Method of using AC electric fields and checkpoint inhibitors

Abstract

A method for improving the survival of a subject with cancer is disclosed, comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering the subject a therapeutically effective amount of a checkpoint inhibitor. A method for treating a subject with cancer is disclosed, comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering the subject a therapeutically effective amount of a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is nivolumab, pembrolizumab, or atezolizumab. Furthermore, a method for improving the survival of a subject with non-small cell lung cancer is disclosed, comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering the subject a therapeutically effective amount of a checkpoint inhibitor. A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (brand name Ributayo), dostallimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), or avelumab (Bavencio).

Description

[Background technology]

[0001] Globally, lung cancer is a leading cause of cancer death, with an estimated 1.8 million deaths in 2020. In the United States, more than 230,000 new cases and over 130,000 deaths from lung cancer are reported annually. Approximately 84% of lung cancer patients have non-surgical lung cancer (NSCLC), and of those, about 60% have distant metastases at the time of diagnosis (stage IV).

[0002] Despite the introduction of immune checkpoint inhibitors, metastatic non-small cell lung cancer (NSCLC) remains a disease that is difficult to cure.

[0003] Immune checkpoint inhibitors are a type of immunotherapy approved for the treatment of various cancers, including melanoma, cervical cancer, colorectal cancer, and lung cancer. These drugs inhibit different checkpoint proteins. They are also sometimes named after these checkpoint proteins, for example, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. The NCCN guidelines do not recommend the use of PD-1 / PD-L1 inhibitors if disease progression occurs during treatment with those inhibitors. The standard treatment for patients whose disease has progressed after treatment with PD-1 / PD-L1 inhibitors is mainly various chemotherapy regimens or combination therapy with docetaxel and ramucirumab. According to the ESMO guidelines, for patients with adenocarcinoma whose disease has progressed after chemotherapy and PD-1 / PD-L1 treatment, combination therapy with docetaxel and nintedanib is an additional option.

[0004] Platinum-based therapies remain in use as part of standard care, either in combination with first-line immune checkpoint inhibitors, as a subsequent treatment, or as part of standard care for patients who cannot tolerate immune checkpoint inhibitors. However, there are few treatments that have been shown to extend survival in patients whose disease progresses with platinum-based therapies. Current approaches include combination therapy with or monotherapy with other chemotherapy regimens (mainly docetaxel) or immune checkpoint inhibitors, or readmission of immune checkpoint inhibitors.

[0005] Tumor-therapeutic electric fields (TT fields, e.g., 150 kHz) are electric fields that inhibit processes essential for cancer cell survival and tumor growth. TT field therapy is delivered locally and non-invasively to the tumor site via two arrays placed on the patient's skin using a portable medical device (Figure 3). Based on two randomized phase 3 trials, TT field therapy has received FDA approval and CE marking for glioblastoma and unresectable pleural mesothelioma. TT field therapy is not associated with systemic toxicity, and the most frequent device-related adverse event is manageable mild to moderate array-based skin irritation resulting from contact with device components.

[0006] The TT field influences cancer cells through unique, multifaceted mechanisms of action, including inhibition of the DNA damage response and disruption of mitosis. In a preclinical model of NSCLC, induction of cellular stress and immunogenic cell death was shown to enhance the antitumor immune response. Furthermore, TT field therapy amplified the preclinical effects of immune checkpoint inhibitors and taxane-based anticancer drugs. The TT field is associated with stimulation of the STING pathway, which leads to its antitumor effects.

[0007] However, STING has been suggested to be involved in promoting tumor burden and worsening prognosis in cancer models. While transient activation appears to be beneficial, adverse effects are thought to depend on the stimulation of chronic inflammatory programs that promote an immunosuppressive tumor environment. STING ligands can also induce the expression of inhibitory molecules, which counteract the tumor-suppressive effects of type I interferons. STING's pro-apoptotic effect on T cells may also contribute to limited removal of tumor cells. In advanced disease environments, STING-mediated inflammation reduction may allow aggressive cancer cells to adapt and overcome the disease, ultimately enabling further proliferation and spread. Therefore, chronic STING signaling is considered an important issue to consider in tumor therapies targeting this pathway (Decout, A., Katz, JD, Venkatraman, S. et al. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol 21, 548-569 (2021)).

[0008] The majority of NSCLC patients eventually experience disease progression, losing resistance to symptoms or developing resistance to existing treatments, resulting in low overall survival (OS) in advanced-stage patients. Therefore, there is a need for new therapies that can extend the survival of this patient population without worsening treatment side effects, including quality of life. [Overview of the project]

[0009] A method for improving the survival time of a subject with cancer is disclosed, which includes applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor.

[0010] A method for improving the survival time of a subject with cancer is disclosed, comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering a therapeutically effective amount of the checkpoint inhibitor to the subject. A method for treating a subject with cancer is also disclosed, comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering a therapeutically effective amount of the checkpoint inhibitor to the subject.

[0011] A checkpoint inhibitor used in a method for treating a subject with cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering a therapeutically effective amount of the checkpoint inhibitor to the subject.

[0012] In some embodiments, the checkpoint inhibitor is nivolumab, pembrolizumab, or atezolizumab.

[0013] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor.

[0014] A checkpoint inhibitor used in a method to improve the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of the checkpoint inhibitor to the subject.

[0015] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the non-small cell lung cancer in the subject has progressed during or after prior treatment with the checkpoint inhibitor.

[0016] A checkpoint inhibitor used in a method to improve the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of the checkpoint inhibitor to the subject, wherein the non-small cell lung cancer in the subject has progressed during or after prior treatment with the checkpoint inhibitor.

[0017] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the non-small cell lung cancer in the subject has progressed during or after prior treatment with the checkpoint inhibitor and chemotherapy.

[0018] A checkpoint inhibitor used in a method to improve the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of the checkpoint inhibitor to the subject, wherein the non-small cell lung cancer in the subject has progressed during or after prior treatment with the checkpoint inhibitor and chemotherapy.

[0019] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has not received prior treatment with non-platinum or platinum-based chemotherapy.

[0020] A checkpoint inhibitor used in a method to improve the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of the checkpoint inhibitor to the subject, wherein the subject has not received prior treatment with non-platinum or platinum-based chemotherapy.

[0021] A method for improving the survival time of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor and has not received prior treatment with platinum-based chemotherapy.

[0022] A checkpoint inhibitor used in a method to improve the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of the checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor and has not received prior treatment with platinum-based chemotherapy.

[0023] A method of treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor.

[0024] A checkpoint inhibitor for use in a method of treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor.

[0025] A method of treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the non-small cell lung cancer in the subject has progressed during or after pre-treatment with the checkpoint inhibitor.

[0026] A checkpoint inhibitor for use in a method of treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the non-small cell lung cancer in the subject has progressed during or after pre-treatment with the checkpoint inhibitor.

[0027] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the non-small cell lung cancer in the subject has progressed during or after pretreatment with the checkpoint inhibitor and chemotherapy.

[0028] A checkpoint inhibitor for use in a method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the non-small cell lung cancer in the subject has progressed during or after pretreatment with the checkpoint inhibitor and chemotherapy.

[0029] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received pretreatment with the checkpoint inhibitor and has not received pretreatment with non-platinum-based chemotherapy or platinum-based chemotherapy.

[0030] A checkpoint inhibitor for use in a method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating current electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received pretreatment with the checkpoint inhibitor and has not received pretreatment with non-platinum-based chemotherapy or platinum-based chemotherapy.

[0031] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor and has not received prior treatment with platinum-based chemotherapy.

[0032] A checkpoint inhibitor used in a method for treating a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of the checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor and has not received prior treatment with platinum-based chemotherapy.

[0033] In some embodiments, the checkpoint inhibitors used are ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (brand name Ributayo), dostallimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), or avelumab (Bavencio).

[0034] A taxane-based anticancer agent used in a method to improve the survival time of a subject with cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering a therapeutically effective amount of the taxane-based anticancer agent to the subject.

[0035] A taxane-based anticancer agent used in a method for treating a subject having cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering a therapeutically effective amount of the taxane-based anticancer agent to the subject.

[0036] A method for improving the survival time of a subject with cancer is disclosed, which includes applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a taxane-based anticancer agent.

[0037] A method for treating a subject having cancer is disclosed, which includes applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a taxane-based anticancer agent.

[0038] In some embodiments, the taxane-based anticancer agents are docetaxel, paclitaxel, cabazitaxel, abraxane, or a combination thereof.

[0039] Additional advantages of the disclosed methods and compositions are partially described in the following description, partially understood from the description, or acquired through practice of the disclosed methods and compositions. The advantages of the present invention are realized and achieved by the elements and combinations specifically pointed out in the appended claims. It should be understood that the above general description and the following detailed description are for illustrative and explanatory purposes only and do not limit the claimed invention. [Brief explanation of the drawing]

[0040] The accompanying drawings incorporated herein and forming part thereof illustrate several embodiments of the disclosed methods and compositions and, together with the description, are useful in illustrating the principles of the disclosed methods and compositions.

[0041] [Figure 1] This shows the overall survival period for the entire target population (estimated overall survival period using the Kaplan-Meier method). [Figure 2] This shows overall survival in the treatment subgroup (estimated overall survival using the Kaplan-Meier method). [Figure 3][Figure 3A] An example of a device that generates and delivers a TT field is shown: a tumor treatment electric field (TT field) medical device. [Figure 3B] An example of a device that generates and delivers a TT field is shown: a tumor treatment electric field (TT field) medical device. [Figure 3C] An example of a device that generates and delivers a TT field is shown: a tumor treatment electric field (TT field) medical device. [Figure 3D] An example of a device that generates and delivers a TT field is shown: a tumor treatment electric field (TT field) medical device. [Figure 3A] Components of the wearable first-generation (NovoTTF-100L) and second-generation (NovoTTF-200T) devices that generate and deliver a TT field are shown. [Figure 3B] Components of the wearable first-generation (NovoTTF-100L) and second-generation (NovoTTF-200T) devices that generate and deliver a TT field are shown. The lighter (1.2kg vs. 2.7kg) NovoTTF-200T device was introduced during the patient enrollment period, and patients were able to use either device. [Figure 3C] An image of a person (not a patient) wearing an array configuration targeting NSCLC. [Figure 3D] A chest X-ray / CT / PET scan image with tumor location highlighted, overlaid with a field simulation projection. [Figure 4] This document outlines the study design and major protocol modifications. The original protocol assigned patients to the NovoTTF-100L system. This was updated to allow the use of the smaller, lighter second-generation NovoTTF-200T system. Following a pre-designated annual review of safety and overall survival data by the Data Monitoring Committee (March 31, 2021), the committee recommended that the study endpoints could be analyzed with a reduced sample size of 276 patients and 12 months of follow-up. CT: Computed Tomography, FDA: Food and Drug Administration, ICI: Immune Checkpoint Inhibitor, OS: Overall Survival, Q6W: Every 6 Weeks, R: Randomization, TT Field: Tumor Therapy Field. [Figure 5] The data shows overall survival in patients with squamous cell carcinoma and non-squamous cell carcinoma, with standard treatment referring to immune checkpoint inhibitors or docetaxel. [Figure 6] This shows progression-free survival in the entire patient population, and standard treatment refers to immune checkpoint inhibitors or docetaxel. [Figure 7] This shows progression-free survival in patients treated with immune checkpoint inhibitors or docetaxel. [Modes for carrying out the invention]

[0042] The disclosed methods and compositions may be more readily understood by referring to the following detailed descriptions of specific embodiments and the examples contained herein, as well as the figures and their preceding and succeeding descriptions.

[0043] It should be understood that the disclosed methods and compositions are not limited to specific synthesis methods, analytical techniques, or reagents, and are subject to change unless otherwise specified. It should also be understood that the terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit them.

[0044] Materials, compositions, and components that can be used in, in combination with, or in preparation of the disclosed methods and compositions, or that are products thereof, are disclosed herein. While specific reference to various individual and collective combinations and permutations of these materials may not be explicitly disclosed, it is understood that each is specifically considered and described herein. For example, if a peptide is disclosed and discussed, and multiple modifications that can be made to multiple molecules containing amino acids are considered, then, unless otherwise stated, all combinations and permutations of the peptide and possible modifications are specifically assumed. Therefore, if classes A, B, and C are disclosed, and further classes D, E, and F and examples of combined molecules AD are disclosed, then each is considered individually and collectively, even if not individually described. Thus, in this example, each combination of AE, AF, BD, BE, BF, CD, CE, and CF is specifically considered and should be considered disclosed from the disclosure of A, B, and C, D, E, and F and example combination AD. Similarly, these subsets or combinations are also specifically considered and disclosed. Therefore, for example, the subgroups AE, BF, and CE are specifically envisioned and should be considered disclosed from the disclosures of A, B, and C, D, E, and F, as well as example combinations A through D. This concept applies to all embodiments of the Application, including but not limited to steps of methods for manufacturing and using the disclosed compositions. Therefore, where there are various additional steps that can be implemented, each of these additional steps can be implemented in any particular embodiment or combination of embodiments of the disclosed method, and each such combination is specifically considered and should be considered disclosed. Section I A.Definition

[0045] The disclosed methods and compositions are not limited to the specific methods, protocols, and reagents described, and it is understood that these may vary. Furthermore, the terms used herein are for illustrative purposes only to describe specific embodiments and are not intended to limit the scope of the invention, and the scope of the invention is limited only by the appended claims.

[0046] In this specification and the attached claims, the singular forms “a,” “an,” and “the” also include plural references unless the context clearly indicates otherwise. For example, a reference to “checkpoint inhibitors” includes multiple such inhibitors, and a reference to “checkpoint inhibitors” includes one or more inhibitors and their equivalents known to those skilled in the art.

[0047] In this specification, “alternating current field” refers to a very low-intensity, directional, medium-frequency alternating current field delivered to a subject, a sample taken from a subject, or a specific location within a subject or patient (e.g., a target site). In some embodiments, the alternating current field may be unidirectional or multidirectional. In some embodiments, the alternating current field may be delivered through two pairs of transducer arrays that generate a field perpendicular to the therapeutic target site. For example, in the Optune® system (alternating current field delivery system), one pair of electrodes is positioned to the left and right (LR) of the target site, and the other pair of electrodes is positioned to the front and back (AP) of the target site. By circulating the electric field between these two directions (LR and AP), it is ensured that the widest range of cellular directions are targeted. In some embodiments, the alternating current field may be referred to as a tumor therapeutic field (TT field).

[0048] In vivo and inhydro studies have shown that the effectiveness of alternating current field therapy increases with increasing electric field intensity. Therefore, the Optune system can be used to optimize the array placement in the patient's tumor area and increase the intensity in the desired area of ​​the tumor. Optimization of array placement can be performed by "rules of thumb" (e.g., placing the array on the tumor as close as possible to the desired area of ​​the target site (e.g., cancer cells)) or by measurements describing the geometric shape of the patient's tumor and the dimensions of the tumor. Measurements used as input may be obtained from image data. Image data includes all kinds of visual data, such as single-photon emission computed tomography (SPECT) image data, X-ray computed tomography (X-ray CT) data, magnetic resonance imaging (MRI) data, positron emission tomography (PET) data, and data that can be acquired by optical instruments (e.g., photographic cameras, charge-coupled device (CCD) cameras, infrared cameras, etc.). In certain embodiments, image data may include 3D data (e.g., point cloud data) acquired from or generated by a 3D scanner. Optimization may depend on understanding how the electric field is distributed at the target site as a function of the array's position, and in some embodiments, taking into account variations in the electrical property distribution of the same target site across different patients.

[0049] The term "subject" refers to the subject of administration, for example, an animal. Therefore, the subject of the disclosed method may be a vertebrate, such as a mammal. For example, the subject may be a human. This term does not indicate a specific age or sex. "Subject" may be used interchangeably with "individual" or "patient." For example, the subject being administered may mean one that is subjected to an alternating electric field.

[0050] "To treat" means administering or applying a treatment, such as an alternating electric field, to a subject, such as a human or other mammal (e.g., an animal model), who has cancer or is at high susceptibility to developing cancer, in order to prevent or slow the progression of the effects of cancer, or to partially or completely reverse the effects of cancer (glioblastoma, ovarian cancer, or metastatic lung cancer).

[0051] "Prevention" means minimizing the likelihood that subjects with a high susceptibility to developing cancer will develop cancer.

[0052] As used herein, the terms “administering” and “administration” refer to any method for providing a therapeutic agent, such as a checkpoint inhibitor, to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, nasal, topical, vaginal, intraocular, intraocular, intracerebral, rectal, sublingual, buccal, and parenteral administration, including injections such as intravenous, intra-arterial, intramuscular, and subcutaneous. Administration may be carried out continuously or intermittently. In various embodiments, formulations may be administered therapeutically, i.e., to treat a pre-existing disease or condition. In various further embodiments, formulations may be administered prophylactically, i.e., to prevent a pre-existing disease or condition. In one embodiment, a skilled technician may determine an effective dose, effective schedule, or effective route of administration to treat a subject. In some embodiments, administration includes exposure. Thus, in some embodiments, exposure of cancer cells to an alternating electric field means administering an alternating electric field to cancer cells.

[0053] In this specification, “therapeutably effective amount” means a therapeutic, prophylactic, and / or diagnostic agent sufficient to treat, alleviate, improve, reduce symptoms, prevent, delay onset, inhibit progression, reduce severity, and / or decrease incidence of a disease, disorder, and / or condition when administered to a subject who has or is highly susceptible to such disease, disorder, and / or condition.

[0054] As used herein, the word "or" means any of the components of a particular list, and also includes any combination of the components of that list.

[0055] In this specification, “sample” means an animal, animal-derived tissue or organ, cell (taken directly from a subject, maintained in culture, or derived from a cultured cell line), cell lysate (or fraction of a lysate) or cell extract, or a solution containing one or more molecules derived from a cell or cell-derived substance (e.g., polypeptide or nucleic acid), which are measured by the methods described herein. A specimen may mean any bodily fluid or excretory material containing cells or cellular components (e.g., blood, urine, feces, saliva, tears, bile, etc.).

[0056] In this specification, the term “subject” refers to a subject of administration, such as an animal. Therefore, the subject of the disclosed method may be a vertebrate, such as a mammal. For example, the subject may be a human. This term does not indicate a specific age or sex. “Subject” can be used interchangeably with “individual” or “patient.”

[0057] In this specification, ranges may be expressed as "approximately" from a particular value and / or "approximately" to another particular value. Where such ranges are expressed, unless otherwise specified in the context, the range from a particular value and / or to another particular value is also specifically assumed and disclosed. Similarly, where the use of the antecedent "approximately" expresses a value as an approximation, it is understood that, unless otherwise specified in the context, that particular value forms another specifically considered embodiment that should be considered disclosed. Furthermore, unless otherwise specified in the context, it is understood that each endpoint of a range is important both in relation to and independently of other endpoints. Finally, it should be understood that all individual values ​​and subranges of values ​​included within an explicitly disclosed range are also specifically assumed and should be considered disclosed unless otherwise indicated in the context. The foregoing applies regardless of whether some or all of these embodiments are explicitly disclosed in a particular case.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the disclosed methods and compositions belong. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the methods and compositions of the present invention, but the methods, apparatus and materials described herein are particularly useful. Publications cited herein and the materials from which they are cited are expressly incorporated herein by reference. Nothing in this specification should be construed as admitting that the present invention does not have prior rights to this disclosure by prior art. No reference is acknowledged to constitute prior art. The descriptions of references state the claims of their authors, and the applicant reserves the right to object to the accuracy and validity of the cited documents. Numerous publications are referenced herein, but it is clear that such references do not acknowledge that any of these documents constitute part of the common general knowledge in the art.

[0059] Throughout this specification and the claims, the word “comprise” and its variations “comprising” and “comprises” mean “not limited to” and are not intended to exclude, for example, other additives, components, integers, or steps. In particular, where a method is described as comprising one or more steps or operations, it is specifically assumed that each step includes what is listed (unless the step contains a limiting term such as “consisting of”). In other words, each step is not intended to exclude other additives, components, integers, or steps, etc., that are not listed in that step. B. AC electric field

[0060] The methods disclosed herein involve alternating current fields. In some embodiments, the alternating current fields used in the methods disclosed herein are tumor therapeutic fields (TTFields). In some embodiments, the alternating current fields may vary depending on the type or state of the cells to which the alternating current fields are applied. In some embodiments, the alternating current fields may be applied via one or more electrodes placed on the body of a subject. In some embodiments, two or more pairs of electrodes may be present. For example, an array may be placed on the front / back and sides of the patient and may be used with the systems and methods disclosed herein. In some embodiments, when two pairs of electrodes are used, the alternating current fields may be generated alternately between the electrode pairs. For example, a first pair of electrodes may be placed on the front and back of the subject, and a second pair of electrodes may be placed on either side of the subject, and then the alternating current fields may be applied alternately between the front and back electrodes, and then between the left and right electrodes.

[0061] In some embodiments, the frequency of the AC electric field is 100 kHz to 500 kHz. The frequency of the AC electric field may be, but is not limited to, 50 to 500 kHz, 100 to 500 kHz, 25 kHz to 1 MHz, 50 to 190 kHz, 25 to 190 kHz, 180 to 220 kHz, or 210 to 400 kHz. In some embodiments, the frequency of the AC electric field may be 50 kHz, 100 kHz, 200 kHz, 300 kHz, 400 kHz, 500 kHz, or any frequency in between. In some embodiments, the frequency of the AC electric field is about 200 kHz to about 400 kHz, about 250 kHz to about 350 kHz, and may be about 300 kHz.

[0062] An AC electric field can be induced by an applied voltage of at least 50 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least 25 to 200 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least about 5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, or 300 V RMS.

[0063] In some embodiments, the electric field strength of the AC electric field may be in the range of 1 to 4 V / cm RMS. In some embodiments, different electric field strengths (e.g., between 0.1 and 10 V / cm) may be used. In some embodiments, the electric field strength may be 1.75 V / cm RMS. In some embodiments, the electric field strength is at least 1 V / cm. In other embodiments, combinations of electric field strengths are applied, for example, by combining two or more frequencies simultaneously or by applying two or more frequencies at different times.

[0064] In some embodiments, the alternating current field may be applied at various intervals ranging from 0.5 hours to 72 hours. In some embodiments, different periods may be used (e.g., from 0.5 hours to 14 days). In some embodiments, the application of the alternating current field may be repeated periodically. For example, the alternating current field may be applied for 2 hours a day.

[0065] In some embodiments, exposure may be continuous for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours or more. C. Method

[0066] A method for improving the survival of a subject with cancer is disclosed, which includes applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor. In some embodiments, the extension of survival is an extension of progression-free survival.

[0067] A method for treating a subject having cancer is disclosed, which includes applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor.

[0068] In some embodiments, the checkpoint inhibitor is nivolumab, pembrolizumab, or atezolizumab.

[0069] In some aspects, this cancer is metastatic non-small cell lung cancer.

[0070] In some embodiments, the frequency of the alternating electric field is between 100 kHz and 1 MHz.

[0071] In some embodiments, these methods further include administering docetaxel or other chemotherapeutic agents. D. Kit

[0072] The compositions and materials described above may be packaged together in any suitable combination as a kit useful for carrying out or assisting in the carrying out of the disclosed method. A kit is useful if the kit components within a given kit are designed and adapted to be used together in the disclosed method. For example, a kit for cancer treatment is disclosed. In some embodiments, the kit may include a device for applying an alternating electric field. Examples A. Example 1: Tumor therapeutic electric field in previously treated metastatic non-small cell lung cancer 1. Method i. Test design and supervision

[0073] The LUNAR trial was a prospective, phase III, randomized, open-label, parallel-group trial (EF-24; NCT02973789) evaluating TT-field (150 kHz) therapy in combination with standard systemic therapy (docetaxel or an investigator-selected immune checkpoint inhibitor) in patients with metastatic NSCLC that had progressed during or after platinum-based therapy. The LUNAR trial was conducted from February 2017 to November 2021 at 124 sites in 17 countries across North America, Europe, and Asia (Table S1). The trial design is shown in Figure 4, and the full trial protocol is available online. A pilot study was also conducted to demonstrate the safety and feasibility of TT-field therapy in combination with pemetrexed in patients with advanced NSCLC. 18 The LUNAR trial was designed by the sponsor (Novocure GmbH) and the researchers. Data were collected by the researchers and analyzed by a statistician employed by the sponsor. The first draft of this paper was written by the authors with professional editorial support. All authors contributed to the interpretation of the data and ensure its completeness, accuracy, and adherence to the protocol.

[0074] An independent Data Monitoring Committee (DMC), comprised of medical oncologists, respiratory physicians, and statisticians, monitored the data, evaluated the results in interim analyses, and made recommendations to the sponsor based on adverse event rates and overall survival. The protocol and all modifications were approved by the relevant ethics committees and competent authorities at each participating site. This trial was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki, the standards for appropriate clinical trials (EN ISO 14155:2011), and all applicable national / local regulations. All patients provided written informed consent. ii. Target patient population

[0075] Eligible participants were adults (22 years of age or older) with a histological or cytological diagnosis of metastatic NSCLC who had experienced radiological progression during or after treatment with platinum-based systemic therapy (previous ICIs were acceptable). Platinum-based therapy was the most recent systemic therapy administered for advanced NSCLC, excluding maintenance therapy. Patients who progressed to metastatic disease within 6 months of completing platinum-based adjuvant therapy were also included. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 and a mean life expectancy of 3 months or more. Protocol modifications allowed for the inclusion of neurologically stable patients who had received treatment for central nervous system metastases. Exclusion criteria included serious comorbidities (including clinically significant hematological, hepatic, renal, or cardiac dysfunction), cerebrovascular events within 6 months of randomization, or another malignant tumor (excluding stage I prostate cancer, non-melanoma skin cancer, or cervical or breast carcinoma in situ) within 3 years of joining the study. The complete eligibility criteria are listed in Table S2. iii. Procedure

[0076] Eligible patients were randomly assigned in a 1:1 ratio (within 28 days of obtaining informed consent) to receive thoracic TT field therapy in combination with a standard of care of the researchers' choice (immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel). Randomization was determined uniformly using variable block randomization and the IxRS system, and stratified by tumor histological type, treatment (docetaxel or immune checkpoint inhibitor), and region (North America, Western Europe / Israel, Eastern Europe).

[0077] Docetaxel was administered intravenously as monotherapy at a dose of 75 mg / m2 over 1 hour every 3 weeks. Nivolumab was administered intravenously at a dose of 240 mg every 2 weeks, or 480 mg every 4 weeks, or at a dose based on body weight. Pembrolizumab was administered by intravenous infusion over 30 minutes at a dose of 200 mg every 3 weeks, or 400 mg every 6 weeks, or at a dose based on body weight. Atezolizumab was administered intravenously at a dose of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks over 1 hour. All systemic therapies were administered until disease progression or unacceptable toxicity occurred, and dosages were adjusted based on local standard care.

[0078] The TT field (150 kHz) was administered continuously for at least 18 hours per day on average using the NovoTTF device system (Figure 3). Patients who initiated the trial using the NovoTTF-100L system were offered the option to switch to the smaller, lighter next-generation NovoTTF-200T system. Array placement was determined by the researchers and modified as needed during the treatment period based on computed tomography scans and provided clinical practice guidelines. Patients received instruction on device use from researchers, other healthcare providers, or device support specialists (DSS, sponsor-provided). The array was replaced every 3–4 days (and moved approximately 2 cm from its original position to minimize skin irritation). TT field usage time (device recorded data) was reported to researchers monthly and presented as a percentage.

[0079] Patients treated with docetaxel were followed up every six weeks (one week before and one week after) for the purpose of radiological evaluation of lesions, based on the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, and patients treated with immune checkpoint inhibitors were followed up based on the immune-related (ir) RECIST criteria. 19、20 TT-site therapy was continued until progression in the chest and / or liver, or until unacceptable toxicity occurred. Treatment interruption of up to 3 weeks was permitted for TT-site related adverse events. Patients could continue TT-site therapy even if systemic therapy was discontinued due to progression in sites other than the chest / liver, or due to unacceptable toxicity. After progression, patients were provided with salvage therapy selected by the researchers based on local practice.

[0080] Safety assessments were conducted at each follow-up visit (from randomization to 100 days after the end of the study treatment), and adverse events were reported according to the National Cancer Institute Common Adverse Event Terminology (CTCAE) version 4.03 21. The modified grading system used to characterize TT-related skin adverse events is shown in Table S3. iv. Trial endpoints

[0081] The primary endpoint was overall survival in the standard treatment group combined with docetaxel compared to the standard treatment monotherapy group. The primary secondary endpoint was overall survival in the subgroups treated with docetaxel or immune checkpoint inhibitors. Other secondary endpoints included progression-free survival and overall response rate (both assessed by radiological diagnosis), overall survival and progression-free survival by histological type of squamous cell carcinoma and non-squamous cell carcinoma, and adverse events. A list of the trial endpoints is provided in Table S4.

[0082] Overall survival was defined as the period from randomization to death from any cause or screening at the final follow-up date. Progression-free survival was defined as the period from randomization to disease progression in the liver or chest, or death from any cause. Deaths that occurred without the researcher detecting tumor progression were considered progression events if they occurred within 6 weeks of the last tumor assessment prior to death. Otherwise, patients were screened on the last tumor assessment date. Patients with no progression or death at the time of analysis were screened on the most recent evaluable tumor assessment date. Patients with no tumor assessment after baseline were screened on the randomization date. The overall radiological response rate was defined as complete response or partial response, and the best response (classified as complete response, partial response, stable disease, disease progression, or unevaluable) was calculated for each treatment group. v. Statistical analysis

[0083] This study aimed to detect a hazard ratio <0.75 for overall survival in the docetaxel-combined standard treatment group versus the standard treatment alone group, and was designed with a two-sided proportional hazards test, two-sided α=0.05, and 80% power. With an 18-month follow-up period and a 10% patient loss rate during follow-up, the required sample size was 534 patients. If the primary endpoint was achieved at a 0.05 (two-sided) level (to maintain a Class I error), the main secondary endpoints of overall survival in the docetaxel and immune checkpoint inhibitor subgroups were to be tested hierarchically.

[0084] Overall survival and progression-free survival were assessed using a two-sided log-rank test with a test level of 0.05, stratified by treatment (immune checkpoint inhibitor or docetaxel) and tumor histological type. Median, confidence interval (CI), and rate were estimated using the Kaplan-Meier method. Hazard ratios (95% CI and P-value) were estimated using a stratified Cox proportional hazards model with the stratification variable as a covariate. For comparisons of overall response rates, the 95% CI was calculated based on an exact binomial distribution (Clopper-Pearson). Differences between treatment groups and associated two-sided 95% confidence intervals were calculated using a chi-squared test with a significance level of 0.05 (two-sided P-value). Best responses were summarized for each treatment group.

[0085] Efficacy endpoints were analyzed across the entire randomized population (intentional treatment population). Safety and treatment data were collected from all patients who received any form of treatment in this study and analyzed based on the actual treatment received. The analyses were performed using SAS software version 9.4 (SAS Institute). The detailed analysis plan is described in the statistical analysis plan, which is available online with this specification.

[0086] Based on the results of the pre-designated DMC annual review and interim analysis, the DMC concluded and recommended that continuing patient enrollment up to 534 patients was unnecessary and ethically problematic, and that enrollment of approximately 276 patients with 12 months of follow-up would provide the necessary toxicity and efficacy data for the planned trial endpoints while maintaining statistical power. The DMC did not recommend any further changes to the study protocol. 2.Results i. Patients and treatments

[0087] Between February 2017 and November 2021, 276 patients underwent eligibility screening and were randomly assigned to either the standard treatment group with TT (n=137) or the standard treatment alone group (n=139) (intentional treatment population, Figure 4).

[0088] Baseline demographic characteristics and features were similar in both groups (Table 1) and representative of patients with metastatic NSCLC (Table S5). The median age was 64.0 years (range 22–86 years), 178 patients (65%) were male, and 232 patients (84.1%) were smokers or former smokers. The majority of patients (151 [56%]) had non-squamous NSCLC histological type, 43 (16%) had liver metastases, and 10 (3.6%) had an ECOG performance status of 2. Most patients (246 [89%]) had received prior first-line systemic therapy, and patients in the docetaxel subgroup had a higher proportion of prior immune checkpoint inhibitor treatment (82 [58%] vs. 3 [2.2%]) (Table 1).

[0089] During the study period, patients received an average of 8.7 cycles (range 1–70) of standard treatment. The average duration of TT therapy was 31.8 weeks (range 0.3–201 weeks) in the immune checkpoint inhibitor combination group and 17.3 weeks (range 0.1–163 weeks) in the docetaxel combination group. Thirteen patients (19.4%) in the immune checkpoint inhibitor group and seventeen patients (25.8%) in the docetaxel group achieved an average monthly device usage time of 18 hours or more per day.

[0090] After disease progression, approximately 25% of patients received salvage systemic therapy. The most frequently administered treatments were docetaxel (24 patients [8.7%]) and gemcitabine (21 patients [7.6%]) (Table S6). ii. Effectiveness

[0091] Combination therapy with TT and checkpoint inhibitors yields particularly favorable results in patients diagnosed with metastatic NSCLC who have progressed during or after treatment with platinum-based systemic therapy and whose previous systemic therapy did not include an ICI. Combination therapy with TT and docetaxel yields particularly favorable results in patients diagnosed with metastatic NSCLC who have progressed during or after systemic therapy that may include an ICI. a. Overall survival

[0092] When TT treatment was combined with standard treatment, overall survival was significantly extended compared to standard treatment alone (Figure 1). After a minimum of 12 months of follow-up, the median overall survival in the TT treatment group was 13.2 months (95% confidence interval [CI], 13.3–15.5), compared to 10.0 months (95% CI, 8.2–12.2) in the standard treatment alone group. The mortality hazard ratio was 0.74 (95% CI, 0.56–0.98; P=0.037). The 1-year overall survival was 53% (95% CI, 44–61) in the TT treatment combined with standard treatment group and 42% (95% CI, 34–50) in the standard treatment alone group (Table 2).

[0093] In patients treated with immune checkpoint inhibitors, TT-field therapy significantly improved overall survival compared to immune checkpoint inhibitors alone. The median overall survival was 18.5 months (95% CI, 10.6–30.3) in the TT-field combination group and 10.6 months (95% CI, 8.2–17.6) in the standard treatment monotherapy group, with a mortality hazard ratio of 0.63 (95% CI, 0.41–0.96; P=0.032) (Figure 2A). The 1-year survival rate was 60% (95% CI, 47–72) in the TT-field therapy and immune checkpoint inhibitor combination group and 45% (95% CI, 33–56) in the immune checkpoint inhibitor monotherapy group. Clinical evidence suggests that combining TT-field therapy with ICIs improves tumor control and enhances anti-tumor immunity. The TT field has demonstrated additive or synergistic effects in combination with a variety of systemic therapies, including but not limited to platinum-based drugs, taxane-based anticancer agents, pemetrexed, and ICIs. When added to ICIs, it significantly increased the expression of markers associated with immunogenic cell death, as well as increased antigen-presenting cell infiltration into tumors in vivo. In the LUNAR trial, combination therapy with the TT field and ICIs significantly extended median survival (OS) from 10.8 months to 18.5 months compared to ICIs alone. These findings suggest that the TT field may enhance the immune response against tumors and reduce resistance by tumor cells through PD-1 / PD-L1 interactions.

[0094] In the docetaxel-administered subgroup, the median overall survival was 11.1 months (95% CI: 8.2–14.1) in the TT therapy group (n=71) and 8.9 months (95% CI: 6.5–12.2) in the docetaxel monotherapy group (n=71), with a mortality hazard ratio of 0.87 (95% CI, 0.60–1.26; P=0.46) (Figure 2B). The one-year survival rates were 45.6% (33.3–57.1) and 39.4% (28.1–50.5), respectively.

[0095] In patients with non-squamous cell carcinoma, the median overall survival in the TT combination group compared to the standard treatment monotherapy group was 12.6 months (95% CI 8.8-19.8) versus 9.9 months (95% CI 6.9-16.4). In patients with squamous cell carcinoma, the median overall survival in the TT treatment group was 13.9 months (95% confidence interval 9.7-17.1), compared to 10.1 months (95% confidence interval 8.3-13.8) in the standard treatment monotherapy group (Figure S4). b. Progression-free survival and overall response rate

[0096] The median progression-free survival was 4.8 months (95% CI, 4.1–5.7) in the TT field and standard therapy combination group, and 4.1 months (95% CI, 3.0–4.7) in the standard therapy monotherapy group. The hazard ratio for progression or death was 0.87 (95% CI, 0.67–1.14; P=0.45) (Figure 6). Progression-free survival in subgroups receiving immune checkpoint inhibitors or docetaxel in combination is shown in Figure 7.

[0097] The overall response rate in the group receiving TT site and standard treatment was 20.4% (95% CI, 14.0-28.2), while in the group receiving standard treatment alone it was 17.3% (95% CI, 11.4-24.6) (Table 2). All complete responses (n=5) were observed in the immune checkpoint inhibitor group (TT site combination group n=4, immune checkpoint inhibitor alone group n=1). iii. Safety

[0098] In the safety evaluation population (267 patients), almost all (251 patients [94%]) reported at least one adverse event. Compared to the standard treatment monotherapy group, the incidence of adverse events of all grades was similar in the TT combination group (129 patients [97%], 122 patients [91%]; Table 3), while the incidence of grade 3-5 adverse events was lower (69 patients [52%], 84 patients [63%]; Table S7). Serious adverse events were reported by 70 patients (52.6%) in the TT combination group and 51 patients (38.1%) in the standard treatment monotherapy group. The most frequent adverse events were those related to systemic therapy or the disease itself: anemia (n=59; 22.1%), dyspnea (n=57; 21.3%), fatigue (n=51; 29.1%), diarrhea (n=50; 18.7%), and nausea (n=45; 16.9%).

[0099] The majority of patients (71.4%) who received TT field treatment experienced at least one device-related adverse event, eight of which (6%) were grade 3. No grade 4 toxicity was observed, and there were no deaths attributable to TT field therapy (Table S8). The most frequent TT field-related adverse events were grade 1-2 skin disorders, including dermatitis (n=16 [12%]), skin irritation (15 [11.3%]), pruritus (13 [9.8%]), and rash (11 [8.3%]). The incidence of TT field-related adverse events was generally similar across treatment subgroups. The incidence of cardiac events was similar in the standard treatment group with TT field therapy and the standard treatment alone group (19 and 18 cases, respectively). No cardiac events were judged to be related to TT field therapy.

[0100] No patients discontinued TT site therapy due to unacceptable toxicity, whereas two patients receiving immune checkpoint inhibitors and four patients receiving docetaxel discontinued the therapy.

[0101] 3. Discussion Since immune checkpoint inhibitors became the standard of care, no additional Phase III trials have demonstrated improved survival in patients with metastatic NSCLC after platinum-based therapy failure. Given the high prevalence of NSCLC and the fact that the majority of patients with metastatic disease progress on one line of treatment, there is an urgent need for additional effective and tolerable treatment options. The randomized Phase III LUNAR trial demonstrated that the innovative topical therapy TT-field therapy, combined with standard systemic therapy, significantly improved overall survival in patients with metastatic NSCLC after platinum-based therapy failure compared to standard systemic therapy alone. The improvement in overall survival with TT-field therapy was achieved without increasing the systemic toxicity associated with standard therapy, and the safety profile was limited primarily to low-grade skin adverse events.

[0102] Platinum-based therapy is frequently used as the central standard of treatment for NSCLC, either in combination with immune checkpoint inhibitors (first-line therapy) or in cases of progression after immune checkpoint inhibitor monotherapy (second-line therapy).1 Optimal treatment for progression after platinum-based therapy remains an unresolved issue. The improvement in overall survival of more than three months achieved by adding platinum-based therapy is clinically significant and justifies its use in this critically ill patient population with limited treatment options. In fact, this magnitude of survival benefit is consistent with the survival improvements reported in groundbreaking studies of immune checkpoint inhibitors (docetaxel-controlled) that established the current second-line standard of treatment for progressive NSCLC. 22-24 The survival benefit of adding Tt-field therapy was comparable to that reported in a recent Phase II trial comparing pembrolizumab and ramucirumab combination therapy (14.5 months) with standard therapy (11.6 months) in patients whose disease had progressed on combination therapy with immune checkpoint inhibitors and platinum-based chemotherapy. 25 Interestingly, the equivalence of progression-free survival between groups observed in this study is consistent with the results of several immunotherapy studies in NSCLC. This result is thought to be due to immunotherapy resulting in a delayed tumor response to treatment and extended survival after disease progression compared to cytotoxic chemotherapy.22-25 TT-field therapy resulted in a significant 8-month survival benefit in a subgroup treated with immune checkpoint inhibitors. These results are supported by findings from preclinical lung cancer models, where TT-field therapy induced immunogenic cell death and activated an anti-cancer immune response. This response was sustained through immune checkpoint inhibitor treatment, and the combined use of both therapies resulted in enhanced efficacy. 16,17 Although the potent efficacy benefit of TT-field therapy in the immune checkpoint inhibitor subgroup was not replicated in the docetaxel-treated subgroup, it is noteworthy that the median duration of TT-field therapy was shorter in patients in the docetaxel subgroup than in the immune checkpoint inhibitor subgroup, and that approximately half of these patients had previously received immune checkpoint inhibitor treatment. Furthermore, the lack of statistically significant benefit in this subgroup may be influenced by the fact that the LUNAR trial was designed solely to detect efficacy benefits in intentionally targeted treatment populations.

[0103] The safety profile of TT field therapy in the LUNAR trial was limited to mild to moderate local skin irritation under the array, and there was no evidence of internal or systemic safety concerns, including cardiac events. These data are consistent with previous clinical trials and real-world studies of TT field therapy in other tumor types. 7,8,26-30 Skin adverse events associated with TT field therapy are usually due to contact with the adhesive or hydrogel on the array, and not the treatment itself. The majority of skin adverse events can be effectively controlled with prophylactic and topical therapies, and the risk of occurrence may be reduced by enhancing patient and caregiver education. 10,11 While QOL data analysis from the LUNAR trial is ongoing, patient-reported outcomes from studies involving newly diagnosed glioblastoma patients indicate that the device did not impair quality of life; rather, TT field therapy slowed the progression of quality of life decline compared to the standard treatment monotherapy group.

[0104] A limitation of the LUNAR trial is its open-label design. This design was deemed appropriate considering the practical challenges and ethical concerns of exposing patients to a sham device. Because only a small number of patients with brain metastases were enrolled in this trial, it may affect the generalizability of these findings to that population. Since the LUNAR trial began before next-generation sequencing-based gene profiling was standardized in NSCLC, information on the relationship between the efficacy of TT-field therapy and tumor genetic subtypes is limited. In any case, this trial included a broad patient population without restrictions on tumor biomarkers, histological status, or prior treatments other than progression after platinum-based therapy.

[0105] Overall, the LUNAR trial demonstrated that adding TT-field therapy to standard systemic therapy significantly improved overall survival in patients with metastatic NSCLC that had progressed during or after platinum-based therapy. No new safety signals were observed, and TT-field therapy did not exacerbate systemic toxicity from immune checkpoint inhibitors or docetaxel. These efficacy and safety data from the Phase 3 trial support TT-field therapy as part of the second-line standard of care for metastatic NSCLC.

[0106] Those skilled in the art will recognize, or can verify by routine experimentation, numerous equivalents to the specific embodiments of the methods and compositions described herein. Such equivalents are intended to be covered by the following claims. List

[0107] Table 1: Shows the demographic characteristics and baseline disease characteristics of the patients. Table 2: Shows performance efficiency. Table 3: Shows adverse events. Table S2 shows the inclusion and exclusion criteria for the study. Table S3-TT shows the grades of device-related skin adverse events. Table S4 shows the main evaluation items for the test. Table S5 - Indicates the representativeness of the test population. Table S6 - Shows the treatments received by patients after the test treatment progress. Table S7 - Shows all adverse events of grade 3 - 5. Table S8 - Shows adverse events related to the TT field device.

Table 1 - 1

Table 1 - 2

[0108] *Radiological progression based on RECIST v1.1. † One patient had metastases in both the liver and the central nervous system (CNS). ‡ Patients with CNS metastases were excluded from the initial test design but were later amended to allow the enrollment of patients with stable metastases.

Table 2

Table 3 - 1

Table 3 - 2

[0109] Adverse events were aggregated from the safety evaluation population. *Observed in 10% or more patients in any group References

[0110] 1. Hendriks LE, Kerr KM, Menis J, et al. Non - oncogene addicted metastatic non - small - cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow - up( † ). Ann Oncol 2023: S0923 - 7534(22)04785 - 8. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non-Small Cell Lung Cancer. Version 3.2022. 2022. (Accessed August 1, 2022, at https: / / www.nccn.org / guidelines / guidelines-detail?category=1&id=1450.) 3. Owen DH, Singh N, Ismaila N, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2. J Clin Oncol 2023;41:e1-e9. 4. Optune®: instructions for use. 2019. (Accessed November 9, 2022, at https: / / www.optune.com / Content / pdfs / Optune_IFU_8.5x11.pdf.) 5. NovoTTF™-100L system: instructions for use for unresectable pleural malignant mesothelioma. 2019. (Accessed July 10, 2022, at https: / / www.novottf100l.com / pdfs / NovoTTF-100L_MPM_IFU.pdf.) 6. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 2012;48:2192-202. 7.Stupp R,Taillibert S,Kanner A,et al. Effect of Tumor-Treating Fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma:a randomized clinical trial. JAMA 2017;318:2306-16. 8.Ceresoli GL,Aerts JG,Dziadziuszko R,et al. Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma(STELLAR):a multicentre,single-arm phase 2 trial. Lancet Oncol 2019;20:1702-9. 9.Humanitarian Device Exemption(HDE):Optune Lua. 2019.(Accessed December 14,2022,at https: / / www.accessdata.fda.gov / scripts / cdrh / cfdocs / cfhde / hde.cfm?id=431319.) 10.Lacouture M,Anadkat MJ,Ballo MT,et al. Prevention and management of dermatologic adverse events associated with Tumor Treating Fields in patients with glioblastoma. Front Oncol 2020;10:1045. 11.Anadkat MJ,Lacouture M,Friedman A,et al. Expert guidance on prophylaxis and treatment of dermatologic adverse events with Tumor Treating Fields(TTFields)therapy in the thoracic region. Front Oncol 2023;12:975473. 12.Karanam NK,Ding L,Aroumougame A,Story MD. Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance:Implications for cancer therapy. Transl Res 2020;217:33-46. 13.Karanam NK,Srinivasan K,Ding L,Sishc B,Saha D,Story MD. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis 2017;8:e2711. 14.Mun EJ,Babiker HM,Weinberg U,Kirson ED,Von Hoff DD. Tumor-Treating Fields:A fourth modality in cancer treatment. 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Lung Cancer 2013;81:445-50. 19.Nishino M,Giobbie-Hurder A,Gargano M,Suda M,Ramaiya NH,Hodi FS. Developing a common language for tumor response to immunotherapy:immune-related response criteria using unidimensional measurements. Clin Cancer Res 2013;19:3936-43. 20.Eisenhauer EA,Therasse P,Bogaerts J,et al. New response evaluation criteria in solid tumours:revised RECIST guideline(version 1.1). Eur J Cancer 2009;45:228-47. 21.Common Terminology Criteria for Adverse Events(CTCAE)Version 4.03. 2010. at https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03 / CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.) 22.Borghaei H,Paz-Ares L,Horn L,et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. 23.Herbst RS,Baas P,Kim DW,et al. Pembrolizumab versus docetaxel for previously treated,PD-L1-positive,advanced non-small-cell lung cancer(KEYNOTE-010):a randomised controlled trial. Lancet 2016;387:1540-50. 24.Rittmeyer A,Barlesi F,Waterkamp D,et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer(OAK):a phase 3,open-label,multicentre randomised controlled trial. Lancet 2017;389:255-65. 25.Reckamp KL,Redman MW,Dragnev KH,et al. Phase II randomized study of ramucirumab and pembrolizumab versus standard of care in advanced non-small-cell lung cancer previously treated with immunotherapy-Lung-MAP S1800A. J Clin Oncol 2022;40:2295-306. 26.Vergote I,von Moos R,Manso L,Van Nieuwenhuysen E,Concin N,Sessa C. Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma:results of the INNOVATE pilot study. Gynecol Oncol 2018;150:471-7. 27.Rivera F,Benavides M,Gallego J,Guillen-Ponce C,Lopez-Martin J,Kung M. Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer:results of the PANOVA phase 2 study. Pancreatology 2019;19:64-72. 28. 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[0111] Patients receiving docetaxel were followed up every six weeks (±1 week) for radiological evaluation of lesions based on the Recognition of Responses to Solid Tumors (RECIST) criteria, or patients receiving immune checkpoint inhibitors were followed up every six weeks (±1 week) based on the immune-related (ir)RECIST criteria. Visits included computed tomography (CT), positron emission tomography (PET), or magnetic resonance imaging (MRI), confirmation of TT field therapy usage, reporting of adverse events, physical examination, and clinical laboratory tests. After one year of follow-up, imaging tests were performed every 12 weeks. Further follow-up to monitor survival was conducted every four weeks (±1 week) via visits to the research center or telephone contact. After progression was observed in the chest and / or liver, additional follow-up was conducted 30, 60, and 100 days (±1 week) after disease progression. 2. Concomitant medications

[0112] If skin irritation or abrasions occurred due to TT field therapy, a high-potency topical steroid (e.g., clobetasol) or antibiotic ointment was prescribed during the treatment period, and the patient / caregiver could apply it (after washing the skin with baby oil and medical alcohol after array removal). [Table 4]

[0113] ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, CNS: Central nervous system, ECOG: Eastern Collaborative Tumor Research Group, ICI: Immune checkpoint inhibitor, NSCLC: Non-small cell lung cancer, ULN: Upper limit of normal [Table 5] [Table 6]

[0114] Efficacy endpoints were measured in an intentional treatment population consisting of all randomized subjects, regardless of treatment status. Overall survival was measured from randomization to death from any cause (or censoring at the most recent follow-up date). Progression-free survival was defined as the time from randomization to progression of liver or chest disease (according to RECIST / irRECIST criteria), death from any cause, or (in the case of no progression or death) screening at the most recent evaluable RECIST / irRECIST assessment time (or randomization time if tumor assessment after baseline was unevaluable). Death without progression within 6 weeks of tumor assessment was considered an event. Otherwise, patients were screened at the most recent tumor assessment time. Radiographic response was defined as the best overall response being a partial response or a complete response.

[0115] ICI: Immune checkpoint inhibitor; SOC: Standard treatment; TTFields: Tumor therapeutic electric fields [Table 7] Additional references

[0116] Borghaei H,Paz-Ares L,Horn L,Spigel DR,Steins M,Ready NE,Chow LQ,Vokes EE,Felip E,Holgado E,Barlesi F,Kohlhaufl M,Arrieta O,Burgio MA,Fayette J,Lena H,Poddubskaya E,Gerber DE,Gettinger SN,Rudin CM,Rizvi N,Crino L,Blumenschein GR,Jr.,Antonia SJ,Dorange C,Harbison CT,Graf Finckenstein F,Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.N Engl J Med. 2015;373:1627-1639. Cao M,Chen W. Epidemiology of lung cancer in China.Thorac Cancer. 2019;10:3-7. Cheng TY,Cramb SM,Baade PD,Youlden DR,Nwogu C,Reid ME. The international epidemiology of lung cancer:latest trends,disparities,and tumor characteristics.J Thorac Oncol. 2016;11:1653-1671. OECD,European Union. Health at a Glance:Europe 2022. Paris 2022. Reckamp KL,Redman MW,Dragnev KH,Minichiello K,Villaruz LC,Faller B,Al Baghdadi T,Hines S,Everhart L,Highleyman L,Papadimitrakopoulou V,Neal JW,Waqar SN,Patel JD,Gray JE,Gandara DR,Kelly K,Herbst RS. Phase II randomized study of ramucirumab and pembrolizumab versus standard of care in advanced non-small-cell lung cancer previously treated with immunotherapy-Lung-MAP S1800A.J Clin Oncol. 2022;40:2295-2306. Rittmeyer A,Barlesi F,Waterkamp D,Park K,Ciardiello F,von Pawel J,Gadgeel SM,Hida T,Kowalski DM,Dols MC,Cortinovis DL,Leach J,Polikoff J,Barrios C,Kabbinavar F,Frontera OA,De Marinis F,Turna H,Lee JS,Ballinger M,Kowanetz M,He P,Chen DS,Sandler A,Gandara DR. Atezolizumab versus docetaxel in patients with previously non-small-cell lung cancer(OAK):a phase 3,open-label,treated multicentre randomized controlled trial.Lancet. 2017;389:255-265. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics,2022.CA Cancer J Clin. 2022;72:7-33. US National Cancer Institute SRP. SEER*Explorer: Interactive website for SEER cancer statistics [Internet]. https: / / seer.cancer.gov / statistics-network / explorer / . [Retrieved February 2023]. Zhou C. Lung cancer molecular epidemiology in China:recent trends.Transl Lung Cancer Res. 2014;3:270-279. [Table 8] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 10]

[0117] Adverse events are aggregated from the safety analysis population. *No Grade 4 or 5 adverse events related to the TT field device were observed. † In both groups, more than 5% of patients experienced all adverse events of grade 3–5. B. Example 2: Combination of tumor therapy field (TT field) therapy and standard treatment (SOC) in metastatic non-small cell lung cancer (mNSCLC) after platinum-based therapy failure: Randomized Phase 3 LUNAR trial 1. Background technology

[0118] The TT field is an electric field that inhibits processes essential for cancer cell survival. The TT field is applied to glioblastoma and mesothelioma using an FDA-approved, non-invasive, portable device. Preclinical NSCLC studies have demonstrated that the TT field enhances the antitumor immune response through inhibition of mitosis and subsequent induction of immunogenic cell death. The TT field has also been shown to exhibit synergistic effects with taxane-based anticancer agents and immune checkpoint inhibitors (ICIs). In this global, randomized, phase 3 LUNAR trial, TT field therapy was evaluated against standard treatment (investigator-selected ICI or docetaxel [DTX]) in previously treated mNSCLC patients. 2. Method

[0119] Adult patients with mNSCLC that progressed during or after platinum-based chemotherapy (prior administration of ICI was permitted), and with an ECOG PS of ≤2, were randomly assigned in a 1:1 ratio to either the TT-environment + SOC group or the SOC group. TT-environment therapy (150 kHz) was administered continuously until disease progression or unacceptable toxicity occurred. The primary endpoint was overall survival (OS). The primary secondary endpoint was OS in the ICI and DTX subgroups. Other secondary endpoints included progression-free survival (PFS) and adverse events (AEs). 3.Results

[0120] Between February 2017 and November 2021, 276 patients were randomly assigned to either the TT+SOC group (n=137) or the SOC group (n=139). Baseline characteristics were balanced, with a median age of 64 years (range 22–86 years), 65% male, 56% non-squamous cell carcinoma, 96% ECOG PS 0–1, 89% with one-line prior systemic therapy, and 31% with prior ICI treatment. Overall survival (OS) was significantly longer in the TT+SOC group compared to the SOC group. After a minimum 12-month follow-up, mOS (95% CI) was 13.2 months (10.3–15.5) in the TT+SOC group and 10.0 months (8.2–12.2) in the SOC monotherapy group (HR 0.74; 95% CI 0.56–0.98; P=0.037). The one-year survival rates (95% CI) were 53% (44-61) and 42% (34-50), respectively (P=0.040). The mPFS was 4.8 (4.1-5.7) months and 4.1 (3.0-4.7) months, respectively (HR 0.87; 95% CI 0.67-1.14). In patients receiving ICI (n=134), the TT field significantly improved OS compared to ICI alone, with mOS (95% CI) of 10.6 (8.2-17.6) months compared to 18.5 (10.6-30.3) months (HR 0.63; 95% CI 0.41-0.96; P=0.032). In the DTX subgroup (n=142), the TT field combination group showed numerically higher mOS compared to the DTX monotherapy group, at 8.9 months (95% CI 6.5–12.2) compared to 11.1 months (95% CI 8.2–14.1) (HR 0.87; 95% CI 0.60–1.26). The incidence of adverse events (AEs) was similar in both groups (TT field + standard treatment group: 97%, standard treatment group: 91%). The incidence of TT field-related AEs was 71%, with the majority being grade 1 and 2 local skin irritations. Eight patients (6%) reported grade 3 AEs. No grade 4 toxicity was observed, and there were no deaths attributable to the TT field. 4. Conclusion

[0121] TT field therapy significantly extended overall survival (OS) without exacerbating systemic toxicity and with fewer device-related high-grade adverse events (AEs) in mNSCLC patients following platinum-based chemotherapy failure. The efficacy and safety demonstrated in this Phase 3 trial justify incorporating TT field therapy as part of the second-line standard of care (SOC) for mNSCLC. Section II A.Definition

[0122] The disclosed methods and compositions are not limited to the specific methods, protocols, and reagents described, and it is understood that these may vary. Furthermore, the terms used herein are for illustrative purposes only to describe specific embodiments and are not intended to limit the scope of the invention, and the scope of the invention is limited only by the appended claims.

[0123] Furthermore, the singular forms "a," "an," and "the" used herein and in the appended claims include plural references unless the context clearly indicates otherwise. Thus, for example, a reference to "checkpoint inhibitors" includes multiple such inhibitors, and a reference to "checkpoint inhibitors" includes one or more inhibitors and their equivalents known to those skilled in the art.

[0124] As used herein, the word "or" means any of the components of a particular list, and also includes any combination of the components of that list.

[0125] In this specification, “target site” refers to a specific site or location located inside or on the surface of a subject or patient. For example, “target site” may refer to, but is not limited to, cells (e.g., cancer cells), a population of cells, an organ, a tissue, or a tumor. Thus, the term “target cell” may be used to refer to a target site, and the target site is a cell. In some embodiments, “target cell” may be a cancer cell. In some embodiments, organs that may be a target site include, but are not limited to, the lungs. In some embodiments, cells or populations that may be a target site or target cell include, but are not limited to, cancer cells (e.g., lung cancer cells). In some embodiments, “target site” may be a tumor target site.

[0126] A “tumor target site” is a site or location within or on the subject or patient that contains, is adjacent to, or previously contained one or more non-small cell lung cancer cells, or is suspected to contain one or more tumor cells. For example, a tumor target site may refer to a site or location within or on the body of a subject or patient that is prone to metastasis (e.g., the chest). In addition, a target site or tumor target site may refer to the site or location of resection of a primary tumor located within or on the surface of the subject or patient. In addition, a target site or tumor target site may refer to a site or location adjacent to the resection of a primary tumor located within or on the body of the subject or patient.

[0127] In this specification, “alternating current field” refers to a very low-intensity, directional, medium-frequency alternating current field delivered to a subject, a sample taken from a subject, or a specific location within a subject or patient (e.g., a target site). In some embodiments, the alternating current field may be unidirectional or multidirectional. In some embodiments, the alternating current field may be delivered through two pairs of transducer arrays that generate a field perpendicular to the target site. For example, in the Optune® system (alternating current field delivery system), one pair of electrodes is positioned to the left and right (LR) of the target site, and the other pair of electrodes is positioned to the front and back (AP) of the target site. By circulating the electric field between these two directions (LR and AP), it is ensured that the widest range of cellular directions is targeted.

[0128] As used herein, an alternating electric field applied to a targeted site of a tumor may be called a tumor therapeutic field or TT field. Because TT fields disrupt proper microtubule assembly during metaphase and ultimately destroy cells during telophase, cytokinesis, or subsequent interphase, they are established as an anti-mitotic cancer therapy. TT fields target solid tumors and are described in a U.S. patent, U.S. Patent No. 7,565,205, which is incorporated herein by reference in its entirety as teachings of TT fields.

[0129] In vivo and inhydro studies have shown that the efficacy of TT field therapy increases with increasing electric field intensity. Therefore, the Optune system can be used to optimize the array placement in the patient's tumor area and increase the intensity in the desired area of ​​the tumor. Optimization of array placement can be performed by "rules of thumb" (e.g., placing the array on the tumor as close as possible to the desired area of ​​the target site (e.g., cancer cells)) or by measurements describing the geometric shape of the patient's tumor and the dimensions of the tumor. Measurements used as input may be obtained from image data. Image data includes all kinds of visual data, such as single-photon emission computed tomography (SPECT) image data, X-ray computed tomography (X-ray CT) data, magnetic resonance imaging (MRI) data, positron emission tomography (PET) data, and data that can be acquired by optical instruments (e.g., photographic cameras, charge-coupled device (CCD) cameras, infrared cameras, etc.). In certain embodiments, image data may include 3D data (e.g., point cloud data) acquired from or generated by a 3D scanner. Optimization may depend on understanding how the electric field is distributed within the head as a function of the array's position, and in some embodiments, taking into account variations in the electrical characteristic distribution within the heads of different patients.

[0130] The term "subject" refers to a subject receiving an administration, such as an animal. Therefore, the subject of the disclosed method may be a vertebrate, such as a mammal. For example, the subject may be a human. This term does not indicate a specific age or sex. "Subject" may be used interchangeably with "individual" or "patient." For example, a subject receiving an administration may mean one receiving a therapeutically effective amount of alternating electric field and a checkpoint inhibitor.

[0131] "To treat" means administering or applying therapies such as alternating electric fields and checkpoint inhibitors to subjects, such as humans or other mammals (e.g., animal models), who have cancer or are at increased susceptibility to developing cancer, in order to prevent or slow the progression of cancer effects, or to partially or completely reverse the effects of cancer (lung cancer).

[0132] "Prevention" means minimizing the likelihood that subjects with a high susceptibility to developing cancer will develop cancer.

[0133] As used herein, the terms “administering” and “administration” refer to any method for providing a therapeutic agent, such as a checkpoint inhibitor, to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, nasal, topical, vaginal, intraocular, intraocular, intracerebral, rectal, sublingual, buccal, and parenteral administration, including injections such as intravenous, intra-arterial, intramuscular, and subcutaneous. Administration may be carried out continuously or intermittently. In various embodiments, formulations may be administered therapeutically, i.e., to treat a pre-existing disease or condition. In various further embodiments, formulations may be administered prophylactically, i.e., to prevent a pre-existing disease or condition. In one embodiment, a skilled technician may determine an effective dose, effective schedule, or effective route of administration to treat a subject. In some embodiments, administration includes exposure. Thus, in some embodiments, exposure of cancer cells to an alternating electric field means administering an alternating electric field to cancer cells.

[0134] In this specification, “therapeutically effective dose” means a therapeutic, prophylactic, and / or diagnostic agent sufficient to treat, alleviate, improve, reduce symptoms, prevent, delay onset, inhibit progression, reduce severity, and / or decrease incidence of a disease, disorder, and / or condition when administered to a subject who has or is highly susceptible to the disease, disorder, and / or condition. In this specification, “therapeutably effective dose of checkpoint inhibitor” means a therapeutic, prophylactic, and / or diagnostic checkpoint inhibitor sufficient to treat, alleviate, improve, reduce symptoms, prevent or delay onset, inhibit progression, reduce severity, and / or decrease incidence of a disease, disorder, and / or condition when administered to a subject who has or is highly susceptible to the disease (e.g., non-small cell lung cancer) or disorder.

[0135] In this specification, “sample” means an animal, animal-derived tissue or organ, cell (taken directly from a subject, maintained in culture, or derived from a cultured cell line), cell lysate (or fraction of a lysate) or cell extract, or a solution containing one or more molecules derived from a cell or cell-derived substance (e.g., polypeptide or nucleic acid), which are measured by the methods described herein. A specimen may mean any bodily fluid or excretory material containing cells or cellular components (e.g., blood, urine, feces, saliva, tears, bile, etc.).

[0136] In this specification, the term “subject” refers to a subject of administration, such as an animal. Therefore, the subject of the disclosed method may be a vertebrate, such as a mammal. For example, the subject may be a human. This term does not indicate a specific age or sex. “Subject” can be used interchangeably with “individual” or “patient.”

[0137] In this specification, ranges may be expressed as "approximately" from a particular value and / or "approximately" to another particular value. Where such ranges are expressed, unless otherwise specified in the context, the range from a particular value and / or to another particular value is also specifically assumed and disclosed. Similarly, where the use of the antecedent "approximately" expresses a value as an approximation, it is understood that, unless otherwise specified in the context, that particular value forms another specifically considered embodiment that should be considered disclosed. Furthermore, unless otherwise specified in the context, it is understood that each endpoint of a range is important both in relation to and independently of other endpoints. Finally, it should be understood that all individual values ​​and subranges of values ​​included within an explicitly disclosed range are also specifically assumed and should be considered disclosed unless otherwise indicated in the context. The foregoing applies regardless of whether some or all of these embodiments are explicitly disclosed in a particular case.

[0138] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the disclosed methods and compositions belong. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the methods and compositions of the present invention, but the methods, apparatus and materials described herein are particularly useful. Publications cited herein and the materials from which they are cited are expressly incorporated herein by reference. Nothing in this specification should be construed as admitting that the present invention does not have prior rights to this disclosure by prior art. No reference is acknowledged to constitute prior art. The descriptions of references state the claims of their authors, and the applicant reserves the right to object to the accuracy and validity of the cited documents. Numerous publications are referenced herein, but it is clear that such references do not acknowledge that any of these documents constitute part of the common general knowledge in the art.

[0139] Throughout this specification and the claims, the word “comprise” and its variations “comprising” and “comprises” mean “not limited to” and are not intended to exclude, for example, other additives, components, integers, or steps. In particular, where a method is described as comprising one or more steps or operations, it is specifically assumed that each step includes what is listed (unless the step contains a limiting term such as “consisting of”). In other words, each step is not intended to exclude other additives, components, integers, or steps, etc., that are not listed in that step. B. AC electric field

[0140] The methods disclosed herein involve applying an alternating current field. In some embodiments, the alternating current field used in the methods disclosed herein is a tumor therapeutic field (TTFields). In some embodiments, the alternating current field may vary depending on the type or state of the cells to which the alternating current field is applied. In some embodiments, the alternating current field may be applied via one or more electrodes placed on the body of a subject. In some embodiments, two or more pairs of electrodes may be present. For example, an array may be placed on the front / back and sides of the patient and may be used with the systems and methods disclosed herein. In some embodiments, when two pairs of electrodes are used, the alternating current field may be generated alternately between the electrode pairs. For example, a first pair of electrodes may be placed on the front and back of the subject, and a second pair of electrodes may be placed on either side of the subject, and then the alternating current field may be applied alternately between the front and back electrodes, and then between the left and right electrodes.

[0141] In some embodiments, the frequency of the AC electric field is 100 kHz to 500 kHz. The frequency of the AC electric field may be, but is not limited to, 50 to 500 kHz, 100 to 500 kHz, 25 kHz to 1 MHz, 50 to 190 kHz, 25 to 190 kHz, 180 to 220 kHz, or 210 to 400 kHz. In some embodiments, the frequency of the AC electric field may be about 50 kHz, 100 kHz, 200 kHz, 300 kHz, 400 kHz, 500 kHz, or any frequency in between. In some embodiments, the frequency of the AC electric field is about 200 kHz to about 400 kHz, about 250 kHz to about 350 kHz, and may be about 150 kHz, about 200 kHz, or about 300 kHz.

[0142] An AC electric field can be induced by an applied voltage of at least 50 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least 25 to 200 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least about 5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, or 300 V RMS.

[0143] In some embodiments, the electric field strength of the AC electric field may be in the range of 1 to 4 V / cm RMS. In some embodiments, different electric field strengths (e.g., between 0.1 and 10 V / cm) may be used. In some embodiments, the electric field strength may be 1.75 V / cm RMS. In some embodiments, the electric field strength is at least 1 V / cm. In other embodiments, combinations of electric field strengths are applied, for example, by combining two or more frequencies simultaneously or by applying two or more frequencies at different times.

[0144] In some embodiments, the alternating current field may be applied at various intervals ranging from 0.5 hours to 72 hours. In some embodiments, different periods may be used (e.g., from 0.5 hours to 14 days). In some embodiments, the application of the alternating current field may be repeated periodically. For example, the alternating current field may be applied for 2 hours a day.

[0145] In some embodiments, exposure may be continuous for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours. In some embodiments, exposure may be continuous or cumulative. In some embodiments, continuous exposure may continue over continuous exposure of at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours. In some embodiments, cumulative exposure may last for at least 42 hours, at least 84 hours, at least 168 hours, at least 250 hours, at least 400 hours, at least 500 hours, or at least 750 hours. In some embodiments, there may be interruptions in treatment, and the alternating electric field is applied for at least 50%, 60%, 70%, or 80% of the treatment time. For example, in some embodiments, cumulative exposure over 24 hours may be at least 12 hours.

[0146] The disclosed method includes the step of applying one or more alternating electric fields to a cell or a subject. In some embodiments, the alternating electric fields are applied to a target site or a tumor target site. When the alternating electric field is applied to a cell, this may mean applying the alternating electric field to the subject that constitutes the cell. Thus, when the alternating electric field is applied to a target site of the subject, the alternating electric field is applied to the cell.

[0147] In some embodiments, exposure may be continuous for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, or at least 72 hours or more.

[0148] Furthermore, when applying an alternating current (AC) electric field to a subject, the duration of application can be measured either as continuous or cumulative time. In other words, the duration of AC application can encompass not only a single session (i.e., continuous application) but also multiple sessions with short breaks in between (i.e., continuous application over a cumulative period). For example, even in the case of continuous application, the subject may be allowed to take breaks during treatment with the AC electric field device, and the device is expected to be attached to the body and operated for at least approximately 50%, at least approximately 60%, at least approximately 70%, or at least approximately 80% of the total treatment period (e.g., 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, etc.). For example, the AC electric field may be applied over a period of 1 week, 1 month, 2 months, 3 months, etc., with a cumulative total of at least 12, 16, or 18 hours per day. C. Checkpoint inhibitors

[0149] The methods disclosed herein involve administering one or more checkpoint inhibitors to a subject. In some embodiments, the checkpoint inhibitors may inhibit CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-1 (programmed cell death protein 1), or PD-L1 (programmed cell death ligand 1).

[0150] In some embodiments, the checkpoint inhibitor may be, but is not limited to, ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (brand name Ributayo), dostallimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), avelumab (Bavencio), or a combination thereof. In some embodiments, the checkpoint inhibitor may be, but is not limited to, tremelimumab, cintilimab (formerly IBI308; Tyvit), tislerizumab (formerly BGB-A317), tripalimab (formerly JS 001), spartalizumab (formerly PRD001); camrelizumab (formerly SHR1210), KN035, cosiberimab (formerly CK-301), CA-170, or BMS-986189, or a combination thereof.

[0151] In some embodiments, the method relates to subjects who have previously received treatment with a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor may be an inhibitor that inhibits CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-1 (programmed cell death protein 1), or PD-L1 (programmed cell death ligand 1). In some embodiments, the checkpoint inhibitor previously administered to the subject may be, but is not limited to, ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (brand name Ributayo), dostallimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), avelumab (Bavencio), or a combination thereof. In some embodiments, the checkpoint inhibitor may be, but is not limited to, tremelimumab, cintilimab (formerly IBI308; Tyvit), tislerizumab (formerly BGB-A317), tripalimab (formerly JS 001), spartalizumab (formerly PRD001); camrelizumab (formerly SHR1210), KN035, cosiberimab (formerly CK-301), CA-170, or BMS-986189, or a combination thereof. D.Chemotherapy

[0152] The methods disclosed herein may further include administering one or more chemotherapy agents to a subject. In some embodiments, the chemotherapy agents may be alkylating agents, plant alkaloids, antimetabolites, anthracyclines, topoisomerase inhibitors, and / or corticosteroids.

[0153] In some embodiments, chemotherapy includes altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechloretamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5-fluorouracil, 6-mercaptopurine, Azacitidine, capecitabine, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, phloxlysine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, thio Guanine, trifluridine / tipiracil combination, etoposide, irinotecan, irinotecan liposome, mitoxantrone, teniposide, topotecan, cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, vinblastine, vincristine, vincristine liposome, vinorelbine, daunorubicin, doxorubicin, doxorubicin liposome, epirubicin, idarubicin, mitoxa You may use one or more of the following: thorone, barrubicin, bleomycin, dactinomycin, mitomycin C, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, ixabepyrone, mitotane, omasetaxin, pegaspargaze, procarbazine, romidepsin, vorinostat, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, or prednisone. E. Method 1. Methods to increase survival time

[0154] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering the subject a therapeutically effective amount of a checkpoint inhibitor. In some embodiments, a method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method further comprising screening the subject to determine whether administration of a therapeutically effective amount of a checkpoint inhibitor would be effective in improving the subject's survival or treating the subject. In some embodiments, a method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method further comprising administering chemotherapy to the subject. In some embodiments, the chemotherapy may include alkylating agents, plant alkaloids, antimetabolites, anthracyclines, topoisomerase inhibitors, and / or corticosteroids.In some embodiments, chemotherapy includes altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechloretamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5-fluorouracil, 6-mercaptopurine, Azacitidine, capecitabine, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, phloxlysine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, thio Guanine, trifluridine / tipiracil combination, etoposide, irinotecan, irinotecan liposome, mitoxantrone, teniposide, topotecan, cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, vinblastine, vincristine, vincristine liposome, vinorelbine, daunorubicin, doxorubicin, doxorubicin liposome, epirubicin, idarubicin, mitoxa You may use one or more of the following: thorone, barrubicin, bleomycin, dactinomycin, mitomycin C, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, ixabepyrone, mitotane, omasetaxin, pegaspargaze, procarbazine, romidepsin, vorinostat, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, or prednisone.

[0155] In some embodiments, a method is disclosed to improve the survival time of subjects with non-small cell lung cancer, extending the survival time by 4, 5, 6, 7, 8, or 9 months or more compared to subjects who do not receive treatment according to the method.

[0156] In some embodiments, the checkpoint inhibitor may be, but is not limited to, ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (brand name Ributayo), dostallimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), avelumab (Bavencio), or a combination thereof. In some embodiments, the checkpoint inhibitor may be, but is not limited to, tremelimumab, cintilimab (formerly IBI308; Tyvit), tislerizumab (formerly BGB-A317), tripalimab (formerly JS 001), spartalizumab (formerly PRD001); camrelizumab (formerly SHR1210), KN035, cosiberimab (formerly CK-301), CA-170, or BMS-986189, or a combination thereof.

[0157] In some embodiments, a method is disclosed to improve the survival time of subjects with non-small cell lung cancer, the method comprising applying an alternating current electric field on day 1, 2, 3, 4, 5, 6, or 7 prior to administration of a checkpoint inhibitor. In some embodiments, a method is disclosed to improve the survival time of subjects with non-small cell lung cancer, the method comprising applying an alternating current electric field on day 1, 2, 3, 4, 5, 6, or 7 after administration of a checkpoint inhibitor. In some embodiments, the application of the alternating current electric field is performed 1, 2, 3, or 4 weeks prior to administration of the checkpoint inhibitor. In some embodiments, the application of the alternating current electric field is performed 1, 2, 3, or 4 weeks after administration of the checkpoint inhibitor. In some embodiments, the alternating current electric field and the checkpoint inhibitor are administered simultaneously. In some embodiments, “simultaneously” means being performed on each other within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some embodiments, subjects may be examined to confirm the presence of checkpoint inhibitors in the bloodstream before the application of an alternating electric field.

[0158] In some embodiments, a method is disclosed for improving the survival of subjects with non-small cell lung cancer, the method further comprising interrupting an alternating electric field during the implementation of the method. In some embodiments, a method is disclosed for improving the survival of subjects with non-small cell lung cancer, the alternating electric field may be applied discontinuously during the treatment period. For example, the alternating electric field may be applied for less than 24 hours a day and less than 7 days a week. In some embodiments, the alternating electric field may be applied for at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 hours per day.

[0159] In some embodiments, the AC electric field may have a predetermined frequency and electric field strength. In some embodiments, the frequency of the AC electric field is 50 kHz to 1 MHz. In some embodiments, the frequency of the AC electric field is 100 kHz to 1 MHz. In some embodiments, the frequency of the AC electric field is 100 kHz to 500 kHz. In some embodiments, the frequency of the AC electric field is 200 kHz. In some embodiments, the AC electric field may be within any of the ranges described herein.

[0160] An AC electric field can be induced by an applied voltage of at least 50 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least 25 to 200 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least about 5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, or 300 V RMS.

[0161] In some embodiments, the alternating electric field has an electric field strength of 0.1 to 10 V / cm RMS. In some embodiments, the alternating electric field has an electric field strength of 0.5 to 4 V / cm RMS. In some embodiments, the alternating electric field has an electric field strength of 1 V / cm RMS. In some embodiments, the alternating electric field has any of the electric field strengths described herein.

[0162] This specification discloses the use of alternating electric fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer.

[0163] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda). In some embodiments, a method is disclosed for improving the survival of a subject with non-small cell lung cancer, the method further comprising screening the subject to determine whether the administration of a therapeutically effective amount of a checkpoint inhibitor would be effective in improving the subject's survival or treating the subject. In some embodiments, a method is disclosed for improving the survival of a subject with non-small cell lung cancer, the method further comprising administering chemotherapy to the subject. In some embodiments, chemotherapy may be administered before, after, or concurrently with the application of an alternating electric field. In some embodiments, chemotherapy may be administered before, after, or concurrently with the administration of a checkpoint inhibitor.

[0164] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda). In some embodiments, the subjects were diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with a checkpoint inhibitor. In some embodiments, the subjects progressed to metastatic disease within 6 months of the completion of prior treatment with a checkpoint inhibitor.

[0165] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not previously received non-platinum or platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0166] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not previously received platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0167] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating current field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not experienced cerebrovascular disease within six months prior to the application of the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0168] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating current field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not had any malignancies other than NSCLC within three years prior to the application of the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0169] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor; and screening the subject to determine whether the administration of a therapeutically effective amount of the checkpoint inhibitor is effective in improving the survival of the subject. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0170] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda). In some embodiments, a method is disclosed for improving the survival of a subject having non-small cell lung cancer, the method further comprising screening the subject to determine whether administering a therapeutically effective amount of a checkpoint inhibitor would be effective in improving the subject's survival or treating the subject. In some embodiments, a method is disclosed for improving the survival of a subject having non-small cell lung cancer, the method further comprising administering chemotherapy to the subject.

[0171] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy. In some embodiments, the subject has been diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with a checkpoint inhibitor and chemotherapy. In some embodiments, the subject has progressed to metastatic disease within six months of the completion of prior treatment with a checkpoint inhibitor and chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0172] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy, and the subject has not previously received non-platinum-based or platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0173] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating current field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy, and the subject has not experienced cerebrovascular disease within six months prior to the application of the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0174] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating current field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy, and the subject has not had any malignancies other than NSCLC within three years prior to the application of the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0175] A method for improving the survival of a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy; and screening the subject to determine whether the administration of a therapeutically effective amount of the checkpoint inhibitor is effective in improving the survival of the subject. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0176] A method for improving the survival of a subject with cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time; and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the cancer is metastatic non-small cell lung cancer, the subject has received prior treatment for non-small cell lung cancer with checkpoint inhibitors and systemic therapy including platinum-based chemotherapy, and the non-small cell lung cancer in the subject has progressed during or after prior systemic treatment, and the frequency of the alternating electric field is 150 kHz. In some embodiments, the checkpoint inhibitor administered in the step of administering a therapeutically effective amount to the subject is a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. In some embodiments, the PD-1 inhibitor may be, but is not limited to, nivolumab, pembrolizumab, or cemiplimab. In some embodiments, the PD-L1 inhibitor may be, but is not limited to, atezolizumab, avelumab, or durvalumab. In some embodiments, the CTLA-4 inhibitor may be, but is not limited to, ipilimumab or tremelimumab. In some embodiments, the checkpoint inhibitor administered in the step of administering a therapeutically effective amount of a checkpoint inhibitor to the subject is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject progressed during or after prior treatment with pembrolizumab (Keytruda).

[0177] This specification discloses the use of alternating current fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors in combination with chemotherapy to improve survival in subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors, and the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors. In some embodiments, the subjects have been diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with checkpoint inhibitors. In some embodiments, the subjects have progressed to metastatic disease within 6 months of the completion of prior treatment with checkpoint inhibitors. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject was pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field was pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject was pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field was pembrolizumab (Keytruda), and the subject progressed during or after prior treatment with pembrolizumab (Keytruda).

[0178] In some embodiments, this specification discloses the use of alternating electric fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors, the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors, and the subjects having not previously received non-platinum or platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subjects have progressed during or after prior treatment with pembrolizumab (Keytruda).

[0179] In some embodiments, this specification discloses the use of alternating electric fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors, the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors, and the subjects having not previously received platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subjects have progressed during or after prior treatment with pembrolizumab (Keytruda).

[0180] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subjects progressing during or after prior treatment with a checkpoint inhibitor, and the subjects having not experienced cerebrovascular events within six months prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subjects have progressed during or after prior treatment with pembrolizumab (Keytruda).

[0181] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subjects progressing during or after prior treatment with a checkpoint inhibitor, and the subjects having no malignancies other than NSCLC within 3 years prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subjects have progressed during or after prior treatment with pembrolizumab (Keytruda).

[0182] This specification discloses the use of alternating current fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors in combination with chemotherapy to improve survival in subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors and chemotherapy, and the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors. In some embodiments, the subjects have been diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with checkpoint inhibitors and chemotherapy. In some embodiments, the subjects have progressed to metastatic disease within 6 months of the completion of prior treatment with checkpoint inhibitors and chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject was pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field was pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject was pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field was pembrolizumab (Keytruda), and the subject progressed during or after prior treatment with pembrolizumab (Keytruda).

[0183] In some embodiments, this specification discloses the use of alternating electric fields and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors and chemotherapy, the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors and chemotherapy, and the subjects having not previously received non-platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subjects have progressed during or after prior treatment with pembrolizumab (Keytruda).

[0184] In certain embodiments, this specification discloses the use of alternating electric fields and checkpoint inhibitors to improve the survival of subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors, the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors and chemotherapy, and the subjects having not previously received platinum-based chemotherapy.

[0185] In some embodiments, this specification discloses the use of alternating current and checkpoint inhibitors to improve survival in subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors and chemotherapy, the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors, and the subjects having not experienced cerebrovascular events within six months prior to the application of the alternating current. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating current. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating current is pembrolizumab (Keytruda), and the subjects have progressed during or after prior treatment with pembrolizumab (Keytruda).

[0186] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to improve the survival of subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors and chemotherapy, the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors and chemotherapy, and the subjects having no malignancies other than NSCLC within three years prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda). 2. Treatment methods for the subjects

[0187] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering the subject a therapeutically effective amount of a checkpoint inhibitor. In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, the method further comprising screening the subject to determine whether administration of a therapeutically effective amount of a checkpoint inhibitor would be effective in improving the subject's survival or in treating the subject. In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, the method further comprising administering chemotherapy to the subject.

[0188] In some embodiments, the checkpoint inhibitor may be, but is not limited to, ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (brand name Ributayo), dostallimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), avelumab (Bavencio), or a combination thereof. In some embodiments, the checkpoint inhibitor may be, but is not limited to, tremelimumab, cintilimab (formerly IBI308; Tyvit), tislerizumab (formerly BGB-A317), tripalimab (formerly JS 001), spartalizumab (formerly PRD001); camrelizumab (formerly SHR1210), KN035, cosiberimab (formerly CK-301), CA-170, or BMS-986189, or a combination thereof.

[0189] In some embodiments, the application of an alternating electric field is performed on day 1, 2, 3, 4, 5, 6, or 7 prior to the administration of the checkpoint inhibitor. In some embodiments, the application of an alternating electric field is performed on day 1, 2, 3, 4, 5, 6, or 7 after the administration of the checkpoint inhibitor. In some embodiments, the application of an alternating electric field is performed one, two, three, or four weeks prior to the administration of the checkpoint inhibitor. In some embodiments, the application of an alternating electric field is performed one, two, three, or four weeks after the administration of the checkpoint inhibitor. In some embodiments, the alternating electric field and the checkpoint inhibitor are administered simultaneously. In some embodiments, “simultaneously” means being administered to each other within one, two, three, four, or 24 hours. In some embodiments, the subject may be examined to confirm the presence of the checkpoint inhibitor in the bloodstream before the application of the alternating electric field.

[0190] In some embodiments, the AC electric field may have a predetermined frequency and electric field strength. In some embodiments, the frequency of the AC electric field is 50 kHz to 1 MHz. In some embodiments, the frequency of the AC electric field is 100 kHz to 1 MHz. In some embodiments, the frequency of the AC electric field is 100 kHz to 500 kHz. In some embodiments, the frequency of the AC electric field is 200 kHz. In some embodiments, the AC electric field may be within any of the ranges described herein.

[0191] An AC electric field can be induced by an applied voltage of at least 50 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least 25 to 200 V RMS. In some embodiments, an AC electric field can be induced by an applied voltage of at least about 5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, or 300 V RMS.

[0192] In some embodiments, the alternating electric field has an electric field strength of 0.1 to 10 V / cm RMS. In some embodiments, the alternating electric field has an electric field strength of 0.5 to 4 V / cm RMS. In some embodiments, the alternating electric field has an electric field strength of 1 V / cm RMS. In some embodiments, the alternating electric field has any of the electric field strengths described herein.

[0193] In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, the method further comprising interrupting an alternating electric field during the implementation of the method. In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, in which the alternating electric field may be applied discontinuously during the treatment period. For example, the alternating electric field may be applied for less than 24 hours a day and less than 7 days a week. In some embodiments, the alternating electric field may be applied for at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 hours per day.

[0194] This specification discloses the use of alternating electric fields and checkpoint inhibitors for the treatment of subjects with non-small cell lung cancer.

[0195] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, the method further comprising screening the subject to determine whether administration of a therapeutically effective amount of a checkpoint inhibitor would be effective in improving the subject's survival or treating the subject. In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, the method further comprising administering chemotherapy to the subject. In some embodiments, chemotherapy may be administered before, after, or concurrently with the application of an alternating electric field. In some embodiments, chemotherapy may be administered before, after, or concurrently with the administration of a checkpoint inhibitor.

[0196] A method for treating a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor. In some embodiments, the subject has been diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with a checkpoint inhibitor. In some embodiments, the subject has progressed to metastatic disease within six months of the completion of prior treatment with a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0197] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not previously received non-platinum or platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0198] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not previously received platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0199] A method for treating a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating current field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not experienced a cerebrovascular event within six months prior to the application of the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0200] A method for treating a subject with non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor, and the subject has not had any malignancies other than NSCLC within three years prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0201] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor; and screening the subject to determine whether the administration of a therapeutically effective amount of the checkpoint inhibitor would be effective in treating the subject. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0202] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor and chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda). In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, which further includes screening the subject to determine whether administering a therapeutically effective amount of a checkpoint inhibitor would be effective in improving the subject's survival or in treating the subject. In some embodiments, a method for treating a subject having non-small cell lung cancer is disclosed, which further includes administering chemotherapy to the subject.

[0203] A method for treating a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor and chemotherapy, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor and chemotherapy. In some embodiments, the subject has been diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with a checkpoint inhibitor and chemotherapy. In some embodiments, the subject has progressed to metastatic disease within six months of the completion of prior treatment with a checkpoint inhibitor and chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0204] A method for treating a subject having non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy, and the subject has not previously received non-platinum-based or platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0205] A method for treating a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy, and the subject has not experienced a cerebrovascular event within six months prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0206] A method for treating a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; and administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with a checkpoint inhibitor or chemotherapy, the non-small cell lung cancer in the subject has progressed during or after prior treatment with a checkpoint inhibitor or chemotherapy, and the subject has not had any malignancies other than NSCLC within three years prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0207] A method for treating a subject with non-small cell lung cancer is disclosed, the method comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time; administering a therapeutically effective amount of a checkpoint inhibitor to the subject, wherein the subject has received prior treatment with checkpoint inhibitors and chemotherapy, and the non-small cell lung cancer in the subject has progressed during or after prior treatment with checkpoint inhibitors and chemotherapy; and screening the subject to determine whether the administration of a therapeutically effective amount of the checkpoint inhibitor would be effective in treating the subject. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda).

[0208] This specification discloses the use of alternating current fields and checkpoint inhibitors for the treatment of subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors in combination with chemotherapy for the treatment of subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors for the treatment of subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors, and the non-small cell lung cancer in the subjects progressing during or after prior treatment with checkpoint inhibitors. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda). In some embodiments, the subjects were diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with a checkpoint inhibitor. In some embodiments, the subjects progressed to metastatic disease within 6 months of the completion of prior treatment with a checkpoint inhibitor.

[0209] A method for treating a subject with cancer is disclosed, comprising: applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more cancer cells for a predetermined period of time; and administering to the subject a therapeutically effective amount of a checkpoint inhibitor, wherein the cancer is metastatic non-small cell lung cancer, the subject has received prior treatment for non-small cell lung cancer with a checkpoint inhibitor and systemic therapy including platinum-based chemotherapy, and the non-small cell lung cancer in the subject has progressed during or after prior systemic treatment, and the frequency of the alternating electric field is 150 kHz. In some embodiments, the checkpoint inhibitor administered in the step of administering a therapeutically effective amount to the subject is a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. In some embodiments, the PD-1 inhibitor may be, but is not limited to, nivolumab, pembrolizumab, or cemiplimab. In some embodiments, the PD-L1 inhibitor may be, but is not limited to, atezolizumab, avelumab, or durvalumab. In some embodiments, the CTLA-4 inhibitor may be, but is not limited to, ipilimumab or tremelimumab. In some embodiments, the checkpoint inhibitor administered in the step of administering a therapeutically effective amount of a checkpoint inhibitor to the subject is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject progressed during or after prior treatment with pembrolizumab (Keytruda).

[0210] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to treat a subject with non-small cell lung cancer, the subject having received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject progressing during or after prior treatment with a checkpoint inhibitor, and the subject having not previously received non-platinum or platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda).

[0211] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to treat a subject with non-small cell lung cancer, the subject having received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject progressing during or after prior treatment with a checkpoint inhibitor, and the subject having not previously received platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda).

[0212] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to treat a subject with non-small cell lung cancer, the subject having received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject progressing during or after prior treatment with a checkpoint inhibitor, and the subject having not experienced a cerebrovascular event within six months prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda).

[0213] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to treat a subject with non-small cell lung cancer, the subject having received prior treatment with a checkpoint inhibitor, the non-small cell lung cancer in the subject progressing during or after prior treatment with a checkpoint inhibitor, and the subject having no malignancies other than NSCLC within three years prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda).

[0214] This specification discloses the use of alternating current fields and checkpoint inhibitors for the treatment of subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors in combination with chemotherapy for the treatment of subjects with non-small cell lung cancer. In some embodiments, this specification discloses the use of alternating current fields and checkpoint inhibitors for the treatment of subjects with non-small cell lung cancer, the subjects having received prior treatment with checkpoint inhibitors and chemotherapy, and the non-small cell lung cancer in the subjects has progressed during or after prior treatment with checkpoint inhibitors. In some embodiments, the checkpoint inhibitor previously administered to the subjects is the same as the checkpoint inhibitor administered in combination with the alternating current field. In some embodiments, the checkpoint inhibitor previously administered to the subjects is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating current field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subjects was pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with an alternating electric field was pembrolizumab (Keytruda), and the subjects progressed during or after prior treatment with pembrolizumab (Keytruda). In some embodiments, the subjects were diagnosed with radiological progression of non-small cell lung cancer during or after prior treatment with checkpoint inhibitors and chemotherapy. In some embodiments, the subjects progressed to metastatic disease within 6 months of the completion of prior treatment with checkpoint inhibitors and chemotherapy.

[0215] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to treat a subject with non-small cell lung cancer, the subject having received prior treatment with a checkpoint inhibitor and chemotherapy, the non-small cell lung cancer in the subject progressing during or after prior treatment with a checkpoint inhibitor and chemotherapy, and the subject having not previously received non-platinum-based chemotherapy. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda).

[0216] In certain embodiments, this specification discloses the use of alternating electric fields and checkpoint inhibitors for the treatment of subjects having non-small cell lung cancer, wherein the subjects have received prior treatment with checkpoint inhibitors, the non-small cell lung cancer in the subjects has progressed during or after prior treatment with checkpoint inhibitors and chemotherapy, and the subjects have not previously received platinum-based chemotherapy.

[0217] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to treat a subject with non-small cell lung cancer, the subject having received prior treatment with a checkpoint inhibitor and chemotherapy, the non-small cell lung cancer in the subject progressing during or after prior treatment with the checkpoint inhibitor, and the subject having not experienced cerebrovascular disease within six months prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda).

[0218] In some embodiments, this specification discloses the use of an alternating electric field and a checkpoint inhibitor to treat a subject with non-small cell lung cancer, the subject having received prior treatment with a checkpoint inhibitor and chemotherapy, the non-small cell lung cancer in the subject progressing during or after prior treatment with a checkpoint inhibitor and chemotherapy, and the subject having no malignancies other than NSCLC within three years prior to the application of the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is the same as the checkpoint inhibitor administered in combination with the alternating electric field. In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), and the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda). In some embodiments, the checkpoint inhibitor previously administered to the subject is pembrolizumab (Keytruda), the checkpoint inhibitor administered in combination with the alternating electric field is pembrolizumab (Keytruda), and the subject has progressed during or after prior treatment with pembrolizumab (Keytruda). F. Kit

[0219] The compositions and materials described above may be packaged together in any suitable combination as a kit useful for carrying out or assisting in the carrying out of the disclosed method. A kit is useful if the kit components within a given kit are designed and adapted to be used together in the disclosed method. For example, a kit for cancer treatment is disclosed. In some embodiments, the kit may include a device for applying an alternating electric field.

[0220] For example, a kit is disclosed comprising one or more checkpoint inhibitors and one or more materials for delivering an alternating electric field, such as an Optune system. For example, a kit is disclosed comprising one or more of ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (brand name Ributayo), dostarimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), and / or avelumab (Bavencio) and one or more materials for applying an alternating electric field (e.g., an Optune system). For example, a kit is disclosed comprising one or more of the following: tremelimumab, cintilimab (formerly IBI308; Tyvit), tislerizumab (formerly BGB-A317), tripalimab (formerly JS 001), spartalizumab (formerly PRD001); camrelizumab (formerly SHR1210), KN035, kosiberimab (formerly CK-301), CA-170, or BMS-986189, and one or more materials for applying an alternating electric field (e.g., an Optune system). Examples A. Example 1: Tumor therapeutic electric field in previously treated non-small cell lung cancer 1. Method i. Test design and supervision

[0221] LUNAR4 is a prospective, randomized trial evaluating combination therapy with checkpoint inhibitors, including patients with NSCLC that have progressed during or after treatment with checkpoint inhibitor monotherapy or checkpoint inhibitors plus chemotherapy, which may include platinum-based chemotherapy.

[0222] The LUNAR4 trial is designed by the sponsor (Novocure GmbH) and the researchers. Data is collected by the researchers and analyzed by statisticians employed by the sponsor.

[0223] The TT field is expected to reconstruct adaptive immunity in the relapsed environment after ICI therapy. Therefore, while retreatment with PD-1 / PD-L1 inhibitor monotherapy is not recommended, combination therapy with the TT field and pembrolizumab may improve prognosis. ii. Target patient population

[0224] Eligible participants are adult patients diagnosed with histologically or cytologically NSCLC who have experienced radiological progression during or after treatment with checkpoint inhibitor monotherapy or checkpoint inhibitor plus chemotherapy. The combination therapy of TT site therapy and the checkpoint inhibitor pembrolizumab yields particularly favorable outcomes in patients diagnosed with metastatic NSCLC who have experienced progression during or after prior treatment with checkpoint inhibitors (PD-1 / PD-L1 inhibitors) and platinum-based chemotherapy.

[0225] procedure Eligible patients will be randomly assigned in a 1:1 ratio (within 28 days of obtaining informed consent) to receive TT field therapy to the chest, in combination with a researcher-selected checkpoint inhibitor. Randomization will be determined uniformly using variable block randomization and the IxRS system, stratified by tumor histological type, treatment (checkpoint inhibitor), and region (North America, Western Europe / Israel, Eastern Europe).

[0226] The TT field (150 kHz) is administered continuously for at least 18 hours per day on average using the NovoTTF device system (Figure 3C). Array placement is determined by the researcher and modified as needed during the treatment period based on computed tomography scans and provided clinical practice guidelines. Patients receive instruction on device use from the researcher, other healthcare providers, or a device support specialist (DSS, sponsored). The array is replaced every 3-4 days (and moved approximately 2 cm from its original position to minimize skin irritation). TT field usage time (device recorded data) is reported to the researcher monthly and presented as a percentage.

[0227] Patients receiving immune checkpoint inhibitors are followed up every 6 weeks (±1 week) based on immune-related (ir)RECIST for radiological evaluation of the disease.

[0228] TT-site therapy is continued until progression in the chest and / or liver, or until unacceptable toxicity occurs. Treatment interruption of up to 3 weeks is permitted for TT-site related adverse events. Patients may continue TT-site therapy even if systemic therapy is discontinued due to progression in sites other than the chest / liver, or due to unacceptable toxicity. iii. Trial endpoints

[0229] The primary endpoint is overall survival of patients receiving TT-environment-combined checkpoint inhibitor therapy compared to checkpoint inhibitor monotherapy. Other secondary endpoints include progression-free survival and overall response rate (both assessed by radiological diagnosis), overall survival and progression-free survival by squamous cell carcinoma and non-squamous cell carcinoma histological subtypes, and adverse events.

[0230] Overall survival is defined as the period from randomization to death from any cause or screening at the final follow-up date. Progression-free survival is defined as the period from randomization to disease progression in the liver or chest, or death from any cause. Deaths that occur without the researcher detecting tumor progression are considered progression events if they occur within 6 weeks of the last tumor assessment prior to death. Otherwise, patients are screened on the last tumor assessment date. Patients with no progression or death at the time of analysis are screened on the most recent evaluable tumor assessment date. Patients with no tumor assessments after baseline are screened on the randomization date. The overall radiological response rate is defined as complete response or partial response, and the best response (classified as complete response, partial response, stable disease, disease progression, or unevaluable) is calculated for each treatment group. iv.Statistical analysis

[0231] Overall survival and progression-free survival were evaluated using a two-sided log-rank test with a significance level of 0.05 and stratified by treatment and tumor histotype. The median, confidence interval (CI), and rates were estimated using the Kaplan-Meier method. Hazard ratios (95% CI and P value) were estimated using a stratified Cox proportional hazards model with stratification variables as covariates. For the comparison of overall response rates, the 95% CI was calculated based on the exact binomial distribution (Clopper-Pearson). Differences between treatment groups and associated two-sided 95% confidence intervals were calculated using a chi-square test at a significance level of 0.05 (two-sided P value). The best response was summarized for each treatment group.

[0232] Effectiveness endpoints were analyzed in all randomized patients (intention-to-treat population). Safety and treatment data were collected from all patients who received the treatment in this trial in some form and were analyzed based on the treatment actually received. The analysis was performed using SAS software version 9.4 (SAS Institute).

[0233] Messenger RNA (mRNA) expression profiling in stored materials (biopsy specimens, peripheral blood) can be performed to evaluate gene expression and attempt to identify gene sets important for clinical response to pembrolizumab combined with TT field therapy. Pembrolizumab combined with TT field can induce a tumor response reflecting an inflammatory / immune phenotype based on a gene expression signature that captures the PD-L1 and interferon gamma transcription programs. Global profiling can also be performed. The expression of individual genes related to the immune system, such as immune signatures and important cytokines (e.g., IL-10), can also be evaluated.

[0234] Tissue and blood-derived substances can be the subject of proteomics analysis using platforms that may include, but are not limited to, immunoassay, flow cytometry, liquid chromatography / mass spectrometry, etc., and can contribute to the identification of novel protein biomarkers useful for patient selection for pembrolizumab combined with TT field therapy.

[0235] The application of new technologies such as next-generation sequencing gives scientists the opportunity to define specific tumor types as "hypermutation states" at the genetic level and to detect specific T cell clones within the tumor microenvironment or in peripheral blood. Hypermutation states and / or increased T cell clonality may correlate with response to pembrolizumab-combined TT field therapy, and / or conversely, a "hypomutation" state or lack of dominant T cell clones may correlate with non-response. Therefore, genetic variations within clinical study populations may correlate with response to the treatment being evaluated. Appearances that constitute the specification [Aspect 1] The use of checkpoint inhibitors in a method to improve the survival time of subjects with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject. [Aspect 2] The use of checkpoint inhibitors in a method for treating a subject with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject. [Aspect 3] A method for improving the survival time of subjects with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject. [Aspect 4] A method for treating a subject with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject. [Aspect 5] The use of a checkpoint inhibitor according to Embodiments 1-2, or the method according to Embodiments 3-4, wherein the checkpoint inhibitor is nivolumab, pembrolizumab, or atezolizumab. [Aspect 6] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, and 5, or the method according to any one of embodiments 2 to 5, wherein the cancer is metastatic non-small cell lung cancer. [Aspect 7] The use or method of a checkpoint inhibitor according to embodiment 6, wherein the subject has a history of prior systemic therapy for the non-small cell lung cancer. [Aspect 8] The use or method of a checkpoint inhibitor according to embodiment 7, wherein the systemic therapy does not include treatment with a checkpoint inhibitor. [Aspect 9] The use or method of a checkpoint inhibitor according to embodiment 7, wherein the systemic therapy includes treatment with a checkpoint inhibitor. [Aspect 10] The use or method of a checkpoint inhibitor according to embodiment 7, wherein the systemic therapy includes platinum-based chemotherapy. [Aspect 11] The use or method of a checkpoint inhibitor according to embodiment 7, wherein the systemic therapy includes treatment with chemotherapy and a checkpoint inhibitor. [Aspect 12] The use or method of a checkpoint inhibitor according to embodiment 11, wherein the chemotherapy includes platinum-based chemotherapy. [Aspect 13] The use or method of a checkpoint inhibitor according to any one of embodiments 7 to 12, wherein the systemic therapy includes treatment with a checkpoint inhibitor. [Aspect 14] The use or method of a checkpoint inhibitor according to any one of embodiments 7 to 13, wherein the non-small cell lung cancer in the subject progresses during or after the aforementioned pre-systemic treatment. [Aspect 15] The aforementioned extension of survival is an extension of progression-free survival, and can be done at will. The aforementioned extension of survival time is compared to the survival time of subjects who were administered the same therapeutically effective dose of a checkpoint inhibitor but were not subjected to an alternating electric field, The aforementioned extension of survival is defined as an extension of survival by at least one month compared to the survival of subjects who were administered the same therapeutically effective dose of a checkpoint inhibitor but were not subjected to an alternating electric field. The cancer is squamous cell NSCLC, and the extension of survival is at least 3 months longer than the survival of subjects who were administered the same therapeutically effective dose of a checkpoint inhibitor but were not subjected to an alternating electric field. The use of the checkpoint inhibitor according to Embodiment 1 or the method according to Embodiment 3, wherein the cancer is non-squamous cell NSCLC, and the extension of survival is an extension of survival by at least two months compared to the survival of a subject who was administered the same therapeutically effective amount of the checkpoint inhibitor but was not subjected to an alternating electric field. [Aspect 16] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, and 5 to 15, wherein the frequency of the AC electric field is between 100 kHz and 1 MHz, or the method according to any one of embodiments 3 to 15. [Aspect 17] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, and 5 to 16, wherein the frequency of the alternating electric field is 150 kHz, or the method according to any one of embodiments 3 to 16. [Aspect 18] The cancer is metastatic non-small cell lung cancer, the subject has received prior treatment with a systemic therapy including platinum-based chemotherapy for non-small cell lung cancer, and the non-small cell lung cancer in the subject has progressed during or after the prior systemic therapy, and the frequency of the alternating current electric field is 150 kHz. Use of the checkpoint inhibitor according to any one of aspects 1 to 2, or the method according to any one of aspects 3 to 4. [Aspect 19] The cancer is metastatic non-small cell lung cancer, the subject has received prior treatment with a systemic therapy including treatment with a checkpoint inhibitor and platinum-based chemotherapy for non-small cell lung cancer, and the non-small cell lung cancer in the subject has progressed during or after the prior systemic therapy. The frequency of the alternating current electric field is 150 kHz. And in the step of administering a therapeutically effective amount of a checkpoint inhibitor to the subject, the checkpoint inhibitor administered is pembrolizumab. Use of the checkpoint inhibitor according to any one of aspects 1 to 2, or the method according to any one of aspects 3 to 4. [Aspect 20] The checkpoint inhibitor of the systemic therapy is a PD-1 / PD-L1 inhibitor. Use or method of the checkpoint inhibitor according to aspect 18 or aspect 19. [Aspect 21] Applying the alternating current electric field to the target site of the subject for a predetermined time includes applying the electric field to the target site continuously for at least 18 hours per day. Use of the checkpoint inhibitor according to any one of aspects 1, 2 and 5 to 20, or the method according to any one of aspects 3 to 20. [Aspect 22] Applying the alternating current electric field to the target site of the subject for a predetermined time includes continuously applying the electric field to the target site until progression of the cancer or unacceptable toxicity occurs. Use of the checkpoint inhibitor according to any one of aspects 1, 2 and 5 to 21, or the method according to any one of aspects 3 to 21. [Aspect 23] The electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage of at least 50 V RMS, and optionally, the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage between 10 and 250 V RMS, using a checkpoint inhibitor according to any one of embodiments 1, 2 and 5 to 22, or the method according to any one of embodiments 3 to 22. [Aspect 24] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, and 5-23, further comprising administering docetaxel, or the method according to any one of embodiments 3-23. [Pattern 25] The use of docetaxel in a method to improve the survival time of subjects with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of docetaxel, comprising administering a therapeutically effective amount of docetaxel to the subject. [Aspect 26] The use of docetaxel in a method for treating a subject with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of docetaxel, comprising administering a therapeutically effective amount of docetaxel to the subject. [Aspect 27] A method for improving the survival time of subjects with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, A method comprising administering a therapeutically effective amount of docetaxel to the subject. [Aspect 28] A method for treating a subject with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, A method comprising administering a therapeutically effective amount of docetaxel to the subject. [Aspect 29] The use of docetaxel according to any one of embodiments 25 to 26, or the method according to any one of embodiments 27 to 28, wherein the cancer is metastatic non-small cell lung cancer. [Aspect 30] The use or method of docetaxel according to embodiment 29, wherein the subject has a history of prior systemic therapy for the non-small cell lung cancer. [Aspect 31] The use or method of docetaxel according to embodiment 30, wherein the systemic therapy does not include treatment with a checkpoint inhibitor. [Aspect 32] The use or method of docetaxel according to embodiment 30, wherein the systemic therapy includes treatment with a checkpoint inhibitor. [Aspect 33] The use or method of docetaxel according to embodiment 30, wherein the systemic therapy includes platinum-based chemotherapy. [Aspect 34] The use or method of docetaxel according to embodiment 30, wherein the systemic therapy includes treatment with chemotherapy and checkpoint inhibitors. [Aspect 35] The use or method of docetaxel according to embodiment 34, wherein the chemotherapy includes a platinum-based chemotherapy regimen. [Aspect 36] The use or method of docetaxel according to any one of embodiments 30 to 35, wherein the systemic therapy includes treatment with a checkpoint inhibitor. [Aspect 37] The use or method of docetaxel according to any one of embodiments 30 to 36, wherein the non-small cell lung cancer in the subject progresses during or after the aforementioned pre-systemic treatment. [Aspect 38] The use of docetaxel according to embodiment 25, or the method according to embodiment 27, wherein the extension of the survival period is an extension of the progression-free survival period. [Aspect 39] The use of docetaxel according to any one of embodiments 25, 26, and 29-38, wherein the frequency of the AC electric field is between 100 kHz and 1 MHz, or the method according to any one of embodiments 27-38. [Aspect 40] The use or method of docetaxel according to embodiment 39, wherein the frequency of the alternating electric field is 150 kHz. [Aspect 41] The use of docetaxel according to any one of embodiments 25 to 26, or the method according to any one of embodiments 27 to 28, wherein the cancer is metastatic non-small cell lung cancer, the subject has received prior systemic therapy including platinum-based chemotherapy for non-small cell lung cancer, the non-small cell lung cancer in the subject has progressed during or after the prior systemic therapy, and the frequency of the alternating electric field is 150 kHz. [Aspect 42] The use or method of docetaxel according to embodiment 41, wherein the checkpoint inhibitor of the systemic therapy is a PD-1 / PD-L1 inhibitor. [Aspect 43] The use of docetaxel according to any one of embodiments 25, 26, and 29-42, or the method according to any one of embodiments 27-42, wherein applying the alternating electric field to the target site of the subject for a predetermined time includes applying the electric field to the target site for an average of at least 18 hours continuously per day. [Aspect 44] The use of docetaxel according to any one of embodiments 25, 26, and 29-43, or the method according to any one of embodiments 27-43, comprising applying the alternating electric field to the target site of the subject for a predetermined time, or continuously applying the electric field to the target site until the cancer progresses or unacceptable toxicity occurs. [Aspect 45] The use of a docetaxel according to any one of embodiments 25, 26 and 29-44, wherein the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage of at least 50 V RMS, and optionally, the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage in the range of 10 to 250 V RMS. [Aspect 46] The use of checkpoint inhibitors in a method to improve the survival time of subjects with non-small cell lung cancer, wherein the method is: a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject. [Aspect 47] The use of checkpoint inhibitors in a method for treating a subject with non-small cell lung cancer, wherein the method is: Applying an alternating electric field having a predetermined frequency and electric field intensity to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject. [Aspect 48] A method for improving the survival time of subjects with non-small cell lung cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject. [Aspect 49] A method for treating a subject with non-small cell lung cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject. [Aspect 50] The use of a checkpoint inhibitor according to any one of embodiments 46 to 47, wherein the checkpoint inhibitor is a PD-1 inhibitor or a PDL-1 inhibitor, or the method according to any one of embodiments 18 to 49. [Aspect 51] The use of a checkpoint inhibitor according to any one of embodiments 46 to 47, wherein the checkpoint inhibitor is ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (trade name Ributayo), dostarimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), and / or avelumab (Bavencio), or the method according to any one of embodiments 18 to 49. [Aspect 52] The use of a checkpoint inhibitor according to embodiment 46, or the method according to embodiment 48, wherein the extension of the survival period is an extension of progression-free survival. [Aspect 53] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-52, wherein the frequency of the AC electric field is between 100 kHz and 1 MHz, or the method according to any one of embodiments 48-52. [Aspect 54] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-53, further comprising administering chemotherapy to the subject, or the method according to any one of embodiments 48-52. [Aspect 55] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-54, further comprising stopping the AC electric field, or the method according to any one of embodiments 48-53. [Aspect 56] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-55, or the method according to any one of embodiments 48-57, wherein the subject has received prior treatment with a checkpoint inhibitor. [Aspect 57] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-56, or the method according to any one of embodiments 48-56, wherein the subject has received prior treatment with a checkpoint inhibitor and chemotherapy. [Aspect 58] The use or method of a checkpoint inhibitor according to aspect 56, wherein the non-small cell lung cancer in the subject progressed during or after the prior treatment with the checkpoint inhibitor. [Aspect 59] The use or method of a checkpoint inhibitor according to aspect 57, wherein the non-small cell lung cancer in the subject progressed during or after the prior treatment with the checkpoint inhibitor and chemotherapy. [Aspect 60] The use or method of a checkpoint inhibitor according to any one of embodiments 56 or 58, wherein the subject is diagnosed with radiological progression of the non-small cell lung cancer during or after the prior treatment with the checkpoint inhibitor. [Aspect 61] The use or method of a checkpoint inhibitor according to any one of aspects 57 or 59, wherein the subject was diagnosed with radiological progression of the non-small cell lung cancer during or after the prior treatment with the checkpoint inhibitor and chemotherapy. [Aspect 62] The use or method of a checkpoint inhibitor according to any one of aspects 56, 58, or 60, wherein the subject progresses to metastatic disease within six months of completing the prior treatment with the checkpoint inhibitor. [Aspect 63] The use or method of a checkpoint inhibitor according to any one of embodiments 57, 59, or 61, wherein the subject progresses to metastatic disease within six months after completing the prior treatment with the checkpoint inhibitor and chemotherapy. [Aspect 64] The use or method of a checkpoint inhibitor according to any one of embodiments 57, 59, 61, or 63, wherein the chemotherapy is a platinum-based chemotherapy. [Aspect 65] The use of a checkpoint inhibitor according to any one of embodiments 47, 48, and 50-55, or the method according to any one of embodiments 48-55, wherein the subject has received prior treatment with a checkpoint inhibitor and chemotherapy, and has not received prior treatment with non-platinum chemotherapy or platinum-based chemotherapy. [Aspect 66] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-55, or the method according to any one of embodiments 8-55, wherein the subject has received prior treatment with a checkpoint inhibitor but has not received prior treatment with platinum-based chemotherapy. [Aspect 67] The use or method of a checkpoint inhibitor according to aspect 66, wherein the non-small cell lung cancer in the subject progressed during or after the prior treatment with the checkpoint inhibitor. [Pattern 68] The use or method of a checkpoint inhibitor according to aspect 67, wherein the subject is diagnosed with radiological progression of the non-small cell lung cancer during or after the prior treatment with the checkpoint inhibitor. [Aspect 69] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-55, or the method according to any one of embodiments 8-55, in which the cancer has progressed during or after treatment with platinum-based systemic therapy. [Aspect 70] The use or method of a checkpoint inhibitor according to aspect 69, wherein the subject is diagnosed with radiological progression during or after treatment with platinum-based systemic therapy. [Aspect 71] The use or method of a checkpoint inhibitor according to any one of embodiments 69 to 70, wherein the platinum-based systemic therapy comprises one or more of nedaplatin, satraplatin, cisplatin, carboplatin, and oxaliplatin. [Aspect 72] The method according to any one of embodiments 69 to 71, wherein the subject progressed to metastatic disease within 6 months after completion of platinum-based systemic therapy. [Aspect 73] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-72, wherein the frequency of the AC electric field is 150 kHz, or the method according to any one of embodiments 48-72. [Aspect 74] The use of a checkpoint inhibitor according to any one of embodiments 1, 47, and 50-73, wherein applying the alternating electric field to the target site of the subject for a predetermined time includes applying the electric field to the target site for an average of at least 18 hours continuously per day. [Aspect 75] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-74, or the method according to any one of embodiments 48-74, comprising applying the alternating electric field to the target site of the subject for a predetermined time, or continuously applying the electric field to the target site until the cancer progresses or unacceptable toxicity occurs. [Aspect 76] The use of a checkpoint inhibitor according to any one of embodiments 46, 47 and 50-75, wherein the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage of at least 50 V RMS, and optionally, the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage between 10 and 250 V RMS, or the method according to any one of embodiments 48-71. [Aspect 77] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-76, further comprising administering a taxane-based anticancer agent, or the method according to any one of embodiments 48-76. [Aspect 78] The use or method of a checkpoint inhibitor according to embodiment 77, wherein the taxane-based anticancer agent is docetaxel, paclitaxel, cabazitaxel, abraxane, or a combination thereof. [Aspect 79] The use of a checkpoint inhibitor according to any one of embodiments 46, 47, and 50-78, further comprising administering a therapeutically effective amount of a second immune checkpoint inhibitor to the subject, or the method according to any one of embodiments 48-74. [Aspect 80] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-79, the use of docetaxel according to any one of embodiments 25, 26 and 29-45, or the method according to any one of embodiments 4-24, 27-45 and 48-79, wherein the alternating electric field is applied to the chest of the subject having cancer. [Aspect 81] The subject has not experienced cerebrovascular disease within six months prior to the application of the alternating electric field, and the method involves the use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-80, the use of docetaxel according to any one of embodiments 25, 26 and 29-45 and 80, or the method according to any one of embodiments 4-24, 27-45 and 48-80. [Aspect 82] The subject has not had any malignant tumors other than NSCLC within three years prior to the application of the alternating electric field, the use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-81, the use of docetaxel according to any one of embodiments 25, 26, 29-45, 80 and 81, or the method according to any one of embodiments 4-24, 27-45 and 48-81. [Aspect 83] The subject has not had any malignant tumors other than NSCLC, excluding stage I prostate cancer, non-melanoma skin cancer, or cervical carcinoma in situ or breast carcinoma in situ, within three years prior to the administration of the alternating electric field, and the method involves the use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-82, the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-82, or the method according to any one of embodiments 4-24, 27-45 and 48-82. [Aspect 84] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-83, further comprising screening the subject to determine whether the administration of a therapeutically effective amount of the checkpoint inhibitor is effective in improving the survival time of the subject or in treating the subject; the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-83; or the method according to any one of embodiments 4-24, 27-45 and 48-83. [Aspect 85] The use of a checkpoint inhibitor as described in any one of embodiments 1, 2, 5-24, 46, 47 and 50-84, the use of docetaxel as described in any one of embodiments 25, 26, 29-45 and 80-84, or the method as described in any one of embodiments 4-24, 27-45 and 48-84, wherein the subject does not have clinically significant blood, liver, kidney, or heart dysfunction. [Aspect 86] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-85, the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-85, or the method according to any one of embodiments 4-24, 27-45 and 48-85, wherein the subject is a non-smoker, a current smoker, or a former smoker. [Aspect 87] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-86, the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-86, or the method according to any one of embodiments 4-24, 27-45 and 48-86, wherein the subject has non-squamous cell carcinoma or squamous cell carcinoma. [Pattern 88] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-87, the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-87, or the method according to any one of embodiments 4-24, 27-45 and 48-87, wherein the subject has liver metastases. [Aspect 89] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-88, the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-88, or the method according to any one of embodiments 4-24, 27-45 and 48-88, wherein the subject having cancer is at least 22 years old. [Aspect 90] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-89, the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-89, or the method according to any one of embodiments 4-24, 27-45 and 48-89, wherein the subject does not have central nervous system metastases. [Aspect 91] The use of a checkpoint inhibitor as described in any one of embodiments 1, 2, 5-24, 46, 47 and 50-90, the use of docetaxel as described in any one of embodiments 25, 26, 29-45 and 80-90, or the method as described in any one of embodiments 4-24, 27-45 and 48-90, wherein the subject does not have a history of second-degree or third-degree atrioventricular block, uncontrolled hypertension, congestive heart failure, a history of symptomatic or treatment-requiring arrhythmias, a history of pericarditis, or a history of interstitial lung disease. [Aspect 92] The use of a checkpoint inhibitor according to any one of embodiments 1, 2, 5-24, 46, 47 and 50-91, the use of docetaxel according to any one of embodiments 25, 26, 29-45 and 80-91, or the method according to any one of embodiments 4-24, 27-45 and 48-91, wherein the subject is not pregnant. [Aspect 93] The use of taxane-based anticancer drugs in a method to improve the survival time of subjects with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of a taxane-based anticancer agent, comprising administering a therapeutically effective amount of the taxane-based anticancer agent to the subject. [Aspect 94] The use of taxane-based anticancer drugs in a method of treating subjects with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of a taxane-based anticancer agent, comprising administering a therapeutically effective amount of the taxane-based anticancer agent to the subject. [Aspect 95] A method for improving the survival time of subjects with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a taxane-based anticancer agent to the subject. [Aspect 96] A method for treating a subject with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a taxane-based anticancer agent to the subject. [Aspect 97] The use of a taxane-based anticancer agent according to any one of embodiments 93 to 94, wherein the taxane-based anticancer agent is docetaxel, paclitaxel, cabazitaxel, abraxane, or a combination thereof, or the method according to any one of embodiments 95 to 96. [Aspect 98] The use of a taxane-based anticancer agent according to any one of embodiments 93-94 and 97, or the method according to any one of embodiments 95-97, wherein the cancer is metastatic non-small cell lung cancer (NSCLC). [Aspect 99] The use of a taxane-based anticancer agent according to any one of embodiments 93-94 and 97-98, wherein the extension of the survival period is an extension of progression-free survival, or the method according to any one of embodiments 95-98. [Aspect 100] The extension of survival is compared to the survival of subjects who were administered the same therapeutically effective amount of taxane-based anticancer agent but were not subjected to an alternating electric field, using a taxane-based anticancer agent as described in any one of embodiments 93-94 and 97-99, or the method as described in any one of embodiments 95-99. [Aspect 101] The use or method of a taxane-based anticancer agent according to embodiment 100, wherein the extension of survival is an extension of survival by at least one month compared to the survival of a subject who was administered the same therapeutically effective amount of taxane-based anticancer agent but was not subjected to an alternating electric field. [Aspect 102] The use of a taxane-based anticancer agent according to any one of embodiments 93-94 and 97-101, wherein the NSCLC is squamous epithelial cell NSCLC, or the method according to any one of embodiments 95-101. [Aspect 103] The use or method of a taxane-based anticancer agent according to embodiment 102, wherein the extension of survival is an extension of survival by at least three months compared to the survival of subjects who were administered the same therapeutically effective amount of taxane-based anticancer agent but were not subjected to an alternating electric field. [Aspect 104] The use of a taxane-based anticancer agent according to any one of embodiments 93-94 and 97-101, wherein the NSCLC is non-squamous epithelial cell NSCLC, or the method according to any one of embodiments 95-101. [Aspect 105] The use or method of a taxane-based anticancer agent according to embodiment 104, wherein the extension of survival is an extension of survival by at least two months compared to the survival of a subject who was administered the same therapeutically effective amount of taxane-based anticancer agent but was not subjected to an alternating electric field. [Aspect 106] The use of a taxane-based anticancer agent according to any one of embodiments 93 to 94 and 97 to 105, wherein the frequency of the alternating electric field is between 100 kHz and 1 MHz, or the method according to any one of embodiments 95 to 101. [Aspect 107] A kit used in any of the methods described in embodiments 1 to 24 and 46 to 92, An electric field generating device configured to generate the aforementioned alternating electric field, A means for applying the alternating electric field to the subject, A kit comprising a checkpoint inhibitor used in the above method. [Aspect 108] A kit used in any of the methods described in embodiments 25-45 and 80-92, An electric field generating device configured to generate the aforementioned alternating electric field, A means for applying the alternating electric field to the subject, A kit comprising docetaxel used in the above method. [Aspect 109] A kit used in the method described in any of embodiments 93 to 106, An electric field generating device configured to generate the aforementioned alternating electric field, A means for applying the alternating electric field to the subject, A kit comprising a taxane-based anticancer agent used in the above method.

Claims

1. The use of checkpoint inhibitors in a method to improve the survival time of subjects with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject.

2. The use of checkpoint inhibitors in a method for treating a subject with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject.

3. A method for improving the survival time of subjects with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject.

4. A method for treating a subject with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject.

5. The use of a checkpoint inhibitor according to claims 1 to 2, or the method according to claims 3 to 4, wherein the checkpoint inhibitor is nivolumab, pembrolizumab, or atezolizumab.

6. The use of a checkpoint inhibitor according to any one of claims 1, 2, and 5, or the method according to any one of claims 2 to 5, wherein the cancer is metastatic non-small cell lung cancer.

7. The use or method of a checkpoint inhibitor according to claim 6, wherein the subject has a history of prior systemic therapy for the non-small cell lung cancer.

8. The use or method of a checkpoint inhibitor according to claim 7, wherein the systemic therapy does not include treatment with a checkpoint inhibitor.

9. The use or method of a checkpoint inhibitor according to claim 7, wherein the systemic therapy includes treatment with a checkpoint inhibitor.

10. The use or method of a checkpoint inhibitor according to claim 7, wherein the systemic therapy includes platinum-based chemotherapy.

11. The use or method of a checkpoint inhibitor according to claim 7, wherein the systemic therapy includes treatment with chemotherapy and a checkpoint inhibitor.

12. The use or method of a checkpoint inhibitor according to claim 11, wherein the chemotherapy includes platinum-based chemotherapy.

13. The use or method of a checkpoint inhibitor according to any one of claims 7 to 12, wherein the systemic therapy includes treatment with a checkpoint inhibitor.

14. The use or method of a checkpoint inhibitor according to any one of claims 7 to 13, wherein the non-small cell lung cancer in the subject progresses during or after the pre-systemic treatment.

15. The use of a checkpoint inhibitor according to claim 1, or the method according to claim 3, wherein the extension of the survival period is an extension of the progression-free survival period.

16. The use of a checkpoint inhibitor according to any one of claims 1, 2, and 5 to 15, wherein the frequency of the alternating electric field is between 100 kHz and 1 MHz, or the method according to any one of claims 3 to 15.

17. The use of a checkpoint inhibitor according to any one of claims 1, 2, and 5 to 16, wherein the frequency of the alternating electric field is 150 kHz, or the method according to any one of claims 3 to 16.

18. The use of a checkpoint inhibitor according to any one of claims 1 to 2, or the method according to any one of claims 3 to 4, wherein the cancer is metastatic non-small cell lung cancer, the subject has received prior systemic therapy including platinum-based chemotherapy for non-small cell lung cancer, the non-small cell lung cancer in the subject has progressed during or after the prior systemic therapy, and the frequency of the alternating electric field is 150 kHz.

19. The cancer is metastatic non-small cell lung cancer, the subject has received prior treatment for non-small cell lung cancer with checkpoint inhibitors and systemic therapy including platinum-based chemotherapy, and the non-small cell lung cancer in the subject progressed during or after the prior systemic treatment. The frequency of the aforementioned AC electric field is 150 kHz. The use of a checkpoint inhibitor according to any one of claims 1 to 2, or the method according to any one of claims 3 to 4, wherein the checkpoint inhibitor administered in the step of administering a therapeutically effective amount of the checkpoint inhibitor to the subject is pembrolizumab.

20. The use or method of a checkpoint inhibitor according to claim 18 or 19, wherein the checkpoint inhibitor in the systemic therapy is a PD-1 / PD-L1 inhibitor.

21. The use of a checkpoint inhibitor according to any one of claims 1, 2, and 5 to 20, or the method according to any one of claims 3 to 20, wherein applying the alternating electric field to the target site of the subject for a predetermined time includes applying the electric field to the target site for an average of at least 18 hours continuously per day.

22. The use of a checkpoint inhibitor according to any one of claims 1, 2, and 5 to 21, or the method according to any one of claims 3 to 21, comprising applying the alternating electric field to the target site of the subject for a predetermined time, or continuously applying the electric field to the target site until the cancer progresses or unacceptable toxicity occurs.

23. The use of a checkpoint inhibitor according to any one of claims 1, 2, and 5 to 22, or the method according to any one of claims 3 to 22, wherein the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage of at least 50 V RMS, and optionally, the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage between 10 and 250 V RMS.

24. The use of a checkpoint inhibitor according to any one of claims 1, 2, and 5-23, further comprising administering docetaxel, or the method according to any one of claims 3-23.

25. The use of docetaxel in a method to improve the survival time of subjects with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of docetaxel, comprising administering a therapeutically effective amount of docetaxel to the subject.

26. The use of docetaxel in a method for treating a subject with cancer, wherein the method is a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) Use of docetaxel, comprising administering a therapeutically effective amount of docetaxel to the subject.

27. A method for improving the survival time of subjects with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of docetaxel to the subject.

28. A method for treating a subject with cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of docetaxel to the subject.

29. The use of docetaxel according to any one of claims 25 to 26, or the method according to any one of claims 27 to 28, wherein the cancer is metastatic non-small cell lung cancer.

30. The use or method of docetaxel according to claim 29, wherein the subject has a history of prior systemic therapy for the non-small cell lung cancer.

31. The use or method of docetaxel according to claim 30, wherein the systemic therapy does not include treatment with a checkpoint inhibitor.

32. The use or method of docetaxel according to claim 30, wherein the systemic therapy includes treatment with a checkpoint inhibitor.

33. The use or method of docetaxel according to claim 30, wherein the systemic therapy includes platinum-based chemotherapy.

34. The use or method of docetaxel according to claim 30, wherein the systemic therapy includes treatment with chemotherapy and checkpoint inhibitors.

35. The use or method of docetaxel according to claim 34, wherein the chemotherapy includes a platinum-based chemotherapy regimen.

36. The use or method of docetaxel according to any one of claims 30 to 35, wherein the systemic therapy includes treatment with a checkpoint inhibitor.

37. The use or method of docetaxel according to any one of claims 30 to 36, wherein the non-small cell lung cancer in the subject progresses during or after the aforementioned pre-systemic treatment.

38. The use of docetaxel according to claim 25, or the method according to claim 27, wherein the extension of the survival period is an extension of the progression-free survival period.

39. The use of docetaxel according to any one of claims 25, 26, and 29-38, wherein the frequency of the alternating electric field is between 100 kHz and 1 MHz, or the method according to any one of claims 27-38.

40. The use or method of docetaxel according to claim 39, wherein the frequency of the alternating electric field is 150 kHz.

41. The use of docetaxel according to any one of claims 25 to 26, or the method according to any one of claims 27 to 28, wherein the cancer is metastatic non-small cell lung cancer, the subject has received prior systemic therapy including platinum-based chemotherapy for non-small cell lung cancer, the non-small cell lung cancer in the subject has progressed during or after the prior systemic therapy, and the frequency of the alternating electric field is 150 kHz.

42. The use or method of docetaxel according to claim 41, wherein the checkpoint inhibitor of the systemic therapy is a PD-1 / PD-L1 inhibitor.

43. The use of docetaxel according to any one of claims 25, 26, and 29-42, or the method according to any one of claims 27-42, wherein applying the alternating electric field to the target site of the subject for a predetermined time includes applying the electric field to the target site for an average of at least 18 hours continuously per day.

44. The use of docetaxel according to any one of claims 25, 26, and 29-43, or the method according to any one of claims 27-43, comprising applying the alternating electric field to the target site of the subject for a predetermined time, or continuously applying the electric field to the target site until the cancer progresses or unacceptable toxicity occurs.

45. The use of a docetaxel according to any one of claims 25, 26, and 29-44, or the method according to any one of claims 27-44, wherein the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage of at least 50 V RMS, and optionally, the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage in the range of 10 to 250 V RMS.

46. The use of checkpoint inhibitors in a method to improve the survival time of subjects with non-small cell lung cancer, wherein the method is: a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject.

47. The use of checkpoint inhibitors in a method for treating a subject with non-small cell lung cancer, wherein the method is: a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) Use of a checkpoint inhibitor, comprising administering a therapeutically effective amount of the checkpoint inhibitor to the subject.

48. A method for improving the survival time of subjects with non-small cell lung cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject.

49. A method for treating a subject with non-small cell lung cancer, a) Applying an alternating electric field having a predetermined frequency and electric field strength to a target site of the subject containing one or more non-small cell lung cancer cells for a predetermined period of time, b) A method comprising administering a therapeutically effective amount of a checkpoint inhibitor to the subject.

50. The use of a checkpoint inhibitor according to any one of claims 46 to 47, or the method according to any one of claims 18 to 49, wherein the checkpoint inhibitor is a PD-1 inhibitor or a PDL-1 inhibitor.

51. The use of a checkpoint inhibitor according to any one of claims 46 to 47, wherein the checkpoint inhibitor is ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (trade name Ributayo), dostarimab (Jemperli), atezolizumab (Tecentriq), durvalumab (Imfinzi), and / or avelumab (Bavencio), or the method according to any one of claims 18 to 49.

52. The use of a checkpoint inhibitor according to claim 46, or the method according to claim 48, wherein the extension of survival is an extension of progression-free survival.

53. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-52, wherein the frequency of the alternating electric field is between 100 kHz and 1 MHz, or the method according to any one of claims 48-52.

54. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-53, or the method according to any one of claims 48-52, further comprising administering chemotherapy to the subject.

55. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-54, further comprising stopping the AC electric field, or the method according to any one of claims 48-53.

56. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-55, or the method according to any one of claims 48-57, wherein the subject has received prior treatment with a checkpoint inhibitor.

57. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-56, or the method according to any one of claims 48-56, wherein the subject has received prior treatment with a checkpoint inhibitor and chemotherapy.

58. The use or method of a checkpoint inhibitor according to claim 56, wherein the non-small cell lung cancer in the subject progressed during or after the prior treatment with the checkpoint inhibitor.

59. The use or method of a checkpoint inhibitor according to claim 57, wherein the non-small cell lung cancer in the subject progressed during or after the prior treatment with the checkpoint inhibitor and chemotherapy.

60. The use or method of a checkpoint inhibitor according to any one of claims 56 or 58, wherein the subject was diagnosed with radiological progression of the non-small cell lung cancer during or after the prior treatment with the checkpoint inhibitor.

61. The use or method of a checkpoint inhibitor according to any one of claims 57 or 59, wherein the subject was diagnosed with radiological progression of the non-small cell lung cancer during or after the prior treatment with the checkpoint inhibitor and chemotherapy.

62. The use or method of a checkpoint inhibitor according to any one of claims 56, 58, or 60, wherein the subject progresses to metastatic disease within six months after completing the prior treatment with the checkpoint inhibitor.

63. The use or method of a checkpoint inhibitor according to any one of claims 57, 59, or 61, wherein the subject progresses to metastatic disease within six months after completing the prior treatment with the checkpoint inhibitor and chemotherapy.

64. The use or method of a checkpoint inhibitor according to any one of claims 57, 59, 61, or 63, wherein the chemotherapy is a platinum-based chemotherapy.

65. The use of a checkpoint inhibitor according to any one of claims 47, 48, and 50-55, or the method according to any one of claims 48-55, wherein the subject has received prior treatment with a checkpoint inhibitor and chemotherapy, and has not received prior treatment with non-platinum chemotherapy or platinum-based chemotherapy.

66. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-55, or the method according to any one of claims 8-55, wherein the subject has received prior treatment with a checkpoint inhibitor and has not received prior treatment with platinum-based chemotherapy.

67. The use or method of a checkpoint inhibitor according to claim 66, wherein the non-small cell lung cancer in the subject progressed during or after the prior treatment with the checkpoint inhibitor.

68. The use or method of a checkpoint inhibitor according to claim 67, wherein the subject was diagnosed with radiological progression of the non-small cell lung cancer during or after the prior treatment with the checkpoint inhibitor.

69. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-55, or the method according to any one of claims 8-55, wherein the cancer progresses during or after treatment with platinum-based systemic therapy.

70. The use or method of a checkpoint inhibitor according to claim 69, wherein the subject is diagnosed with radiological progression during or after treatment with platinum-based systemic therapy.

71. The use or method of a checkpoint inhibitor according to any one of claims 69 to 70, wherein the platinum-based systemic therapy comprises one or more of nedaplatin, satraplatin, cisplatin, carboplatin, and oxaliplatin.

72. The method according to any one of claims 69 to 71, wherein the subject progressed to metastatic disease within six months after completion of platinum-based systemic therapy.

73. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-72, wherein the frequency of the alternating electric field is 150 kHz, or the method according to any one of claims 48-72.

74. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-73, or the method according to any one of claims 48-73, wherein applying the alternating electric field to the target site of the subject for a predetermined time includes applying the electric field to the target site for an average of at least 18 hours continuously per day.

75. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-74, or the method according to any one of claims 48-74, comprising applying the alternating electric field to the target site of the subject for a predetermined time, or continuously applying the electric field to the target site until the cancer progresses or unacceptable toxicity occurs.

76. The use of a checkpoint inhibitor according to any one of claims 46, 47 and 50-75, or the method according to any one of claims 48-71, wherein the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage of at least 50 V RMS, and optionally, the electric field strength of the AC electric field is generated by generating an AC electric field with an applied voltage between 10 and 250 V RMS.

77. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-76, or the method according to any one of claims 48-76, further comprising administering a taxane-based anticancer agent.

78. The use or method of a checkpoint inhibitor according to claim 77, wherein the taxane-based anticancer agent is docetaxel, paclitaxel, cabazitaxel, abraxane, or a combination thereof.

79. The use of a checkpoint inhibitor according to any one of claims 46, 47, and 50-78, or the method according to any one of claims 48-74, further comprising administering a therapeutically effective amount of a second immune checkpoint inhibitor to the subject.

80. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5 to 24, 46, 47 and 50 to 79, the use of docetaxel according to any one of claims 25, 26 and 29 to 45, or the method according to any one of claims 4 to 24, 27 to 45 and 48 to 79, wherein the alternating electric field is applied to the chest of the subject having cancer.

81. The subject has not experienced cerebrovascular disease within six months prior to the application of the alternating electric field, the use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-80, the use of docetaxel according to any one of claims 25, 26 and 29-45 and 80, or the method according to any one of claims 4-24, 27-45 and 48-80.

82. The subject has not had any malignant tumors other than NSCLC within three years prior to the application of the alternating electric field, the use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-81, the use of docetaxel according to any one of claims 25, 26, 29-45, 80 and 81, or the method according to any one of claims 4-24, 27-45 and 48-81.

83. The subject has not had any malignant tumors other than NSCLC, excluding stage I prostate cancer, non-melanoma skin cancer, or cervical carcinoma in situ or breast carcinoma in situ, within three years prior to the administration of the alternating electric field, and the use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-82, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-82, or the method according to any one of claims 4-24, 27-45 and 48-82.

84. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-83, further comprising screening the subject to determine whether the administration of a therapeutically effective amount of the checkpoint inhibitor is effective in improving the survival time of the subject or in treating the subject; the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-83; or the method according to any one of claims 4-24, 27-45 and 48-83.

85. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-84, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-84, or the method according to any one of claims 4-24, 27-45 and 48-84, wherein the subject does not have clinically significant blood, liver, kidney, or heart dysfunction.

86. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-85, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-85, or the method according to any one of claims 4-24, 27-45 and 48-85, wherein the subject is a non-smoker, a current smoker, or a former smoker.

87. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-86, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-86, or the method according to any one of claims 4-24, 27-45 and 48-86, wherein the subject has non-squamous cell carcinoma or squamous cell carcinoma.

88. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-87, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-87, or the method according to any one of claims 4-24, 27-45 and 48-87, wherein the subject has liver metastases.

89. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-88, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-88, or the method according to any one of claims 4-24, 27-45 and 48-88, wherein the subject having cancer is at least 22 years old.

90. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-89, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-89, or the method according to any one of claims 4-24, 27-45 and 48-89, wherein the subject does not have central nervous system metastases.

91. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-90, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-90, or the method according to any one of claims 4-24, 27-45 and 48-90, wherein the subject does not have a history of second-degree or third-degree atrioventricular block, uncontrolled hypertension, congestive heart failure, symptomatic or treatment-requiring arrhythmia, a history of pericarditis, or a history of interstitial lung disease.

92. The use of a checkpoint inhibitor according to any one of claims 1, 2, 5-24, 46, 47 and 50-91, the use of docetaxel according to any one of claims 25, 26, 29-45 and 80-91, or the method according to any one of claims 4-24, 27-45 and 48-91, wherein the subject is not pregnant.

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