Methods of treating cancer

Abstract

Provided herein are methods for treating cancer, including pancreatic cancer, lung cancer, or breast cancer, comprising administering to a subject in need thereof a FAP-targeted radiotherapeutic as a monotherapy or in combination with one or more chemotherapeutic agents.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 627,853, filed February 1, 2024, and U.S. Provisional Patent Application No. 63 / 642,999, filed May 6, 2024. The contents of these applications are hereby incorporated by reference in their entirety. Technical Field

[0002] This application relates to the use of FAP-targeted radiotherapy agents (including in combination with chemotherapy) for the treatment of cancer. Background Technology

[0003] Fibroblast activating protein (FAP) is a cell surface protein highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers, while limited expression of FAP is observed in normal tissues. In some mesenchymal-derived cancers (particularly sarcomas and mesotheliomas), FAP expression is also observed on the tumor cells themselves. Given its limited expression profile, FAP is a promising target for radionuclide imaging and therapeutic agents in cancer therapy, particularly for solid tumors.

[0004] In particular, pancreatic cancer is difficult to treat due to the challenging tumor microenvironment that makes chemotherapy drug delivery difficult. The tumor microenvironment is rich in stromal cells with high FAP expression, and it has been proposed that pancreatic adenocarcinoma cells themselves can also express FAP. FAP has been involved in cancer progression, immunosuppression, and treatment resistance. Unfortunately, FAP expression in pancreatic ductal adenocarcinoma (PDAC) is also associated with poor survival, highlighting a significant need for more treatment options in this patient population (Cheng, Cs et al. (2022) Front. Oncol [Frontiers in Oncology]; 12:969731). Therefore, PDAC is a promising target for FAP-targeted therapy.

[0005] Lung cancer is the second most common cancer in both men and women and is a leading cause of cancer-related death worldwide (Thandra KC et al. (2021) Contemp Oncol (Pozn) [Contemporary Oncology (Pozn)]; 25 (1):45-52). These patients were diagnosed with advanced disease and had a 5-year survival rate of approximately 18% (Yanagawa N et al. (2022) Thorac Cancer [Breast Cancer]; 13:2377-2384).

[0006] NSCLC is known to have a tumor microenvironment (TME), in which the cancer cell artery (CAF) exhibits high FAP expression. In a recent study, 54.1% of patients with NSCLC (N = 126) were found to have high FAP expression, as defined by IHC staining intensity and the percentage of FAP-positive cells (Zhao Y et al. (2023) J Can Res Clin Onc [Journal of Cancer Research and Clinical Oncology];149:3469-3483). FAP expression on lung cancer cells and in the CAF of the tumor microenvironment has also been associated with poorer survival outcomes and lower response to immunotherapy (Yanagawa et al. 2022; Zhao et al. 2023).

[0007] FAP-expressing NSCLC tumors can also be easily identified by imaging. Using 68 PET scans using Ga-FAPI as a tracer show high uptake in primary lung tumors and metastases, allowing for visualization and measurement of FAP-expressing diseases (Borgonje PE et al. (2022) Cancers; 14:5566). NSCLC is also a promising target for FAP-targeted therapy.

[0008] Despite recent advances in NSCLC, there remains a high level of unmet need regarding this disease. Patients who progress on first-line chemoimmunotherapy have limited options, including docetaxel plus / - ramucirumab, pemetrexed, gemcitabine, or nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (National Comprehensive Cancer Network (NCCN) (2023). NCCNClinical Practice Guideline in Oncology. Non-Small Cell Lung Cancer [NCCN Clinical Practice Guideline for Oncology: Non-Small Cell Lung Cancer] 3.2023 version; National Comprehensive Cancer Network). Based on two studies, docetaxel has become the preferred 2-L option for patients with NSCLC (Shepherd FA et al. (2000) J Clin Oncol; 18:2095-2103; Fossella F et al. (2000) J Clin Oncol; 18:2354-2362; Weiss JM, Stinchcombe TE (2013) The Oncologist; 18:947-953). However, in both studies, the median OS was 7.5 months and 5.7 months, respectively, when docetaxel was administered as a 2L at 75 mg / m2 every 3 weeks (ORR 5.8%, mDOR 26.1 weeks (Shepherd FA et al. 2000); ORR 6.7%, mDOR 9.1 months (Fossella F et al. 2000)). Docetaxel is typically poorly tolerated and has significant toxicity (Weiss JM et al. 2013). New therapies are needed for patients who progress during first-line treatment in order to improve efficacy.

[0009] Breast cancer (BC) is the most frequently diagnosed malignancy and a leading cause of cancer-related death among women worldwide. Despite clinical advancements, BC mortality has increased over the past few decades, highlighting the urgent need for innovative treatments (Lukasiewicz S et al. (2021) Cancers; 13:4287).

[0010] Patients with BC can receive endocrine therapy in combination with cyclin-dependent kinase 4 and 6 inhibitors in the first line of treatment (1L), HER2-targeted therapy in HER2-positive disease if hormone receptor-positive, or cytotoxic therapy if hormone receptor-negative and HER2-negative. Beyond second- and third-line therapy, response rates and durability of treatment are limited regardless of subtype. In the Destiny-04 trial, participants with hormone receptor-positive disease who underwent a median of three prior lines of therapy had a median progression-free survival (PFS) of 5.4 months under physician-selective therapy (mOS 17.5 months, ORR 16.3%, and DOR 6.8 months) (Modi S et al. (2022) N Engl J Med [New England Journal of Medicine];387:9-20). In the TROPiCS-02 trial, in this ongoing cohort of hormone receptor-positive patients with a median of three prior lines of therapy, median PFS was 4.0 months, OS was 11.2 months, ORR was 14%, and mDOR was 5.6 months, depending on the physician's choice of therapy (Rugo HS et al. (2023) Lancet; 10411:1423-1433). Sacituzumab also showed a 4.8-month PFS in patients with relapsed / refractory hormone receptor-negative HER2-negative BC compared to the investigator's choice of cytotoxic chemotherapy (mOS 11.8 months, ORR 31%, mDOR 6.3 months, Bardia A et al. (2021) N Engl J Med; 384(16):1529-1541). Finally, in recent trials of patients with HER2-positive disease who have been deeply pretreated with anti-HER2 therapy, tucatinib showed a median PFS of 7.8 months compared to placebo (mOS of 21.9 months, ORR of 40.6%, Murthy RK et al. (2020) N Engl J Med [New England Journal of Medicine];382(7):597-609).

[0011] Breast cancer also exhibits a strong FAP signal. A review of available data on FAP in the BC literature shows the following evidence, compared with traditional […]. 18 Compared to FDG PET, FAP-based imaging can provide better diagnostic information (Zhao Y et al. (2023) J Can Res Clin Onc [Journal of Cancer Research and Clinical Oncology]; 149:3469-83). Furthermore, recent imaging trials have used IHC to […]. 68Ga]Ga-FAPi-46 PET uptake is associated with FAP tissue expression (Mona CE et al. (2022) J Nucl Med [Journal of Nuclear Medicine]; 63:1021-1026). Therefore, breast cancer is also a good target for FAP-targeted therapy.

[0012] In summary, the overexpression of FAP in both tumor cells and the surrounding stroma across multiple tumor types makes it a valuable target for targeted therapy. Utilizing RLT while targeting FAP represents a unique therapeutic opportunity for treating cancers such as PDAC, NSCLC, and BC, where there is a high demand for new treatment options that are both effective and safe. Summary of the Invention

[0013] This article provides methods for treating cancer, including the administration of FAP-targeted radiotherapy agents.

[0014] In one aspect, this article provides a method for treating FAP-expressing cancers (e.g., solid tumors) in subjects of need, the method comprising administering a FAP-targeted radiotherapy agent to the subjects of need, wherein the FAP-targeted radiotherapy agent is administered at a single daily dose approximately every four weeks ± three days or approximately every six weeks ± three days to achieve a cumulative dose of approximately 40 to approximately 60 GBq.

[0015] In one aspect, this article provides a method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject of need, comprising administering a therapeutically effective dose to the subject:

[0016] (a) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0017] (b) Chemotherapy, comprising at least one, two, three or four agents selected from 5-fluorouracil (5-FU), folate, irinotecan and oxaliplatin.

[0018] In one respect, this article provides a method for treating non-small cell lung cancer (NSCLC) in a subject of need, comprising administering a therapeutically effective dose to the subject:

[0019] (A) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0020] (B) Taxanes (e.g., paclitaxel, nanoparticle albumin-bound paclitaxel, or docetaxel).

[0021] In one respect, this article provides a method for treating non-small cell lung cancer (NSCLC) in a subject of need, comprising administering a therapeutically effective dose to the subject:

[0022] (A) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0023] (B) Nanoparticle albumin-bound paclitaxel.

[0024] In one aspect, this article provides a method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject of need, comprising administering a FAP-targeted radiotherapy agent to the subject of need, wherein the FAP-targeted radiotherapy agent is administered once every four weeks ± three days or every six weeks ± three days at a single daily dose to achieve a cumulative dose of about 40 to about 60 GBq.

[0025] On the other hand, this article provides a method for treating non-small cell lung cancer (NSCLC) in subjects in need, comprising administering a FAP-targeted radiotherapy agent to the subjects in need, wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

[0026] On the other hand, this article provides a method for treating breast cancer in a subject in need, the method comprising administering a FAP-targeted radiotherapy agent to the subject in need, wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq. Attached Figure Description

[0027] Figure 1 The scheme of the Phase 1 study described in Example 2 is shown.

[0028] Figure 2 The protocol for the Phase 2 monotherapy study described in Example 2 is presented.

[0029] Figure 3 The protocol for the phase 2 combination therapy study described in Example 2 is presented. Detailed Implementation

[0030] This article provides methods for treating cancer, including administering FAP-targeted radiotherapy agents to subjects in need.

[0031] FAP targeted radiopharmaceuticals

[0032] As used herein, “FAP-targeted” means that a compound exhibits an affinity for fibroblast activating protein (FAP). Techniques for measuring FAP affinity for FAP are known in the art and readily available to those skilled in the art to identify compounds as having an affinity for FAP. For example, the dissociation constant (Ki) of certain FAP-targeting radiopharmaceuticals disclosed herein... D The surface plasmon resonance assay can be measured according to the following literature: WO 2021 / 005125 A1 and US Publication No. 2022 / 0273831 A1 or Zboralski et al. (Eur. J. Nuc. Med. [European Journal of Nuclear Medicine], 2022, 49:3651-3667), each of which is incorporated herein by reference in its entirety.

[0033] In some embodiments, the FAP-targeting radiopharmaceuticals disclosed herein exhibit a dissociation constant (K0.05) for human FAP of approximately 100 nM or lower. D ), as measured by surface plasmon resonance assays disclosed in the following literature: WO 2021 / 005125 A1 and US Publication No. 2022 / 0273831 A1 or Zboralski et al. (Eur. J. Nuc. Med. [European Journal of Nuclear Medicine], 2022, 49:3651-3667).

[0034] In some embodiments, the FAP-targeting radiopharmaceuticals disclosed herein exhibit a dissociation constant (K0) for human FAP of approximately 10 nM or lower. D ), as measured by surface plasmon resonance assays disclosed in the following literature: WO 2021 / 005125 A1 and US Publication No. 2022 / 0273831 A1 or Zboralski et al. (Eur. J. Nuc. Med. [European Journal of Nuclear Medicine], 2022, 49:3651-3667).

[0035] In some embodiments, the FAP-targeting radiopharmaceuticals disclosed herein exhibit a dissociation constant (K0) of approximately 5 nM or lower for human FAP. D ), as measured by surface plasmon resonance assays disclosed in the following literature: WO 2021 / 005125 A1 and US Publication No. 2022 / 0273831 A1 or Zboralski et al. (Eur. J. Nuc. Med. [European Journal of Nuclear Medicine], 2022, 49:3651-3667).

[0036] Consider that the FAP-targeting radiopharmaceuticals used in the methods disclosed herein may also exhibit selectivity (or limited off-target activity) for FAP relative to, for example, DPP4 and / or PREP (see the methods disclosed for FAP-2286 by Zboralski et al. (Eur. J. Nuc. Med. [European Journal of Nuclear Medicine], 2022, 49:3651-3667)).

[0037] FAP-targeting radiopharmaceuticals are known. Such FAP-targeting radiopharmaceuticals comprise at least one FAP-targeting portion and a radionuclide. FAP-targeting radiopharmaceuticals may further comprise one or more chelating agents. FAP-targeting radiopharmaceuticals may further comprise one or more connectors that, for example, link at least one FAP-targeting portion to a radionuclide or a chelating agent (if present).

[0038] In this embodiment, the FAP-targeted radiopharmaceutical comprises:

[0039] i) FAP target portion; and

[0040] ii) At least one radionuclide or at least one chelating agent labeled with a radionuclide,

[0041] The FAP targeting portion is conjugated to at least one radionuclide or at least one chelating agent labeled with a radionuclide via a bond or a connector.

[0042] In some embodiments, the radiopharmaceutical has the following structure:

[0043] ,

[0044] Or its pharmaceutically acceptable salts or solvates,

[0045] Where F is the FAP target portion; M is a radionuclide or a chelating agent labeled with a radionuclide; L 1 It is a connector suitable for forming chemical bonds between P and M; and n is 0 or 1.

[0046] In some embodiments, M is a DOTA (2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl)tetraacetic acid) residue or a derivative thereof labeled with a radionuclide.

[0047] In some embodiments, M is

[0048] It is labeled with a radioactive nuclide.

[0049] When a chelating agent is labeled with a radionuclide and chelates or complexes with a radionuclide, the chelating agent can be said to be radiolabeled.

[0050] FAP-targeted radiopharmaceuticals (radiotherapy agents and radioimaging agents) that may be used in the methods disclosed herein include those disclosed and characterized in the following publications: WO 2021 / 005125 and U.S. Publication No. 2022 / 0273831; WO 2021 / 005131 and U.S. Publication No. 2022 / 0315554; WO 2022 / 148851; and WO 2022 / 148843, each of which is incorporated herein by reference in its entirety. FAP-targeted radiopharmaceuticals (radiotherapy agents and radioimaging agents) that may be used in the methods disclosed herein include those disclosed and characterized in the following publications: WO 2021 / 195198 and U.S. Publication No. 2022 / 0370647, each of which is incorporated herein by reference in its entirety.

[0051] FAP targeted radiotherapy agent

[0052] In some embodiments, the FAP-targeted radiotherapy agent has the following structure:

[0053] ,

[0054] Or its pharmaceutically acceptable salts or solvates,

[0055] Where F is the FAP target fraction; M is the therapeutic radionuclide or a chelating agent labeled with a therapeutic radionuclide; L 1 It is a linker suitable for forming chemical bonds between F and M; and n is 0 or 1.

[0056] In some embodiments, the therapeutic radionuclide is selected from... 47 Sc、 67 Cu、 90 Y、 131 I, 153 Sm、 161 Tb, 169 Er or 177 Lu. In some embodiments, the therapeutic radionuclide is 177 Lu.

[0057] In some embodiments, M comprises DOTA (2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) or a DOTA residue or a derivative thereof labeled with a therapeutic radionuclide.

[0058] In some embodiments, M is

[0059] It is labeled with therapeutic radionuclides.

[0060] In some embodiments, M is

[0061] .

[0062] In any embodiment of the method disclosed herein, the FAP-targeted radiotherapy agent is compound (I):

[0063] (I), or a pharmaceutically acceptable salt or solvate thereof, which uses a therapeutic radionuclide, for example 177 Lu tag.

[0064] Compound (I) can also be called FAP-2286. When used... 177 When labeled with Lu, compound (I) can also be called [ 177 Lu]Lu-FAP-2286.

[0065] In some embodiments of any of the methods disclosed herein, the FAP-targeted radiotherapy agent is or its pharmaceutically acceptable salts or solvates (i.e. [ 177 Lu]Lu-FAP-2286 or a pharmaceutically acceptable salt or solvate thereof.

[0066] In some embodiments of any of the methods disclosed herein, the FAP-targeted radiotherapy agent is .

[0067] In some embodiments, when radiolabeled with a therapeutic radionuclide, the FAP-targeted radiotherapy agent is selected from any of the following: PNT6555, CAM-FAP (e.g., [ 225 Ac]Ac-CAM-FAP or [ 131 I]I-CAM-FAP), OncoFAP, 3BP-3940, RPS-309, NM-05, and FAP-46. In some embodiments, the therapeutic radionuclide is 177 Lu.

[0068] In any embodiment of the method disclosed herein, the FAP-targeted radiotherapy agent is compound (II):

[0069] (II), or a pharmaceutically acceptable salt or solvate thereof, which uses a therapeutic radionuclide, for example 177 Lu is used for radioactive labeling.

[0070] Compound (II), also known as PNT6555, is disclosed in WO 2021 / 195198. When used...177 When Lu is radiolabeled, compound (II) can be called [ 177 Lu]-PNT6555 (see Bodei, L. et al., JCO [Journal of Clinical Oncology] 41, TPS3161(2023)). 177 Lu]-PNT6555 was also disclosed in Poplawski et al. (J. Nucl. Med [Journal of Nuclear Medicine] 2024; 65:100-108).

[0071] In some embodiments, FAP-targeted radiotherapy agents are 177 Lu-OncoFAP-DOTAGA (Philogen).

[0072] FAP Targeted Radiographic Imaging Agent

[0073] In some embodiments, the FAP-targeted radioimaging agent has the following structure:

[0074] ,

[0075] Or its pharmaceutically acceptable salts or solvates,

[0076] Where F is the FAP target region; M is a diagnostic radionuclide or a chelating agent labeled with a diagnostic radionuclide; L 1 It is a linker suitable for forming chemical bonds between F and M; and n is 0 or 1.

[0077] In some embodiments, the diagnostic radionuclide is selected from... 68 Ga、 64 Cu and 18 F.

[0078] In some embodiments, M comprises components suitable for chelating Al 18 The chelating agent of F, such as NOA (where NOA is 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid).

[0079] In some embodiments, M comprises DOTA (2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) or a DOTA residue or a derivative thereof labeled with a diagnostic radionuclide.

[0080] In some embodiments, M is

[0081] It is labeled with diagnostic radionuclides.

[0082] In some embodiments, M is

[0083] .

[0084] FAP-targeted radioimaging agents that can be used in the methods disclosed herein include those disclosed in WO 2021 / 005125A1 and U.S. Publication No. 2022 / 0273831 A1.

[0085] In any embodiment of the method disclosed herein, the FAP-targeted radioimaging agent is compound (I):

[0086] (I), or its pharmaceutically acceptable salts or solvates, for use 68 Ga is used for radioactive labeling.

[0087] When compound (I) is used 68 When Ga is used for radioactive labeling, it can also be called [ 68 Ga]Ga-FAP-2286.

[0088] In some embodiments of any of the methods disclosed herein, the FAP-targeted radiographic imaging agent is:

[0089] Or, or a pharmaceutically acceptable salt or solvate thereof.

[0090] In some embodiments of any of the methods disclosed herein, the FAP-targeted radiographic imaging agent is:

[0091] .

[0092] In some embodiments, the FAP targeted radiographic imaging agent is selected from... 18 F-FAPI-74, [ 68 Ga]Ga-FAPI-46, FL-L3- 99m Tc, [ 68 Ga]Ga-MHLL1、[ 68 Ga]Ga-DOTA.SA.FAPi、[ 68 Ga]Ga-RPS-309, [ 68 Ga]Ga-FAPI-02、[ 68 Ga]Ga-FAPI-04、[ 68 Ga]Ga-FAPI-21, 99m TcFAPI-34, [ 18 F]FGlc-FAPI, [ 18 F]AlF NOTA-FAPI-04、[ 68Ga]Ga-PNT6555, radiolabeled CAM-FAP, [ 68 Ga]Ga-OncoFAP or [ 68 Ga]Ga-OncoFAP-DOTAGA (Filogen Corporation), [ 68 Ga]Ga-3BP-3940, 68 Ga-RPS-309 and 64 Cu-RTX-1363S. In some embodiments, the FAP targeted radiographic imaging agent is [ 68 Ga]Ga-FAPI-46.

[0093] In any embodiment of the method disclosed herein, the FAP-targeted radioimaging agent is compound (II):

[0094] (II), or a pharmaceutically acceptable salt or solvate thereof, which is indicated by a diagnostic radionuclide, for example... 68 Ga marker.

[0095] Methods for treating cancer

[0096] This article discloses methods for treating cancer, including the administration of FAP-targeted radiotherapy agents. The methods disclosed herein offer greater efficacy against cancer than current standard of care treatments and have an acceptable safety profile.

[0097] As used herein, “treating” or “treatment” is a means of obtaining a beneficial or desired outcome (i.e., clinical outcome) in a subject. These outcomes may include one or more of the following: (a) reducing the severity of the disease, stabilizing the disease; (b) reducing or alleviating symptoms caused by the disease; (c) preventing or delaying the spread of the disease (e.g., preventing or delaying metastasis); (d) preventing or delaying the recurrence of the disease; (e) improving the disease status, providing remission of the disease (partial or complete), reducing the dosage of one or more other therapeutic agents used to treat the subject's disease; (f) improving the subject's quality of life; and / or (g) prolonging survival, whether it be overall survival or progression-free survival.

[0098] In various embodiments, the methods described herein relate to treating cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer or solid tumor expresses FAP (i.e., the cancer is a cancer that expresses FAP). In some embodiments, the cancer is a solid tumor selected from: appendix, breast, colorectal, connective tissue proliferative small round cell tumor, gallbladder, head and neck, lung, peritoneal mesothelioma, pancreas, prostate, rectum, solitary fibrous tumor, sarcoma (such as soft tissue sarcoma), and uterine / endometrial (particularly uterine leiomyosarcoma) solid tumors. In some embodiments, the solid tumor is selected from breast, colorectal, head and neck, lung, and pancreatic solid tumors. In some embodiments, the cancer is pancreatic cancer, lung cancer, or breast cancer. In a particular embodiment, the cancer is pancreatic ductal adenocarcinoma (PDAC). In another particular embodiment, the cancer is non-small cell lung cancer (NSCLC). In yet another particular embodiment, the cancer is breast cancer (BC).

[0099] solid tumors

[0100] In one aspect, this article provides a method for treating cancer in a subject in need, the method comprising administering a FAP-targeted radiotherapy agent to the subject, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every 28 ± 3 days to achieve a cumulative dose of approximately 40 to approximately 60 GBq, wherein the cancer is a solid tumor expressing FAP.

[0101] On the other hand, this article provides a method for treating cancer in a subject in need, the method comprising administering a FAP-targeted radiotherapy agent to the subject, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every 28 ± 3 days to achieve a cumulative dose of about 40 to about 60 GBq, wherein the cancer is a solid tumor expressing FAP and wherein the single dose is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq or about 9.3 GBq.

[0102] In one respect, this article provides a method for treating cancer in a subject in need, the method comprising administering to the subject a substance containing... 177 Lu's FAP-targeted radiotherapy agent, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every 28 ± 3 days to achieve a cumulative dose of approximately 40 to approximately 60 GBq, wherein the cancer is a solid tumor expressing FAP.

[0103] On the other hand, this article provides a method for treating cancer in a subject in need, the method comprising administering to the subject a substance containing... 177Lu's FAP-targeted radiotherapy agent, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every 28 ± 3 days to achieve a cumulative dose of approximately 40 to approximately 60 GBq, wherein the cancer is a solid tumor expressing FAP and wherein the single dose is approximately 3.7 GBq, approximately 5.6 GBq, approximately 7.4 GBq or approximately 9.3 GBq.

[0104] In one respect, this article provides a method for treating cancer in a subject in need, the method comprising administering to the subject a FAP-targeted radiotherapy agent, the FAP-targeted radiotherapy agent being...

[0105] or a pharmaceutically acceptable salt or solvate thereof, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every 28 ± 3 days to achieve a cumulative dose of approximately 40 to approximately 60 GBq, wherein the cancer is a solid tumor expressing FAP.

[0106] On the other hand, this article provides a method for treating cancer in a subject in need, the method comprising administering a FAP-targeted radiotherapy agent to the subject, the FAP-targeted radiotherapy agent being...

[0107] or a pharmaceutically acceptable salt or solvate thereof, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every 28 ± 3 days to achieve a cumulative dose of about 40 to about 60 GBq, wherein the cancer is a solid tumor expressing FAP and wherein the single dose is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq or about 9.3 GBq.

[0108] In this embodiment, the single dose of the FAP-targeted radiotherapy agent is approximately 9.3 GBq.

[0109] In this embodiment, the cumulative dose of the FAP-targeted radiotherapy agent is approximately 55.5 GBq.

[0110] In some embodiments, the method disclosed herein further includes administering a therapeutically effective amount of chemotherapy to the subject.

[0111] In some embodiments, the chemotherapy includes taxane. In some embodiments, taxane is paclitaxel, nanoparticle albumin-bound paclitaxel, docetaxel, or cabazitaxel.

[0112] In some embodiments, the chemotherapy includes nanoparticle albumin-bound paclitaxel, FOLFIRINOX, mFOLFIRINOX, or NALIRIFOX.

[0113] In some embodiments, the chemotherapy includes nanoparticle albumin-bound paclitaxel, FOLFIRINOX, or mFOLFIRINOX.

[0114] In some embodiments, the solid tumor is selected from solid tumors of the appendix, breast, colorectal region, connective tissue proliferative small round cell tumors, gallbladder, head and neck, lung, peritoneal mesothelioma, pancreas, prostate, rectum, solitary fibrous tumors, sarcomas (e.g., soft tissue sarcomas), and uterine / endometrial solid tumors (particularly uterine leiomyosarcoma). In some embodiments, the solid tumor is selected from solid tumors of the breast, colorectal region, head and neck, lung, and pancreas.

[0115] In one aspect, this article provides a FAP-targeted radiotherapy agent for use in the treatment of FAP-expressing solid tumors (i.e., for use in any of the methods disclosed herein for the treatment of FAP-expressing solid tumors), wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of about 40 GBq to about 60 GBq.

[0116] pancreatic cancer

[0117] This article provides methods for treating pancreatic cancer, including the administration of FAP-targeted radiotherapy agents to subjects in need. In cases of significant FAP expression in PDAC, this is an excellent therapeutic target for novel therapies. FAP-targeted radiotherapy agents (e.g., like, […]) 177 [Lu]Lu-FAP-2286) allows for the direct delivery of targeted radiation to the tumor bed. Through FAP expression on the CAF, FAP-targeted radiotherapy agents (e.g., [Lu-FAP-2286) can be used. 177 [Lu-FAP-2286] can cause destruction of the tumor stroma via direct radiation damage. Furthermore, tumor cells near FAP-positive target cells may also die due to the radiation effect, which causes DNA damage leading to cell death. Therefore, administering FAP-targeted radiotherapy agents (e.g., like, [Lu-FAP-2286] alone and at an appropriate dose is recommended. 177 Lu]Lu-FAP-2286 can lead to improved tumor control.

[0118] Monotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC)

[0119] This article provides a method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject of need, comprising administering a FAP-targeted radiotherapy agent to the subject of need, wherein the FAP-targeted radiotherapy agent is administered as a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of approximately 40 to approximately 60 GBq.

[0120] In this embodiment, the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days.

[0121] In this embodiment, the single dose of the FAP-targeted radiotherapy agent is from about 3 GBq to about 10 GBq.

[0122] In the embodiments, the single dose of the FAP targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0123] In this embodiment, the single dose of the FAP-targeted radiotherapy agent is approximately 9.3 GBq.

[0124] In this embodiment, the cumulative dose of the FAP-targeted radiotherapy agent is approximately 55.5 GBq.

[0125] In some embodiments, the FAP targeted radiotherapy agent comprises 47 Sc、 67 Cu、 90 Y、 131 I, 153 Sm、 161 Tb, 169 Er or 177 Lu.

[0126] In an embodiment, the FAP-targeted radiotherapy agent comprises 177 Lu.

[0127] In this embodiment, the FAP-targeted radiotherapy agent is Or, or a pharmaceutically acceptable salt or solvate thereof.

[0128] In this embodiment, the FAP-targeted radiotherapy agent is .

[0129] In this embodiment, the PDAC expresses FAP.

[0130] In this embodiment, the PDAC is transferable.

[0131] In this embodiment, the PDAC is not an endocrine tumor or a neuroendocrine tumor.

[0132] In this embodiment, the subject has received at least one prior therapy for treating PDAC, wherein each of the at least one prior therapy is not a therapy that includes a fibroblast activating protein (FAP)-targeting radiotherapy agent.

[0133] In this example, the subject had progressed after at least one, but no more than two, prior chemotherapy regimens for locally advanced unresectable or metastatic PDAC.

[0134] In this embodiment, the subject had received at least two prior therapies for treating PDAC, each of which was not a therapy that included a fibroblast activator protein (FAP)-targeting radiotherapy agent.

[0135] In one aspect, this article provides a FAP-targeted radiotherapy agent for use in the treatment of pancreatic ductal adenocarcinoma (PDAC) (i.e., for use in any of the methods of treating PDAC disclosed herein), wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

[0136] In one aspect, this article provides a FAP-targeted radiotherapy agent for use in the treatment of pancreatic ductal adenocarcinoma (PDAC) (i.e., for use in any of the methods of treating PDAC disclosed herein), wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq, and wherein a single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0137] Combination therapy for the treatment of pancreatic ductal adenocarcinoma (PDAC)

[0138] In addition, by administering FAP-targeted radiotherapy agents (e.g., [ 177 [Lu]Lu-FAP-2286) directly targets the tumor microenvironment, potentially improving chemotherapy delivery to tumor cells and leading to additional cytotoxic destruction. By combining chemotherapy with FAP-targeted radiotherapy agents (e.g., [Lu-FAP-2286]... 177 The combination of Lu]Lu-FAP-2286 may enable a multimodal approach to tumor destruction.

[0139] Therefore, chemotherapy combined with FAP-targeted radiotherapy agents (e.g., [ 177 When administered together with Lu-FAP-2286, it can show efficacy exceeding and surpassing the improvement of each treatment as a single therapy.

[0140] FOLFIRINOX is a commonly used first-line treatment for metastatic PDAC in participants with good performance status (Conroy T et al. (2011) The New England Journal of Medicine; 364(19):1817-1825). mFOLFIRINOX was developed to reduce the incidence and severity of cytopenia and GI toxicity. In studies of participants with local and metastatic PDAC, mFOLFIRINOX has shown a more favorable safety profile without compromising efficacy (Mahaseth H et al. (2013) Pancreas; 42(8):1311-1315). Further studies have shown an improved safety profile with the use of mFOLFIRINOX (Stein SM et al. (2016) BrJ Cancer; 114(7):737-743). Therefore, in participants with 1L PDAC, mFOLFIRINOX every two weeks could be FAP-targeted radiotherapy every 4 weeks (28 days) (e.g., [ 177 [Lu]Lu-FAP-2286) is a suitable partner chemotherapy. Other variants of FOLFIRINOX (such as NALIRIFOX) can also be FAP-targeted radiotherapy agents (e.g., [ 177 Suitable pairing chemotherapy for Lu-FAP-2286 (see, for example, Wainberg Z et al. (2023) Lancet [The Lancet]; 402: 1272-1281).

[0141] In patients with PDAC, FAP-targeted radiotherapy agents (e.g., […]) are combined with mFOLFIRINOX (or its variants, such as NALIRIFOX). 177 Lu-FAP-2286 can further demonstrate improved tumor response compared to chemotherapy alone. FAP-targeted radiotherapy agents can induce direct cell death of FAP-positive cells and surrounding cells in the tumor microenvironment through a "cross-fire" radiation effect. Furthermore, modulation of the tumor microenvironment can improve the delivery of cytotoxic drugs to tumor cells, thus creating a synergistic effect with cytotoxic chemotherapy. Finally, 5-FU-based chemotherapy can sensitize tumors to radiation effects. Therefore, FAP-targeted radiotherapy agents combined with mFOLFIRINOX (e.g., […]) can enhance tumor response. 177Lu-FAP-2286 is a promising combination approach for tumor destruction. mFOLIRINOX comprises (modified) leucovorin calcium (leucovorin), fluorouracil, irinotecan, and oxaliplatin. NALIRIFOX comprises liposomal irinotecan, oxaliplatin, 5-fluorouracil, and leucovorin.

[0142] Therefore, in one respect, this article provides a method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject of need, the method comprising administering a therapeutically effective dose to the subject:

[0143] (a) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0144] (b) Chemotherapy comprising one, two, three, or four agents selected from 5-fluorouracil (5-FU), folate, irinotecan, and oxaliplatin. Any agent in part (b) may be in the form of a pharmaceutically acceptable salt. For example, a description of folate includes its pharmaceutically acceptable salt, such as calcium folate. When an amount of an agent is specified, that amount corresponds to the active agent in its free acid or base form.

[0145] In some embodiments, the FAP targeted radiotherapy agent comprises 47 Sc、 67 Cu、 90 Y、 131 I, 153 Sm、 161 Tb, 169 Er or 177 Lu.

[0146] In some embodiments, the FAP targeted radiotherapy agent comprises 177 Lu.

[0147] In some embodiments, the FAP-targeted radiotherapy agent is [ 177 Lu]Lu-FAP-2286 or its pharmaceutically acceptable salts or solvates.

[0148] In some embodiments, the FAP-targeted radiotherapy agent is [ 177 Lu]Lu-FAP-2286.

[0149] In some embodiments, the chemotherapy includes 5-FU, formyltetrahydrofolate, and irinotecan.

[0150] In some embodiments, the chemotherapy includes 5-FU, formyltetrahydrofolate, and oxaliplatin.

[0151] In some embodiments, the chemotherapy includes 5-FU, leucovorin, irinotecan, and oxaliplatin. In some embodiments, the chemotherapy includes 5-FU, calcium leucovorin, irinotecan, and oxaliplatin.

[0152] In some embodiments, the chemotherapy includes liposomal irinotecan.

[0153] In some embodiments, the subject is given chemotherapy prior to the administration of the FAP-targeted radiotherapy agent.

[0154] In some embodiments, the subject is given chemotherapy in one to two cycles prior to the administration of the FAP-targeted radiotherapy agent.

[0155] In some embodiments, the chemotherapy is administered on a 14-day cycle.

[0156] In some embodiments, the chemotherapy is administered in 14-day cycles, wherein:

[0157] i. Administer oxaliplatin on the first day of the 14-day cycle;

[0158] ii. Administer formyltetrahydrofolate on the first day of the 14-day cycle;

[0159] iii. Irinotecan is administered on the first day of the 14-day cycle; and

[0160] iv. Administer 5-fluorouracil on the first and second days of the 14-day cycle (e.g., the 5-FU is administered via continuous intravenous infusion over 46 hours).

[0161] In some embodiments, oxaliplatin is administered at a dose of approximately 60 mg / m². 2 Approximately 100 mg / m 2 The dosage is administered intravenously.

[0162] In some embodiments, oxaliplatin is administered at approximately 85 mg / m². 2 The dosage is administered intravenously.

[0163] In some embodiments, formyltetrahydrofolate is administered at a concentration of about 50 mg / m³. 2 Approximately 500 mg / m 2 The dosage is administered intravenously.

[0164] In some embodiments, formyltetrahydrofolate is administered at a concentration of about 300 mg / m³. 2 Approximately 500 mg / m 2 The dosage is administered intravenously.

[0165] In some embodiments, formyltetrahydrofolate is administered at approximately 400 mg / m². 2The dosage is administered intravenously.

[0166] In some embodiments, irinotecan is administered at a dose of approximately 100 mg / m². 2 Approximately 200 mg / m 2 The dosage is administered intravenously.

[0167] In some embodiments, irinotecan is administered at approximately 150 mg / m². 2 The dosage is administered intravenously.

[0168] In some embodiments, 5-fluorouracil is administered at a concentration from about 1000 mg / m². 2 Approximately 3000 mg / m 2 The dosage is administered intravenously.

[0169] In some embodiments, 5-fluorouracil is administered at approximately 2400 mg / m². 2 The dosage is administered intravenously.

[0170] In some embodiments, the FAP-targeted radiotherapy agent is administered intravenously as a single dose every three weeks ± three days, every four weeks ± three days, every five weeks ± three days, or every six weeks ± three days.

[0171] In some embodiments, the FAP-targeted radiotherapy agent is administered intravenously in a single dose every four weeks ± three days.

[0172] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is from about 3 GBq to about 10 GBq.

[0173] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0174] In some embodiments, the FAP-targeted radiotherapy agent is administered to the subject in a single dose every four weeks ± three days for a period of time to achieve a cumulative dose of approximately 55.5 GBq.

[0175] In some embodiments, the FAP-targeted radiotherapy agent is administered on any one of the first, second, third, fourth, or fifth days of each 14-day chemotherapy cycle.

[0176] In some embodiments, the PDAC expresses FAP.

[0177] In some embodiments, the PDAC is transferable.

[0178] In this embodiment, the PDAC is not an endocrine tumor or a neuroendocrine tumor.

[0179] In some embodiments, the subject has not received any prior systemic therapy for metastatic PDAC (i.e., the method is 1L therapy for metastatic PDAC or the method is used for subjects newly diagnosed with metastatic PDAC).

[0180] On the other hand, this article provides a drug combination comprising a therapeutically effective amount of:

[0181] (a) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0182] (b) Chemotherapy, comprising at least one, two, three or four agents selected from 5-fluorouracil (5-FU), folate, irinotecan and oxaliplatin;

[0183] This drug combination is intended for use in any of the methods disclosed herein for the treatment of pancreatic ductal adenocarcinoma (PDAC).

[0184] On the other hand, this article provides fibroblast activating protein (FAP) targeted radiotherapy agents for use in the treatment of pancreatic ductal adenocarcinoma (PDAC) (i.e., for use in any of the methods disclosed herein), wherein the treatment further comprises administration of chemotherapy comprising at least one, two, three or four agents selected from 5-fluorouracil (5-FU), folate, irinotecan and oxaliplatin.

[0185] On the other hand, this article provides for use in the treatment of pancreatic ductal adenocarcinoma (PDAC) (i.e., for use in any of the methods disclosed herein), the chemotherapy comprising at least one, two, three or four agents selected from 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin, wherein the treatment further comprises administration of a fibroblast activating protein (FAP) targeted radiotherapy agent.

[0186] Non-small cell lung cancer (NSCLC)

[0187] This article provides methods for treating non-small cell lung cancer, which include administering FAP-targeted radiotherapy agents to subjects in need.

[0188] Monotherapy for the treatment of non-small cell lung cancer (NSCLC)

[0189] This article provides a method for treating non-small cell lung cancer (NSCLC) in a subject in need, comprising administering a FAP-targeted radiotherapy agent to the subject in need, wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of approximately 40 to approximately 60 GBq.

[0190] In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose every four weeks ± three days.

[0191] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is from about 3 GBq to about 10 GBq.

[0192] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0193] In some embodiments, a single dose of the FAP-targeted radiotherapy agent is approximately 9.3 GBq.

[0194] In some embodiments, the cumulative dose of the FAP-targeted radiotherapy agent is approximately 55.5 GBq.

[0195] In some embodiments, the FAP targeted radiotherapy agent comprises 47 Sc、 67 Cu、 90 Y、 131 I, 153 Sm、 161 Tb, 169 Er or 177 Lu.

[0196] In some embodiments, the FAP targeted radiotherapy agent comprises 177 Lu.

[0197] In some embodiments, the FAP-targeted radiotherapy agent is Or, or a pharmaceutically acceptable salt or solvate thereof.

[0198] In some embodiments, the FAP-targeted radiotherapy agent is .

[0199] In some embodiments, the NSCLC expresses FAP.

[0200] In some embodiments, the NSCLC is transferable.

[0201] In some embodiments, the NSCLC is characterized as adenocarcinoma or squamous cell carcinoma.

[0202] In some embodiments, the NSCLC is not characterized as an endocrine carcinoma, neuroendocrine carcinoma, or small cell carcinoma.

[0203] In some embodiments, the subject has received at least one prior therapy for the treatment of NSCLC, wherein each of the at least one prior therapy is not a therapy that includes a fibroblast activating protein (FAP)-targeting radiotherapy agent.

[0204] In some embodiments, the subject has received at least two prior therapies for the treatment of NSCLC, wherein each of the two prior therapies is not a therapy that includes a fibroblast activator protein (FAP)-targeting radiotherapy agent.

[0205] In this example, the subject had progressed after at least one, but no more than two, prior chemotherapy and / or immunotherapy regimens for the treatment of NSCLC.

[0206] In this example, the subject had previously received adjuvant or neoadjuvant platinum doublet chemotherapy and a previous immune checkpoint inhibitor regimen.

[0207] In this embodiment, the subject had received prior treatment including adjuvant or neoadjuvant platinum-based chemotherapy and an immune checkpoint inhibitor regimen, and had developed recurrent or metastatic disease during or within 12 months of the prior treatment including adjuvant or neoadjuvant platinum-based chemotherapy and an immune checkpoint inhibitor.

[0208] In one example, the subject developed recurrent NSCLC more than 12 months after prior adjuvant or neoadjuvant platinum-based chemotherapy, and the subject subsequently progressed during or after prior platinum doublet regimens and prior immune checkpoint inhibitor regimens.

[0209] In this embodiment, the subject had progressed after receiving prior platinum-based chemotherapy and a prior immune checkpoint inhibitor regimen for advanced or metastatic NSCLC; wherein the prior platinum-based chemotherapy and the prior immune checkpoint inhibitor regimen were administered in parallel (together, in the same treatment line) or sequentially (in two different treatment lines).

[0210] In one aspect, this article provides a FAP-targeted radiotherapy agent for use in the treatment of non-small cell lung cancer (NSCLC) (i.e., for use in any of the methods of treating NSCLC disclosed herein), wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

[0211] In one aspect, this article provides a FAP-targeted radiotherapy agent for use in treating non-small cell lung cancer (NSCLC) in subjects in need (i.e., for use in any of the methods of treating NSCLC disclosed herein), wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq, and wherein a single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0212] Combination therapy for the treatment of non-small cell lung cancer

[0213] In one respect, this article provides a method for treating non-small cell lung cancer (NSCLC) in a subject of need, comprising administering a therapeutically effective dose to the subject:

[0214] (A) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0215] (B) Taxane.

[0216] In some embodiments, taxane is paclitaxel, nanoparticle albumin-bound paclitaxel, or docetaxel.

[0217] In one respect, this article provides a method for treating non-small cell lung cancer (NSCLC) in a subject of need, comprising administering a therapeutically effective dose to the subject:

[0218] (A) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0219] (B) Nanoparticle albumin-bound paclitaxel.

[0220] In some embodiments, the FAP targeted radiotherapy agent comprises 47 Sc、 67 Cu、 90 Y、 131 I, 153 Sm、 161 Tb, 169 Er or 177 Lu.

[0221] In some embodiments, the FAP targeted radiotherapy agent comprises 177 Lu.

[0222] In some embodiments, the FAP-targeted radiotherapy agent is Or, or a pharmaceutically acceptable salt or solvate thereof.

[0223] In some embodiments, the FAP-targeted radiotherapy agent is

[0224] In some embodiments, the subject has previously received at least one prior therapy for the treatment of NSCLC, wherein each of the at least one prior therapy is not a therapy that includes a fibroblast activating protein (FAP)-targeting radiotherapy agent.

[0225] In some embodiments, the subject has previously received at least two prior therapies for the treatment of NSCLC, wherein each of these prior therapies is not a therapy that includes a fibroblast activator protein (FAP)-targeting radiotherapy agent.

[0226] In this example, the subject had progressed after at least one, but no more than two, prior systemic regimens for the treatment of NSCLC.

[0227] In this example, the subject had progressed after at least one, but no more than two, prior chemotherapy and / or immunotherapy regimens for the treatment of NSCLC.

[0228] In this example, the subject had previously received adjuvant or neoadjuvant platinum doublet chemotherapy and an immune checkpoint inhibitor.

[0229] In this embodiment, the subject had received prior treatment including adjuvant or neoadjuvant platinum-based chemotherapy and an immune checkpoint inhibitor, and had developed recurrent or metastatic disease during or within 12 months of the prior treatment including adjuvant or neoadjuvant platinum-based chemotherapy and an immune checkpoint inhibitor.

[0230] In one example, the subject developed recurrent NSCLC more than 12 months after prior adjuvant or neoadjuvant platinum-based chemotherapy, and the subject subsequently progressed during or after a prior platinum doublet regimen and immune checkpoint inhibitor.

[0231] In one example, the subject had progressed after receiving prior platinum-based chemotherapy and an immune checkpoint inhibitor for advanced or metastatic NSCLC; wherein the prior platinum-based chemotherapy and the immune checkpoint inhibitor were administered in parallel (together, in the same line of treatment) or sequentially (in two different lines of treatment).

[0232] In this example, the subject had not received any prior taxane therapy (i.e., previous taxane regimens) as a single therapy or in combination.

[0233] In some embodiments, the nanoparticle albumin-bound paclitaxel is administered to the subject prior to the administration of the FAP-targeted radiotherapy agent.

[0234] In some embodiments, the nanoparticle albumin-bound paclitaxel is administered to the subject over one to two cycles prior to the administration of the FAP-targeted radiotherapy agent.

[0235] In some embodiments, the nanoparticle albumin-bound paclitaxel is administered once during a seven-day cycle.

[0236] In some embodiments, the nanoparticle albumin-bound paclitaxel is administered on the first day of a seven-day cycle (i.e., the nanoparticle albumin-bound paclitaxel is administered once a week or weekly).

[0237] In some embodiments, the albumin-bound paclitaxel nanoparticles are used at a concentration of approximately 50 mg / m³. 2 Approximately 150 mg / m 2 The dosage is administered intravenously.

[0238] In some embodiments, the albumin-bound paclitaxel nanoparticles are used at approximately 100 mg / m³ 2 The dosage is administered intravenously.

[0239] In some embodiments, the FAP-targeted radiotherapy agent is administered on any one of the first, second, third, fourth, or fifth days of the seven-day cycle of the nanoparticle albumin-bound paclitaxel.

[0240] In some embodiments, the FAP-targeted radiotherapy agent is administered intravenously as a single dose every three weeks ± three days, every four weeks ± three days, every five weeks ± three days, or every six weeks ± three days.

[0241] In some embodiments, the FAP-targeted radiotherapy agent is administered intravenously in a single dose every four weeks ± three days.

[0242] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is from about 3 GBq to about 10 GBq.

[0243] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0244] In some embodiments, the FAP-targeted radiotherapy agent is administered to the subject once every four weeks ± three days for a period of time to achieve a cumulative dose of approximately 55.5 GBq.

[0245] In some embodiments, the NSCLC expresses FAP.

[0246] In some embodiments, the NSCLC is transferable.

[0247] On the other hand, this article provides a drug combination comprising a therapeutically effective amount of:

[0248] (A) Fibroblast activating protein (FAP) targeted radiotherapy agents; and

[0249] (B) Nanoparticle albumin-bound paclitaxel;

[0250] This drug combination is intended for use in any of the methods disclosed herein for the treatment of non-small cell lung cancer (NSCLC).

[0251] On the other hand, this article provides a fibroblast activating protein (FAP) targeted radiotherapy agent for use in the treatment of non-small cell lung cancer (NSCLC) (i.e., for use in any of the methods disclosed herein), wherein the treatment further comprises administration of chemotherapy comprising albumin-bound paclitaxel nanoparticles.

[0252] On the other hand, this article provides a chemotherapy therapy comprising nanoparticle albumin-bound paclitaxel for use in the treatment of non-small cell lung cancer (NSCLC) (i.e., for use in any of the methods disclosed herein), wherein the treatment further comprises administration of a fibroblast activating protein (FAP) targeted radiotherapy agent.

[0253] Breast cancer

[0254] This article provides methods for treating breast cancer, including administering FAP-targeted radiotherapy agents to subjects in need.

[0255] In one aspect, this article provides a method for treating breast cancer in a subject in need, the method comprising administering a FAP-targeted radiotherapy agent to the subject in need, wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

[0256] In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose every four weeks ± three days.

[0257] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is from about 3 GBq to about 10 GBq.

[0258] In some embodiments, the single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0259] In some embodiments, a single dose of the FAP-targeted radiotherapy agent is approximately 9.3 GBq.

[0260] In some embodiments, the cumulative dose of the FAP-targeted radiotherapy agent is approximately 55.5 GBq.

[0261] In some embodiments, the FAP targeted radiotherapy agent comprises 47 Sc、 67 Cu、 90 Y、 131 I, 153 Sm、 161 Tb, 169 Er or 177 Lu.

[0262] In some embodiments, the FAP targeted radiotherapy agent comprises 177 Lu.

[0263] In some embodiments, the FAP-targeted radiotherapy agent is Or, or a pharmaceutically acceptable salt or solvate thereof.

[0264] In some embodiments, the FAP-targeted radiotherapy agent is .

[0265] In some embodiments, the breast cancer expresses FAP.

[0266] In some embodiments, the breast cancer is metastatic.

[0267] In some embodiments, the breast cancer is HR-positive and HER2-negative, and the subject has progressed with at least one prior line of hormone-based therapy (alone or in combination) and at least one but no more than two prior lines of chemotherapy (including cytotoxic therapy, targeted therapy, and / or antidrug conjugate therapy).

[0268] In some embodiments, the breast cancer is HER2-positive, and the subject has progressed after at least two prior lines of HER2-targeted therapy.

[0269] In some embodiments, the breast cancer is triple-negative breast cancer (TNBC), and the subject has progressed after at least two prior lines of cytotoxic chemotherapy, including cytotoxic, antidrug conjugate, targeted therapy, and / or immuno-oncology (IO) therapy.

[0270] In some embodiments, the subject has received at least one prior therapy for the treatment of breast cancer, wherein each of the at least one prior therapy is not a therapy that includes a fibroblast activating protein (FAP)-targeting radiotherapy agent.

[0271] In some embodiments, the subject has received at least two prior therapies for the treatment of breast cancer, wherein each of the two prior therapies is not a therapy that includes a fibroblast activator protein (FAP)-targeting radiotherapy agent.

[0272] In one aspect, this article provides a FAP-targeted radiotherapy agent for use in the treatment of breast cancer (i.e., for use in any of the methods of treating breast cancer disclosed herein), wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days or every six weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

[0273] In one aspect, this document provides a FAP-targeted radiotherapy agent for use in the treatment of breast cancer (i.e., for use in any of the methods of treating breast cancer disclosed herein), wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq, and wherein a single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

[0274] Fap expression and subject selection

[0275] In some embodiments, the cancer to be treated by the methods disclosed herein expresses FAP (also referred to as "FAP-expressing cancer"). FAP-expressing cancer, or cancer as FAP-expressing cancer, means that any of the cancer cells, extracellular matrix (ECM), or cancer-associated fibroblasts (CAF) express FAP.

[0276] Solid tumors expressing FAP can be imaged by positron emission tomography (PET) scans following administration of a FAP-targeting radioimaging agent. In some embodiments, subjects are selected for treatment by any of the methods described herein through a diagnostic process that includes administration of a FAP-targeting radioimaging agent to the subject followed by imaging of the subject by positron emission tomography (PET) scans.

[0277] In some embodiments, if the target lesion exhibits positive uptake, the subject has cancer suitable for treatment by any of the methods disclosed herein, and positive uptake is defined as a mediastinal blood pool SUVmax (maximum normalized uptake) being ≥ 1.5 times higher than SUVmean (mean normalized uptake), which is not attributable to other causes of tracer distribution.

[0278] In some embodiments, if the target lesion has positive uptake, the subject has cancer suitable for treatment by any of the methods disclosed herein, and positive uptake is defined as SUVmax ≥ 8 (where SUVmax is the maximum normalized uptake value) of the FAP-targeted radioimaging agent in at least 50% of the target lesions, and the uptake of the remaining target lesions is higher than the surrounding background.

[0279] Therefore, in some embodiments of any method disclosed herein, the method further includes administering a FAP-targeted radioimaging agent prior to administering the FAP-targeted radiotherapy agent.

[0280] In some embodiments, the FAP targeted radiographic imaging agent contains 68 Ga or 18 F.

[0281] In some embodiments, the FAP-targeted radioimaging agent is:

[0282] Or, or a pharmaceutically acceptable salt or solvate thereof.

[0283] In some embodiments, the FAP-targeted radioimaging agent is:

[0284] .

[0285] Dosage, timing and administration

[0286] The methods described herein include administering a therapeutically effective dose (also referred to as a "therapeutic effective dose") of a FAP-targeted radiotherapy agent, alone or in combination with one or more chemotherapeutic agents.

[0287] A therapeutically effective dose is a dose that 1) effectively improves the symptoms of a disease (e.g., cancer as described herein); 2) inhibits or reduces the proliferation or amplification of cancer cells; and / or 3) reduces cancer cells, tumor size, and / or tumor burden.

[0288] Therapeutic effective doses can also be the doses that achieve antitumor effects. "Antitumor effect" or "antitumor activity" can be achieved by administering a therapeutically effective dose of FAP-targeted radiotherapy agents, alone or in combination with one or more chemotherapeutic agents. Antitumor effect (or antitumor activity) refers to biological effects that may manifest as a reduction in tumor volume, a decrease in the number of tumor cells, a reduction in tumor cell proliferation, a decrease in the number of metastases, an increase in overall survival or progression-free survival, an increase in life expectancy, or an improvement in various tumor-related physiological symptoms.

[0289] In some embodiments of any of the methods disclosed herein, the antitumor activity will exceed the following ORR (objective response rate): about 10% or higher, about 15% or higher, about 20% or higher, about 25% or higher, about 30% or higher, about 35% or higher, about 40% or higher, or about 45% or higher, about 50% or higher, about 55% or higher, about 60% or higher, about 65% or higher, about 70% or higher, or about 75% or higher. Those skilled in the art will understand that the ORR cannot exceed 100%.

[0290] The effective therapeutic dose of FAP-targeted radiotherapy agents will also depend on the specific radionuclide and whether the radionuclide is β. - The emitter (also referred to in the art as a β-negative emitter) (e.g., 32 P, 47 Sc、 67 Cu、 89 Sr、 90 Y、 131 I, 153 Sm、 161 Tb, 166 Ho、 169 Er、 177 Lu、 188 Re and 212 Pb) or α-emitter (e.g., ... 211 As、 212 Pb, 212 Bi、 223 Ra、 225 Ac or 227 Th) to determine. In some embodiments of the methods provided herein, the FAP-targeted radiotherapy agent comprises 177 Lu, a β-negative radionuclide.

[0291] In some embodiments, a β-emitter (e.g., like...) 177The total dose of the radiolabeled FAP-targeted radiotherapy agent (also referred to herein as the “cumulative dose” during the treatment regimen) is from about 1 GBq to about 200 GBq. In some embodiments, a FAP-targeted radioligand containing a β-emitter is administered to achieve a cumulative dose of radiation from about 40 to about 100 GBq. In some embodiments, a FAP-targeted radioligand containing a β-emitter is administered to achieve a cumulative dose of radiation from about 40 to about 60 GBq. In some embodiments, a FAP-targeted radioligand containing a β-emitter is administered to achieve a cumulative dose of about 55.5 GBq. As used herein (and throughout this disclosure), the term “about” may mean ± 10%. Thus, in some embodiments, a FAP-targeted radioligand containing a β-emitter is administered to achieve a cumulative dose of 55.5 GBq ± 10%.

[0292] In some embodiments, a FAP-targeted radioligand containing a β-emitter is administered as a single dose (once over a 24-hour period) to deliver radiation of about 1 to about 20 GBq. In some embodiments, a FAP-targeted radiotherapy agent containing a β-emitter is administered as a single dose (once over a 24-hour period) to deliver radiation of from about 3 to about 15 GBq. In some embodiments, a FAP-targeted radiotherapy agent containing a β-emitter is administered as a single dose (once over a 24-hour period, followed by a period without FAP-targeted radiotherapy agent doses, e.g., 28 ± 3 days) to deliver radiation of from about 3 to about 10 GBq. In some embodiments, a FAP-targeted radiotherapy agent containing a β-emitter is administered as a single dose of about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq. In some embodiments, a FAP-targeted radiotherapy agent containing a β-emitter is administered in a single dose of 3.7 GBq ± 10%, 5.6 GBq ± 10%, 7.4 GBq ± 10%, or 9.3 GBq ± 10%.

[0293] In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose approximately every 2 to 10 weeks. In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose approximately every 2 to 6 weeks. In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose approximately every 3 weeks. In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose approximately every 4 weeks. In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose approximately every 5 weeks. In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose approximately every 6 weeks within a -1 day and +7 day window (i.e., approximately every 41-49 days).

[0294] In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose every three weeks ± three days (i.e., 21 ± 3 days). In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose every four weeks ± three days (i.e., 28 ± 3 days). In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose every five weeks ± three days (i.e., 35 ± 3 days). In some embodiments, the FAP-targeted radiotherapy agent is administered as a single dose every six weeks within a window of -1 day and +7 days (i.e., every 41-49 days).

[0295] In some embodiments of the methods provided herein, when FAP-targeted radiotherapy agents are combined with chemotherapy agents, the combination exhibits a synergistic effect. The terms “synergistic effect,” “synergistic action,” and “synergistic” each refer to the measured effect of the combined application of compounds, where the measured effect is greater than the sum of the individual effects of each of the agents when the agents are applied alone (i.e., as single agents).

[0296] In some embodiments, for the treatment of the same cancer or tumor type, the administration of FAP-targeted radiotherapy and chemotherapy allows for a lower dose of chemotherapy compared to the administration of chemotherapy as a single agent.

[0297] In some embodiments of any of the methods disclosed herein, the FAP-targeted drug (whether a FAP-targeted radiotherapy agent or a FAP-targeted radioimaging agent) is administered intravenously (IV) to the subject.

[0298] Reagent test kit

[0299] This document also describes a kit containing one or more single-dose active agents, such as FAP-targeted radiotherapy agents or components for on-site production of FAP-targeted radiotherapy agents. The kit may further include one or more additional chemotherapeutic agents (e.g., FOLFIRINOX / mFOLFIRINOX / NALIRIFOX components and / or nanoparticle albumin-bound paclitaxel). The kit may further include FAP-targeted radioimaging agents or components for on-site production of FAP-targeted radioimaging agents. The kit may also include a label indicating the intended use of the kit contents, and instructions for use of the kit components.

[0300] Medical use form

[0301] Any aspect or embodiment described herein as a treatment method or example may also be described as having other medical uses.

[0302] By incorporating via reference

[0303] For all purposes, all publications, patents and patent applications cited herein are incorporated herein by reference in their full text. Example

[0304] The following examples further illustrate this disclosure, and these examples should not be construed as limiting the scope or spirit of this disclosure. Those skilled in the art will readily recognize that several non-critical parameters can be changed or modified to produce substantially the same or similar results.

[0305] Example 1: Preparation of FAP-targeted radiotherapy agents and FAP-targeted radioimaging agents

[0306] The synthesis of the FAP-targeting compounds is described in PCT Publication WO 2021 / 005125 A1 and US Publication 2022 / 0273831 A1, each of which is hereby incorporated by reference in its entirety. Specifically, the synthesis and characterization of compound I are as follows:

[0307] (Compound I)

[0308] The method described in Example 2 of PCT Publication No. WO 2021 / 005125 A1 and U.S. Publication No. 2022 / 0273831 A1 is provided. The method of labeling compound I with a radioisotope is provided in Example 11 of PCT Publication No. WO 2021 / 005125 A1 and U.S. Publication No. 2022 / 0273831 A1 is provided.

[0309] Manufactured for injection using the following methods 177 Lu-compound I: will 177 Lu(III) complexed with compound I, and was then immediately prepared and filtered through a 0.22 μm membrane into pre-sterilized vials. The complexation step was performed using the following method. 177 Add radiolabeled buffer (containing, for example, approximately 74 mg / mL sodium acetate; approximately 18 mg / mL ascorbic acid; approximately 25 mg / mL N-acetyl-L-cysteine) to the LuCl3 solution, such that 100 μL of buffer is added for every 1 GBq of activity. 177The precursor (compound I, approximately 310 μg) was dissolved in sterile water for injection (SWFI, 0.3 mL) in LuCl3 solution. The mixture was heated to 90°C ± 5°C for 10 ± 1 min while mixing. The reaction mixture was diluted with a reconstitution buffer to a final volume of approximately 22 mL. The reconstitution buffer contained approximately 0.2 mg / mL DTPA, approximately 100 mg / mL ascorbic acid, approximately 40 mg / mL N-acetyl-L-cysteine, approximately 33 mg / mL sodium hydroxide, and approximately 44 mg / mL ethanol, all contained in the SWFI.

[0310] Used for compound I and 177 The reaction scheme for the complexation of Lu can be found in the following:

[0311]

[0312] Manufactured for injection according to the following method 68 Ga-compound I. GMP-grade [produced in-situ using a 68Ge / 68Ga generator]. 68 Gallium chloride (Ga) is used to […]. 68 Gallium chloride (Ga) was eluted with 0.1 M hydrochloric acid. The eluted [Ga] chloride was then added to a radiolabeled vial. 68 [Ga] gallium chloride, a reaction mixture containing compound 1 (41 ± 4 μg net peptide) in ultra-high purity (UHP) water (50 ± 5 μL), 1 M ammonium acetate (0.8 mL), and 0.125 M sodium ascorbate (0.2 mL). The reaction mixture was heated to 95°C for 10 minutes. Heating was stopped, and the reaction mixture was allowed to cool for 5 minutes. This mixture was transferred to an ISO-5 environment. Environmental monitoring was initiated, and the solution was passed through a sterile 0.22-micron membrane filter into a pre-assembled sterile vial for final product collection.

[0313] .

[0314] Example 2: Used for research on FAP-targeted radiopharmaceuticals [ 177 Safety and tolerability, pharmacokinetics, dosing assays and preliminary activity of Lu-FAP2286 in participants with advanced solid tumors: a phase 1 / 2, multicenter, open-label, non-randomized study.

[0315] The Phase 1 design of this study was used to evaluate [ 177 The safety of LuFAP2286 monotherapy in participants with FAP-expressing solid tumors was evaluated, and a recommended intravenous (IV) phase 2 dose (RP2D) was established. The phase 2 design was intended to evaluate […]. 177The safety and efficacy of LuFAP2286 as a monotherapy in participants with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and breast cancer (BC), and its safety and efficacy in combination with chemotherapy in participants with treatment-naïve PDAC or recurrent NSCLC. Based on the […] used to determine tumor FAP expression 68 Ga]GaFAP2286 imaging has been and will be used by participants from both phase 1 and phase 2. 177 Lu]LuFAP2286 treatment.

[0316] Objectives and endpoints: Table 1 presents the research objectives and endpoints.

[0317]

[0318] Research Design

[0319] This is a Phase 1 / 2 open-label study. Phase 1 will focus on evaluating […]. 177 The safety of Lu-FAP-2286 monotherapy in participants with advanced or metastatic FAP-expressing solid tumors (who had relapsed after prior treatment) and the determination of the RP2D were established. In Phase 1, a dose-escalation strategy was designed to identify the maximum tolerated dose (MTD) and RP2D. Phase 2 will establish RP2D in combination with mFOLFIRINOX, RP2D in combination with nanoparticle albumin-bound paclitaxel, and further evaluate […]. 177 Safety and efficacy of Lu-FAP-2286 in both monotherapy and combination with chemotherapy. Participants in the monotherapy group received RP2D established in Phase 1. 177 Lu]Lu-FAP-2286. A combination therapy with chemotherapy will be administered at 100 mCi [ 177 The escalation phase of Lu]Lu-FAP-2286 begins, followed by an extension phase with doses determined in the escalation portion. Therefore, the combination group is independent of RP2D from phase 1.

[0320] Both Phase 1 and Phase 2 will consist of a screening period, a treatment period, and an LTFU period. Participants must meet all inclusion criteria to be enrolled in the study. Participants enrolled in Phase 1 will experience […] at any time during the screening period prior to Day 1 of Cycle 1 (C1D1). 18 PET imaging with fluoro-D-glucose (FDG). During phase 1, patients who had not previously used [F] fluoro-D-glucose (FDG) were enrolled. 68 All participants who underwent previous PET / CT imaging with Ga]Ga-FAP-2286 and all participants in Phase 2 will use [Ga]Ga-FAP-2286 68Ga]Ga-FAP-2286 was used for PET / CT scans. Eligible candidates for Phase 1 and Phase 2 [ 177 Participants treated with Lu-FAP-2286 will have […] on PET / CT scans. 68 Ga]Ga-FAP-2286 uptake, such as "continue [ 177 As described in the "Standards of Lu-FAP-2286 Therapy", in order to begin using [ 177 Lu]Lu-FAP-2286 treatment. Based on the above criteria, [Lu-FAP-2286 treatment.] 68 Participants who did not have FAP-positive tumors and underwent Ga-FAP-2286 imaging will have their studies terminated.

[0321]

[0322] Phase 1

[0323] Phase 1 will enroll participants with advanced or metastatic solid tumors that have relapsed after previous treatment. Upon enrollment, participants with […] on PET / CT scans will be considered. 68 Participants with Ga]Ga-FAP-2286 positive uptake disease (such as those continuing [ 177 The standard of Lu-FAP-2286 therapy (as defined in Table 2) will be used to begin [ 177 Lu-FAP-2286 treatment. Participants will receive up to 6 doses administered at 6-week intervals. 177 Lu]Lu-FAP-2286; This interval can be modified based on newly emerging data (through scheme modification and demonstration).

[0324] Dosage escalation

[0325] Phase 1 dose escalation and determination of MTD (maximum tolerated dose) will be based on a Bayesian optimal interval (BOIN) design. There will be an estimated four dose escalation cohorts, each with a minimum of 3 and a maximum of 12 evaluable participants. For DLT (dose-limiting toxicity) assessment to be evaluable, participants must have already received their first dose. 177 Lu]Lu-FAP-2286 and complete Cycle 1, or experience DLT before completing Cycle 1. If a participant withdraws from treatment or study during the first 6 weeks (42 days) for reasons other than DLT and is not evaluable, additional participants may be enrolled in the cohort.

[0326] Researchers will base their assessments on the National Cancer Institute-Adverse Events Common Terminology Standard (NCI-CTCAE v5.0) or higher toxicity levels, and on […]. 177 The possible relationship between Lu]Lu-FAP-2286 treatment and DLT was evaluated.

[0327] When at least 3 evaluable participants complete the [ 177 Upon completion of the first cycle of Lu-FAP-2286 treatment and consent to escalation to the next dose level, extension of the current dose level, or reduction to a lower or intermediate dose level, the Dose Cohort Review Committee (DCRC) will review safety and dosimetry data. The DCRC will not recommend dose escalations above the dose levels recommended according to the BOIN design. These steps will be repeated until the maximum sample size is reached, or until the number of participants treated at a given dose level reaches n = 12, or until the study is discontinued for safety or other reasons. The DCRC may also decide to modify the total number of doses allowed for participants in the current and / or previous cohorts based on available clinical, safety, and dosimetry data. Any changes to the maximum number of doses will be made through protocol revision and will include justification for the change.

[0328] After completing the dose escalation portion with a maximum sample size of 30 participants with evaluable DLT or a maximum of 12 participants with evaluable DLT at a given dose level, MTD will be estimated based on a BOIN design. Single-dose MTD is defined as the dose level at which ≤ 30% of participants experience a decrease in MTD after administration of the first dose. 177 DLT was experienced during the 6 weeks (42 days) following Lu]Lu-FAP-2286 administration. Multiple-dose MTD will be determined based on evaluation of the cumulative treatment received at any dose level. RP2D will not exceed the MTD identified in Phase 1.

[0329] Phase 2

[0330] During phase 2, five groups will study each 4-week interval. 177 Lu]LuFAP-2286. Phase 2 will be evaluated [ 177 The efficacy of Lu-FAP-2286 as a monotherapy in participants with PDAC, NSCLC, and BC, and its efficacy in combination with chemotherapy in participants with PDAC and NSCLC. The PDAC combination group will be studied every 4 weeks. 177 Lu]Lu-FAP-2286 combined with mFOLFIRINOX (1L metastatic). The NSCLC combination group will be studied every 4 weeks in patients with recurrent disease. 177 Lu]Lu-FAP-2286 and weekly nanoparticle albumin-bound paclitaxel.

[0331] Phase 2 participants will undergo screening and evaluation for further […] 177 Lu]Lu-FAP-2286 of [ 68 Ga]Ga-FAP-2286 imaging, and (if applicable) using [177 Lu]Lu-FAP-2286 treatment, EOT (end of treatment) visit, and subsequent safety follow-up and LTFU (long-term follow-up). Efficacy, safety, and tolerability will be continuously evaluated for all participants enrolled in the study.

[0332] A maximum of 192 participants will be enrolled in the Phase 2 dose-escalation and expansion groups. Participants in the dose-escalation of the combination group receiving the recommended dose will contribute to the expansion analysis of that combination group. Participants will only be enrolled in one different part of the study (i.e., Phase 1 dose-escalation or Phase 2) and will not switch from one part to another. The Phase 1 and Phase 2 protocols are shown in [details omitted]. Figure 1 , Figure 2 and Figure 3 middle.

[0333] Imaging dose measurement

[0334] Phase 1:

[0335] All participants will undergo SPECT / CT scans at four time points during each cycle, including scans on days 1, 2, 3, and 8. The time windows for post-infusion SPECT / CT scans are: 4 hours (± 2 hours); 24 hours (± 4 hours); 48 hours (± 4 hours); and 168 hours (± 8 hours). All SPECT / CT scans should cover two or more consecutive bed positions to ensure imaging of all target lesions and both kidneys at each time point.

[0336] Phase 2:

[0337] Two dose measurements will be performed on selected participants in each group. In the monotherapy groups, approximately 10 participants enrolled for each disease indication (PDAC, NSCLC, and BC) will receive a quantitative dose measurement. In the PDAC + mFOLFIRINOX and NSCLC + nanoparticle albumin-bound paclitaxel combination groups, at least 3 participants at each dose level will require SPECT / CT imaging assessment for the quantitative dose measurement during the dose escalation phase. Approximately 10 participants at the recommended dose for each combination group in the subsequent extension phase will also require SPECT / CT imaging assessment for the quantitative dose measurement. To further reduce the burden on participants who must undergo dose measurement imaging at all four time points in each cycle during the Phase 1 phase, dose measurements will only be performed in cycles 1, 3, and 5 of Phase 2.

[0338] Dose levels in Phase 1:

[0339] [ 177The initial radiation dose and preliminary dose levels for Lu-FAP-2286 are defined in Table 3. The initial dose is 3.70 GBq (100 mCi), which is increased in increments of 1.85 GBq (50 mCi), with a total of four dose levels to be evaluated. The maximum radiation dose to be administered is 9.25 GBq (250 mCi). The planned administration schedule is every 6 weeks (within a window of -1 to +7 days), for a maximum of 6 doses in total.

[0340] In the first dose [ 177 Following Lu]Lu-FAP-2286, dosing, clinical, and safety evaluations will be conducted. Intermediate dose levels, adjustments to the total number of doses, or changes to the dosing intervals can be evaluated after the protocol is modified, and the modification will include justification for the changes.

[0341]

[0342] Screening period

[0343] All participants will be applied [ 68 Prior to the Ga]Ga-FAP-2286 screening, participants underwent a disease assessment via CT or MRI according to RECIST v1.1 criteria. Each participant was required to provide informed consent and agree to provide archived tumor tissue samples (if available) and blood samples for potential biomarker evaluation.

[0344] In Phase 1, all participants will also be treated with […]. 177 Lu]Lu-FAP-2286 previously underwent FDG-PET imaging.

[0345] Used to continue [ 177 Lu]Lu-FAP-2286 therapy [ 68 Ga]Ga-FAP-2286 imaging

[0346] Participants who meet the inclusion criteria will be enrolled. In Phase 1, those who have not used [[] in the previous 3 months...] 68 Participants who had previously undergone PET / CT imaging with Ga-FAP-2286 will begin using [ 177 Prior to treatment with Lu-FAP-2286, [[...]] 68 PET imaging performed using Ga]Ga-FAP-2286.

[0347] Treatment period

[0348] At the start of Phase 1, [treatment will initially be administered every 6 weeks (within a window of -1 day to +7 days).] 177 Lu]Lu-FAP-2286, up to a maximum of 6 doses.

[0349] Safety will be monitored in all participants throughout the treatment phase. Furthermore, the disease status of all participants will be assessed every 6 weeks (42 days) according to RECIST v1.1. Participants will receive […]. 177 Lu]Lu-FAP-2286, until the maximum permissible dose (e.g., up to 6 doses) has been administered, or until radiographic disease progression is confirmed by investigator assessment based on RECIST v1.1 criteria, clear clinical disease progression, unacceptable toxicity or intolerance to further treatment, loss to follow-up, or withdrawal of consent.

[0350] Post-treatment visit

[0351] Following treatment discontinuation, regardless of the reason (except for participant withdrawal of consent from the study or death), participants will undergo an EOT visit. Note that only participants who have withdrawn their consent from treatment will undergo an EOT visit and enter the LTFU phase.

[0352] Each participant's EOT visit will be at the final dose. 177 The procedure was performed 6 to 8 weeks after Lu-FAP-2286, or for any reason other than the participant withdrawing their consent from the study or death (including withdrawal of treatment consent, suspension of the last dose). 177 Lu]Lu-FAP-2286, or not qualified to be used [ 68 After Ga]Ga-FAP-2286, continue [ 177 The Lu-FAP-2286 therapy was administered within one week of the decision to discontinue treatment. Based on [ 68 Ga-FAP-2286 imaging was not performed on participants who were assessed as not having FAP-positive tumors and / or no longer met the inclusion criteria. 177 Lu]Lu-FAP-2286 treatment; these participants will discontinue the study and will not continue the treatment period or LTFU, but will be assessed for safety during an EOT visit.

[0353] Long-term follow-up period

[0354] After the EOT visit is completed, the participant will enter the LTFU period (from withdrawal of consent, death, or ineligibility to continue the study). 177 Participants receiving Lu-FAP-2286 therapy are excluded. LTFU includes safety, disease, and survival assessments (if applicable).

[0355] • Safety assessments will be conducted on all participants in the LTFU. Assessments (including hematology, clinical chemistry, and urinalysis) will be performed every 12 weeks (± 1 week) for 2 years, then every 6 months for up to 5 years.

[0356] • Disease assessment will be performed on all participants in the LTFU who complete the EOT for reasons other than progression of radiographic disease. Participants should continue tumor scanning until progression of radiographic disease as assessed by the investigator, death, loss to follow-up, withdrawal from the study, study completion, or initiation of subsequent anticancer therapy. Tumor assessments should be performed every 12 weeks (± 1 week) for 2 years, then every 6 months for up to 5 years.

[0357] • Survival assessments will be conducted for all participants in the LTFU. Participants will be followed up from the EOT visit until death, loss to follow-up, withdrawal of consent from the study, or study completion, and information on subsequent treatment and survival will be collected every 12 weeks (± 1 week). Follow-up may be conducted by telephone or other means of communication and may be completed to coincide with scheduled oncology and / or safety assessments.

[0358] • SAEs considered to be related to the investigational treatment will be reported during the LTFU period.

[0359] Determination and extension of RP2D

[0360] The RP2D will be selected based on overall safety, tolerability, dosimetry, pharmacokinetic (PK), and efficacy data, and may be the same as or different from the MTD identified in the dose-escalation design. The RP2D will not exceed the MTD identified in Phase 1. For example, the RP2D may differ from, but not exceed, the MTD if the MTD is not met, if the exposure at the specified MTD is significantly higher than what is believed to be necessary for efficacy, or if subsequent treatments provide further insight into the safety profile.

[0361] Dose levels in Phase 2

[0362] Single therapy expansion group:

[0363] Participants diagnosed with PDAC, NSCLC, and BC will receive RP2D every 4 weeks (28 days) in the extension, as announced in Phase 1. 177 Lu]Lu-FAP-2286. Safety assessments will be conducted after the first 10 participants have been treated, regardless of the study indication.

[0364] The combination of PDAC and mFOLFIRINOX:

[0365] Participants diagnosed with PDAC in the combined group will receive [treatment] every 4 weeks (28 days). 177 Lu]Lu-FAP-2286 (combined with mFOLFIRINOX). 177The starting dose of Lu]Lu-FAP-2286 (dose level 1 in the escalation) will be 100 mCi, and 3 additional dose levels will be used for escalation (Table 4). This starting dose is independent of RP2D from phase 1.

[0366] Table 4. Dosage levels of the PDAC and mFOLFIRINOX combination

[0367]

[0368] mFOLFIRINOX will be applied on day 1 of each 14-day cycle.

[0369] Participants can [ 177 Chemotherapy must begin before Lu-FAP-2286 is completed. [The following text appears to be unrelated and possibly a separate sentence fragment: "must be received after completing the second cycle of mFOLFIRINOX."] 177 Lu]Lu-FAP-2286. 177 Lu]Lu-FAP-2286 must begin on day 1 of cycle 1 or 2 (or up to and including day 5), and then continue every 4 weeks (window ± 3 days).

[0370] After determining the dose in the increment, the PDAC combination group will move to the dose extension at the determined dose level.

[0371] Combination of NSCLC with albumin-bound paclitaxel nanoparticles

[0372] Participants diagnosed with NSCLC will receive [treatment] every 4 weeks (28 days). 177 The combination of Lu]Lu-FAP-2286 and albumin-bound paclitaxel in nanoparticles. 177 The starting dose of Lu]Lu-FAP-2286 (dose level 1 in the escalation) will be 100 mCi, and three additional dose levels will be used for escalation (Table 5). This starting dose is independent of RP2D from phase 1.

[0373] Table 5. Dosage levels of NSCLC combined with nanoparticle albumin-bound paclitaxel

[0374]

[0375] Nanoparticle albumin-bound paclitaxel will be administered weekly.

[0376] Participants can [ 177 [Lu]Lu-FAP-2286 can be administered before starting chemotherapy. It can be given on day 1 (or up to and including day 5) after chemotherapy. 177Lu-FAP-2286. It can be started at any time during the first week of weekly albumin-bound paclitaxel and up to and including week 3. 177 Lu]Lu-FAP-2286. Continue every 4 weeks (window ± 3 days) [ 177 Lu]Lu-FAP-2286.

[0377] After determining the dose in the escalation, the NSCLC combination group will move to the dose extension from the determined dose level.

[0378] For each participant, multiple administrations are planned, up to 55.5 GBq. 177 ECD (estimated cumulative dose) of Lu]Lu-FAP-2286. A consecutive cohort of 3 to 9 participants will be treated during dose escalation in each of the following escalation groups, for a total of approximately 27 participants: PDAC combination and NSCLC combination.

[0379] Dosage escalation process for combination groups

[0380] The dose escalation decision will be made by the investigator and researchers. The decision will be based on a comprehensive assessment of all relevant data available from all dose levels to be evaluated in ongoing studies, including safety information, DLT, all CTCAE ≥ Grade 2 toxicity data during the DLT observation period, available PK and dosimetry data. The DLT period for the PDAC and NSCLC combination group will be from the first administration […]. 177 Lu]Lu-FAP-2286 was administered for 4 weeks (28 days). For the combination group, two full doses of mFOLFIRINOX and at least 3–4 doses of nanoparticle albumin-bound paclitaxel were administered during the four-week DLT period, which was considered sufficient to observe any trend in the occurrence or severity of adverse events. Additionally, phase 2 [ 177 The dosing interval for Lu-FAP-2286 is every 4 weeks, therefore the DLT period should be adjusted to suit […]. 177 Lu-FAP-2286 was administered in combination with chemotherapy. The recommended dose for the next cohort of participants will be guided by the BOIN design. In the PDAC and NSCLC combination group, [ 177 The initial dose of Lu]Lu-FAP-2286 will be 100 mCi every 4 weeks (28 days), during which a provisional dose level will be determined to guide dose selection.

[0381] MTD is the highest drug dose that is not expected to induce DLT in more than 30% of treated participants during the DLT evaluation period. For dose escalation purposes, each cohort will consist of 3 to 6 evaluable participants treated at the considered dose level.

[0382] If participants accepted at least 90% of [ 177 If a participant has a planned dose of Lu-FAP-2286, 75% of their chemotherapy dose, and has completed the DLT observation period, then their dose escalation / decrease decision is considered evaluable.

[0383] The treatment will be administered to a consecutive cohort of 3 to 6 participants. The BOIN design uses the following rules to guide dose escalation / decrease, which have been optimized to minimize the probability of erroneous dose allocation.

[0384] • If the observed DLT rate at the current dose is ≤ 23.6%, the dose will be increased to the next higher dose level;

[0385] • If the observed DLT rate is > 35.9% at the current dose, the dose is reduced to the next lower dose level;

[0386] • Otherwise, maintain the current dose.

[0387] For the purpose of controlling overdose, if Pr(pj > 0.30 | data) > 0.95, and at least 3 participants with evaluable DLT have been treated at dose level j (where pj is the true DLT rate at dose level j), dose j and higher levels will be removed from further examination. When the lowest dose is removed, the study must be stopped for safety reasons.

[0388] Determination of the extension in Phase 2

[0389] Single-therapy and combination therapy groups will be enrolled in the expansion (Table 6).

[0390] Table 6. Disease Indication Expansion Group

[0391]

[0392] Treatment ended

[0393] After the study treatment is completed or terminated early, all participants will undergo an EOT follow-up visit within 28 days of the last administration of the study treatment, followed by post-treatment safety follow-up and LTFU period, unless these participants have died, been lost to follow-up, or have withdrawn their consent.

[0394] Post-treatment safety follow-up

[0395] All participants will be subject to a safety follow-up visit 42 days (± 7 days) after their last administration of study treatment, except in cases of death, loss to follow-up, or withdrawal of consent.

[0396] Inclusion criteria

[0397] Eligible participants must meet the following inclusion criteria. Unless otherwise specified, the following criteria apply to participants enrolled in Phase 1 and Phase 2.

[0398] 1. Before conducting any study-specific evaluations, an ICF approved by the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) was signed and dated.

[0399] 2. Must be 18 years of age or older when signing the ICF.

[0400] 3. Agree to submit fresh or archived tumor tissue (if available).

[0401] 4. When applying [ 68 Prior to Ga-FAP-2286 and in the combination therapy group prior to the first cycle of chemotherapy, the patient had sufficient organ function confirmed by the following laboratory values ​​obtained during the screening period:

[0402] a. Bone marrow function (as planned for the first administration) 177 (Lu]Lu-FAP-2286 is unrelated to blood transfusions or growth factor support within the previous 21 days).

[0403] i. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L;

[0404] ii. Platelet count > 100 × 10 9 / L; and

[0405] iii. Hemoglobin ≥ 9 g / dL.

[0406] b. Liver function:

[0407] i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of institutional normal (ULN); if liver metastasis is present, ≤ 5 × institutional ULN;

[0408] ii. Serum bilirubin ≤ 1.5 × institutional ULN, or ≤ 3 × institutional ULN if Gilbert syndrome is known;

[0409] iii. Serum albumin ≥ 30 g / L (3 g / dL); and

[0410] iv. INR ≤ 1.5 x ULN, and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. This applies to participants not receiving therapeutic anticoagulation; participants receiving therapeutic anticoagulation should take a stable dose.

[0411] c. Kidney function:

[0412] i.eGFR ≥ 60 mL / min, using the Croft-Gorth formula.

[0413] 5. The Eastern Co-oncology Group (ECOG) performance status is 0 or 1.

[0414] 6. Life expectancy ≥ 6 months.

[0415] 7. Suffering from a measurable disease according to RECIST v1.1 that meets the following criteria:

[0416] a. For non-lymph nodes, the longest diameter of at least one lesion is ≥ 10 mm, or for lymph nodes, the short axis diameter is ≥ 15 mm, which can be continuously measured using conventional CT and / or MRI according to RECIST v1.1.

[0417] i. Lesions that have undergone external beam radiotherapy or localized therapy (such as radiofrequency ablation) must show evidence of subsequent significant size increase to be considered target lesions.

[0418] For Phase 1 only:

[0419] 8. Having a histologically and / or cytologically confirmed advanced / metastatic solid tumor that is not suitable for treatment with a curative intent.

[0420] a. The tumor must be refractory to previous treatment or have progressed after previous treatment, and there must be no satisfactory alternative treatment options.

[0421] For Phase 2 only:

[0422] 9. Having recurrent or metastatic disease confirmed by cytology, histology, and radiology, as outlined below:

[0423] a. Pancreatic cancer single-therapy group:

[0424] i. Pancreatic ductal adenocarcinoma (ductal adenocarcinoma and related subtypes are eligible; endocrine and neuroendocrine tumors are excluded)

[0425] ii. Participants must have progressed after at least one but no more than two prior chemotherapy regimens for locally advanced unresectable or metastatic disease.

[0426] b. Pancreatic cancer combination group (with mFOLFIRINOX)

[0427] i. Pancreatic ductal adenocarcinoma (ductal adenocarcinoma and related subtypes are eligible; endocrine and neuroendocrine tumors are excluded).

[0428] ii. Participants had not previously received systemic therapy for metastatic disease.

[0429] c. Non-small cell lung cancer monotherapy group

[0430] i. Non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma are eligible; endocrine, neuroendocrine, and small cell tumors are excluded)

[0431] ii. If eligible, the participant must have progressed following at least one but no more than two prior systemic regimens, including chemotherapy and immunotherapy.

[0432] iii. Subjects who have received adjuvant or neoadjuvant platinum doublet chemotherapy (after surgery and / or radiation therapy) and immune checkpoint inhibitors and who develop recurrent or metastatic disease at the time of treatment or within 12 months of completing treatment are eligible.

[0433] iv. Subjects who have relapsed disease for more than 12 months following platinum-based adjuvant or neoadjuvant chemotherapy (whose disease also progressed during or after platinum doublet regimens and immune checkpoint therapy (administered together or sequentially to treat relapse)) are eligible.

[0434] v. Participants must have already received platinum-based chemotherapy and immune checkpoint inhibitors for advanced or metastatic disease, either together (in the same line of treatment) or sequentially (in two different lines of treatment), and then progressed.

[0435] d. Non-small cell lung cancer combination group

[0436] i. Non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma are eligible; endocrine, neuroendocrine, and small cell tumors are excluded)

[0437] ii. If eligible, the participant must have progressed following at least one but no more than two prior systemic regimens, including chemotherapy and immunotherapy.

[0438] iii. Subjects who have received adjuvant or neoadjuvant platinum doublet chemotherapy (after surgery and / or radiation therapy) and immune checkpoint inhibitors and who develop recurrent or metastatic disease at the time of treatment or within 12 months of completing treatment are eligible.

[0439] iv. Subjects who have relapsed disease for more than 12 months following platinum-based adjuvant or neoadjuvant chemotherapy (whose disease also progressed during or after platinum doublet regimens and immune checkpoint therapy (administered together or sequentially to treat relapse)) are eligible.

[0440] v. Participants must not have received prior taxane therapy as a single therapy or in combination.

[0441] e. Breast cancer monotherapy group

[0442] i. HR positive, HER2 negative

[0443] • Participants have a diagnosis of HR-positive, HER2-negative metastatic breast cancer with histological and / or cytological records (tissue samples based on recent analysis of local laboratory tests).

[0444] • Participants must have progressed on at least one hormone-based line of therapy (alone or in combination) and at least one but no more than two lines of chemotherapy (including cytotoxic therapy, targeted therapy and / or antidrug conjugate therapy) for metastatic disease.

[0445] ii. HER2 positive

[0446] • Participants have a diagnosis of HER2-positive metastatic breast cancer with histological and / or cytological records (tissue samples based on recent analysis of local laboratory tests).

[0447] • Participants must have progressed with at least two lines of HER2-targeted therapy for metastatic disease.

[0448] iii. Triple-negative breast cancer (TNBC)

[0449] • Participants have a diagnosis of TNBC with histological and / or cytological records (tissue samples based on recent analysis of local laboratory tests).

[0450] • Participants must have progressed while undergoing at least two lines of cytotoxic chemotherapy for metastatic disease (including cytotoxic therapy, antidrug conjugate therapy, targeted therapy, and / or IO).

[0451] The general principles of previous anti-cancer treatments:

[0452] • Prior chemoradiotherapy is permitted and counted as a chemotherapy regimen (unless low-dose cytotoxic drugs are used only for radiosensitization), provided that the measurable disease is evaluable outside one or more radiation fields, or if a significant increase in size has been shown within the previous radiation field to qualify as a target lesion, and the participant has disease progression within 6 months of the last treatment.

[0453] • Any change in the medication within the same regimen (e.g., switching from paclitaxel to nanoparticle albumin-bound paclitaxel due to intolerance) will still be considered a chemotherapy regimen.

[0454] continue[ 177 Standard of Lu]Lu-FAP-2286 therapy

[0455] Deemed eligible to use [ 177Participants receiving Lu-FAP-2286 treatment will meet all eligibility criteria and will present with […] on PET / CT. 68 Ga]Ga-FAP-2286 uptake, as assessed by the investigator according to specific criteria for each stage of the study. Target lesions are defined based on independent CT or MRI.

[0456] For Phase 1:

[0457] Positive uptake was defined as a mediastinal blood pool SUVmax being ≥ 1.5 times higher than SUVmean in all target lesions, which was not attributable to other causes of tracer distribution.

[0458] For Phase 2:

[0459] In phase 2, positive uptake was defined as PET / CT scans showing up in at least 50% of the target lesions. 68 The SUVmax of Ga]Ga-FAP uptake was ≥ 8 and higher than the surrounding background in other target lesions.

[0460] if[ 68 Ga]Ga-FAP-2286 PET scans identified in tissues or organs that, in the researchers' view, would increase [the activity of] [Ga-FAP-2286]. 177 If the non-tumor uptake of Lu-FAP-2286 is associated with treatment-related risks, the participant will not be eligible to use […]. 177 Lu]Lu-FAP-2286 treatment. This may include, but is not limited to, fibrotic processes, such as those involving the liver or lungs.

[0461] get[ 68 Ga]Ga-FAP-2286 imaging and does not conform to [continue] 177 Participants who meet the criteria for inclusion in the Lu]Lu-FAP-2286 treatment period will have their study terminated.

[0462] Exclusion criteria

[0463] Participants meeting any of the following criteria will be excluded from the study. The following criteria apply to participants enrolled in Phase 1 or Phase 2.

[0464] 1. Participants with active malignancies other than the specific cancers studied in this study, i.e., those known to have potentially fatal cancers and who may (but not necessarily) be currently receiving treatment, except for the following:

[0465] a. History of a second malignant tumor that has been successfully treated, with no signs of active cancer in the 3 years prior to enrollment;

[0466] b. Low-risk tumors that have been surgically cured, such as early-stage cervical or endometrial cancer, any cancer in situ, or non-melanoma skin cancer; and

[0467] c. A prior or concurrent malignant tumor whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the study protocol.

[0468] 2. Symptomatic and / or untreated CNS metastases or leptomeningeal disease, or primary tumors of CNS origin.

[0469] a. Participants with asymptomatic, previously treated CNS metastases are eligible if they are clinically stable for at least 4 weeks and have completed RT for > 2 weeks prior to treatment. Participants may take corticosteroids if they are taking a stable dose equivalent to 10 mg or less of prednisone daily.

[0470] 3. In application [ 177 Patients who have received anticancer treatment with chemotherapy, antibody therapy or other immunotherapies, gene therapy, vaccine therapy, angiogenesis inhibitors or experimental drugs ≤ 14 days prior to Lu-FAP-2286 (≤ 28 days prior in the case of checkpoint inhibitor therapy and other antibody therapy).

[0471] 4. Received prior radiopharmaceutical therapy targeting more than 25% of the bone marrow (e.g., radium-223). 223 Ra-dichloride, [ 177 Lu]Lu-DOTA-TATE、[ 177 Lu]Lu-Prostate-Specific Membrane Antigen (PSMA)-617, Actinium 225[ 225 Ac]Ac-PSMA-617, etc.) or previous EBRT, or received any previous EBRT directly targeting the kidney, or in the administration of [ 177 Lu]Lu-FAP-2286 was accepted within 2 weeks prior to any EBRT.

[0472] • Previous administration of radiopharmacological drugs, unless administered via injection / infusion [ 68 Ga]Ga-FAP-2286 or [ 177 Lu]Lu-FAP-2286 has already passed 10 or more half-lives.

[0473] 5. Ongoing NCI-CTCAE v5.0 Grade 1 (or higher) adverse reactions from anticancer therapy, other than hair loss and vitiligo.

[0474] 6. Impaired cardiac function or clinically significant heart disease, including any of the following:

[0475] a. Clinically significant and / or uncontrolled heart disease, such as congestive heart failure requiring treatment (New York Heart Association Class 2), uncontrolled hypertension, clinically significant arrhythmias, or congenital prolonged QT syndrome;

[0476] b. During screening, the corrected QT interval (Fridericia formula) is > 450 msec (male) or > 470 msec (female); or

[0477] c. In application [ 177 Lu]Lu-FAP-2286 indicates acute coronary syndrome or acute myocardial infarction ≤ 6 months prior.

[0478] 7. Active severe urinary incontinence, severe voiding dysfunction, or urinary tract obstruction requiring an indwelling / condom catheter may, in the investigator's judgment, prevent compliance with radiation safety instructions.

[0479] 8. Severe chronic or active HIV infection:

[0480] a. In the first dose [ 177 Participants who had an unacceptable viral load and received effective antiretroviral therapy within the six months prior to Lu]Lu-FAP-2286 were eligible.

[0481] 9. In application [ 177 Lu]Lu-FAP-2286 was administered ≤ 5 days prior to a study-unrelated minor surgery, or ≤ 21 days prior to a major surgery; in all cases, participants must have been fully recovered and stable before treatment administration.

[0482] 10. The following are exclusion criteria (if applicable):

[0483] a. Female participants with reproductive potential:

[0484] i. Refusing to use highly effective contraceptive methods or refusing to practice true abstinence during treatment and for 6 months after the last dose of the trial drug.

[0485] ii. Pregnancy, suspected pregnancy, or breastfeeding.

[0486] iii. Planning to become pregnant during treatment and within 6 months after the last dose of the trial drug.

[0487] b. Male participants with female partners of reproductive potential:

[0488] i. Refusing to use highly effective contraceptive methods or refusing to practice true abstinence during treatment and for 6 months after the last dose of the trial drug.

[0489] c. All male participants:

[0490] i. Refuse to use condoms during sexual intercourse.

[0491] ii. Sperm donation is planned during treatment and within 6 months after the last dose of the trial drug.

[0492] 11. Significant weight loss (>10% of body weight loss within 28 days prior to providing informed consent for this study).

[0493] 12. The presence of any other circumstances that may increase the risk associated with research participation or interfere with the interpretation of research results, and which, in the researcher's view, would make the participant unsuitable for the study.

[0494] 13. Unable to complete the required studies and standard imaging examinations for any reason (e.g., severe claustrophobia, inability to lie still throughout the imaging period).

[0495] 14. Participants who have known hypersensitivity to surfactants or excipients.

[0496] 15. Severe chronic or active infection (including active tuberculosis, HBV or HCV infection) requiring systemic antibacterial, antifungal or antiviral therapy within 2 weeks prior to enrollment.

[0497] Standard nursing care chemotherapy

[0498] The combination group will receive SOC chemotherapy and [ 177 Lu]Lu-FAP-2286. The mFOLFIRINOX regimen is considered the standard of care in 1L PDAC. Participants in the PDAC combination group will be treated with mFOLFIRINOX every 2 weeks until disease progression. mFOLFIRINOX and supportive medications should be administered according to local guidelines and prescribing information. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is permitted.

[0499] Table 7. mFOLFIRINOX Application Regimen

[0500]

[0501] Similarly, nanoparticle albumin-bound paclitaxel is considered the standard of care in 2L+ NSCLC. Participants in the NSCLC combination group will be treated weekly with 100 mg / m2 of nanoparticle albumin-bound paclitaxel administered over 30 minutes via intravenous infusion until progression. Initial prophylaxis with G-CSF is permitted.

[0502] Table 8. Administration regimen of nanoparticle albumin-bound paclitaxel

[0503]

[0504] Table 9. Treatment Group

[0505]

[0506] Efficacy Evaluation

[0507] Disease / tumor assessment

[0508] CT / MRI imaging assessments according to RECIST v1.1 will be performed at screening / baseline within 28 days of treatment initiation (day -28 to day -1 prior to day 1 of cycle 1 for the monotherapy group, and within 28 days of chemotherapy initiation for the combination group). Any imaging assessments completed by participants during regular check-ups within 28 days prior to treatment initiation (including prior to signing the primary study ICF) will be considered baseline images for this study. Any imaging assessments obtained after the start of treatment in the study will not be considered baseline images for response assessment.

[0509] Evidence of radiographic responses in target and non-target lesions will be evaluated based on RECIST v1.1 criteria.

[0510] Tumor evaluation scans will be performed throughout the treatment period until radiographic disease progression, death, loss to follow-up, withdrawal of consent / objection to use of data / biological samples, study completion, or initiation of subsequent anticancer therapy. The first […] should be used. 177 Tumor imaging assessments were scheduled on the date of Lu]Lu-FAP-2286 treatment (for the monotherapy group) and the first day of chemotherapy (for the combination group), and continued every 6 weeks (42 days). This schedule should be followed whether study treatment was temporarily suspended or an unscheduled assessment was being performed, unless disease progression was being assessed at the time of imaging.

[0511] For participants who completed EOT and entered LTFU for reasons other than radiographic disease progression, tumor scans should be performed every 6 weeks (± 1 week) for 1 year, then every 12 weeks for up to 2 years, and then every 6 months for up to 5 years.

[0512] If an in-treatment scan is collected within the last 6 weeks (42 days), a repeat EOT scan is not required, and if radiography has already shown disease progression, an EOT scan is not required. For participants who complete EOT and enter LTFU, tumor assessment measurements will be performed relative to the first treatment until disease progression, loss to follow-up, withdrawal from the study, initiation of subsequent anticancer therapy, death, or study termination as assessed by the investigator according to RECIST v1.1.

[0513] For any participant who discontinues study treatment for reasons other than radiographic disease progression or death, a scan should be performed at the time of treatment discontinuation, unless a scan has already been performed within the previous ≥ 6 weeks. Disease / tumor assessment will include clinical examination and appropriate imaging techniques according to RECIST v1.1 (i.e., CT scans of the chest, abdomen, and pelvis with appropriate slice thickness); other assessments may also be performed as clinically indicated (MRI, X-ray, PET, bone scan, and color radiography). MRI may be used in place of CT scans to assess target lesions if requested by local authorities. All disease sites should be tracked throughout the clinical study, and the same methods used to detect lesions at baseline should be used to track the same lesions. If a participant has known brain metastases, the disease should be evaluated at each requested assessment time. Tumor markers should be collected in parallel with disease assessment as clinically indicated and evaluated locally.

[0514] Table 10. Imaging Evaluation Collection Plan

[0515]

[0516] Local researchers will evaluate the data to be used for tumor response and treatment decisions using RECIST v1.1. Disease progression will be determined solely through RECIST v1.1.

[0517] Will use [ 177 The Lu-FAP-2286 SPECT / CT scan is used for quantitative analysis to calculate dosimetry for selected organs and regions of interest (including tumors). The resulting dosimetry data is generated by a central reviewer. Tumor dosimetry data can be compared with tumor response data from disease / tumor assessments.

[0518] use[ 68 Ga]Ga-FAP-2286 for PET imaging

[0519] [ 68 Ga-FAP-2286 PET allows for the assessment of target molecules (FAPs) on the surface of CAFs present in the tumor microenvironment. 177 Lu-FAP-2286 will then bind to the target molecule, and the intensity of this expression will be evaluated. In the current study, baseline PET / CT will be performed to select for […]. 177 Participants treated with Lu]Lu-FAP-2286.

[0520] As a standard of conformity 68 Ga]Ga-FAP-2286 PET / CT

[0521] In the current study, [ 68Ga]Ga-FAP-2286 PET positive is used in both stage 1 and stage 2 [ 177 Eligibility criteria for Lu-FAP-2286 treatment. (Compared to [...]) 68 Ga]Ga-FAP-2286 intake-related specific eligibility criteria apply to each period, as assessed by each field investigator.

[0522] For Phase 1

[0523] If the participant's PET / CT findings in all target lesions were [ 68 If the mediastinal blood pool SUVmax of Ga-FAP-2286 uptake is ≥ 1.5 times higher than SUVmean (which cannot be attributed to other causes of tracer distribution), then these participants will be considered eligible for treatment with [Ga-FAP-2286]. 177 Treatment with Lu]Lu-FAP-2286.

[0524] For Phase 2

[0525] Eligible participants were required to have an SUVmax ≥ 8 for at least 50% of their target lesions, and for the remaining target lesions to have uptake above the surrounding background.

[0526] PET scan image quality

[0527] As [ 68 As part of the technical performance evaluation of Ga-FAP-2286, the image quality of baseline PET scans obtained in the Phase 2 portion of the study will be determined. A qualitative rating scale will be used to evaluate all PET scans obtained in Phase 2 (Delpassand ES et al. (2020). J Nucl Med [Journal of Nuclear Medicine];61(6):890-896). Image quality will be assessed by local reviewers.

[0528] Table 11. 68 Ga-FAP-2286 Visual Image Quality Rating Scale

[0529]

[0530] exist[ 177 Following the last dose of Lu-FAP-2286 68 Ga]Ga-FAP-2286 PET / CT

[0531] exist[ 177 Following the final dose of Lu-FAP-2286 (4–8 weeks after that dose), Phase 2 participants will experience […]. 68The second PET / CT was performed on Ga-FAP-2286. This PET / CT will assess changes in the number of all measurable lesions (visual evaluation) and semi-quantitative parameters (SUVmax, SUVmean, and TBR) compared to the baseline PET / CT. [The text abruptly ends here, likely due to an incomplete sentence or missing information.] 177 In the case of Lu]Lu-FAP-2286, this second PET / CT will not be performed.

[0532] The injection in this second PET / CT scan 68 The radioactive dose and acquisition characteristics of Ga-FAP-2286 should be the same as those used at baseline. 68 The Ga-FAP-2286 radioactivity and scan time optimization subset includes 6-9 participants who will receive radioactive doses within the same dose range as at baseline. 68 Ga]Ga-FAP-2286, thus providing sufficient image quality. If these participants need [ 177 Since data analysis of baseline PET is not available when undergoing PET / CT after the last dose of Lu]Lu-FAP-2286 (and therefore the optimal acquisition time range has not been defined), a second PET / CT will be acquired at 60 ± 10 min, as this is the time range for scanning most participants in phase 1 and has already shown good performance in visual identification of tumor lesions and low background activity.

[0533] This objective will be assessed through a central review. These results will not be used to define efficacy, but rather to support evidence of treatment effectiveness beyond standard criteria of response.

[0534] Efficacy Analysis

[0535] use[ 177 Efficacy analysis will be conducted on the Lu]Lu-FAP-2286 efficacy set. The following efficacy endpoints will be analyzed separately for each group. For the combination, only participants who selected the extended dose will be included to aid in the efficacy summary.

[0536] Objective reaction

[0537] For objective response, the primary efficacy endpoint in Phase 2 and the secondary endpoint in Phase 1 were defined as the best confirming response (CR, complete response) or partial response (PR) as assessed by the investigator according to RECIST v1.1. A confirmed CR or PR was a response maintained and recorded during subsequent oncology assessments performed at least 28 days after the initial response. For Phase 2, the ORR (objective response rate) was analyzed, defined as the frequency and percentage of participants with a best confirming response of CR or PR.

[0538] Statistical models, assumptions, and analytical methods

[0539] The primary objective of the phase 2 portion of the study was to evaluate the antitumor activity in the following treatment groups:

[0540] • In second or third line of treatment, in participants with PDAC [ 177 Lu]Lu-FAP-2286 monotherapy

[0541] • In participants with NSCLC, as a second or third line of treatment [ 177 Lu]Lu-FAP-2286 monotherapy

[0542] • In the third or subsequent line of treatment, in participants with BC [ 177 Lu]Lu-FAP-2286 monotherapy

[0543] • In first-line treatment, in participants with PDAC [ 177 Lu]Lu-FAP-2286 +mFOLFIRINOX

[0544] • In participants with NSCLC, as a second or third line of treatment [ 177 Lu]Lu-FAP-2286 + Nanoparticle Albumin-Bound Paclitaxel

[0545] As measured by ORR according to the researcher's assessment based on RECIST v1.1. ORR based on RECIST v1.1 will be based on [ 177 The efficacy of Lu]Lu-FAP-2286 is calculated.

[0546] Antitumor activity will be evaluated against the following benchmarks: 10% ORR for PDAC 2 / 3L monotherapy (Hua J, Shi S, Liang D et al. (2018) OncoTargets and Therapy:11:4591-4608; Cherri S et al. (2021) World J Gastroenteral:27(17):1847-1863) and NSCLC 2 / 3L (Garon EB et al. (2014) Lancet:384:665-673; Borghaei H et al. (2015) N Engl J Med:373(17):1627-1639; Herbst RS et al. (2016) Lancet:387:1540-1550; Rittmeyer:10%). A et al. (2017) Lancet; 389:255-265); 15% ORR for BC 2 / 3L monotherapy group (Modi S et al. (2022) N Engl J Med; 387:9-20; Rugo HS et al. (2023) Lancet; S0140-6736(23)01245-X); and 30% ORR for 1L PDAC and FOLFIRINOX combination group (Conroy T et al. (2011) The New England Journal of Medicine; 364(19):1817-1825); and 10% ORR for 2 / 3L NSCLC and nanoparticle albumin-bound paclitaxel combination group (Auclin E et al. (2023) Lung Cancer; 178:116-122; Moliner L et al. (2023). ESMO Open; 8(2):1-3. / / doi.org / 10.1016 / j.esmoop.2023.100879).

[0547] The binary endpoint of ORR will be modeled using a binomial distribution and analyzed via a Bayesian method. The posterior distribution of ORR will be derived from the prior distribution and from […]. 177The Lu-FAP-2286 power set includes all available data from the subjects. The ORR in each group will be calculated using a neutral prior, β(1 / 3, 1 / 3) (Kerman J (2011) Electronic J of Stats; 5:1450-1470).

[0548] Additionally, ORR will be summarized group-wise along with bilateral precise binomial 95% confidence intervals (Clopper CJ and Pearson (1934) Biometrical; 26:404-413). Waterfall plots will be used to depict antitumor activity in each group, showing the best percentage change from baseline in the sum of diameters of all target lesions in each subject with measurable disease at baseline.

[0549] Response evaluation criteria in solid tumor diagnostics - RECIST v1.1

[0550] The RECIST version 1.1 guidelines are described in the following literature: Eisenhauer EA et al. (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer; 45(2):228-47; and / / eortc.be / Recist / Default.htm. A brief summary is given below.

[0551] Measurable diseases:

[0552] tumor lesions Measurable lesions are defined as those lesions that can be accurately measured in at least one dimension (the longest diameter to be recorded), and which have the following characteristics:

[0553] • Minimum size of 10 mm (CT scan thickness not greater than 5 mm) via CT scan.

[0554] • The minimum size is 10 mm, measured by calipers during clinical examination (lesions that cannot be accurately measured with calipers should be recorded as unmeasurable); or

[0555] • Minimum size of 20 mm via chest X-ray.

[0556] All tumor measurements must be recorded in millimeters (or centimeters).

[0557] Malignant lymph nodes When assessed by CT scan, the short axis length of lymph nodes must be ≥ 15 mm (the recommended slice thickness for CT scans is no greater than 5 mm) to be considered pathologically enlarged and measurable. Only the short axis will be measured and tracked at baseline and during follow-up.

[0558] Unmeasurable diseases:

[0559] All other lesions (or disease sites), including small lesions (pathological lymph nodes with a longest diameter < 10 mm or a short axis ≥ 10 mm to < 15 mm) and truly unmeasurable lesions, are considered unmeasurable diseases. Lesions considered truly unmeasurable include leptomeningeal diseases that cannot be measured by reproducible imaging techniques as determined by physical examination, ascites, pleural / pericardial effusions, inflammatory breast diseases, lymphatic involvement of the skin and lungs, and abdominal masses / abdominal distension.

[0560] Bone lesions

[0561] Bone lesions, cystic lesions, and lesions previously treated with local therapies require special annotation. Bone scans, PET scans, or plain films are not considered appropriate imaging techniques for measuring bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.

[0562] If the soft tissue component meets the definition of measurability above, then osteolytic lesions or mixed osteolytic-blastic lesions with identifiable soft tissue components that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered measurable lesions.

[0563] Bone lesions are unmeasurable.

[0564] cystic lesions

[0565] Lesions that meet the criteria for simple cysts as defined by radiography should not be considered malignant (as they are neither measurable nor non-measurable) because, by definition, they are simple cysts.

[0566] If the above definition of measurability is met, cystic lesions considered to represent cystic metastases can be regarded as measurable lesions. However, if non-cystic lesions are present in the same participant, these non-cystic lesions are preferred as target lesions.

[0567] lesions that have undergone previous local treatment

[0568] Tumor lesions located in previously irradiated areas or areas that have undergone other local therapies are generally not considered measurable unless progression is shown in the lesion.

[0569] target lesions

[0570] All measurable lesions representing all affected organs (up to a maximum of two lesions per organ and a total of five lesions) should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected based on lesion size (the lesion with the longest diameter) and the suitability of the lesion for accurate repeat measurements (by imaging techniques or clinically). The sum of the longest diameters (LDs) of all target lesions will be calculated and reported as the baseline summed LD. The baseline summed LD will be used as a reference to characterize objective tumor response.

[0571] Non-target lesions

[0572] RECIST criteria require clearly quantifying changes in tumor size to adequately account for the total number of target lesions. Therefore, when the boundaries of the primary lesion are difficult to define, the tumor should not be considered a target lesion.

[0573] Guidelines for evaluating measurable diseases

[0574] The same assessment methods and techniques should be used at baseline and during follow-up to characterize each identified and reported lesion. When using both methods to assess the antitumor effect of treatment, imaging-based evaluation is superior to evaluation performed through clinical examination.

[0575] Table 12. Evaluation of target lesions

[0576]

[0577] Table 13. Evaluation of non-target lesions

[0578]

[0579] If tumor markers are initially higher than the institutional ULN, they must be normalized for a participant to be considered a full responder.

[0580] Evaluation of the best overall response

[0581] The best overall response is the best response recorded from the start of treatment until disease progression / relapse (with the minimum measurement recorded from the start of treatment as a reference for PD). The allocation of the best response to participants will depend on the achievement of both the measurement criteria and the confirmation criteria.

[0582] Table 14. Evaluation of the best overall response

[0583]

[0584] Participants whose health condition deteriorates significantly and requires discontinuation of treatment, and who at that time have no objective evidence of disease progression, should be classified as having worsening symptoms. Even after discontinuation of treatment, every effort should be made to record objective progression.

[0585] In some cases, it may be difficult to distinguish residual lesions from normal tissue. When the evaluation of complete response (CR) depends on this determination, it is recommended to investigate residual lesions (fine-needle aspiration / biopsy) before confirming a state of complete response.

[0586] Confirmatory measurement / reaction duration

[0587] confirm

[0588] If an initial CR or PR is recorded, a confirmatory scan should be performed at least 4 weeks (28 days) after the first recorded response.

[0589] Duration of the overall response

[0590] The duration of the overall response is measured from the time when the measurement criteria for CR or PR are met (based on the first record) until the first date of objective recording of relapse or PD (based on the minimum measurement result recorded since the start of treatment as a reference for PD).

[0591] The duration of overall CR is measured from the time when the first CR measurement criteria are met until the first date of objectively recording disease recurrence.

[0592] Duration of disease stability

[0593] Using the minimum measurement recorded since the start of treatment as a reference, the SD was measured from the start of treatment until the progression criteria were met.

[0594] Treatment group

[0595] Phase 2: After completing Phase 1 of the study, a regimen of administration every 6 weeks for up to 6 cycles will be established. 177 Lu]Lu-FAP-2286 monotherapy RP2D.

[0596] The phase 2 portion of the study seeks to evaluate single or combination therapy every 4 weeks. 177 Safety and efficacy of Lu]Lu-FAP-2286 in five treatment groups.

[0597] Single therapy group: These three treatment groups relied on RP2D, which was announced in the Phase 1 portion of the study.

[0598] • Participants with metastatic (2 / 3L) pancreatic ductal adenocarcinoma (PDAC) expressing FAP were administered [every 4 weeks with] 177 Lu]Lu-FAP-2286 monotherapy with RP2D treatment

[0599] • Participants with metastatic (2 / 3L) non-small cell lung cancer (NSCLC) expressing FAP were given [every 4 weeks] 177Lu]Lu-FAP-2286 monotherapy with RP2D treatment

[0600] • Participants with FAP-expressing metastatic (3L+) breast cancer (BC) were given [ [] every 4 weeks. 177 Lu]Lu-FAP-2286 monotherapy with RP2D treatment

[0601] Combination group: Both treatment groups will begin with dose escalation at 100 mCi (dose level 1) every 4 weeks. 177 Lu]Lu-FAP-2286 begins. Therefore, the combinatorial group does not depend on RP2D announced in the Phase 1 part of the study.

[0602] • Participants with metastatic (1L) PDAC expressing FAP were treated every 4 weeks [ 177 Treatment with Lu]Lu-FAP-2286 in combination with modified FOLFIRINOX (starting with a dose increase of 100 mCi, followed by a dose extension at the selected dose).

[0603] • Participants with FAP-expressing metastatic (2 / 3L) NSCLC were given [every 4 weeks] 177 Treatment with Lu]Lu-FAP-2286 in combination with nanoparticle albumin-bound paclitaxel (starting with a dose increase of 100 mCi, followed by dose expansion at the selected dose).

[0604] Gallium-68 FAP-based imaging has demonstrated its ability to detect tumor lesions in PDAC, NSCLC, and BC. Within these tumor types, 68 Ga-FAPI imaging has shown significant uptake and similar SUVs in both primary and metastatic lesions (Kratochwil C. et al. J Nucl Med. [Journal of Nuclear Medicine]; 60(6):801-805). Hypothesis [ 68 Ga]Ga-FAP-2286 imaging acquisition predicts [ 177 The response to Lu]Lu-FAP-2286 therapy was selected for the Phase 2 study design to replace the originally planned cohorts, including the basket cohort.

[0605] Phase 2 dosing interval

[0606] Phase 1 study part investigated the application every 6 weeks [ 177 Lu]Lu-FAP-2286, while Phase 2 will study the application every 4 weeks [ 177Lu]Lu-FAP-2286. The Phase 1 participant cohort consisted of participants with advanced malignancies from the deeply pre-treated cohort. Disease progression in these participants typically occurred within weeks, therefore many Phase 1 participants received only one treatment cycle and discontinued the study due to disease progression. This was due to […] identified in the 26 participants treated in the Phase 1 portion. 177 The safety profile of Lu]Lu-FAP-2286 is manageable and has not shown any associated trend toward increasing the frequency of hematologic cytopenia or other adverse events. Therefore, the dosing interval in Phase 2 will be every 4 weeks to increase the chance of administering an effective cumulative dose.

[0607] Example 3. Phase I dosing results

[0608] use[ 68 Imaging of 34 participants was performed using Ga-FAP-2286, and four dose levels ranging from 100 mCi to 250 mCi were used according to the Phase 1 protocol described in Example 2. 177 Lu]Lu FAP 2286 was administered to 27 participants (see also NCT04939610). The most common treatment-related adverse events (TEAEs) of any cause occurring in ≥ 20% of participants included fatigue (n = 7, 25.9%), abdominal pain (n = 6, 22.2%), and anemia (n = 6, 22.2%). Treatment-related TEAEs reported in ≥ 10% of participants included fatigue (n = 3, 11.1%) and anemia (n = 4, 14.8%). No cardiac-related events have been reported to date.

[0609] After each cycle, an evaluation was conducted for each patient. 177 Full dose assays of Lu-FAP-2286 were performed (hybridization method (4 whole-body planar images + 1 SPECT / CT) or quantitative SPECT / CT (4 SPECT / CT images)). Favorable biodistribution was observed both overall and cumulatively (a dose of 55.5 GBq, equivalent to 6 administrations of 250 mCi (9.25 GBq)) based on dose assay data at each dose level in cycle 1.

[0610] on the whole,[ 177 Lu]Lu-FAP-2286 was well tolerated in patients with deep pretreatment, and a low incidence of DLT and ≥ grade 3 AEs was observed, thus supporting the initiation of phase 2.

[0611] Based on the safety profile and dosimetry data, the optimal dosage of 250 mCi (9.25 GBq) has been determined. 177Lu-FAP-2286 monotherapy is the recommended phase 2 dose (RP2D) relative to the test dose. Furthermore, due to the known benefits of cumulative radiation and the potential for tumor radiosensitization when chemotherapy is administered concurrently with radiation, further investigation will be conducted in phase 2. 177 The 4-week dosing interval for Lu-FAP-2286. Regarding its use in the context of chemotherapy... 177 The safety profile of Lu-FAP-2286 in Phase 1 and the absence of cumulative hematologic toxicity, along with the opportunity for more timely direct delivery of therapy to tumors, support increased administration frequency.

[0612] a use[ 177 The 27 participants treated with Lu-FAP-2286 had the following types of solid tumors: appendix, colorectal, connective tissue proliferative small round cell tumor, gallbladder, head and neck, peritoneal mesothelioma, pancreas, prostate, rectum, solitary fibrous tumor, soft tissue sarcoma, and uterus / endometrium (especially uterine leiomyosarcoma).

Claims

1. A method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of: (a) Fibroblast activating protein (FAP) targeted radiotherapy agents; and (b) Chemotherapy, comprising one, two, three or four agents selected from 5-fluorouracil (5-FU), folate, irinotecan and oxaliplatin.

2. The method of claim 1, wherein the FAP-targeted radiotherapy agent comprises 177 Lu.

3. The method of claim 1 or 2, wherein the FAP-targeted radiotherapy agent is Or, or a pharmaceutically acceptable salt or solvate thereof.

4. The method according to any one of claims 1-3, wherein the FAP-targeted radiotherapy agent is .

5. The method of any one of claims 1-4, wherein the chemotherapy comprises 5-FU, formyltetrahydrofolate, and irinotecan.

6. The method of any one of claims 1-4, wherein the chemotherapy comprises 5-FU, formyltetrahydrofolate, and oxaliplatin.

7. The method of any one of claims 1-4, wherein the chemotherapy comprises 5-FU, formyltetrahydrofolate, irinotecan, and oxaliplatin.

8. The method of any one of claims 1-6, wherein chemotherapy is administered to the subject prior to the administration of the FAP-targeted radiotherapy agent.

9. The method of any one of claims 1-8, wherein the chemotherapy is administered to the subject in one or two cycles prior to the administration of the FAP-targeted radiotherapy agent.

10. The method of any one of claims 1-9, wherein the chemotherapy is administered in a 14-day cycle.

11. The method of claim 10, wherein the chemotherapy is administered in a 14-day cycle, wherein: i. Administer oxaliplatin on the first day of the 14-day cycle; ii. Administer formyltetrahydrofolate on the first day of the 14-day cycle; iii. Irinotecan is administered on the first day of the 14-day cycle; and iv. Administer 5-fluorouracil on the first and second days of the 14-day cycle.

12. The method of claim 11, wherein the oxaliplatin is administered at a concentration from about 60 mg / m². 2 Approximately 100 mg / m 2 The dosage is administered intravenously.

13. The method of claim 11 or 12, wherein the oxaliplatin is administered at approximately 85 mg / m². 2 The dosage is administered intravenously.

14. The method of any one of claims 11-13, wherein the formyltetrahydrofolate is administered at a concentration of about 300 mg / m³. 2 Approximately 500 mg / m 2 The dosage is administered intravenously.

15. The method according to any one of claims 11-14, wherein the formyltetrahydrofolate is administered at about 400 mg / m³ 2 The dosage is administered intravenously.

16. The method of any one of claims 11-15, wherein the irinotecan is administered at a dose from about 100 mg / m². 2 Approximately 200 mg / m 2 The dosage is administered intravenously.

17. The method of any one of claims 11-16, wherein the irinotecan is administered at about 150 mg / m² 2 The dosage is administered intravenously.

18. The method of any one of claims 11-17, wherein the 5-fluorouracil is administered at a concentration from about 1000 mg / m². 2 Approximately 3000 mg / m 2 The dosage is administered intravenously.

19. The method of claims 11-18, wherein the 5-fluorouracil is administered at approximately 2400 mg / m². 2 The dosage is administered intravenously.

20. The method of any one of claims 1-19, wherein the FAP-targeted radiotherapy agent is administered intravenously once in a single dose every three weeks ± three days, every four weeks ± three days, every five weeks ± three days, or every six weeks ± three days.

21. The method of any one of claims 1-20, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every four weeks ± three days.

22. The method of claim 20 or 21, wherein a single dose of the FAP-targeted radiotherapy agent is from about 3 GBq to about 10 GBq.

23. The method of any one of claims 20-22, wherein a single dose of the FAP-targeted radiotherapy agent is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

24. The method of any one of claims 1-23, wherein the FAP-targeted radiotherapy agent is administered to the subject once every four weeks ± three days for a period of time to achieve a cumulative dose of approximately 55.5 GBq.

25. The method of any one of claims 10-24, wherein the FAP-targeted radiotherapy agent is administered on any one of the first, second, third, fourth, or fifth days of each 14-day chemotherapy cycle.

26. The method of any one of claims 1-25, wherein the PDAC expresses FAP.

27. The method of any one of claims 1-26, wherein the PDAC is transferable.

28. A method for treating a subject with non-small cell lung cancer (NSCLC) in need, the method comprising administering to the subject a therapeutically effective amount of: (A) Fibroblast activating protein (FAP) targeted radiotherapy agents; and (B) Nanoparticle albumin-bound paclitaxel.

29. The method of claim 28, wherein the FAP-targeted radiotherapy agent comprises 177 Lu.

30. The method of claim 28 or 29, wherein the FAP-targeted radiotherapy agent is Or, or a pharmaceutically acceptable salt or solvate thereof.

31. The method of any one of claims 28-30, wherein the FAP-targeted radiotherapy agent is .

32. The method of any one of claims 28-31, wherein the subject has previously received at least one prior therapy for the treatment of NSCLC, wherein each of the at least one prior therapy is not a therapy comprising a fibroblast activating protein (FAP) targeted radiotherapy agent.

33. The method of any one of claims 28-32, wherein the subject has previously received at least two prior therapies for the treatment of NSCLC, wherein each of the prior therapies is not a therapy comprising a fibroblast activator protein (FAP)-targeted radiotherapy agent.

34. The method of any one of claims 28-33, wherein nanoparticle albumin-bound paclitaxel is administered to the subject prior to the administration of the FAP-targeted radiotherapy agent.

35. The method of any one of claims 28-34, wherein the nanoparticle albumin-bound paclitaxel is administered to the subject in one or two cycles prior to the administration of the FAP-targeted radiotherapy agent.

36. The method of any one of claims 28-35, wherein the nanoparticle albumin-bound paclitaxel is administered once during a seven-day cycle.

37. The method of claim 36, wherein the nanoparticle albumin-bound paclitaxel is administered on the first day of the seven-day cycle of the nanoparticle albumin-bound paclitaxel.

38. The method of any one of claims 28-37, wherein the albumin-bound paclitaxel nanoparticles are administered at a concentration from about 50 mg / m³. 2 Approximately 150 mg / m 2 The dosage is administered intravenously.

39. The method of any one of claims 28-38, wherein the albumin-bound paclitaxel nanoparticles are administered at about 100 mg / m³ 2 The dosage is administered intravenously.

40. The method of any one of claims 36-39, wherein the FAP targeted radiotherapy agent is administered on any one of the first, second, third, fourth, or fifth days of the seven-day cycle of the nanoparticle albumin-bound paclitaxel.

41. The method of any one of claims 28-40, wherein the FAP-targeted radiotherapy agent is administered intravenously once in a single dose every three weeks ± three days, every four weeks ± three days, every five weeks ± three days, or every six weeks ± three days.

42. The method of any one of claims 28-41, wherein the FAP-targeted radiotherapy agent is administered intravenously in a single dose every four weeks ± three days.

43. The method of claim 41 or 42, wherein the single dose is from about 3 GBq to about 10 GBq.

44. The method of any one of claims 41-43, wherein the single dose is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

45. The method of any one of claims 28-44, wherein the FAP-targeted radiotherapy agent is administered to the subject once every four weeks ± three days for a period of time to achieve a cumulative dose of approximately 55.5 GBq.

46. ​​The method of any one of claims 28-45, wherein the NSCLC expresses FAP.

47. The method of any one of claims 28-46, wherein the NSCLC is transferable.

48. A method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject of need, the method comprising administering a FAP-targeted radiotherapy agent to the subject, wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

49. A method for treating a subject with non-small cell lung cancer (NSCLC) in need, the method comprising administering an FAP-targeted radiotherapy agent to the subject, wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

50. A method for treating breast cancer in a subject in need, the method comprising administering a FAP-targeted radiotherapy agent to the subject, wherein the FAP-targeted radiotherapy agent is administered in a single dose every four weeks ± three days to achieve a cumulative dose of about 40 to about 60 GBq.

51. The method of any one of claims 48-50, wherein the single dose is from about 3 GBq to about 10 GBq.

52. The method of any one of claims 48-51, wherein the single dose is about 3.7 GBq, about 5.6 GBq, about 7.4 GBq, or about 9.3 GBq.

53. The method of any one of claims 48-52, wherein the single dose is about 9.3 GBq.

54. The method of any one of claims 48-53, wherein the cumulative dose is about 55.5 GBq.

55. The method of any one of claims 48-54, wherein the FAP-targeted radiotherapy agent comprises 177 Lu.

56. The method of any one of claims 48-55, wherein the FAP-targeted radiotherapy agent is Or, or a pharmaceutically acceptable salt or solvate thereof.

57. The method of any one of claims 48-56, wherein the FAP-targeted radiotherapy agent is .

58. The method of any one of claims 48 and 51-57, wherein the PDAC expresses FAP.

59. The method of any one of claims 48 and 51-58, wherein the PDAC is transferable.

60. The method of any one of claims 48 and 51-59, wherein the subject has received at least one prior therapy for treating PDAC, wherein each of the at least one prior therapy is not a therapy comprising a fibroblast activator protein (FAP)-targeted radiotherapy agent.

61. The method of any one of claims 48 and 51-60, wherein the subject has received at least two prior therapies for treating PDAC, wherein each of the prior therapies is not a therapy comprising a fibroblast activator protein (FAP)-targeting radiotherapy agent.

62. The method of any one of claims 49 and 51-57, wherein the NSCLC expresses FAP.

63. The method of any one of claims 49, 51-57 and 62, wherein the NSCLC is transferable.

64. The method of any one of claims 49, 51-57, 62 and 63, wherein the subject has received at least one prior therapy for the treatment of NSCLC, wherein each of the at least one prior therapy is not a therapy comprising a fibroblast activating protein (FAP) targeted radiotherapy agent.

65. The method of any one of claims 49, 51-57, and 62-64, wherein the subject has received at least two prior therapies for the treatment of NSCLC, wherein each of the two prior therapies is not a therapy comprising a fibroblast activator protein (FAP)-targeted radiotherapy agent.

66. The method of any one of claims 50-57, wherein the breast cancer expresses FAP.

67. The method of any one of claims 50-57 and 66, wherein the breast cancer is metastatic.

68. The method of any one of claims 50-57, 66 and 67, wherein the subject has received at least one prior therapy for the treatment of breast cancer, wherein each of the at least one prior therapy is not a therapy comprising a fibroblast activator protein (FAP) targeted radiotherapy agent.

69. The method of any one of claims 50-58, 67 and 68, wherein the subject has received at least two prior therapies for the treatment of breast cancer, wherein each of the two prior therapies is not a therapy comprising a fibroblast activator protein (FAP)-targeted radiotherapy agent.

70. The method of any one of claims 1-69, the method further comprising administering a FAP-targeted radioimaging agent prior to administering the FAP-targeted radiotherapy agent.

71. The method of claim 70, wherein the FAP-targeted radioimaging agent comprises 68 Ga、 64 Cu or 18 F.

72. The method of claim 70 or 71, wherein the FAP-targeted radioimaging agent is: Or, or a pharmaceutically acceptable salt or solvate thereof.

73. The method of any one of claims 70-72, wherein the FAP-targeted radioimaging agent is: 。 74. A method for treating cancer in a subject of need, the method comprising administering to the subject a substance comprising 177 Lu's FAP-targeted radiotherapy agent, wherein the FAP-targeted radiotherapy agent is administered intravenously once every 28 ± 3 days at a daily dose to achieve a cumulative dose of about 40 to about 60 GBq, wherein the cancer is a solid tumor expressing FAP.

75. The method of claim 74, wherein the method further comprises administering a therapeutically effective amount of chemotherapy to the subject.

76. The method of claim 75, wherein the chemotherapy comprises nanoparticle albumin-bound paclitaxel, FOLFIRINOX, or mFOLFIRINOX.

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