group exhibiting even better safety data. The combination of PV#10 injection with carboplatin and pemetrexed demonstrated manageable safety in patients with driver gene-negative advanced NSCLC. Specific data are shown in Table 19. Table 19. Safety Data

[0196] The above data demonstrate that PV#10 injection at doses of 10 mg / kg or 20 mg / kg, in combination with carboplatin and pemetrexed, exhibits excellent therapeutic efficacy and manageable safety in driver gene-negative advanced non-squamous NSCLC that has not undergone systemic therapy. Example 4: A randomized, double-blind, multicenter phase III study comparing the anti-PD-1 and VEGF bispecific antibody PV#10 injection in combination with platinum-based chemotherapy versus tislelizumab in combination with platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer. 1. Study Objective

[0197] Main research objective: To evaluate the efficacy of anti-PD-1 and VEGF bispecific antibody PV#10 injection combined with chemotherapy versus tislelizumab combined with chemotherapy as first-line treatment for advanced non-small cell lung cancer.

[0198] Secondary objectives: • To evaluate the safety and tolerability of anti-PD-1 and VEGF bispecific antibody PV#10 injection combined with chemotherapy versus tislelizumab combined with chemotherapy as first-line treatment for advanced non-small cell lung cancer (NSCLC). • To evaluate the pharmacokinetic characteristics of anti-PD-1 and VEGF bispecific antibody PV#10 injection combined with chemotherapy as first-line treatment for advanced NSCLC. • To evaluate the immunogenicity of anti-PD-1 and VEGF bispecific antibody PV#10 injection combined with chemotherapy as first-line treatment for advanced NSCLC. • To evaluate the correlation between PD-L1 expression and efficacy. • To evaluate patient-reported outcomes (PROs) of anti-PD-1 and VEGF bispecific antibody PV#10 injection combined with chemotherapy versus tislelizumab combined with chemotherapy for advanced NSCLC. 2. Study endpoints

[0199] Primary endpoint: Progression-free survival (PFS) as assessed by the Blinded Independent Imaging Review Committee (BIRC) according to the RECIST v1.1 criteria for evaluating efficacy in solid tumors.

[0200] Secondary endpoints: • Overall Survival (OS) • PFS as assessed by the investigator according to RECIST v1.1 • Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate (DCR), and Time to Response (TTR) as assessed by BIRC according to RECIST v1.1 • ORR, DoR, DCR, and TTR as assessed by the investigator according to RECIST v1.1 • Treatment Emergent Adverse Events (TEAEs), vital signs, physical examination, electrocardiogram (ECG), laboratory tests, etc. during treatment • Description of PV#10 plasma concentrations at each time point • Characterization of PV#10 PK features based on PopPK analysis (reported separately) • Incidence, time of onset, duration, and titer of PV#10 anti-adverse antibodies (ADAs), and incidence of neutralizing antibodies (NAbs), etc. (if applicable) • Correlation between PD-L1 expression in tumor tissue and efficacy in subjects • Change from baseline assessed using EORTC QLQ-C30 and EORTC QLQ-LC29 3. Study population

[0201] Treatment-naïve patients with histologically or cytologically confirmed locally advanced (stage IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer, and negative for driver genes. 4. Study Design

[0202] This study is a randomized, double-blind, multicenter phase III trial designed to evaluate the efficacy and safety of anti-PD-1 and VEGF bispecific antibody PV#10 injection in combination with platinum-based chemotherapy versus tislelizumab in combination with platinum-based chemotherapy in patients with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer (NSCLC) who have not received first-line treatment.

[0203] This study plans to enroll 538 participants, who will be randomly assigned in a 1:1 stratified block randomization to the following two groups: • Experimental group: Anti-PD-1 and VEGF bispecific antibody PV#10 injection combined with platinum-based chemotherapy • Control group: Tislelizumab combined with platinum-based chemotherapy

[0204] Randomized stratification factors included: tumor pathological histological type (squamous cell carcinoma vs. non-squamous cell carcinoma), PD-L1 expression level (TPS<1% vs. TPS≥1%), clinical stage (stage IIIB / C vs. stage IV), and brain metastasis (yes vs. no).

[0205] The proportion of subjects with squamous cell carcinoma in the study will be no less than 40%.

[0206] Throughout the study, efficacy and safety indicators will be monitored in participants. The primary efficacy endpoint is progression-free survival (PFS) as assessed by the BIRC according to RECIST v1.1. Participants must undergo baseline imaging assessment during the screening period and must have measurable lesions. During the study, tumor assessments will be performed every 6 weeks (±7 days) for the first 60 weeks after randomization, and every 12 weeks (±7 days) thereafter, until disease progression (confirmed by the BIRC), initiation of new anti-tumor therapy, loss to follow-up, withdrawal of informed consent, or death (whichever occurs first). Tumor assessment time points are not affected by dose adjustments or interruptions. This study will have the BIRC assess participants' imaging data in a blinded manner. For participants assessed by the investigator as having disease progression, the BIRC will conduct an independent, standardized rapid image review and assess according to RECIST v1.1 criteria to confirm disease progression. If the BIRC does not confirm disease progression, the participant will continue study treatment until disease progression is confirmed by the BIRC (unless the investigator assesses circumstances requiring discontinuation of study treatment, such as rapid progression or clinical deterioration).

[0207] Safety will be assessed through vital signs, physical examination, laboratory tests, electrocardiogram, ECOG score, number and severity of adverse events (AEs), and serious adverse events (SAEs). The safety of the investigational drug will be assessed according to CTCAE v5.0 criteria. Safety follow-up will be conducted 28 days (+7 days) after the last dose and 90 days (+7 days) after the last dose of the anti-PD-1 and VEGF bispecific antibody PV#10 injection / tislelizumab. Survival follow-up will be conducted every 90 days (±14 days) after the end of study treatment. Except for subjects who discontinue treatment due to disease progression as determined by imaging assessment, other subjects must continue to undergo imaging assessments at the prescribed intervals until disease progression (confirmed by BIRC), initiation of new anti-tumor therapy, loss to follow-up, withdrawal of informed consent, or death (whichever occurs first). 5. Investigational drug, dosage, and administration method.

[0208] This study plans to enroll 538 participants, who will be randomly assigned in a 1:1 ratio to the following two groups using a stratified block randomization method: • Experimental group: Anti-PD-1 and VEGF bispecific antibody PV#10 injection combined with platinum-based chemotherapy • Control group: Tislelizumab combined with platinum-based chemotherapy Table 4. Study drug, dosage, and administration method 6. Planned number of participants

[0209] This study plans to enroll 538 participants who will be randomly assigned in a 1:1 ratio to either the experimental or control group, with approximately 269 participants in each group. 7. Inclusion Criteria

[0210] General requirements: 1. Voluntary participation in the study and signing of an informed consent form; 2. Willingness and ability to comply with the trial and follow-up procedures; 3. Male or female, aged 18–75 years (inclusive); 4. Expected survival ≥ 3 months; 5. ECOG performance status score of 0 or 1.

[0211] Disease characteristics: 6. Histopathologically or cytologically confirmed locally advanced or metastatic NSCLC (AJCC 8th edition) that is not suitable for radical treatment (complete surgical resection, concurrent / sequential chemoradiotherapy); 7. No prior systemic anti-tumor therapy for advanced or metastatic NSCLC. Subjects who have received neoadjuvant / adjuvant therapy or radical concurrent / sequential chemoradiotherapy and have experienced recurrence or metastasis more than 6 months after the end of their last treatment are eligible to participate in this study; 8. At least one measurable non-brain lesion according to RECIST v1.1 criteria, and the lesion is suitable for repeated and accurate measurement (if the lesion at the previous radiotherapy site is the only selectable target lesion, the investigator must provide imaging evidence showing significant progression of the lesion); 9. All subjects must provide a report of PD-L1 expression level detected by an approved kit that meets the requirements before enrollment; subjects with non-squamous non-small cell lung cancer must provide a report of driver gene (at least EGFR, ALK) testing that meets the requirements of this study. If the above test report does not meet the requirements of this study or cannot be provided, a tumor tissue sample from when or after the diagnosis of locally advanced or metastatic tumor must be provided, and a paraffin block or a freshly prepared unstained FFPE pathological section of freshly obtained tumor tissue (preferably a recently obtained tumor tissue sample) archived within the last three years must be used for driver gene or PD-L1 expression level detection (if the subject's archived sample does not meet the above requirements, and the researcher judges that a biopsy is not in the best interests of the subject, the archived sample may be accepted after discussion with the sponsor).

[0212] Organ Function and Contraception Requirements 10. Sufficient cardiac, bone marrow, liver, kidney, and coagulation functions should meet the following standards (normal values ​​are based on clinical trial center standards): • Cardiac function: Left ventricular ejection fraction ≥50%; QT interval calculated according to the Fridricia method (QTcF), male <470ms, female <480ms (corrected using the Fridricia formula); • No platelet or red blood cell transfusions within 14 days prior to the complete blood count, and no use of thrombopoietin (TPO), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), or interleukin-11 (IL-11) for correction; Bone marrow function: Hemoglobin ≥9g / dL; Absolute neutrophil count (ANC) ≥1.5×10⁹ / L; Platelet count ≥100×10⁹ / L; • Liver function: Serum total bilirubin ≤1.5 times the upper limit of normal (ULN) (≤2.5×ULN for patients with liver metastases); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (≤5×ULN for patients with liver metastases); albumin (ALB) ≥30g / L; • Kidney function: Creatinine clearance (CrCl) ≥50mL / min calculated according to the Cockcroft-Gault formula; urinalysis results showing urine protein <++; for subjects whose baseline urine test strip results show urine protein ≥++, a 24-hour urine sample should be collected and the protein content in the urine within 24 hours should be <1g (if both testing methods are used, the value obtained from the 24-hour urine sample will be used for eligibility); • Coagulation function: Activated partial thromboplastin time (APTT) ≤1.5×ULN, international normalized ratio (INR) ≤1.5×ULN (INR should be in the range of 2-3 for subjects receiving anticoagulation therapy); 11. Female participants should be surgically sterilized or postmenopausal patients. Women of reproductive age must agree to use at least one medically approved method of contraception (such as an intrauterine device, birth control pill, or condom) during the study and for 6 months after the study. A negative blood pregnancy test must be obtained within 7 days prior to study enrollment. Participants must also be non-lactating. Male participants should agree to use at least one medically approved method of contraception during the study and for 6 months after the study. 8. Interim / Final Analysis

[0213] This study includes an interim analysis and a final analysis of PFS. The superiority termination boundary was calculated using the O'Brien Fleming asymptotic Lan-DeMets type I error consumption function, and the total type I error was strictly controlled at two-sided α = 0.05.

[0214] An interim PFS analysis was conducted when approximately 217 BIRC-assessed PFS events were reached or the last enrolled subject completed approximately 3 months of follow-up. The interim analysis superiority margin α1 was 0.015 (two-sided). A final PFS analysis was conducted when approximately 310 BIRC-assessed PFS events were reached or the last enrolled subject completed 9 months of follow-up. The final analysis superiority margin α2 was 0.046 (two-sided). Actual margins will be updated based on observed events. If the cumulative number of events at the time of the final analysis differs from the planned number of events by no more than 5%, α2 will not be recalculated.

[0215] The interim analysis of PFS will be performed by IDMC, which will determine whether the trial has achieved statistical superiority based on the pre-defined superiority threshold. 9. Statistical Analysis

[0216] All statistical tests are two-tailed, and unless otherwise specified, the overall Type I error level is set at 0.05. Descriptive statistics for continuous variables will include number of cases, mean, standard deviation, median, minimum, and maximum. Descriptive statistics for categorical variables will be provided using frequency and percentage.

[0217] Analysis Sets: • Intention-to-Track (ITT) Analysis Set: Consists of all randomly assigned participants, regardless of whether they received the study drug or completed all treatments. Analysis of this population will be based on the treatment group to which participants were randomly assigned. ITT will be used for primary and secondary estimating goals analysis, as well as summarizing participant distribution, protocol deviation, demographic and baseline characteristics, medical history, and previous and concomitant medications. • Efficacy-Evaluable Analysis Set (RES): Consists of all randomized participants who received at least one treatment with the study drug and at least one post-baseline tumor assessment. Analysis of this population will be based on the treatment group to which participants were randomly assigned. RES will support analysis of secondary estimating goals such as objective response rate. • Safety Analysis Set (SS): Consists of all participants who received at least one treatment with the study drug (experimental or control group). Participant grouping will be based on the actual treatment received. SS will be used for analysis of drug exposure and safety assessment indicators. • Pharmacokinetic Analysis Set (PKCS): Composed of all randomly enrolled subjects who received at least one dose of the anti-PD-1 and VEGF bispecific antibody PV#10 injection and had at least one post-dosage effective concentration data for the anti-PD-1 and VEGF bispecific antibody PV#10 injection during the trial. PKCS will be used for descriptive analysis of blood drug concentrations and PopPK model analysis. • Immunogenicity Analysis Set (ADAS): Composed of all randomly enrolled subjects who received at least one dose of the anti-PD-1 and VEGF bispecific antibody PV#10 injection and had evaluable post-dosage immunogenicity data. ADAS will be used for immunogenicity analysis. • PRO Analysis Set (PROS): Composed of all randomly enrolled subjects who received at least one dose of the study drug and had baseline and at least one post-baseline assessment using the corresponding quality of life assessment scale (EORTC QLQ-C30 or EORTC QLQ-LC29). This analysis set will be used for analysis of the EORTC QLQ-C30 and EORTC QLQ-LC29 scales. The analysis of this population will be based on the subjects being randomly assigned to the treatment group.

[0218] Efficacy Analysis: Hypothesis testing for the primary endpoint will be conducted within the estimation target framework, defined by “Population,” “Variables,” “Treatment,” “Comorbidities,” and “Population-level Summary,” detailed in Section 10.5.3. For PFS and OS analysis, a stratified Log-rank test adjusted for randomization stratification was used to compare survival differences between the experimental and control groups. The hazard ratios (HRs) for both groups were estimated using a stratified Cox regression model. Median survival, time-varying event incidence, and their 95% CIs were estimated using the Kaplan-Meier method. For ORR analysis, the Clopper-Pearson method was used to calculate the objective response rate and its two-sided 95% confidence interval (CI), and the Cochran-Mantel-Haenszel (CMH) method (Mantel & Haenszel, 1959) was used for intergroup comparisons to calculate P-values. The stratified Miettinen-Nurminen method was used to calculate the intergroup rate difference and its 95% CI.

[0219] Safety Analysis: Safety analysis will be based on SS (Safety Standards) and conducted according to actual medication groups. Summary statistics of AEs will summarize all treatment-related adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs), as well as AEs leading to dose reduction, drug discontinuation, drug cessation, and death. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Laboratory abnormalities will be summarized according to NCI CTCAE version 5.0; the cross-tabulation of clinical laboratory tests will show the change in baseline CTCAE grade and the most severe grade since baseline.

[0220] Pharmacokinetic analysis: Descriptive statistics of blood drug concentrations at each time point were performed using PKCS. The number of subjects, mean, standard deviation, median, quartiles, maximum, minimum, geometric mean, and coefficient of variation were summarized. If the data allowed, box plots of exposure levels at each time point were plotted.

[0221] Immunogenicity analysis: An immunogenicity analysis set was used to list the antidote antibody (ADA) positive samples, including the time of occurrence and duration of occurrence. The incidence of ADA was summarized. If applicable, the incidence of nonacid antibodies (NAb) was summarized.

[0222] Population pharmacokinetic and exposure-effect (ER) analysis: Where data permit, all plasma concentration data for PV#10 obtained in this study will be combined with plasma concentration data from other completed clinical studies for PopPK analysis (using a nonlinear mixed-effects model [NONMEM]) to establish a PK model to characterize the PK profile of PV#10 in serum after intravenous infusion. The effects of various intrinsic / extrinsic factors on the PK profile of PV#10 will also be assessed, including age, sex, weight, and ethnicity. Then, based on the final PK model parameter estimates, individual exposure parameters for subjects will be estimated for further ER analysis, including correlation analysis between exposure and efficacy, and exposure and adverse events.

[0223] The above description discloses only some embodiments of the present invention and is not intended to limit the present invention in any way. Those skilled in the art will understand that the present invention is not limited to the specific embodiments described above. For those skilled in the art, various improvements and modifications can be made to the present invention without departing from its principles, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for treating non-small cell lung cancer (NSCLC), wherein the method comprises administering an effective amount of an anti-PD-1 and VEGF bispecific antibody liquid formulation to an individual having said cancer, wherein the bispecific antibody comprises (a) a first binding domain specifically binding to PD-1, and (b) a second binding domain specifically binding to VEGF, the second binding domain specifically binding to VEGF being a VHH, the VHH comprising a CDR1 amino acid sequence as shown in SEQ ID NO: 1, a CDR2 amino acid sequence as shown in SEQ ID NO: 2, and a CDR3 amino acid sequence as shown in SEQ ID NO: 3; Preferably, the first binding domain that specifically binds to PD-1 is an antibody or its antigen-binding fragment, the first binding domain comprising VH and VL, wherein VH comprises the HCDR1 amino acid sequence as shown in SEQ ID NO: 5, the HCDR2 amino acid sequence as shown in SEQ ID NO: 6, and the HCDR3 amino acid sequence as shown in SEQ ID NO: 7, and VL comprises the LCDR1 amino acid sequence as shown in SEQ ID NO: 9, the LCDR2 amino acid sequence as shown in SEQ ID NO: 10, and the LCDR3 amino acid sequence as shown in SEQ ID NO: 11; Preferably, the VHH comprises the amino acid sequence shown in SEQ ID NO: 4; Preferably, the VH comprises the amino acid sequence shown in SEQ ID NO: 8; Preferably, the VL contains an amino acid sequence as shown in SEQ ID NO: 12; Preferably, the bispecific antibody comprises a heavy chain amino acid sequence as shown in SEQ ID NO: 13; Preferably, the bispecific antibody comprises a light chain amino acid sequence as shown in SEQ ID NO:

14.

2. The method according to claim 1, wherein the NSCLC is a scaly NSCLC or a non-scaly NSCLC; Preferably, the NSCLC is PD-L1 negative NSCLC; preferably, the PD-L1 negative status is TPS < 1%; Preferably, the NSCLC is PD-L1 positive NSCLC; preferably, the PD-L1 positivity is TPS ≥ 1%; Preferably, the NSCLC has brain metastases; Preferably, the NSCLC does not have brain metastases; Preferably, the NSCLC is driver gene-negative NSCLC; Preferably, the NSCLC is a driver gene-positive NSCLC; Preferably, the NSCLC is an NSCLC with an EGFR-sensitive mutation; Preferably, the NSCLC is an NSCLC that is positive for other driver genes besides EGFR-sensitive mutations; Preferably, the other driver genes are ALK, RET, ROS1, BRAF, NTRK, MET 14, KRAS, or HER2; Preferably, the NSCLC is NSCLC that has not undergone systemic treatment; Preferably, the NSCLC is NSCLC following EGFR-TKI treatment; Preferably, the NSCLC is NSCLC following first-line TKI treatment; Preferably, the NSCLC is locally advanced NSCLC; more preferably, the NSCLC is inoperable locally advanced NSCLC; even more preferably, the locally advanced stage is stage IIIB or IIIC. Preferably, the NSCLC is a metastatic NSCLC; more preferably, the NSCLC is an NSCLC classified as IV in the TNM staging. More preferably, the cancer is driver gene-negative squamous NSCLC that has not undergone systemic treatment; More preferably, the cancer is driver gene-negative, untreated non-squamous NSCLC; More preferably, the cancer is driver gene negative, PD-L1 positive, and untreated NSCLC; More preferably, the cancer is non-squamous NSCLC with EGFR-sensitive mutations and after EGFR-TKI treatment; More preferably, the cancer is non-squamous NSCLC that is positive for other driver genes besides EGFR-sensitive mutations and has undergone first-line TKI treatment.

3. The method according to claim 1 or 2, wherein the method comprises intravenously infusing the individual with a liquid formulation of anti-PD1 and VEGF bispecific antibodies; Preferably, the dosage of the anti-PD1 and VEGF bispecific antibody in the liquid formulation administered to the individual in a single dose ranges from 1 mg / kg to 100 mg / kg; Preferably, the dosage range of the anti-PD1 and VEGF bispecific antibody in the liquid formulation administered to the individual in a single dose is selected from 5 mg / kg-50 mg / kg, 10 mg / kg-50 mg / kg, 15 mg / kg-50 mg / kg, 20 mg / kg-50 mg / kg, 25 mg / kg-50 mg / kg, 30 mg / kg-50 mg / kg, 35 mg / kg-50 mg / kg, 40 mg / kg-50 mg / kg, 45 mg / kg- 50mg / kg, 5mg / kg-45mg / kg, 10mg / kg-45mg / kg, 15mg / kg-45mg / kg, 20mg / kg-45mg / kg, 25mg / kg-45mg / kg, 30mg / kg-4 5mg / kg, 35mg / kg-45mg / kg, 40mg / kg-45mg / kg, 5mg / kg-40mg / kg, 10mg / kg-40mg / kg, 15mg / kg-40mg / kg, 20mg / kg-40 mg / kg, 25mg / kg-40mg / kg, 30mg / kg-40mg / kg, 35mg / kg-40mg / kg, 5mg / kg-35mg / kg, 10mg / kg-35mg / kg, 15mg / kg-35m g / kg, 20mg / kg-35mg / kg, 25mg / kg-35mg / kg, 30mg / kg-35mg / kg, 5mg / kg-30mg / kg, 10mg / kg-30mg / kg, 15mg / kg-30mg / kg, 20mg / kg-30mg / kg, 25mg / kg-30mg / kg, 5mg / kg-25mg / kg, 10mg / kg-25mg / kg, 15mg / kg-25mg / kg, 20mg / kg-25mg / kg, 5mg / kg-20mg / kg, 10mg / kg-20mg / kg, 15mg / kg-20mg / kg, 5mg / kg-15mg / kg, 10mg / kg-15mg / kg and 5mg / kg-10mg / kg; Preferably, the amount of anti-PD1 and VEGF bispecific antibody in the liquid formulation administered to the individual in a single dose is 10 mg / kg; Preferably, the amount of anti-PD1 and VEGF bispecific antibody in the liquid formulation administered to the individual in a single dose is 20 mg / kg.

4. The method according to any one of claims 1-3, wherein the liquid formulation of the anti-PD1 and VEGF bispecific antibody is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the administration frequency is once every 3 weeks.

5. The method according to any one of claims 1-4, wherein the anti-PD1 and VEGF bispecific antibody liquid formulation is administered alone or in combination with one, two or three of paclitaxel, carboplatin and pemetrexed.

6. The method of claim 5, wherein the method comprises intravenously infusing the individual with a liquid formulation of anti-PD1 and VEGF bispecific antibodies, and / or paclitaxel, and / or carboplatin, and / or pemetrexed disodium for injection; Preferably, the method comprises intravenously infusing the individual with a liquid formulation of anti-PD1 and VEGF bispecific antibodies, paclitaxel injection, and carboplatin injection; Preferably, the method comprises intravenously infusing the individual with a liquid formulation of anti-PD1 and VEGF bispecific antibodies, pemetrexed disodium for injection, and carboplatin injection.

7. The method of claim 6, wherein the dose range for a single administration of paclitaxel to the individual is 100 mg / m². 2 -300mg / m 2 ; Preferably, the dose range for a single administration of paclitaxel to the individual is selected from 100 mg / m². 2 -300mg / m 2 125mg / m 2 -300mg / m 2 150mg / m 2 -300mg / m 2 175mg / m 2 -300mg / m 2 200mg / m 2 -300mg / m 2 225mg / m 2 -300mg / m 2 250mg / m 2 -300mg / m 2 275mg / m 2 -300mg / m 2 100mg / m 2 -275mg / m 2 125mg / m 2 -275mg / m 2 150mg / m 2 -275mg / m 2 175mg / m 2 -275mg / m 2 200mg / m 2 -275mg / m 2 225mg / m 2 -275mg / m 2 250mg / m 2 -275mg / m 2 100mg / m 2 -250mg / m 2 125mg / m 2 -250mg / m 2 150mg / m 2 -250mg / m 2 175mg / m 2 -250mg / m 2 200mg / m 2 -250mg / m 2 225mg / m 2 -250mg / m 2 100mg / m 2 -225mg / m 2 125mg / m 2 -225mg / m 2 150mg / m 2 -225 mg / m 2 、175 mg / m 2 -225 mg / m 2 、200 mg / m 2 -225 mg / m 2 、100 mg / m 2 -200 mg / m 2 、125 mg / m 2 -200 mg / m 2 、150 mg / m 2 -200 mg / m 2 、175 mg / m 2 -200 mg / m 2 、100 mg / m 2 -175 mg / m 2 、125 mg / m 2 -175 mg / m 2 、150 mg / m 2 -175 mg / m 2 、100 mg / m 2 -150 mg / m 2 、125 mg / m 2 -150 mg / m 2 and 100 mg / m 2 -125 mg / m 2 ; Preferably, the dose of paclitaxel administered to the individual in a single dose is 175 mg / m². 2 .

8. The method according to claim 6 or 7, wherein the paclitaxel is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the administration frequency is once every 3 weeks.

9. The method of claim 6, wherein the dose range for a single administration of injectable pemetrexed disodium to the individual is 100 mg / m². 2 -1000mg / m 2 ; Preferably, the dose range for a single administration of pemetrexed disodium for injection to the individual is selected from 100 mg / m². 2 -1000mg / m 2 200mg / m 2 -1000mg / m 2 300mg / m 2 -1000mg / m 2 400mg / m 2 -1000mg / m 2 500mg / m 2 -1000mg / m 2 600mg / m 2 -1000mg / m 2 700mg / m 2 -1000mg / m 2 800mg / m 2 -1000mg / m 2 900mg / m 2 -1000mg / m 2 100mg / m 2 -900mg / m 2 200mg / m 2 -900mg / m 2 300mg / m 2 -900mg / m 2 400mg / m 2 -900mg / m 2 500mg / m 2 -900mg / m 2 600mg / m 2 -900mg / m 2 700mg / m 2 -900mg / m 2 800mg / m 2 -900mg / m 2 100mg / m 2 -800mg / m 2 200mg / m 2 -800mg / m 2 300mg / m 2 -800mg / m 2 400mg / m 2 -800mg / m 2 500mg / m 2 -800mg / m 2 600mg / m 2 -800mg / m 2 、 700 mg / m 2 - 800 mg / m 2 、 100 mg / m 2 - 700 mg / m 2 、 200 mg / m 2 - 700 mg / m 2 、 300 mg / m 2 - 700 mg / m 2 、 400 mg / m 2 - 700 mg / m 2 、 500 mg / m 2 - 700 mg / m 2 、 600 mg / m 2 - 700 mg / m 2 、 100 mg / m 2 - 600 mg / m 2 、 200 mg / m 2 - 600 mg / m 2 、 300 mg / m 2 - 600 mg / m 2 、 400 mg / m 2 - 600 mg / m 2 、 500 mg / m 2 - 600 mg / m 2 、 100 mg / m 2 - 500 mg / m 2 、 200 mg / m 2 - 500 mg / m 2 、 300 mg / m 2 - 500 mg / m 2 、 400 mg / m 2 - 500 mg / m 2 、 100 mg / m<​​​​​​​​​​​​​​​​​​​​​​​ Preferably, the dose of pemetrexed disodium for injection administered to the individual in a single dose is 500 mg / m². 2 .

10. The method according to claim 6 or 9, wherein the pemetrexed disodium for injection is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the administration frequency is once every 3 weeks.

11. The method of claim 6, wherein the dose range of a single administration of carboplatin to the individual is AUC = 1-10; Preferably, the dose range for a single administration of carboplatin injection to the individual is selected from AUC = 1-10, 2-10, 3-10, 4-10, 5-10, 6-10, 7-10, 8-10, 9-10, 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, 8-9, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3, and 1-2; Preferably, the dose of carboplatin injection administered to the individual in a single administration is AUC = 5.

12. The method according to claim 6 or 11, wherein the carboplatin injection is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the administration frequency is once every 3 weeks.

13. The method of claim 12, wherein the administration is carried out for a maximum of 3, 4, or 5 cycles; preferably, the administration is carried out for a maximum of 4 cycles.

14. The method according to any one of claims 1-13, wherein the NSCLC is driver gene-negative, systemically untreated squamous NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, paclitaxel injection, and carboplatin injection, wherein the dosage of the PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, administered once every 3 weeks, and the dosage of the paclitaxel injection is 175 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO:

14.

15. The method according to any one of claims 1-13, wherein the NSCLC is driver gene-negative, systemically untreated squamous NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, paclitaxel injection, and carboplatin injection, wherein the dosage of the PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, administered once every 3 weeks, and the dosage of the paclitaxel injection is 175 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO:

14.

16. The method according to any one of claims 1-13, wherein the NSCLC is driver gene-negative, untreated non-squamous NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection, wherein the dose of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, administered once every 3 weeks, and the dose of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO:

14.

17. The method according to any one of claims 1-13, wherein the NSCLC is driver gene-negative, untreated non-squamous NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection, wherein the dose of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, administered once every 3 weeks, and the dose of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO:

14.

18. The method according to any one of claims 1-13, wherein the NSCLC is driver gene negative, PD-L1 expression TPS ≥ 1%, and untreated NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, wherein the dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, the frequency of administration of the anti-PD-1 and VEGF bispecific antibody liquid formulation is once every 3 weeks, and the heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is as shown in SEQ ID NO: 13, and the light chain amino acid sequence is as shown in SEQ ID NO:

14.

19. The method according to any one of claims 1-13, wherein the NSCLC is driver gene negative, PD-L1 expression TPS ≥ 1%, and untreated NSCLC, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, wherein the dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, the frequency of administration of the anti-PD-1 and VEGF bispecific antibody liquid formulation is once every 3 weeks, and the heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is as shown in SEQ ID NO: 13, and the light chain amino acid sequence is as shown in SEQ ID NO:

14.

20. The method according to any one of claims 1-13, wherein the NSCLC is non-squamous NSCLC with EGFR-sensitive mutations and following EGFR-TKI treatment, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection, wherein the dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, the frequency of administration of the anti-PD-1 and VEGF bispecific antibody liquid formulation is once every 3 weeks, and the dosage of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO:

14.

21. The method according to any one of claims 1-13, wherein the NSCLC is non-squamous NSCLC with EGFR-sensitive mutations and following EGFR-TKI treatment, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection, wherein the dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, the frequency of administration of the anti-PD-1 and VEGF bispecific antibody liquid formulation is once every 3 weeks, and the dosage of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO:

14.

22. The method according to any one of claims 1-13, wherein the NSCLC is non-squamous NSCLC with positive driver genes other than EGFR-sensitive mutations, following first-line TKI treatment, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection, wherein the dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 10 mg / kg, the frequency of administration of the anti-PD-1 and VEGF bispecific antibody liquid formulation is once every 3 weeks, and the dosage of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO:

14.

23. The method according to any one of claims 1-13, wherein the NSCLC is non-squamous NSCLC with positive driver genes other than EGFR-sensitive mutations, following first-line TKI treatment, the method comprising intravenously infusing an individual with a liquid formulation of an anti-PD-1 and VEGF bispecific antibody, pemetrexed disodium for injection, and carboplatin injection, wherein the dosage of the anti-PD-1 and VEGF bispecific antibody liquid formulation is 20 mg / kg, the frequency of administration of the anti-PD-1 and VEGF bispecific antibody liquid formulation is once every 3 weeks, and the dosage of the pemetrexed disodium for injection is 500 mg / kg. 2 The administration frequency is once every 3 weeks. The dosage of the carboplatin injection is AUC=5, and the administration frequency is once every 3 weeks, for a maximum of 4 cycles. The heavy chain amino acid sequence of the anti-PD-1 and VEGF bispecific antibody is shown in SEQ ID NO: 13, and the light chain amino acid sequence is shown in SEQ ID NO: 14.

Images