Methods for treating non-small cell lung cancer with 2,2'-dithio-BIS-ethane sulfonate, carboplatin, and pemetrexed

Abstract

Methods for treating non-small cell lung cancer (NSCLC) include the administration of a combination of 2,2'-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed. The methods are based on tumor mutational burden (TMB) assessment, with specific treatment regimens tailored to the mutational profile of the tumor. When a low tumor mutational burden is detected in a tumor sample, the combination therapy of 2,2'-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed is administered, offering enhanced therapeutic efficacy.

Description

METHODS FOR TREATING NON-SMALL CELL LUNG CANCER WITH 2,2’- DITHIO-BIS-ETHANE SULFONATE, CARBOPLATIN, AND PEMETREXEDPRIOR RELATED APPLICATION DATA

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 679,505, filed August 5, 2025, which is incorporated by reference herein in its entirety.FIELD

[0002] The disclosure relates generally to the field of treatments for non-small cell lung cancer (NSCLC). More particularly, the disclosure relates to methods of administering a dimesna-based regimen to patients whose tumors have a low or medium tumor mutation burden.BACKGROUND

[0003] Worldwide, lung cancer is the most common cancer in terms of both incidence and mortality. It is the leading cause of cancer death globally among both men and women. In 2015, the cost of lung cancer care in the United States was $13.4 billion. According to the American Cancer Society, of the 234,580 new cases of lung cancer in the United States in 2018, 112,350 were in women. Non-Small Cell Lung Cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of cases, with adenocarcinoma, squamous cell carcinoma, and large cell carcinoma as the three subtypes in decreasing prevalence.

[0004] Approximately 10-15% of all lung cancers occur in never smokers, making lung cancer in never smokers one of the leading causes of cancer-related mortality. Despite the significant impact of this disease, there is surprisingly little information available on the descriptive epidemiology of lung cancer in never smokers. General population statistics are largely uninformative because cancer registries and routinely collected death certificates do not provide reliable information on lifetime smoking histories. Additionally, reports on smoking from next-of-kin or in medical records are incomplete and often unreliable. Only large-scale cohort studies can measure age- and sex-specific lung cancer rates in never smokers with reasonable precision, and these have generally focused on mortality rather than incidence. Currently, there are no approved therapies specifically for the growing indication of non-smokers with NSCLC.

[0005] Approximately 40% of all NSCLC cases are adenocarcinomas, with more than half occurring in women. The majority of people diagnosed with lung cancer today are not active smokers. Unlike the recent decrease in lung cancer in general, lung cancer is significantly increasing in one group of people: women who do not smoke. The prevalence of lung cancer in non-smokers has been increasing over time, with over half of cases occurring in current non- smokers.

[0006] Studies have found that high tumor mutational burden (TMB) levels in NSCLC are associated with improved response rates, progression-free survival, and overall survival. Pre- clinical data suggests that this may be because mutations create neoantigens, which increase tumor immunogenicity and response to immune checkpoint inhibitors (ICIs). For example, one study found that patients with high TMB and PD-L1 expression of 50% or higher had an objective response rate (ORR) to PD-1 / PD-L1 inhibition of up to 57%, compared to 8.7% for patients with low TMB and PD-L1 expression less than 1%. The harder category of patients is those with medium and low TMB. Nonsmokers and never smokers are less likely to respond to immunotherapies.

[0007] Recent data suggest that lung cancer mortality rates among women are projected to rise globally by 43% by 2030, surpassing deaths from breast cancer. It has been argued that lung cancer in female non-smokers is a distinct type of cancer, but studies describing this population are scant. This population remains underserved, and lung cancer in female non-smokers should be classified as a rare disease. The poor prognosis of advanced NSCLC is likely due to tumor resistance to chemotherapy.

[0008] Accordingly, there is a need for a treatment specifically for nonsmoking female NSCLC patients. This application is directed to addressing this need, among others.SUMMARY

[0009] One aspect of the invention is a method of treating an individual having non-small cell lung cancer (NSCLC). A tumor sample from the individual is tested, and its tumor mutational burden is determined. Upon determining a low tumor mutational burden in the tumor sample, a combination therapy comprising 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed is administered to the individual.

[0010] Another aspect of the invention is a method for predicting the response of an individual with NSCLC to treatment with a combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, andpemetrexed. A tumor sample from the individual is tested, and a high or low tumor mutational burden is detected. When a low tumor mutational burden is detected, one predicts that the individual is likely to respond with a therapeutic effect to treatment with the combination of 2,2’ - dithio-bis-ethane sulfonate, carboplatin, and pemetrexed.

[0011] Still another aspect of the invention is a method of determining if a treatment regimen for an individual with NSCLC should include treatment with a combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed. Atumor sample from the individual with NSCLC is tested, and tumor mutational burden is detected.

[0012] Yet another aspect of the invention is a method of determining if a treatment regimen for an individual with NSCLC should include treatment with a combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed. Atumor sample from the individual with NSCLC is tested, and tumor mutational burden is detected. When a low tumor mutational burden is detected, one determines that the treatment regimen will include the combination of 2,2’ -dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, and the individual will be treated with this combination.

[0013] Another aspect of the invention is a method of treating an individual having NSCLC. A tumor sample from the individual is tested, and the expression of cellular processes, often related to cancer genes, is determined. Upon determining a low level of expression of cellular processes, often related to cancer genes, TCR signaling genes, or inflammatory response genes in the tumor sample, a therapy that does not comprise 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed is administered to the individual. Upon determining a high level of expression of cellular processes, often related to cancer genes, TCR signaling genes, or inflammatory response genes in the tumor sample, administering to the individual a combination of 2,2’ -dithio-bis-ethane sulfonate, carboplatin, and pemetrexed.

[0014] A further aspect of the invention is a method for predicting the response of an individual with NSCLC to treatment with a combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed. Atumor sample from the individual is tested, and a high or low level of expression of cellular processes, often related to cancer genes, is determined. When a low level of expression of these genes is determined in the tumor sample, one predicts that the individual is likely to respond with a therapeutic effect to treatment with the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed.

[0015] Another aspect of the invention is a method of determining if a treatment regimen for an individual with NSCLC should include treatment with the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed. Atumor sample from the individual with NSCLC is tested, and the expression of cellular processes, often related to cancer is determined. When a low level of expression of cellular processes, often related to cancer genes, TCR signaling genes, or inflammatory response genes is detected, one determines that the treatment regimen will not include the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, and the individual will not be treated with this combination.

[0016] Still another aspect of the invention is a method of determining if a treatment regimen for an individual with NSCLC should include treatment with the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed. Atumor sample from the individual with NSCLC is tested, and the expression levels of cellular processes, often related to cancer genes are determined. When a low level of the expression is detected, one determines that the treatment regimen will include the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, and the individual will be treated with this combination.BRIEF DESCRIPTION OF THE FIGURES

[0017] FIG. 1 illustrates the change in the size of cancer target lesions from baseline over time.

[0018] FIG. 2 presents the changes in the size of cancer target lesions at 9 weeks from baseline for the sampled patients.DETAILED DESCRIPTION

[0019] This application provides methods and compositions for treating a non-small-cell lung cancer (NSCLC) patient with a combination of a composition of 2,2’-dithio-bis-ethane sulfonate, or a pharmaceutically acceptable salt thereof; carboplatin; and pemetrexed. In one embodiment, the patient has a low to medium tumor mutation burden.

[0020] Tumor mutational burden (TMB) can serve as a critical biomarker for predicting treatment efficacy in NSCLC. By stratifying patients based on TMB, this invention provides a personalized therapeutic strategy that maximizes clinical benefits while minimizing unnecessary side effects. This stratification also helps guide the decision-making process for healthcare providers, ensuring that patients with low or medium TMB receive the most effective treatment options tailored to their genetic profile.

[0021] 2,2’-dithio-bis-ethane sulfonate, commonly known as dimesna, has been primarily utilized as a chemoprotective agent to reduce the toxicity associated with certain chemotherapeutic agents. Various salts and analogs of 2,2’-dithio-bis-ethane sulfonate, as well as other dithioethers, may also be synthesized as outlined in US Pat. No. 5,808,160, U.S. Pat. No. 6,160,167, and U.S. Pat. No. 6,504,049, the disclosures of which are hereby incorporated by reference in their entirety. Additionally, the compositions of the present invention also comprise a medically sufficient dose of the metabolite of disodium 2,2’-dithio-bis-ethane sulfonate, known as 2-mercaptoethane sulfonate sodium.

[0022] One embodiment includes methods for treating patients with NSCLC and other cancers by administering a combination of dimesna, carboplatin, and pemetrexed, tailored to the patient’s tumor mutation burden. The methods include maintenance dosing regimens and additional supportive care measures to mitigate side effects and improve patient tolerance to treatment.

[0023] Patients can be stratified based on their tumor mutation burden, determined through testing of tumor samples. For example, those with low or medium mutation burdens are treated with specific combinations of dimesna, carboplatin, and pemetrexed. Low mutation burden can be defined as less than 10 mutations per million base pairs, while medium mutation burden can be defined as less than 50 mutations per million base pairs. One embodiment is a treatment method for NSCLC and metastatic cancer from NSCLC in patients with low or medium tumor burden, characterized by 10 mutations per million (low) and 50 mutations per million (medium), respectively. The treatment regimen includes the administration of dimesna, carboplatin, and pemetrexed, aiming to maximize therapeutic efficacy while minimizing adverse side effects.

[0024] One embodiment includes a method of treating an individual having a tumor or NSCLC. A tumor sample from the individual is tested, and its tumor mutational burden is determined. Upon determining a low or medium mutational burden in the tumor sample, a combination of 2,2’-dithio- bis-ethane sulfonate, carboplatin, and pemetrexed is administered to the individual.

[0025] One aspect of this application provides a combination therapy of disodium 2,2’-dithio-bis- ethane sulfonate to treat non-small cell lung cancer. In some embodiments, the therapy includes one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and a Raf kinase inhibitor.

[0026] In one example, patients can be classified in thirds according to tumor mutation burden (TMB): low TMB (0-100 mutations), medium TMB (100-242 mutations), and high TMB (above 243 mutations). Patients treated with dimesna and harboring low TMB had significantly increased objective response rates (ORR) and longer median progression-free survival (PFS) than patients treated with chemotherapy alone.

[0027] Another aspect includes a method of treating advanced and / or metastatic non-small cell lung cancer in patients, the method comprising administering to a human patient having non-small cell lung cancer who has received a second-line or higher-line therapy a pharmaceutical composition of 2,2’-dithio-bis-ethane sulfonate, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent. The non-small cell lung cancer can be lung adenocarcinoma.

[0028] In one embodiment, pemetrexed is administered as a maintenance dose following initial combination therapy (e.g., carboplatin and dimesna). Additionally, supportive care measures, including the administration of folic acid and vitamin Bl 2, can be provided to reduce hematologic and gastrointestinal toxicides. Antiemetic therapy can also be employed to manage chemotherapy- induced nausea and vomiting.

[0029] In one embodiment, the combination of dimesna, carboplatin, and pemetrexed offers a promising treatment approach for metastatic tumors originating from non-small cell lung cancer (NSCLC). This regimen leverages the chemoprotective properties of dimesna to mitigate the nephrotoxic effects of carboplatin, allowing for higher dosing and improved patient tolerance. Carboplatin, a platinum-based chemotherapeutic agent, disrupts cancer cell DNA replication and repair leading to apoptosis. Pemetrexed, an antifolate agent, further enhances the antitumor activity by inhibiting key folate-dependent enzymes essential for cancer cell proliferation. By tailoring this combination therapy to patients with low or medium tumor mutation burdens, based on precise genetic profding, the treatment maximizes efficacy while minimizing adverse effects. This individualized therapeutic strategy not only targets the primary tumor but also addresses metastatic lesions, thereby offering a comprehensive approach to managing advanced stages of NSCLC.

[0030] Carboplatin is a chemotherapy drug that belongs to a class of platinum-based compounds. It works by binding to DNA in cancer cells, causing crosslinking and interfering with DNA repair and replication processes. This leads to apoptosis (programmed cell death) of the cancer cells. Unlike its predecessor, cisplatin, carboplatin forms fewer reactive oxygen species and has a different toxicity profile, making it generally less nephrotoxic and ototoxic. Carboplatin isadministered intravenously, with the dosage often calculated based on the patient’s body surface area (BSA) and renal function.

[0031] Pemetrexed is a chemotherapy drug used to treat certain types of cancer, primarily nonsmall cell lung cancer (NSCLC) and malignant pleural mesothelioma. It works by interfering with the growth of cancer cells, which are eventually destroyed by the body. Pemetrexed is a multitargeted antifolate that disrupts folate-dependent metabolic processes essential for cell replication. Pemetrexed is administered as an intravenous (IV) infusion, typically over a period of 10 minutes. It is usually given once every 21 days (a treatment cycle).

[0032] In one embodiment, pemetrexed can be administered intravenously. It is also dosed based on the patient’s body surface area and given in cycles every 3 weeks in combination with carboplatin.

[0033] In one example, genes such as EGT, APC, MET, ROS1, BRAF, ALK, and NTRK, when associated with a low tumor mutational burden (TMB), suggest a scenario in which the tumor exhibits fewer genetic alterations overall. In this context, mutations in genes such as APC, BRAF, MET, ALK, and NTRK may be less frequent or less pronounced, leading to a reduced genetic diversity within the tumor. This decreased molecular complexity may affect the tumor’s interaction with the immune system and influence its response to various therapies. Specifically, mutations in these genes, when associated with a low TMB, have been shown to enhance the efficacy of certain therapeutic agents, particularly in combination with disodium 2,2’-dithio-bis-ethane sulfonate. The combination of these gene alterations and disodium 2,2’-dithio-bis-ethane sulfonate may result in improved therapeutic outcomes, potentially by modulating tumor characteristics that influence the tumor’s response to treatment, such as its immune profile, cell signaling pathways, or tumor microenvironment.

[0034] In one embodiment, the patient to be treated has failed or is unresponsive to tyrosine kinase inhibitors (TKIs). For example, a patient with non-small cell lung cancer (NSCLC) may initially respond to a TKI like osimertinib, erlotinib, or gefitinib, but then experience disease progression, intolerance, or insufficient response. In these cases, a combination therapy of dimesna, carboplatin, and pemetrexed offers a multi-pronged approach. This regimen not only targets tyrosine kinase receptors and cell redox enzymes through a distinct mechanism but also disrupts cancer cell DNA replication and repair via carboplatin, potentially inducing apoptosis and providing therapeutic benefit to patients who have exhausted TKI options.

[0035] In one embodiment, the inventors have observed that in cancer, low mutational burden, as opposed to high mutational burden, serves as an accurate indicator of whether a cancer patient is likely to respond positively to the combination of dimesna, carboplatin, and pemetrexed. Tumor mutational burden (TMB) refers to the number of mutations within the coding region of a tumor genome. Mutated genes were assessed and classified according to their status as passenger genes using a passenger gene index, which was used as a metric to identify passenger genes from a large- scale cancer genome analysis. It was observed that identified passenger genes were enriched for gene families known for excessive passenger mutations, including genes encoding large proteins, genes with low expression levels, and genes with late DNA replication times. The total mutational burden of passenger genes positively correlated with tumor immunogenicity and favorably predicted patient clinical outcomes. Accordingly, the disclosure features methods to classify patients according to their passenger gene mutation burden as part of an immunotherapy regimen.

[0036] Tumor mutational burden (TMB) can be computed by analyzing the number of mutations per million bases (mut / Mb) of the tumor genome. For non-small cell lung cancer (NSCLC), this typically involves sequencing the DNA extracted from tumor tissue using next-generation sequencing (NGS) technology. The process starts with obtaining a biopsy or surgical specimen of the tumor. The DNA is then isolated and subjected to whole exome sequencing (WES) or targeted gene panel sequencing to identify mutations across a broad spectrum of genes. Bioinformatics algorithms are employed to filter and count the somatic mutations, excluding known germline variants and sequencing artifacts. The total number of non-synonymous mutations (mutations that result in a change in the amino acid sequence of proteins) is then divided by the total exonic coverage in megabases to calculate the TMB. A TMB of 10 mutations per million bases is considered low, whereas 50 mutations per million bases is classified as medium. This quantification provides insights into the tumor’s genomic complexity and can help guide treatment decisions, including the suitability of immunotherapies and other targeted treatments.

[0037] Tumor mutational burden (TMB) can be determined through next-generation sequencing (NGS) technology, which allows for the comprehensive analysis of a tumor’s genomic landscape. TMB is calculated by counting the total number of somatic mutations, including single nucleotide variants (SNVs), insertions, and deletions, present in the tumor’s DNA. The mutation count is normalized per megabase (Mb) of the genome analyzed, often focusing on the coding regions, such as exons, or a predefined set of genes. NGS platforms generate high-throughput data bysequencing the tumor DNA alongside a normal control sample, allowing the identification of mutations specific to the tumor. This data can then be used to calculate the TMB, providing valuable insights into the mutation load within the tumor.

[0038] 2,2’-dithio-bis-ethane sulfonate may be delivered orally using formulations that protect the compound from oxidation in acidic environments and allow intestinal absorption.

[0039] The biological sample may comprise a tissue sample, a cancerous sample, a tumor sample, or a sample obtained from a biopsy. The biological sample may also comprise a biological sample described herein. The biological sample may comprise a blood sample.

[0040] “Non-smoker” means an individual who, at the time of evaluation, is not a smoker. This includes individuals who have never smoked as well as individuals who in the past have smoked but have not used tobacco products within the past year. In one example, the term “non-smoker” means a human that has a smoking history of 15 pack-years or less, or who has not smoked for over 25 years. Appropriate categories can be selected with no more than routine experimentation by those of ordinary skill in the art. In certain embodiments, the test subject is a non-smoker. A “never smoker” is an adult who has never smoked, or who has smoked less than 100 cigarettes in his or her lifetime.

[0041] The term “effective amount” as used herein refers to the amount of an agent needed to alleviate at least one or more symptoms of the disease or disorder and relates to a sufficient amount of pharmacological composition to provide the desired effect. The term “therapeutically effective amount” therefore refers to an amount of the agent that is sufficient to provide a particular effect when administered to a typical subject. An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom of the disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact “effective amount.” However, for any given case, an appropriate “effective amount” can be determined by one of ordinary skill in the art using only routine experimentation.

[0042] The therapeutic agents of the disclosure may be administered via the same route or different routes of administration. In some embodiments, the cancer therapy may be administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.Similarly, the antibiotic may be administered by any of these routes, including intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. The appropriate dosage for each therapeutic agent may be determined based on factors such as the type of disease being treated, the severity and progression of the disease, the clinical condition of the patient, the patient’s clinical history, and their response to prior treatments, all in accordance with the discretion of the attending physician.

[0043] The terms also encompass the prediction of a disease or condition. The terms “predicting” or “prediction” generally refer to an advance declaration, indication, or foretelling of a disease or condition in a subject who does not (yet) have the disease or condition. For example, a prediction of a disease or condition in a subject may indicate the probability, chance, or risk that the subject will develop the disease or condition, potentially within a specific time period or by a certain age. This probability, chance, or risk may be expressed, inter alia, as an absolute value, range, or statistical figure, or may be expressed relative to a suitable control subject or population (such as, e.g., relative to a general, normal, or healthy subject or subject population). Therefore, the probability, chance, or risk that a subject will develop a disease or condition may be advantageously presented as increased or decreased, or as fold-increased or fold-decreased relative to a suitable control subject or population. As used herein, the term “prediction” of a disease or condition in a subject may also refer to a “positive” prediction, i.e., the subject is at risk of developing the disease or condition (e g., the risk is significantly higher compared to a control subject or population). Conversely, the term “prediction of no disease or condition,” as taught herein, may refer to a “negative” prediction, i.e., the subject’s risk of developing the disease or condition is not significantly higher compared to a control subject or population. Hence, the methods described herein may rely on comparing the quantity of biomarkers, or gene or gene product signatures, measured in samples from patients with reference values. These reference values represent known predictions, diagnoses, and / or prognoses of diseases or conditions as outlined in this disclosure.

[0044] The dosage ranges for the administration of an agent according to the methods described herein depend upon, for example, the form of the agent, its potency, and the extent to which symptoms, markers, or indicators of a condition described herein are desired to be reduced, for example the percentage reduction desired for tumor growth. The dosage should not be so large asto cause adverse side effects. Generally, the dosage will vary with the age, condition, and sex of the patient and can be determined by one of skill in the art. The dosage can also be adjusted by the individual physician in the event of any complication.

[0045] The efficacy of an agent described herein in, e.g., the treatment of a condition described herein, or to induce a response as described herein (e.g., lung cancer) can be determined by the skilled clinician. However, a treatment is considered “effective treatment,” as the term is used herein, if one or more of the signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically accepted symptoms are improved, or even ameliorated, or a desired response is induced (e.g., by at least 10%) following treatment according to the methods described herein. Efficacy can be assessed, for example, by measuring a marker, indicator, symptom, and / or the incidence of a condition treated according to the methods described herein or any other measurable parameter appropriate, e.g., tumor size and / or growth rate. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and / or are described herein. Treatment includes any treatment of a disease in an individual or an animal (some non-limiting examples include a human or an animal) and includes: (1) inhibiting the disease, e.g., preventing a worsening of symptoms (e.g., pain or inflammation); or (2) relieving the severity of the disease, e.g., causing regression of symptoms. An effective amount for the treatment of a disease means that amount which, when administered to a subject in need thereof, is sufficient to result in effective treatment as that term is defined herein, for that disease. Efficacy of an agent can be determined by assessing physical indicators of a condition or desired response. It is well within the ability of one skilled in the art to monitor efficacy of administration and / or treatment by measuring any one of such parameters, or any combination of parameters. Efficacy can be assessed in animal models of a condition described herein, for example treatment of lung cancer in a mouse model. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant change in a marker is observed, e.g., tumor size and / or growth rate.EXAMPLES

[0046] The following examples are included for purposes of illustration and are not intended to limit the scope of the invention.

[0047] Patients (3 male and 4 female) from various geographies were treated with a combination of 2,2’-dithio-bis-ethane sulfonate, pemetrexed, and carboplatin. The treatment was administered intravenously (IV) on Day 1 of each 21 -day cycle for 4-6 cycles, based on the institutional practice for standard-of-care (SOC). After completing 4-6 cycles, pemetrexed was administered as maintenance therapy, dosed IV on Day 1 of each 21 -day cycle. Tumor assessments were conducted after every 3 cycles (9 weeks) and then every 4 cycles (3 months) after one year of pemetrexed maintenance. No dose-limiting toxicities were observed. Progressive disease cutoffs vary depending on the specific condition and the context (e.g., clinical trials, medical practice). Generally, they involve a threshold for worsening of a disease state, such as a decline in lung function, an increase in tumor size, or a worsening of neurological symptoms. A “partial response cut-off’ refers to the specific percentage decrease in tumor size or burden that signifies a partial response to treatment.

[0048] In the study, seven patients were enrolled, dosed, and evaluated. The key patient characteristics for this study include individuals who are never smokers and diagnosed with lung cancer, specifically stage III or IV primary lung adenocarcinoma, as confirmed by histopathological evidence. These patients have molecular alterations, such as EGFR mutations, MET exon 14 skipping, ROS1, BRAF, ALK, and NTRK fusions. Additionally, all patients in the study have relapsed after one or more lines of therapy with tyrosine kinase inhibitors. The patient cohort consisted of three females and four males, with an average age of 62 years. The median number of prior lines of therapy was two, ranging from one to four. These patients had relapsed after receiving multiple lines of treatment, and recent historical trials involving similar patient groups who received the chemotherapy doublet have reported an Objective Response Rate (ORR) ranging from 26% to 36%, with a progression-free survival (PFS) of 5.1 months.

[0049] The phase has now been completed, and the results show that six out of the seven patients experienced clinical benefit from the treatment. Specifically, three patients achieved partial responses, with an average reduction in tumor size of approximately 51%. Three additional patients showed stable disease, with an average tumor size reduction of 13%. These outcomes result in an overall clinical benefit rate of 86% and an objective response rate (ORR) of 43% in this initial cohort. FIG. 1 illustrates the change in cancer target lesion size from baseline over time, demonstrating that each patient either exhibited a partial response or a partial response cutoff, with one patient showing a substantial decrease in lesion size over time. FIG. 2 presents the changes incancer target lesion size at 9 weeks from baseline for the sampled patients, showing that each patient had either stable disease or a partial response. Table 1 shows or outlines genetic mutations and molecular markers from various tumor samples, which were used to determine appropriate treatment strategies. The samples show mutations in several key genes, including EGFR, TP53, BRAF, and PIK3CA, which are known to be associated with tumor growth and may inform the use of targeted therapies. For instance, EGFR mutations, such as L858R, are commonly seen in non-small cell lung cancer and may respond well to EGFR inhibitors. At 9 weeks, none of the patients showed new lesions.

[0050] PD-L1 expression, which allows tumors to evade immune detection, varies across the samples. In some instances, PD-L1 expression is high (e.g., 50% in one sample), indicating the potential for effective treatment with PD-L1 inhibitors, which block this immune checkpoint. However, in other samples, PD-L1 expression is either moderate or absent (0%), which may reduce the effectiveness of therapies targeting this pathway. Compared to smokers with non-small cell lung cancer (NSCLC), never smokers are less likely to exhibit high PD-L1 expression, a key biomarker for immunotherapies, and are therefore significantly less likely to be eligible for or respond to such treatments. PD-1 inhibitors have shown greater efficacy in smoking NSCLC patients compared to chemotherapy. However, no significant survival benefit was observed in nonsmoking patients treated with PD-1 inhibitors compared to those receiving chemotherapy.

[0051] Tumor mutational burden (TMB), which represents the number of mutations within the tumor genome, is also an important factor in determining response to immunotherapy. A higher TMB, as seen in some samples (e.g., 7.9 mutations per megabase), may indicate a better response to therapies that stimulate the immune system to recognize and attack cancer cells. Conversely, tumors with a lower TMB (e.g., 3.4 mutations per megabase) might not respond as effectively to these treatments.

[0052] Additionally, some tumors show MSI stable results, meaning there are no significant genetic instabilities in the microsatellite regions of the genome, which is characteristic of tumors that are less likely to respond to treatments aimed at MSI-high tumors.TABLE 1

[0053] Further patient or subject no. 107-003 at 52 weeks showed a complete response of target lesions, which is also shown in FIG. 1.

[0054] The patients had histopathological evidence of stage III or IV primary lung adenocarcinoma with molecular alterations, including EGFR, MET exon 14 skipping, ROS1, BRAF, ALK, and NTRK fusions. All patients had relapsed after one or more lines of therapy with tyrosine kinase inhibitors.

[0055] The attached results indicate that out of the 7 patients treated, 6 experienced disease control or clinical benefit. Three patients achieved partial responses, with an average tumor volume reduction of approximately 5%. Three patients had stable disease, resulting in an average tumor volume reduction of approximately 13%. This initial cohort demonstrated an overall clinical benefit rate of 86%, and an objective response rate (ORR) of 43%. No dose-limiting toxicities were observed, and no adverse events exceeded those typically associated with SOC chemotherapy doublets. Initial patient responses demonstrate an 86% disease control rate in the cohort of lead-inpatients, with a 43% objective response rate (ORR). Notably, one patient has maintained a tumor size reduction of over 50% for more than 14 months.

[0056] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions, and subcombinations thereof. It is therefore intended that the following appended claims and claims hereafter are interpreted to include all such modifications, permutations, additions, and subcombinations as are within their true spirit and scope.

Claims

CLAIMS1. A method of treating a patient having non-small cell lung cancer (NSCLC) comprising the step of administering to the patient in need thereof(a) a composition of 2,2’-dithio-bis-ethane sulfonate, or a pharmaceutically acceptable salt thereof,(b) an effective dose of carboplatin, and(c) an effective dose of pemetrexed.

2. The method of claim 1, wherein the effective dose of pemetrexed is given as a maintenance dose.

3. The method of claim 1, wherein the effective dose of pemetrexed is given as a maintenance dose after administration of an effective amount of 2,2’-dithio-bis-ethane sulfonate, or a pharmaceutically acceptable salt thereof.

4. A method of treating a patient suffering from NSCLC comprising the step of administering to the patient in need thereof a composition of 2,2’-dithio-bis-ethane sulfonate, or a pharmaceutically acceptable salt thereof, wherein the patient has a low or medium tumor mutation burden.

5. A method for treating NSCLC in a patient with low tumor mutation burden, comprising administering an effective amount of dimesna, carboplatin, and pemetrexed.

6. The method of claim 5, wherein the low tumor mutation burden is less than 10 mutations per million base pairs.

7. The method of claim 5, wherein the low tumor mutation burden is less than 50 mutations per million base pairs.

8. A method for treating NSCLC in a patient with medium tumor mutation burden, comprising administering an effective amount of dimesna, carboplatin, and pemetrexed.

9. The method of claim 8, wherein the medium tumor mutation burden is less than 10 mutations per million base pairs.

10. The method of claim 8, wherein the medium tumor mutation burden is less than 50 mutations per million base pairs.

11. A method for treating metastatic cancer originating from NSCLC in a patient with low or medium tumor mutation burden, comprising administering an effective amount of dimesna, carboplatin, and pemetrexed.

12. The method of any of claims 1-11, wherein dimesna is administered intravenously prior to and following carboplatin infusion.

13. The method of any of claims 1-11, wherein carboplatin is administered intravenously at a target area under the concentration-time curve (AUC) of 5 mg / mL per minute.

14. The method of any of claims 1-11, wherein pemetrexed is administered intravenously at a dose of 500 mg / m2.

15. The method of any of claims 1-11, further comprising the administration of folic acid and vitamin B 12 to reduce hematologic and gastrointestinal toxicities.

16. The method of any of claims 1-11, wherein the patient receives antiemetic therapy to manage chemotherapy-induced nausea and vomiting.

17. The method of any of claims 1-11, wherein the treatment cycle is repeated every 3 weeks, with regular monitoring and adjustment based on patient response and tolerance.

18. A method of treating an individual having a tumor, comprising testing a tumor sample from the individual and determining its tumor mutation burden, wherein:(a) upon determining a medium mutation burden in the tumor sample, administering to the individual a therapy comprising 2,2’-dithio-bis-ethane sulfonate; or(b) upon determining a low mutation burden in the tumor sample, administering to the patient a combination including 2,2’-dithio-bis-ethane sulfonate.

19. The method of claim 18, wherein the combination includes carboplatin and pemetrexed.

20. A method of treating an individual having a NSCLC, comprising:(a) testing a tumor sample from the individual and determining its tumor mutation burden; and(b) upon determining a low or medium mutation burden in the tumor sample, administering to the individual a combination including 2,2’-dithio-bis-ethane sulfonate.

21. The method of claim 1, wherein the tumor is NSCLC and a medium tumor mutation burden is less than 50 mutations per million base pairs and a low tumor mutation burden is less than 10 mutations per million base pairs.

22. The method of any of claims 1 -21 , wherein the tumor or cancer is metastatic.

23. The method of claim 1, wherein the dimesna is administered intravenously at a dose of 1,000 mg / m2 prior to carboplatin infusion.

24. The method of claim 4, wherein the tumor sample is tested using next-generation sequencing (NGS) technology to determine the tumor mutation burden.

25. The method of claim 5, wherein the carboplatin is administered at a dose corresponding to a target area under the concentration-time curve (AUC) of 4.5 mg / mL per minute.

26. The method of claim 8, wherein the pemetrexed is administered in combination with folic acid and vitamin B12 to prevent hematologic toxicity.

27. The method of claim 19, wherein the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed is administered as a single intravenous infusion over a period of 60 minutes.

28. A method of treating a patient with non-small cell lung cancer (NSCLC), comprising:(a) testing a tumor sample from the patient to determine its tumor mutational burden;(b) if the tumor sample has a low mutational burden, administering to the patient an immunotherapeutic agent comprising the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed.

29. A method for predicting the response of an individual with non-small cell lung cancer (NSCLC) to treatment with a combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, the method comprising:(a) testing a tumor sample from the individual to determine the tumor mutational burden, wherein the tumor mutational burden is classified as high or low;(b) predicting that the individual is likely to respond with a therapeutic effect to treatment with the combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed when a low tumor mutational burden is detected.

30. A method of determining if a treatment regimen for an individual with non-small cell lung cancer (NSCLC) should include treatment with a combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, the method comprising:(a) testing a tumor sample from the individual with cancer and detecting a low tumor mutational burden;(b) detecting a low tumor mutational burden in the tumor sample; and(c) determining that the treatment regimen will include the combination of 2,2’-dithio- bis-ethane sulfonate, carboplatin, and pemetrexed.

31. The method of claim 25-30, wherein a low tumor mutation burden is less than 10 variants per megabase (Mb).

32. A method of treating a patient with non-small cell lung cancer (NSCLC) who has a history of relapse after one or more lines of therapy with tyrosine kinase inhibitors, comprising administering an intravenous (IV) combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, wherein the treatment is administered on Day 1 of each 21-day cycle for 4-6 cycles, followed by pemetrexed maintenance therapy.

33. The method of claim 32, wherein tumor assessments are conducted after every 3 cycles (9 weeks) during the combination therapy, and then every 4 cycles (3 months) following 1 year of pemetrexed maintenance therapy.

34. A method of treating a patient with NSCLC, comprising administering an intravenous (IV) combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, wherein the patient has a tumor mutation burden (TMB) of less than 10 mutations per megabase and has been previously treated with one or more lines of tyrosine kinase inhibitors.

35. The method of claim 34, wherein the tumor mutation burden (TMB) is determined using next-generation sequencing (NGS) technology.

36. A method of treating NSCLC with a combination of 2,2’-dithio-bis-ethane sulfonate, carboplatin, and pemetrexed, wherein the treatment results in a partial response (PR) as defined by a tumor volume reduction of at least 30% within 3 cycles of therapy, based on clinical assessments using tumor size measurements.

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