First-line combination therapy with plinabulin for treating small cell lung cancer

Abstract

Disclosed herein are compositions and methods for treating cancer, specifically extensive-stage small-cell lung cancer (ES-SCLC), through the administration of a combination therapy. In some embodiments, the method comprises administering plinabulin, one or more immune checkpoint inhibitors, including but not limited to pembrolizumab, and a regimen of etoposide with a platinum-based agent (EP). The disclosed methods enhance tumor reduction, prolong progression-free survival, and improve overall treatment efficacy compared to traditional therapies.

Description

DALWC.212WO PATENTFIRST-LINE COMBINATION THERAPY WITH PLIN AB ULIN FOR TREATINGSMALL CELL LUNG CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 718526, filed November 8, 2024, the content of which is incorporated by reference in its entirety.Field of the Disclosure

[0002] The present disclosure relates to the field of chemistry and medicine. More particularly, the present disclosure relates to compositions and methods for first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC).Description of related art

[0003] Small-cell lung cancer (SCLC) is a particularly aggressive form of cancer, representing about 15% of all lung cancer cases. It is known for its rapid proliferation, high mutation rate, and early metastasis, contributing to poor long-term outcomes. The disease is divided into two stages: limited-stage and extensive- stage (ES-SCLC). ES-SCLC refers to cases where cancer has spread beyond the thoracic region, often involving distant organs, which complicates treatment and lowers survival rates significantly. Patients diagnosed with ES-SCLC face a median survival of approximately 10 months, with less than 7% surviving beyond five years, highlighting the urgent need for better therapeutic strategies.

[0004] Despite extensive study of different combinations, standard-of-care first- line therapy for ES-SCLC has remained chemotherapy with Etoposide and platinum-based therapy (EP) such as cisplatin or carboplatin for the past 30 years. Although EP is associated with high response rates, responses are not durable, and median overall survival (OS) is approximately 10 months. While this regimen often provides high initial response rates, the benefits are typically short-lived, with many patients experiencing relapse within months. The rapid recurrence and resistance to chemotherapy reflect the difficulty in effectively treating SCLC.

[0005] Recent advances in immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting the PD-1 / PD-L1 pathway, have opened new possibilities for cancertreatment. For example, Pembrolizumab, an anti-PD-1 monoclonal antibody, is thought to work by blocking the interaction between PD-1 on T-cells and its ligands (PD-L1 and PD-L2), thus reactivating T-cells to mount an immune response against tumors. However, while ICIs have shown significant success in other cancers, their impact in SCLC has been more limited. PD-L1 antibodies, including Atezolizumab and Durvalumab, and EP have been approved for first line ES-SCLC. with overall survival around 12 months, response rate >60%, but still limited median progression-free survival (PFS) at 2-4 months. Trials like KEYNOTE-604, which tested pembrolizumab with chemotherapy, demonstrated modest improvements in PFS, but the overall benefit remained insufficient to meet clinical expectations.

[0006] The combination of ICIs with chemotherapy is promising but unpredictable, with uncertainties regarding the efficacy of such regimens in ES-SCLC. Chemotherapy, while effective at reducing tumor burden, also suppresses the immune system by depleting lymphocytes, which are implicated in the action of ICIs like pembrolizumab. The interplay between chemotherapy-induced immunosuppression and immune activation through ICIs is not fully understood, raising concerns that the therapies could counteract each other rather than produce the desired synergistic effect.

[0007] Thus, there remains an unmet need for first-line therapies for treating ES- SCLC.SUMMARY OF THE DISCLOSURE

[0008] Some aspects of the disclosure relate to methods of treating cancer. In some embodiments, the treatment comprises administering an immune checkpoint inhibitor; a tubulin binding agent; a podophyllotoxin derivative and a platinum-based agent. In some embodiments, the tubulin binding agent is selected from a group consisting of vinblastine, vincristine, vinorelbine. vinflunine, crytophycin 52, halichondrins, dolastatins, hemiasterlins, colchicine, combretastatins, 2-methyoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide, and plinabulin. In some embodiments, the tubulin binding agent is plinabulin.

[0009] In some embodiments, the immune checkpoint inhibitor is selected from inhibitors targeting PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or TIM3. In some embodiments, the immune checkpoint inhibitor is a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody, or a combination thereof. In someembodiments, the a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody is selected from a-CD3-APC, a-CD3-APC-H7, a-CD4-ECD, a-CD4-PB, a-CD8-PE-Cy7, a- CD-8-PerCP-Cy5.5. a-CDl lc-APC. a-CDl lb-PE-Cy7, a-CDl lb-AF700. a-CD14-FITC, a- CD16-PB, a-CD19-AF780, a-CD19-AF700, a-CD20-PO, a-CD25-PE-Cy7, a-CD40-APC, a- CD45-Biotin, Streptavidin-BV605, a-CD62L-ECD, a-CD69-APC-Cy7, a-CD80-FITC, a- CD83-Biotin, Streptavidin-PE-Cy7, a-CD86-PE-Cy7, a-CD86-PE, a-CD123-PE, a-CD154- PE, a-CD161-PE, a-CTLA4-PE-Cy7, a-FoxP3-AF488 (clone 259D), IgGl-isotype-AF488, a- ICOS (CD278)-PE, a-HLA-A2-PE, a-HLA-DR-PB, a-HLA-DR-PerCPCy5.5, a-PDl-APC, VISTA, co-stimulatory molecule 0X40, and CD137.

[0010] In some embodiments, one or more immune checkpoint inhibitor is selected from nivolumab, pembrolizumab. pidilizumab, ipilimumab, BMS 936559, atezolizumab, durvalumab, or combinations thereof. In some embodiments, the one or more immune checkpoint inhibitor is pembrolizumab, either used as a single immune checkpoint inhibitor or in combination with other immune checkpoint inhibitors.

[0011] In some embodiments, the podophyllotoxin derivative is selected from etoposide, etoposide phosphate, teniposide, and their analogs. In some embodiments, the platinum-based agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, and satraplatin or combinations thereof. In some embodiments, the platinum-based agent is carboplatin. Some embodiments include administering etoposide and a platinum-based agent.

[0012] Some aspects of the disclosure relate to a method for small-cell lung cancer (SCLC). Some embodiments include treatment of extensive-stage SCLC (ES-SCLC), where cancer has metastasized beyond the thoracic region.

[0013] In some embodiments, the disclosed combination therapy may be administered to specific patient populations, such as those with high tumor mutation burdens (TMB) or microsatellite instability-high (MSI-H) cancers, which are more likely to respond to immune checkpoint inhibitors. In these cases, plinabulin's ability to enhance dendritic cell activity and immune response may demonstrate additional therapeutic benefits including synergy.

[0014] In some embodiments, the disclosed combination therapy may follow a variety of treatment regimens to optimize clinical outcomes for patients with extensive-stage small-cell lung cancer (ES-SCLC). In some embodiments, the regimens may involveadministering an immune checkpoint inhibitor, such as pembrolizumab, in combination with a tubulin-binding agent like plinabulin, and etoposide and a platinum-based compound. These agents can be delivered concurrently or sequentially, depending on patient- specific factors, such as tolerability, disease progression, and response to prior therapies.

[0015] In some embodiments, the immune checkpoint inhibitor may be administered intravenously at regular intervals, ranging from every three to six weeks, while etoposide and carboplatin, may be delivered in 21 -day cycles. In some embodiments, plinabulin can be administered on Day 1 of the cycle, immediately following etoposide and carboplatin, to provide both immune enhancement and protection against neutropenia. Alternatively, the regimen may involve variations in dosing schedules, such as maintenance phases where only pembrolizumab and plinabulin are continued after initial cycles of full combination therapy. In further embodiments, the combination can be modified by including alternative platinum-based agents (e.g., cisplatin) or adjusting doses based on adverse events, with the goal of maintaining treatment efficacy while minimizing toxicity.

[0016] In some embodiments, the inclusion of plinabulin in the disclosed combination therapies, such as with pembrolizumab, etoposide and carboplatin, aims to address the limitations of immune checkpoint therapies by providing synergistic effects that enhance immune activity while also managing treatment-related side effects.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows a trial schema for investigation of a first-line treatment regimen combining pembrolizumab, plinabulin, etoposide, and platinum-based therapy in ES- SCLC patients.

[0018] FIG. 2 is a waterfall chart summarizing the tumor response for 14 patients in a clinical study.DETAILED DESCRIPTION

[0019] The present disclosure provides methods for a therapeutic approach for treating small-cell lung cancer. In some embodiments, the methods are a first line treatment specifically focusing on extensive-stage small-cell lung cancer (ES-SCLC). Some embodiments include compositions and methods involving a synergistic combination of atubulin binding agent, an immune checkpoint inhibitor, a podophyllotoxin derivative and a platinum-based agent. The disclosed combinations enhance treatment outcomes by maximizing tumor reduction, extending progression-free survival, and minimizing treatment- related adverse events. Embodiments of the compositions and methods disclosed herein provide structured administration protocols, adaptable for first-line treatment, maintenance phases, and labelling instructions for, for example, dose modification involving complex patient conditions.

[0020] In some embodiments, methods for treating small-cell lung cancer (SCLC) may include administering an immune checkpoint inhibitor, a tubulin binding agent, a podophyllotoxin derivative and a platinum-based agent. In certain embodiments, the tubulin binding agent is plinabulin. In some embodiments, the immune checkpoint inhibitor is selected from those targeting PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or TIM3. In particular embodiments, the immune checkpoint inhibitor is chosen from nivolumab. pembrolizumab, pidilizumab, ipilimumab, BMS 936559, atezolizumab, durvalumab, or combinations thereof, with pembrolizumab specifically referenced in some embodiments.

[0021] In certain embodiments, the podophyllotoxin derivative is selected from etoposide, etoposide phosphate, teniposide, and their analogs. Additionally, in some embodiments, the platinum-based agent may include cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, or combinations thereof, with carboplatin noted as a preferred agent in certain contexts. Some embodiments include administering etoposide and a platinum-based agent.

[0022] In some embodiments, a method for treating SCLC in a subject involves administering a therapeutically effective amount of the compounds described herein. In particular embodiments, administration may be part of a first-line treatment for extensive- stage SCLC (ES-SCLC). The immune checkpoint inhibitor, in certain embodiments, may be administered intravenously at a frequency ranging from every three weeks to every six weeks. In some embodiments, the tubulin binding agent, plinabulin, is administered at a dose ranging from 10 mg / m2to 30 mg / m2. In particular embodiments, the etoposide and platinum-based agent are administered on days 1, 2, and 3 of each 21 -day cycle.

[0023] In some embodiments, the patient population includes individuals diagnosed with ES-SCLC, defined as Stage IV (T any, N any, M la / b) according to the American Joint Committee on Cancer (AJCC), Eighth Edition. In certain embodiments, these patients may have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating minimal to no symptoms affecting daily activities. In some embodiments, the method includes selecting patients who have at least one measurable lesion as defined by RECIST 1.1 criteria, suitable for target lesion assessment.

[0024] In other embodiments, the method includes a treatment regimen where pembrolizumab is administered at a dose of 200 mg intravenously on Day 1 of a 21 -day cycle, plinabulin at a dose of 30 mg / m2intravenously, etoposide at 100 mg / m2intravenously on Days 1, 2, and 3 of each 21 -day cycle, and a platinum-based agent, selected from cisplatin or carboplatin, intravenously on Day 1. In particular embodiments, carboplatin may be administered at an AUC (area under the curve) of 5, or cisplatin at a dose of 75 mg / m2.

[0025] In certain embodiments, patients with prior brain metastases may be included in the treatment, provided they have completed treatment, shown no evidence of new or enlarging brain metastases, and have had no corticosteroids for at least seven days prior to the first dose of treatment. In some embodiments, prophylactic medications, including 5-HT3 receptor antagonists and dexamethasone, are administered prior to the infusion of plinabulin to prevent nausea and vomiting.

[0026] In certain embodiments, the treatment is continued for up to 35 cycles or until disease progression, unacceptable toxicity, or withdrawal of consent. In other embodiments, following completion of four cycles of the full regimen, a maintenance phase is initiated, involving continued administration of pembrolizumab and plinabulin every three weeks until progression or toxicity. In particular embodiments, the method further includes monitoring for treatment-related toxicides, such as neutropenia, thrombocytopenia, or anemia, and applying dose modifications or delays as necessary to manage adverse events. In some embodiments, the method may further include administering radiation to the subject as part of the therapeutic approach.Definitions

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which thisdisclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0028] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety. The pharmaceutically acceptable excipient can be a monosaccharide or monosaccharide derivative.

[0029] The term “subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0030] The term “mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, or the like.

[0031] The terms “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and can include curing a disease or condition.

[0032] The terms “treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that thepatient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.

[0033] The term “ameliorate” as used herein refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular condition.

[0034] The term “antibody” or “antibody moiety” is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope. Antibodies utilized in the present disclosure may be polyclonal antibodies or monoclonal antibodies. Antibodies also include free antibodies and antigen binding fragments derived therefrom, and conjugates, e.g. pegylated antibodies, drug, radioisotope, or toxin conjugates, and the like. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the targeting and / or depletion of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No. 5,985,660; and Morrison et al. Cell, 96:737-49 (1999)). These techniques allow for the screening of particular populations of cells: in immunohistochemistry of biopsy samples; in detecting the presence of markers shed by cancer cells into the blood and other biologic fluids, and the like. Humanized versions of such antibodies are also within the scope of this disclosure. Humanized antibodies are especially useful for in vivo applications in humans due to their low antigenicity.

[0035] The terms “cancer”, “neoplasm”, and “carcinoma”, are used interchangeably herein to refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. Detection of cancerous cells is of particular interest.

[0036] The term “immune checkpoint inhibitor” as used herein refers to a molecule (e.g., small molecule, peptide, polypeptide, protein, antibody, antibody fragment and the like)that acts as an inhibitor (antagonist) of an immune checkpoint pathway. Inhibition of a pathway can include blockade of the pathway through binding to a receptor or signaling molecule that is part of the immune checkpoint pathway.

[0037] The term “pharmaceutical carrier”, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety. The pharmaceutically acceptable excipient can be a monosaccharide or monosaccharide derivative.Compositions

[0038] Some aspects of the disclosure relate to a pharmaceutical composition. In some embodiments, the pharmaceutical compositions used as described herein include, as separate compositions or as any combination in a composition: an immune checkpoint inhibitor; a tubulin binding agent; a podophyllotoxin derivative and a platinum-based agent. In some embodiments, the tubulin binding agent is selected from a group consisting of vinblastine, vincristine, vinorelbine. vinflunine, crytophycin 52, halichondrins, dolastatins, hemiasterlins, colchicine, combretastatins, 2-methyoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide, and plinabulin. In some embodiments, the tubulin binding agent is plinabulin.

[0039] Without being bound to a single theory of operation, it is believed that plinabulin promotes the maturation of dendritic cells, which in turn enhances the immune response by increasing antigen- specific CD4 T cell proliferation and supporting tumor antigen presentation. This dendritic cell stimulation may result in improved T-cell-mediated tumor targeting when used in combination with immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors.

[0040] In some embodiments, plinabulin may also exert pro-apoptotic effects on tumor cells and reduce tumor blood flow. In some embodiments, plinabulin may potentiate the efficacy of immune checkpoint inhibition. In some embodiments, plinabulin may target immune evasion mechanisms in tumor cells. In some embodiments, plinabulin may exhibit anti-inflammatory properties. In some embodiments, plinabulin may mitigate immune-related adverse events (irAEs) often associated with immune checkpoint inhibitors.

[0041] In some embodiments, the immune checkpoint inhibitor is selected from inhibitors targeting PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or TIM3. In some embodiments, the immune checkpoint inhibitor is a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody, or a combination thereof. In some embodiments, the a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody is selected from a-CD3-APC, a-CD3-APC-H7, a-CD4-ECD, a-CD4-PB, a-CD8-PE-Cy7, a- CD-8-PerCP-Cy5.5, a-CDl lc-APC, a-CDl lb-PE-Cy7, a-CDllb-AF700, a-CD14-LITC, a- CD16-PB, a-CD19-AF780. a-CD19-AE700, a-CD20-PO, a-CD25-PE-Cy7, a-CD40-APC, a- CD45-Biotin, Streptavidin-BV605, a-CD62L-ECD, a-CD69-APC-Cy7, a-CD80-LITC, a- CD83-Biotin, Streptavidin-PE-Cy7, a-CD86-PE-Cy7, a-CD86-PE, a-CD123-PE, a-CD154- PE, a-CD161-PE, a-CTLA4-PE-Cy7, a-FoxP3-AF488 (clone 259D), IgGl-isotype-AF488, a- ICOS (CD278)-PE, a-HLA-A2-PE, a-HLA-DR-PB, a-HLA-DR-PerCPCy5.5, a-PDl-APC, VISTA, co-stimulatory molecule 0X40, and CD137.

[0042] In some embodiments, the immune checkpoint inhibitor is an inhibitor targeting PD-1 and / or PD-L1. For example, one or more immune checkpoint inhibitor may be selected from the following examples: Cemiplimab (Libtayo®), a PD-1 inhibitor, Retifanlimab (Zynyz®), a PD-1 inhibitor, Dostarlimab (Jemperli®), a PD-1 inhibitor, Avelumab (Bavencio®), a PD-L1 inhibitor, Tislelizumab (Tevimbra®), a PD-1 inhibitor, Toripalimab (Loqtorzi®), a PD-1 inhibitor, Sintilimab (Tyvyt®), a PD-1 inhibitor, and ABP 206, as referenced in NCT05907122.

[0043] In some embodiments, immune checkpoint inhibitor may include PD-1 inhibitors selected from pembrolizumab (Keytruda®), nivolumab, tislelizumab, dostarlimab, toripalimab, sintilimab, and retifanlimab. In other embodiments, the immune checkpoint inhibitor may include PD-L1 inhibitors selected from durvalumab, atezolizumab, cemiplimab, avelumab, and ABP 234, as referenced in NCT06311721. In further embodiments, the immunecheckpoint inhibitor may include CTLA-4 inhibitors, such as ipilimumab and tremelimumab. Additionally, in certain embodiments, PD-l+LAG-3 combination therapies may be included, such as Opdualag® (a combination of nivolumab and relatlimab). Some embodiments may also include LAG-3 inhibitors, such as fianlimab.

[0044] In further embodiments, the immune checkpoint inhibitor may include the PD-1 inhibitors budigalimab and cetrelimab. Some embodiments may also include bispecific inhibitors, which may include but are not limited to ivonesimab (PD-lxVEGF), cadonilimab (PD-LlxCTLA-4), and IB 1363 (PD-lxIL-2a).

[0045] In some embodiments, the disclosed methods may include biosimilars of the immune checkpoint inhibitors. For example, in certain embodiments, biosimilars of PD-1 inhibitors may be used, including biosimilars of pembrolizumab, nivolumab, tislelizumab, dostarlimab, toripalimab, sintilimab, and retifanlimab. In further embodiments, biosimilars of PD-L1 inhibitors may be used, such as biosimilars of durvalumab, atezolizumab, cemiplimab, and avelumab. In some embodiments, the methods may use biosimilars of CTLA-4 inhibitors, such as biosimilars of ipilimumab and tremelimumab. In some embodiments, the methods may also use biosimilars of PD-l+LAG-3 combination therapies, including biosimilars of Opdualag® (a combination of nivolumab and relatlimab). Additionally, in certain embodiments, biosimilars of LAG-3 inhibitors, such as biosimilars of fianlimab, may be utilized.

[0046] In some embodiments, the methods described herein may include, in addition to or as an alternative, biosimilars of budigalimab and cetrelimab as PD-1 inhibitors. Furthermore, in specific embodiments, the methods may use biosimilars of bispecific inhibitors, such as biosimilars of ivonesimab (PD-lxVEGF), cadonilimab (PD-LlxCTLA-4), and IB 1363 (PD-lxIL-2a). These biosimilars may be employed to achieve comparable therapeutic effects to the reference biologies in treating cancer and other immune-responsive conditions, providing alternative options within the disclosed compositions.

[0047] In some embodiments, one or more immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, Cemiplimab, Dostarlimab, Retifanlimab, Toripalimab, Tislelizumab, Sintilimab, Vopratelimab, Spartalizumab. Camrelizumab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Avelumab, KN035, Cosibelimab, AUNP12, CA-170, BMS-986189, tremelimumab, Opdualag(nivolumab + Relatlimab), Finalimab, Budigalimab, Cetrelimab, Ivonesimab (PD-lxVEGF), Cadonilimab (PD-LlxCTLA-4), IB 1363 (PD-lxIL-2alpha) or combinations thereof. In some embodiments, the one or more immune checkpoint inhibitor is pembrolizumab, either used as a single immune checkpoint inhibitor or in combination with other immune checkpoint inhibitors.

[0048] In some embodiments, the one or more immune checkpoint inhibitor may be incorporated in a pharmaceutically acceptable formulation. In some embodiments, the one or more immune checkpoint inhibitor is incorporated in a pharmaceutically acceptable aqueous formulation. Examples of acceptable aqueous formulations include isotonic buffered and pH 4.5-8 adjusted saline solutions such as Lactated Ringer's Solution and the like.

[0049] In some embodiments, the immune checkpoint inhibitor compound is incorporated in a pharmaceutically acceptable liposome formulation, wherein the formulation is a passive or targeted liposome formulation. Examples of methods for the preparation of suitable liposome formulations of antibodies are described U.S. Pat. No. 5,399,331 (Loughrey), U.S. Pat. No. 8,304,565 (Wu) and U.S. Pat. No. 7,780,882 (Chang), which are incorporated herein by reference in their entirety.

[0050] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, durvalumab. or any combinations thereof. In some embodiments, the one or more immune checkpoint inhibitor may include an anti-PD-1 HuMAbs can be selected from 17D8, 2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A1 1, 7D3 and 5F4, all of which are described in U.S. Pat. No. 8,008.449, which is incorporated herein by reference in its entirety. In some embodiments, the anti-PD-1 HuMAbs can be selected from 3G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10, IB 12, 7H1, 1 1E6, 12B7. and 13G4, all of which are described in U.S. Pat. No. 7,943,743, which is incorporated herein by reference in its entirety.

[0051] In some embodiments, pembrolizumab and plinabulin may be provided as injectable solutions. Additional injectable formulations may include etoposide, carboplatin, and cisplatin. In some embodiments, these products may be labeled according to regulatory guidelines, and may include instructions for use as described herein.

[0052] In some embodiments, pembrolizumab, a humanized TgG4 monoclonal antibody, may target the programmed cell death protein 1 (PD-1) receptor to inhibit interactions with its ligands, PD-L1 and PD-L2. This inhibition may enhance T-cell responses by reducing PD-1 mediated immune suppression, a mechanism exploited by certain tumor cells to evade immune detection. Without being bound to a single theory of operation, Pembrolizumab may have high binding affinity and receptor blocking activity. Without being bound to a single theory of operation, plinabulin, may function as an immunomodulatory microtubule-binding agent that promotes dendritic cell maturation. Without being bound to a single theory of operation, this combination may enhance antigen presentation, thereby increasing T-cell activation against tumor cells.

[0053] Some embodiments include administration of pembrolizumab as an immune checkpoint inhibitor, plinabulin as a tubulin binding agent, a podophyllotoxin derivative, and a platinum-based agent, such as etoposide and carboplatin. Without being bound to a single theory of operation, it is believed that the combination of an immune checkpoint inhibitor with a tubulin binding agent, a podophyllotoxin derivative and a platinumbased agent may produce a synergistic effect in treating extensive-stage Small-Cell Lung Cancer (ES-SCLC), by enhancing immune activation, reducing tumor burden, and overcoming immune evasion mechanisms commonly associated with ES-SCLC.

[0054] In some embodiments, the immune checkpoint inhibitor, such as pembrolizumab, may be administered intravenously at a dosage of approximately 200 mg on Day 1 of each 21 -day cycle. In certain embodiments, pembrolizumab may act by inhibiting the interaction of PD-1 with its ligands, thereby promoting T-cell activation and immune surveillance. Additionally, plinabulin may be administered at a dose ranging from 10 mg / m2to 30 mg / m2intravenously on Day 1 of each 21 -day cycle. Without limiting to a specific mechanism, plinabulin may function by promoting dendritic cell maturation, thereby enhancing antigen presentation and facilitating a more robust antitumor T-cell response.

[0055] In some embodiments, the podophyllotoxin derivative is selected from etoposide, etoposide phosphate, teniposide, and their analogs. In some embodiments, the platinum-based agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, and satraplatin or combinations thereof. In some embodiments, the platinum-based agent is carboplatin. Some embodiments include administering etoposide and a platinum-based agent.

[0056] Some embodiments include administering a podophyllotoxin derivative, such as etoposide, and a platinum-based agent, which may be selected from carboplatin, cisplatin, oxaliplatin, or combinations thereof. For example, in some embodiments, etoposide and a platinum-based agent, such as carboplatin, may be administered on Days 1, 2, and 3 of each 21 -day cycle. This regimen is anticipated to provide cytotoxic effects on tumor cells while concurrently augmenting the immune- stimulating effects of pembrolizumab and plinabulin.

[0057] In certain embodiments, the methods may be particularly suitable for use as a first-line treatment for ES-SCLC, particularly in patients classified as Stage IV (T any, N any, M la / b) according to the American Joint Committee on Cancer, Eighth Edition. In some embodiments, the patient population may comprise individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, reflecting minimal to no limitations in daily activities. Such selection criteria may support improved patient tolerance and response to the treatment regimen.

[0058] In some embodiments, the compounds described herein may be formulated as an injectable solution for administration via intravenous (IV) infusion. The compositions may comprise separately or in combination one or more immune checkpoint inhibitors, a tubulin binding agent such as plinabulin, a podophyllotoxin derivative, and a platinum-based compound. These components may be provided in pharmaceutically acceptable carriers suitable for IV administration, ensuring solubility, stability, and compatibility of the active ingredients in an aqueous medium.

[0059] In certain embodiments, the injectable formulations may include pembrolizumab as an immune checkpoint inhibitor, provided as a solution or lyophilized powder for reconstitution to achieve a concentration appropriate for intravenous delivery. Similarly, plinabulin may be prepared as a stable injectable solution with a concentration tailored to achieve the desired dosage (e.g., 30 mg / m2). To maintain efficacy and patient safety, these formulations may be buffered to a physiologically acceptable pH and may include stabilizers or preservatives as suggested to ensure stability throughout storage and administration.

[0060] In some embodiments, the podophyllotoxin derivatives such as etoposide and platinum-based agents like carboplatin may also be provided as injectable solutions, either individually or in combination. Each agent in the composition may be packaged in single-usevials, with labeling that clearly specifies the drug name, potency, and recommended dosage. Such an approach allows for flexibility in administration, as the agents can be sequentially or concurrently infused based on a treatment protocol suitable for, for example, Small-Cell Lung Cancer (SCLC) management.

[0061] Without being limited to a specific formulation approach, in some embodiments, the composition may be prepared as a multi-component injectable kit, where each component (immune checkpoint inhibitor, tubulin binding agent, podophyllotoxin derivative, and platinum-based agent) is provided in separate, pre-measured containers. Such a configuration allows precise dosing adjustments based on individual patient needs and facilitates tailored combination therapy.

[0062] In further embodiments, the composition may incorporate excipients such as pharmaceutically acceptable diluents, antioxidants, solubilizers, or osmotic agents to ensure the physical and chemical stability of the formulation during storage and administration. For example, the use of non-ionic surfactants or polyethylene glycol (PEG) derivatives may aid in solubilizing hydrophobic agents like plinabulin, enhancing compatibility with the aqueous vehicle used for IV infusion. Preservatives may be omitted or minimized, particularly in singleuse formulations, to reduce potential adverse reactions and comply with standards for injectables.Methods of Treatment

[0063] Some aspects of the disclosure relate to a method for treating SCLC. Some embodiments relate to a method for ameliorating SCLC in a subject. Some embodiments relate to a method for preventing SCLC in a subject. In some embodiments, the subject can be an animal, e.g., a mammal, a human. In some embodiments, the subject is a human. In some embodiments, the method comprises administering pharmaceutical composition comprises an immune checkpoint inhibitor; a tubulin binding agent; a podophyllotoxin derivative and a platinum-based agent.

[0064] In some embodiments, certain combination compositions comprising an immune checkpoint inhibitor, a tubulin-binding agent, podophyllotoxin derivative, such as etoposide, and platinum compounds, may be applied to the treatment of SCLC. In someembodiments, compositions according to the disclosure can be used for ES-SCLC, where cancer has metastasized beyond the thoracic region and suggests aggressive first-line therapy.

[0065] In certain embodiments, disclosed methods and formulations may be applicable as a first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC). In some embodiments, disclosed methods and formulations may be used by patients who have developed resistance to prior checkpoint inhibitors or chemotherapy regimens. In some cases, SCLC patients receiving second-line or third-line therapies may experience enhanced therapeutic outcomes from the synergistic effects of combining plinabulin in with the disclosed formulations.

[0066] In some embodiments, the combination may be administered to specific patient populations, such as those with high tumor mutation burdens (TMB) or microsatellite instability-high (MSLH) cancers, which are more likely to respond to immune checkpoint inhibitors. In these cases, plinabulin's ability to enhance dendritic cell activity and immune response may demonstrate additional therapeutic benefits including synergy.

[0067] In some embodiments, the disclosed combination therapy may follow a variety of treatment regimens to optimize clinical outcomes for patients with extensive- stage small-cell lung cancer (ES-SCLC). In some embodiments, the regimens may involve administering an immune checkpoint inhibitor, such as pembrolizumab, in combination with a tubulin-binding agent like plinabulin, a podophyllotoxin derivative , including etoposide, and a platinum-based compound. These agents can be delivered concurrently or sequentially, depending on patient-specific factors, such as tolerability, disease progression, and response to prior therapies.

[0068] In some embodiments, the immune checkpoint inhibitor may be administered intravenously at regular intervals, ranging from every three to six weeks, while the podophyllotoxin derivative and platinum-based agent, such as etoposide and carboplatin, may be delivered in 21 -day cycles. In some embodiments, plinabulin can be administered on Day 1 of the cycle,, to provide both immune enhancement and protection against neutropenia. Alternatively, the regimen may involve variations in dosing schedules, such as maintenance phases where only pembrolizumab and plinabulin are continued after initial cycles of full combination therapy. In further embodiments, the combination can be modified by includingaltemative platinum-based agents (e.g., cisplatin) or adjusting doses based on adverse events, with the goal of maintaining treatment efficacy while minimizing toxicity.

[0069] In some embodiments, the inclusion of plinabulin in the disclosed combination therapies, such as with pembrolizumab, etoposide and carboplatin, aims to address the limitations of immune checkpoint therapies by providing synergistic effects that enhance immune activity while also managing treatment-related side effects.

[0070] Without being restricted to a specific dosing schedule, in some embodiments, the treatment regimen may be repeated every 21 days until disease progression, unacceptable toxicity, or a decision by the treating physician to discontinue treatment. Patients receiving this regimen may be monitored for immune-related adverse events, including but not limited to pneumonitis, colitis, and hepatitis, which may arise due to checkpoint inhibitor activity. Additional monitoring may include regular blood counts to assess neutropenia risk.

[0071] Some aspects of the disclosure are directed to methods comprising administering pembrolizumab, plinabulin, etoposide, and a platinum-based agent for treating aggressive cancers. For example, small-cell lung cancer (SCLC) is recognized as a neuroendocrine malignancy with a rapid doubling time, high growth fraction, and strong association with tobacco use.

[0072] Without being bound to a single theory of operation, it is hypothesized that the combination of pembrolizumab, plinabulin, etoposide, and a platinum-based agent may increase therapeutic efficacy through a multi-mechanistic approach. Pembrolizumab may augment the immune system's response by blocking the PD-1 / PD-L1 interaction, thereby enhancing T-cell activation and immune-mediated tumor suppression. Plinabulin may further support this process by promoting dendritic cell maturation and tumor antigen presentation, which could lead to more robust and sustained T-cell responses. Additionally, plinabulin’ s anti-inflammatory properties through PDE4 inhibition may reduce the occurrence of immune- related adverse events (irAEs), potentially improving patient tolerability. In some embodiments, the inclusion of plinabulin in the composition may provide additional benefits by enhancing the effects of the PD-1 inhibitor and mitigating some chemotherapy-induced toxicities.

[0073] In some embodiments, this composition provides first-line treatment for ES- SCLC, providing a synergistic effect that enhances both efficacy and safety. Methodsaccording to the disclosure may yield benefits in terms of extended PFS, reduced toxicity profiles (particularly in terms of neutropenia), and durable responses, thereby addressing the substantial unmet needs in, for example, the ES-SCLC patient population. Proof-of-concept evidence is included herein and ongoing studies support the efficacy and safety of this combination as a successful treatment option in ES-SCLC therapy.

[0074] In certain embodiments, the disclosed methods for treating extensive- stage small-cell lung cancer involve a structured 21 -day cycle protocol administered over multiple cycles. During Cycles 1 to 4, all patients receive a combination therapy beginning with pembrolizumab at a fixed dose of 200 mg, which is administered via intravenous (IV) infusion over approximately 30 minutes, with a permissible timing variation of ±5 minutes, on Day 1 of each cycle. Etoposide follows at a dose of 100 mg / m2, administered via IV infusion on Days 1, 2, and 3. A platinum-based agent is then administered, with patients receiving either Carboplatin, dosed to achieve an area under the curve (AUC) of 5. or Cisplatin at a dose of 75 mg / m2, both administered via IV infusion on Day 1. Plinabulin is administered subsequently at a dose of 30 mg / m2, delivered via IV infusion over 60 minutes with an acceptable variation of ±5 minutes, and this infusion begins 60 minutes (±5 minutes) after the completion of the Carboplatin or Cisplatin infusion on Day 1.

[0075] Following the completion of Cycles 1 to 4, patients may transition to a maintenance phase, where treatment continues in 21-day cycles (Cycle 5 onward), with pembrolizumab and plinabulin administered every three weeks until one of the specified end- of-treatment criteria is reached. During each maintenance cycle, patients receive pembrolizumab at a fixed dose of 200 mg via IV infusion over approximately 30 minutes, allowing for a timing variation of ±5 minutes, on Day 1. Plinabulin may be administered at a dose of 30 mg / m2via IV infusion over 60 minutes (±5 minutes), with the infusion beginning 60 minutes (±5 minutes) after the pembrolizumab infusion is completed on Day 1.

[0076] In some embodiments, the SCLC comprises cancer cells expressing a binding ligand of PD-1. In some embodiments, the binding ligand of PD-1 is PD-L1. In some embodiments, the binding ligand of PD-1 is PD-L2.

[0077] In some embodiments, the method of treating SCLC described herein further includes identifying SCLC cells expressing a binding ligand of PD-1. In some embodiments, the method of ameliorating SCLC in a subject described herein further includesidentifying cancer cells expressing a binding ligand of PD-1. In some embodiments, the method of treating SCLC described herein further includes identifying SCLC cells expressing PD-L1. In some embodiments, the method of treating SCLC described herein further includes identifying SCLC cells expressing PD-L2. In some embodiments, the method of treating SCLC described herein further includes identifying SCLC cells expressing PD-L3 or PD-L4.

[0078] In some embodiments, identifying SCLC cells expressing a binding ligand of PD-1 includes using an assay to detect the presence of the binding ligand. Examples of applicable assay include but are not limited to PD-L1 IHC 22C3 pharmDx kit and PD-L1 IHC 28-8 pharmDx available from Dako. In some embodiments, identifying SCLC cells with FPPS expression includes using a FPPS diagnostic based on IHC, gene expression-based assay or other relevant assay.

[0079] In some embodiments, the SCLC comprises cancer cells expressing a binding ligand of CTLA-4. In some embodiments, the binding ligand of CTLA-4 is B7.1 or B7.2. In some embodiments, the method of treating, ameliorating, or preventing SCLC in a subject described herein further includes identifying SCLC cells expressing a binding ligand of CTLA-4. In some embodiments, the method of treating SCLC described herein further includes identifying SCLC cells expressing B7.1 or B7.2.

[0080] In some embodiments, the SCLC does not have any cells expressing PD-1, PD-L1, or PD-L2 at detectable levels.

[0081] In some embodiments, a method for halting or reversing a progressive cancer in a subject comprising administering a tubulin binding agent, an immune checkpoint inhibitor, a podophyllotoxin derivative and a platinum-based agent, as described in the claimed invention.

[0082] In some embodiments, the present disclosure provides a method for treating a solid small cell lung cancer tumor. In some embodiments, the present disclosure provides a method for ameliorating a solid small cell lung cancer tumor. In some embodiments, the present disclosure provides a method for preventing a solid small cell lung cancer tumor. In some embodiments, the present disclosure provides a method for treating an immune suppressed small cell lung cancer tumor. An immune suppressed small cell lung cancer tumor is a tumor that contains immune suppressive associated cells such as for example TRegcells,myeloid derived suppressor cells (MDSC), M2 macrophages, and the like or immune suppressive factors such as inducible nitric oxide synthase (iNOS), PD-L1, and the like.

[0083] In some embodiments, the treatment cycle can include administering plinabulin, one or more immune checkpoint inhibitors, a podophyllotoxin derivative, and a platinum-based agent in combination, or administering each component individually in subsequent administrations. For example, in certain embodiments, plinabulin and one or more immune checkpoint inhibitors are administered on day 1, followed by administration of plinabulin alone after 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, or 3 weeks, and then followed by administration of plinabulin, one or more immune checkpoint inhibitors, and the podophyllotoxin derivative and platinum-based agent after 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, or 3 weeks.

[0084] In other embodiments, plinabulin, one or more immune checkpoint inhibitors, a podophyllotoxin derivative, and a platinum-based agent are administered simultaneously on day 1. followed by administration of plinabulin or one or more immune checkpoint inhibitors alone on a selected day between day 2 and day 31, and then followed by administration of the combination of plinabulin, one or more immune checkpoint inhibitors, the podophyllotoxin derivative, and the platinum-based agent on a selected day between day 3 and day 31. In some embodiments, plinabulin, one or more immune checkpoint inhibitors, the podophyllotoxin derivative, and the platinum-based agent are administered on day 1. followed by administration of plinabulin alone on day 8, and then followed by administration of plinabulin, one or more immune checkpoint inhibitors, the podophyllotoxin derivative, and the platinum-based agent on day 15. In some embodiments, the treatment cycle can be repeated two or more times.

[0085] In some embodiments, methods according to the disclosure may include the simultaneous or sequential delivery of two or more therapeutic agents to maximize potential synergistic effects. For example, methods according to the disclosure may include delivering a tubulin binding agent, such as plinabulin, in combination with one or more immune checkpoint inhibitors, the podophyllotoxin derivative, and the platinum-based agent within a structured timeframe to achieve enhanced therapeutic efficacy.

[0086] Methods according to the disclosure may include delivering plinabulin and an immune checkpoint inhibitor, such as pembrolizumab, on the same day to initiate a robustimmune response. Such a coadministration approach may be followed by a sequential dosing strategy where plinabulin is administered alone on subsequent days to maintain immune stimulation. Additional cycles may involve reintroducing the immune checkpoint inhibitor, the podophyllotoxin derivative, and the platinum-based agent in combination with plinabulin to sustain or enhance the therapeutic response.

[0087] In other embodiments, methods according to the disclosure may include a cyclical treatment regimen. For instance, methods according to the disclosure may include plinabulin, pembrolizumab, a podophyllotoxin derivative, and a platinum-based agent, such as etoposide and carboplatin, could occur on Day 1 of a 21-day cycle, followed by specific agents administered individually or in pairs on subsequent days within the cycle. This structured coadministration method may allow each agent to maximize individual effects while supporting and / or potentiating the actions of the others.

[0088] An aspect of the disclosure is directed to methods and compositions that provide a treatment approach for extensive-stage small-cell lung cancer (ES-SCLC) through a combination therapy comprising pembrolizumab, plinabulin, etoposide, and a platinum-based agent, administered within a structured 21-day cycle. Without being limited to a single theory, the disclosed compositions and methods may harness synergistic effects of immune checkpoint inhibition, tubulin binding, and cytotoxic chemotherapy to achieve enhanced therapeutic outcomes in patients diagnosed with ES-SCLC.

[0089] In certain embodiments, the disclosed treatment regimen involves administering pembrolizumab at a dosage of 200 mg intravenously on Day 1 of each cycle, with plinabulin coadministered at a dosage of 30 mg / m2, also on Day 1, to augment immune activation and enhance antigen presentation. Etoposide may be administered at 100 mg / m2on Days 1, 2, and 3, contributing cytotoxic effects against tumor cells. Additionally, a platinumbased agent, either carboplatin (AUC 5) or cisplatin (75 mg / m2), may be administered on Day 1, which may further potentiate cell death. In some embodiments, following the initial treatment cycles, maintenance therapy with pembrolizumab and plinabulin is administered every three weeks, sustaining immunotherapeutic effects until disease progression or toxicity becomes limiting.

[0090] An aspect of the disclosure is related to selecting patients or patient populations for these disclosed methods and compositions based on specific eligibility criteriato ensure optimal safety and efficacy outcomes. Tn some embodiments, patients eligible for treatment have confirmed ES-SCLC classified as Stage IV per the American Joint Committee on Cancer (AJCC) standards and at least one measurable lesion according to RECIST 1.1 criteria. Additionally, patients may exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, ensuring a level of physical capability that supports multiple treatment cycles. Patients with stable, previously treated brain metastases may also be eligible if they have demonstrated no disease progression and have not had corticosteroids within seven days prior to treatment initiation. Baseline renal, hepatic, and hematologic function may be assessed to reduce the risk of adverse events.

[0091] The disclosed methods and compositions may specify dosing and administration protocols to maximize efficacy while managing potential side effects. In some embodiments, the sequential administration of pembrolizumab, plinabulin, etoposide, and a platinum-based agent on Day 1 of each cycle provides a well-tolerated and effective administration schedule. Furthermore, ongoing maintenance dosing of pembrolizumab and plinabulin every three weeks after initial cycles may contribute to extended progression-free survival (PFS) and enhance long-term clinical benefit.

[0092] In some embodiments, these methods and compositions significantly improve clinical outcomes, as reflected by extended PFS and a higher objective response rate (ORR).

[0093] In further embodiments, the disclosed compositions may include specific labeling and regulatory guidelines to inform healthcare providers on dosing and administration for pembrolizumab when used with plinabulin in the context of the quadruple regimen. The labeling may outline the structured 21 -day cycle, administration sequence, and guidance for monitoring treatment progress, facilitating safe and effective clinical application.

[0094] In some embodiments, the labeling for the disclosed combination therapy involving pembrolizumab and plinabulin for treating extensive-stage small-cell lung cancer (ES-SCLC) may include specific dosing guidelines, patient selection criteria, and monitoring instructions tailored to optimize safety and efficacy for this patient population. In particular, the label may specify administration of pembrolizumab at 200 mg intravenously on Day 1 of each 21 -day cycle, administered with plinabulin at 30 mg / m2intravenously on Day 1, andcombined with etoposide and a platinum-based agent, such as carboplatin or cisplatin, according to standard dosing protocols for these agents.

[0095] The labeling may further recommend that patients selected for this treatment regimen meet specific clinical criteria, including confirmed ES-SCLC as defined by AJCC Stage IV standards, at least one measurable lesion according to RECIST 1.1 criteria, and an ECOG performance status of 0 or 1. For patients with previously treated brain metastases, the label may instruct that only those without evidence of progression and those who have been off corticosteroids for at least seven days prior to treatment are eligible.

[0096] The label may also contain monitoring guidelines for potential adverse events and toxicity management, recommending regular assessments of hematologic, hepatic, and renal function prior to each cycle. Special monitoring may be advised for immune-related adverse events, particularly for those involving immune checkpoint inhibitors, such as fatigue, hypertension, and neutropenia. The label may provide guidance on managing such events, including the potential use of dose adjustments or temporary treatment discontinuation if specific adverse effects exceed Grade 3. In addition, the label may advise on continuing maintenance therapy with pembrolizumab and plinabulin every three weeks following the initial cycles, to prolong progression-free survival (PFS) and achieve sustained clinical benefit.

[0097] In some embodiments, the disclosure relates to methods for selecting a patient group suitable for treatment with a pharmaceutical composition comprising pembrolizumab, plinabulin, etoposide, and a platinum-based agent. This selection process may include identifying patients diagnosed with extensive-stage small-cell lung cancer , specifically defined as Stage IV according to American Joint Committee on Cancer (AJCC) criteria. Patients chosen for this treatment may exhibit at least one measurable lesion in line with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, allowing for standardized monitoring of response to therapy.

[0098] To ensure patient tolerance to the therapeutic regimen, this method may also involve selecting individuals with a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, reflecting sufficient physical function. In some embodiments, the selection may extend to patients with previously treated brain metastases, provided there is no evidence of progression and corticosteroid therapy has not been used in the seven days preceding treatment initiation. Additionally, patients may be confirmed to have adequate renal,hepatic, and hematologic function, ensuring they are capable of tolerating the combined effects of the disclosed therapeutic agents. This method aims to optimize therapeutic outcomes by selecting patients most likely to benefit from the combination therapy while minimizing risks associated with treatment.

[0099] In certain embodiments, the disclosed methods involve a schedule for the administration of pembrolizumab, plinabulin, the podophyllotoxin derivative (e.g.. etoposide), and the platinum-based agent , with dose timing and adjustments monitored closely by staff. Pembrolizumab may be administered at a dose of 200 mg as an intravenous (IV) infusion, targeting a 30-minute infusion time every three weeks. A timing window of -5 to +10 minutes is permitted to account for site-to-site variability in infusion equipment. For cycles following Cycle 1 Day 1, pembrolizumab may be administered up to three days before or after the scheduled Day 1 of each cycle for administrative reasons.

[0100] Plinabulin administration may be adjusted based on the patient’s health status on dosing days. Plinabulin dosing will be withheld if the patient exhibits any signs of infection, elevated absolute neutrophil count (ANC) >1500, or any other medical condition that, in the investigator’s judgment, would contraindicate dosing. As suitable, dosing of plinabulin may be delayed up to 14 days to allow for patient recovery from adverse events. Dose adjustments to 20 mg / m2may be permitted if adverse effects, such as Grade 2 tumor pain, elevated blood pressure, or constipation, necessitate modification. In cases of Grade 3 or 4 hematologic toxicides that resolve within two weeks, plinabulin may resume at the initial 30 mg / m2dose. However, if severe non-hematologic adverse events suggest further delay or recur, plinabulin will be reduced to 20 mg / m2, with only one dose reduction permitted. If toxicides persist or increase in severity despite dose reduction, plinabulin will be discontinued.

[0101] The podophyllotoxin derivative and a platinum-based agent administration may include administration of either carboplatin or cisplatin along with etoposide. Carboplatin, dosed to achieve an area under the curve (AUC) of 5, is infused over approximately 60 minutes every three weeks (Q3W) on Day 1 for up to four cycles, with a maximum dose of 750 mg per infusion. Cisplatin may be used as an alternative, administered at 75 mg / m2IV over 60 minutes, though an infusion window of 30 to 180 minutes is acceptable based on institutional standards of care (SOC). Body surface area (BSA) for cisplatin dosing is calculated using the Duboisand Dubois or Mosteller formula, with dose adjustments suggested if patient weight changes by more than 10%.

[0102] Etoposide may be administered at 100 mg / m2via IV on Days 1. 2, and 3 of each 21 -day cycle, with the infusion scheduled consecutively over three days without interruption. A 30 to 60-minute infusion time is recommended for etoposide, although an infusion time of up to 120 minutes may be implemented as necessary based on local SOC. Body surface area calculations for etoposide dosing remain consistent across cycles unless patient weight fluctuates by more than 10%.

[0103] The disclosed methods also encompass criteria for re-treatment, ensuring that each patient meets baseline laboratory and clinical parameters before beginning a new cycle. Laboratory parameters include AST and ALT <2.5 x ULN (or <1.5 x ULN if alkaline phosphatase >2.5 x ULN), serum bilirubin <ULN (or <3.0 x ULN in cases of Gilbert’s disease), creatinine <1.5 x ULN, hemoglobin >9 g / dL, ANC >1.5 x 109 / L, and platelet count >100 x 109 / L. In cases where adverse events occur between cycles, patients must recover to at least baseline levels or to levels consistent with eligibility criteria before re-treatment.

[0104] In some embodiments, methods and compositions disclosed herein include dose modification and toxicity management protocols for a therapeutic regimen involving pembrolizumab, plinabulin, etoposide, and a platinum-based agent. Dose modifications are informed by the clinician’s assessment of adverse events (AEs) and causality, with specific consideration for individual drugs within the combination. Toxicity assessment may be based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0, where the dose modification is determined by the most severe AE experienced during a treatment cycle. All dose modifications may suggest that the toxicity resolve to Grade <1 or baseline prior to resuming the next cycle, with exceptions made for certain non-severe, persistent AEs such as alopecia, Grade 2 fatigue, or endocrine -related AEs requiring hormone replacement.

[0105] For immune-related AEs (irAEs) associated with pembrolizumab and any immuno-oncology (IO) agents, severe or life-threatening irAEs may suggest corticosteroid administration, starting with intravenous (IV) corticosteroids followed by a tapering course of oral corticosteroids. If irAEs do not resolve or if corticosteroid doses cannot be reduced to <10 mg / day within 12 weeks, IO therapy may be permanently discontinued. The resumption ofstudy treatment following an irAE suggests that the AE resolve to Grade <1 , supported by a completed corticosteroid taper lasting at least four weeks.

[0106] The following table provides a summary of dose levels and dose modification protocols for each agent in the combination, alongside general toxicity management guidelines. Dose reductions for etoposide, carboplatin / cisplatin, and plinabulin are implemented in response to toxicity severity, with predefined dose levels shown below. Notably, pembrolizumab does not allow for dose reductions; instead, dose interruptions or discontinuation are employed based on AE severity.

[0107] Table 1: dose levels and dose modification

[0108] For irAE management in patients on pembrolizumab, specific dose modification guidelines are applied based on AE grade. For Grade 2 pneumonitis, pembrolizumab is withheld, and corticosteroids are initiated with prophylactic antibiotics if necessary. Persistent or recurrent Grade 2 pneumonitis, as well as Grade 3 or 4 pneumonitis, result in permanent discontinuation of pembrolizumab. For other irAEs, including diarrhea / colitis, elevated liver enzymes, and thyroid disorders, dose adjustments or treatment discontinuation are determined based on the severity and recurrence of the AE.

[0109] Additionally, infusion-related reactions, particularly with pembrolizumab, may be managed according to the intensity of the reaction. For Grade 1 reactions, increased monitoring is recommended, while Grade 2 reactions may suggest infusion interruption and symptomatic treatment, with premedication administered for subsequent doses. Severe (Grade 3) and life-threatening (Grade 4) reactions suggest permanent discontinuation of pembrolizumab and may involve emergency medical interventions such as corticosteroids or pressors.

[0110] For patients receiving plinabulin, specific dose delays or reductions may be indicated for certain adverse reactions. If Grade 3 or 4 hematologic toxicides resolve tobaseline within two weeks, plinabulin may be reintroduced at the original dose level (30 mg / m2). In cases of recurrent severe toxicity or delayed resolution, plinabulin may be reduced to 20 mg / m2, with permanent discontinuation if severe toxicity recurs after dose reduction.

[0111] An aspect of the disclosure relates to certain concomitant medications that are not recommended to be taken with the disclosed method and compositions. In certain embodiments, methods of the disclosure suggest against specific concomitant medications during therapy. Participants are advised to avoid receiving antineoplastic systemic chemotherapy or biological therapy, as well as immunotherapy or chemotherapy not specified within the disclosure. Radiation therapy may be similarly advised against. Live or attenuated vaccines should be avoided within 30 days prior to the first dose and throughout participation.

[0112] Regarding COVID-19 vaccinations, any licensed vaccine (including those approved for Emergency Use) is allowed, provided it is an mRNA-based, adenoviral vectorbased, or inactivated formulation. Investigational vaccines, specifically those not licensed or approved for Emergency Use, are suggested against during treatment. Systemic glucocorticoids are suggested only for specific conditions, including managing adverse events with suspected immunologic etiology, preventing emesis, premedicating for IV contrast allergies, or treating COPD exacerbations, with short-term oral or IV use limited to a daily dose not exceeding 10 mg prednisone equivalent. Chronic systemic replacement of glucocorticoids may be used up to 10 mg / day prednisone equivalent. Other forms of glucocorticoid administration, such as topical, ocular, intraarticular joint injections, or inhalational use for asthma or chronic obstructive pulmonary disease, are generally acceptable within the study parameters.

[0113] In certain embodiments, the disclosed methods include identifying molecular biomarkers, such as genomic, metabolic, and proteomic markers, that may provide insight into clinical response, resistance profiles, safety, or the mechanisms of action for the combination therapy of pembrolizumab, plinabulin, and EP (etoposide and platinum-based agent). These biomarkers, which may include tumor mutational burden (TMB), circulating tumor cells (CTCs), and other relevant markers, are analyzed using blood samples and / or tumor tissue collected from participants. Such biomarkers correlate with the therapeutic efficacy and tolerability of the treatment regimen and may also elucidate underlying pathways driving clinical outcomes.ExamplesExample 1: Combination Regimen with Plinabulin

[0114] A Phase II clinical study evaluated the efficacy and safety of a combination regimen for treating first line extensive-stage small-cell lung cancer (ES-SCLC), comprising pembrolizumab, plinabulin, etoposide, and a platinum-based agent. The protocol involved a 21 -day treatment cycle in which pembrolizumab was administered intravenously at 200 mg on Day 1 , followed by plinabulin at 30 mg / m2on Day 1 , etoposide at 100 mg / m2on Days 1 , 2, and 3, and either carboplatin (AUC 5) or cisplatin (75 mg / m2) on Day 1. Following completion of the initial cycles, maintenance therapy with pembrolizumab and plinabulin was continued every three weeks until disease progression or unacceptable toxicity. Prophylactic anti-emetic medications, including 5-HT3 receptor antagonists and dexamethasone, may be provided prior to plinabulin administration to prevent nausea and vomiting. The trial schema is depicted in Figure 1.

[0115] Patients undergo up to 35 cycles, with imaging assessments conducted every few cycles for response evaluation and periodic hematology and chemistry assessments to monitor for adverse events. Upon completing or discontinuing treatment, an end-of- treatment assessment captures final response data. Follow-up occurs every 9 weeks, allowing for long-term monitoring of adverse events and disease progression. This protocol ensures consistent evaluation of patient outcomes and detailed tracking of therapeutic impact throughout the study.

[0116] Endpoints monitored during the study include progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). PFS may be assessed using RECIST 1.1 criteria, with imaging performed every 6 to 9 weeks to evaluate disease progression. ORR may be measured by the percentage of patients achieving partial or complete tumor shrinkage. Safety assessments may be conducted throughout the study, with particular focus on immune-related adverse events (irAEs) such as fatigue and hypertension, as well as hematologic toxicides, including neutropenia.

[0117] The clinical results demonstrated a significant improvement in key outcomes for the quadruple regimen. Patients receiving the combination exhibited an objective response rate (ORR) of 86% (12 PR in 14 evaluable patients), with the majority of patients showing partial response with >50% tumor reduction. Additionally, the incidence of grade 4neutropenia was reduced to 5%, a substantial decrease compared to historical data, which often reported 20% in chemotherapy-based regimens without plinabulin. Safety monitoring indicated better tolerance, with fewer hospitalizations due to treatment-related infections, and manageable immune-related adverse events (irAEs), such as fatigue and hypertension. Patients with previously treated brain metastases tolerated the regimen well, showing no significant neurological complications. These findings underscore the potential of this quadruple regimen as an effective and well-tolerated first-line therapy for ES-SCLC, demonstrating both enhanced efficacy and a favorable safety profile.

[0118] Figure 2 depicts a waterfall plot illustrating the tumor response from 14 patients. The chart displays individual patient responses in terms of percentage tumor reduction over multiple treatment cycles. Each bar represents a different patient, with the height of the bar indicating the extent of tumor shrinkage as a percentage. Tumor response percentages are shown at different intervals, reflecting cumulative reductions following treatment cycles. The number of cycles when the tumor reduction occurs are indicated for each patient. The highest tumor reduction of 61.0% was observed in a patient by the 2nd cycle, and several patients maintained reductions greater than 50% by the 4th and 6th cycles, indicating sustained tumor shrinkage over time.

Claims

WHAT TS CLAIMED TS:

1. A method for treating Small-Cell Lung Cancer (SCLC) in a subject, comprising administering to the subject: a) an immune checkpoint inhibitor; b) a tubulin binding agent; c) a podophyllotoxin derivative; and d) a platinum-based agent.

2. The method of claim 1, wherein the tubulin binding agent is plinabulin.

3. The method of claim 2, wherein plinabulin is administered at a dose ranging from 10 mg / m2to 30 mg / m2.

4. The method of any one of claims 1-3, wherein the immune checkpoint inhibitor is selected from inhibitors targeting PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7- H3, B7-H4, KIR, or TIM3.

5. The method of claim 4, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, atezolizumab, durvalumab, Cemiplimab, Dostarlimab, Retifanlimab, Toripalimab, Tislelizumab, Sintilimab, Vopratelimab, Spartalizumab, Camrelizumab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Avelumab, KN035, Cosibelimab, AUNP12, CA-170, BMS-986189, ABP 234, ABP 206, or combinations thereof.

6. The method of claim 5, wherein the immune checkpoint inhibitor is pembrolizumab.

7. The method according to any of the preceding claims, wherein the podophyllotoxin derivative is selected from etoposide, etoposide phosphate, teniposide, and their analogs.

8. The method according to any of the preceding claims, wherein the platinum-based agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, and satraplatin or combinations thereof.

9. The method of claim 8, wherein the platinum-based agent is carboplatin.

10. The method according to any of the preceding claims, wherein the podophyllotoxin derivative is etoposide.

11. The method of claim 10, wherein the etoposide and platinum-based agent are administered on days 1, 2, and 3 of each 21 -day cycle.

12. The method of any one of the preceding claims, wherein the administration is performed as part of a first-line treatment for extensive- stage Small-Cell Lung Cancer (ES- SCLC).

13. The method of any one of the preceding claims, wherein the immune checkpoint inhibitor is administered intravenously at a frequency ranging from every three weeks to every six weeks.

14. The method of any one of the preceding claims, wherein the subject has been diagnosed with extensive-stage small-cell lung cancer (ES-SCLC), defined as Stage IV (T any, N any, M la / b) according to the American Joint Committee on Cancer, Eighth Edition.

15. The method of claim 14, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

16. The method of any one of the preceding claims, further comprising identifying the subject as having at least one measurable lesion as defined by RECIST 1.1 criteria.

17. The method of claim 1, comprising: a) administering pembrolizumab at a dose of 200 mg intravenously on Day 1 of a 21 -day cycle; b) administering plinabulin at a dose of 30 mg / m2intravenously on Day 1 of the 21 -day cycle; c) administering etoposide at 100 mg / m2intravenously on Days 1, 2, and 3 of the 21 -day cycle; d) administering a platinum-based agent, selected from cisplatin or carboplatin, intravenously on Day 1 : and repeating the 21 -day cycle one or more times.

18. The method of any one of the preceding claims, further comprising administering one or more prophylactic medications prior to the infusion of plinabulin.

19. The method of claim 18, wherein the one or more prophylactic medications comprise 5-HT3 receptor antagonists and / or dexamethasone.

20. The method of any one of the preceding claims, comprising repeating the administration for up to 35 cycles or until disease progression or unacceptable toxicity occurs.

21. The method of any one of the preceding claims, further comprising administering radiation to the subject.

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