N-(1-((R)-1-acryloyl azepan-3-yl)-7-chloro-6-(((R)-tetrahydrofuran-3-yl) oxy)-1h-benzo [d] imidazol-2-yl)-2-methyl isonicotinamide (NX-019) for treatment of EGFR mutant cancer

Abstract

The NX-019 is a potent small molecule EGFR (epidermal growth factor receptor) inhibitor which can be orally administered and shows selective inhibitory activity on EGFR with one or more mutations. The present disclosure provides a method of treating EGFR mutant cancer comprising orally administering to a human patient suffering from cancer having at least one mutation in the epidermal growth factor receptor (EGFR) gene a therapeutically effective amount, i.e., a daily dose of 37.5 mg to 450 mg, of NX-019. Also provided are methods of treating cancer in a patient having CNS metastasis comprising orally administering to a human patient having cancer having at least one mutation in CNS metastasis and epidermal growth factor receptor (EGFR) gene a therapeutically effective amount, i.e., a daily dose of 37.5 mg to 450 mg. In some embodiments, the EGFR mutant cancer is NSCLC.

Description

[0001] Treatments for EGFR-mutated cancers Background Art

[0002] Epidermal growth factor receptor (EGFR) mutations occur in a variety of tumor types, including head and neck cancer and colon cancer; however, the vast majority of cancers with EGFR mutations are found in patients with non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer death worldwide, with NSCLC accounting for the vast majority (85%) of all lung malignancies. Although the prognosis of NSCLC is significantly better than that of small cell lung cancer (SCLC), the overall 5-year survival rate remains low (approximately 15%) because most patients are diagnosed at an advanced stage and the disease itself is molecularly heterogeneous. EGFR mutations in non-small cell lung cancer (NSCLC) are a heterogeneous group of mutations, including the common mutations L858R and exon 19 deletions, as well as the rare mutations exon 20 insertions (ex20ins), G719X, S768I, and L861Q mutations (Riess JW, et al. J Thorac Oncol, 2018; 13(10): 1560-1568).

[0003] CNS involvement, brain metastases, and / or leptomeningeal disease are common in NSCLC patients with EGFR mutations, occurring in 25%-50% of patients and are associated with poor clinical outcomes. Despite the activity and enhanced CNS penetration of new-generation EGFR inhibitors, the treatment of CNS disease remains a clinical challenge. Due to limited CNS activity, most approved EGFR inhibitors fail to address the unmet needs of patients with CNS disease (Ernani V, et al. J Oncol Pract, 2019; 15(11): 563-570 and D'Aiello A, et al. Cancers, 2023; 15(3): 84).

[0004] The development of targeted therapies for lung cancer, such as NSCLC, has focused primarily on tumors that exhibit genetic alterations, including specific oncogenic drivers, namely mutations in the epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK), KRAS mutations, BRAF V600E substitutions, MET exon 14 mutations, and fusion genes involving ROS proto-oncogene 1, rearranged during transfection (RET), and neurotrophic tyrosine receptor kinase. Three generations of tyrosine kinase inhibitors (TKIs) have been developed for the most common EGFR-mutated cancers. Other oncogenic drivers in the EGFR receptor tyrosine kinase family include insertions in the exon 20 gene of EGFR, which require approved anticancer therapies.

[0005] Brain metastases and bone metastases are the two most common metastatic sites in patients with NSCLC. Bone metastases correlate poorly with progression-free survival (PFS), brain metastases correlate poorly with overall survival (OS), and the number of metastatic organ sites correlates poorly with PFS and OS time and with quality of life. In EGFR mutant (EGFRm)+ tumors, metastases to all sites, including bone and brain, are increased because these patients tend to survive longer due to effective therapies (e.g., EGFR kinase inhibitors).

[0006] Many cancer patients with EGFR mutations do not gain clinical benefit from current therapies. Therefore, it is of great significance to develop new therapies for cancers associated with EGFR mutations. Summary of the invention

[0007] The present disclosure provides methods for treating EGFR mutant cancer patients using EGFR inhibitor compounds. NX-019 is a potent, orally administrable, small molecule inhibitor of EGFR that exhibits selective inhibitory activity against EGFR with one or more mutations.

[0008] This disclosure describes a clinical study of patients with EGFR mutant cancers to demonstrate the efficacy and safety of NX-019 when it is administered to patients according to the clinical protocol. This is a two-part, first-in-human international open-label study designed to evaluate the efficacy of single-agent NX-019 in patients with EGFR mutant, locally advanced or metastatic NSCLC who have progressed after previous treatment. Patients with ECOG performance status 0-2 and EGFR mutant cancers (including stable, asymptomatic brain metastases) are eligible for dose escalation. Patients with known EGFR C797S mutations and secondary drivers (such as MET amplification and RET fusion) are excluded. The primary endpoints are to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), PK, safety and tolerability (Part 1), and to assess the activity of RP2D by RECIST v1.1 and RANO-BM, preliminary evidence of anti-tumor activity, and confirm safety characteristics (Part 2). Secondary endpoints are pharmacokinetic (PK) and antitumor activity assessed by RECIST v1.1 (Part 1) and PK, safety, tolerability, and CNS antitumor activity (Part 2). Dose escalation will be performed using a 3+3 design, with a maximum of 6 patients per cohort in Part 1. Part 2 will enroll patients in 5 cohorts (n=10 or 29), including patients with the following NSCLC: (1) new or progressive CNS metastases, including leptomeningeal disease, after treatment with osimertinib; (2) active CNS disease and ex20ins mutations; (3) presence of ex20ins mutations but no CNS disease; and (4) other rare mutations, based on a Simon 2-stage design. The first patient was treated in October 2022, and enrollment is ongoing.

[0009] Accordingly, the present disclosure provides a method of treating EGFR mutant cancer comprising orally administering a therapeutically effective amount, i.e., 37.5 mg to 450 mg daily dose of NX-019 to a human patient suffering from cancer having at least one mutation in the epidermal growth factor receptor (EGFR) gene.

[0010] In some embodiments, the patient has a systemic EGFR mutation cancer. In some embodiments, the patient has NSCLC. In some embodiments, the patient's cancer has a central nervous system (CNS) lesion.

[0011] Accordingly, the present disclosure provides a method of treating cancer in a patient with CNS metastasis, comprising orally administering a therapeutically effective amount, i.e., 37.5 mg to 450 mg daily dose of NX-019 to a human patient having cancer with CNS metastasis and at least one mutation in the epidermal growth factor receptor (EGFR) gene.

[0012] In some embodiments, the patient's cancer does not have an insertion in exon 20 of the EGFR gene. In some embodiments, the patient's cancer has an insertion in exon 20 of the EGFR gene. In some embodiments, the EGFR mutant cancer is NSCLC. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] These and other features, aspects and advantages of the present invention will become more readily understood with reference to the following description and accompanying drawings, in which:

[0014] Figure 1, panels AC, illustrate the activity of NX-019 in a brain cancer mouse model (PC9-GFP) carrying an EGFR exon 19 insertion mutation (DelE746-A750) in the mouse brain. NX-019 resulted in complete tumor regression, as shown in the tumor reduction graph (panel A), GFP fluorescent tumor photos of control mice and treated mice (75 mg / kg) on ​​day 22 (panel B), and downregulation of phosphorylated EGFR in tumors at various time points after dosing (175 mg / kg) (panel C).

[0015] Figure 2, Panel A illustrates GFP fluorescent tumors on day 22 in treated mice that received a higher dose (125 mg / kg) compared to the controls in Figure 1. Panel B shows that the body weight of treated mice remained consistent throughout the treatment period.

[0016] Figure 3 The efficacy of NX-019 against EGFR mutations in the cancer cell line Ba / F3 expressing wild-type or mutant EGFR is depicted.

[0017] Figure 4, sub-figures AC illustrate the selective inhibition of mutant EGFR relative to wild-type EGFR. Sub-figure A shows Western blot analysis of normal skin and exon 20ins (D770_N771insSVD) tumors. Sub-figure B shows that the expression level of phosphorylated EGFR protein decreases in response to the increase in NX-019 dose. β-actin levels serve as an internal control. Sub-figure A shows that phosphorylated EGFR levels have been quantified and normalized to total EGFR and β-actin levels. Sub-figure C shows the selectivity of NX-019 for EGFR exon 20ins mutations.

[0018] Figure 5, panels AB illustrate tumor regression in EGFR exon 20ins xenografts. Panel A shows the efficacy of NX-019 in a PDX model of exon 20ins (LU0387-H773_V774insNPH). Panel B shows that the body weight of treated mice changed only slightly or not during the entire treatment period.

[0019] Figure 6, panels AC illustrate that NX-019 exhibits significant CNS / brain exposure in animal models. Panel A shows the exposure ratios of NX-019 brain and plasma in mice and rats. Shown are the area under the curve (AUC) ratio of rat brain / plasma, the AUC ratio of mouse brain / plasma, the Cmax ratio of rat brain / plasma, and the Cmax ratio of mouse brain / plasma. The vertical dashed line indicates a ratio of 1:1 or greater. Panel B shows the NX-019 Kp,uu values ​​for mice and rats. Kp,uu is the ratio of unbound drug in brain to plasma. Panel C shows the calculated plasma free fraction / CSF ratio for cynomolgus monkeys, dogs, and rats. Panel D shows the NX-019 Kp,uu values ​​for rats, dogs, and monkeys. Panel E shows the Kpuu of NX-019 compared to osimertinib. CSF value.

[0020] Figure 7 is a flow chart illustrating the human studies of NX-019 in patients with advanced EGFR-mutated cancers.

[0021] Figure 8 NX-019 was shown to be active across a broad range of mutations.

[0022] Figure 9 is another flow chart illustrating the human study of NX-019 in patients with advanced EGFR-mutated cancers. DETAILED DESCRIPTION

[0023] 4.1. Methods for treating EGFR-mutated cancers

[0024] The present disclosure provides a method for treating EGFR mutation cancer in a patient in need of treatment. The methods of the present disclosure described herein can be extended to a variety of cancers, particularly NSCLC. Examples of cancers associated with the methods described herein include, but are not limited to, breast cancer, lung cancer, head and neck cancer, and colon cancer.

[0025] In some embodiments, the patient has lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0026] The term "cancer" refers to a malignant tumor characterized by uncontrolled cell proliferation, in which cells have lost the normal regulatory controls that control how fast the cells grow. These unregulated dividing cells can spread throughout the body and invade normal tissues, a process called "metastasis."

[0027] In some embodiments, the cancer is human epidermal growth factor receptor 2 positive (HER2 + )of.

[0028] EGFR-mutated cancers

[0029] In some embodiments, the patient has a cancer that has at least one mutation in the epidermal growth factor receptor (EGFR) gene, also known as an EGFR mutation, i.e., "(EGFRm)+." In this case, the cancer may be referred to as an EGFR mutation (EGFRm) cancer.

[0030] These EGFR mutations are oncogenic, promoting cell proliferation, survival and anti-apoptotic signaling, angiogenesis, and potentially metastasis. The signaling network in EGFR mutant cells depends on functional mutant EGFR for survival, which makes them "addicted" to activated receptors.

[0031] The spectrum of EGFR mutations, for example in NSCLC, includes classical EGFRm, such as L858R and exon 19 deletions, which lead to receptor activation and cellular oncogenic transformation by stabilizing the active dimer conformation of the receptor. Classic mutations account for approximately 88% of EGFRm. Another group of EGFRm, rare mutations, which account for approximately 12% of EGFRm in NSCLC, is a heterogeneous group of mutations, including mutations in exons 18, 19, 20, and 21 of the EGFR gene. These mutations, like classical mutations, are located in or near the EGFR activation site or activation domain region of the receptor and lead to activated ligand-independent EGFR. It is well known that these activating mutations in NSCLC lead to worse patient outcomes in many cases.

[0032] In some embodiments, EGFRm cancer includes an insertion mutation in the EGFR gene. In some embodiments, the insertion mutation is located in exon 20 of the EGFR gene. In other embodiments, the insertion mutation is not an insertion in exon 20 of the EGFR gene. In some embodiments, the insertion mutation is located in exon 19 of the EGFR gene.

[0033] In some embodiments, EGFRm cancer comprises a deletion of the EGFR gene. In some embodiments, the deletion is located in exon 19 of the EGFR gene.

[0034] In some embodiments, EGFRm cancer includes a point mutation in the EGFR gene. In some embodiments, the point mutation is located at one or more of the amino acid positions L858, G719, L861, S768 and E709 of the EGFR gene. In some embodiments, the point mutation is located at G719 of the EGFR gene. In some embodiments, the point mutation is located at L861 of the EGFR gene. In some embodiments, the point mutation is located at S768 of the EGFR gene. In some embodiments, the point mutation is located at E709 of the EGFR gene.

[0035] In some embodiments, the EGFRm cancer comprises a frameshift mutation in the EGFR gene.

[0036] In some embodiments of the disclosed methods, the patient has previously received EGFR targeted therapy. In some embodiments, the patient has previously received osimertinib treatment.

[0037] In some embodiments of the disclosed methods, the patient has not been previously treated with an EGFR targeted therapy targeting an insertion in exon 20.

[0038] 4.1.1. Patients with systemic tumors

[0039] In some embodiments, the cancer treated is locally advanced.

[0040] In some embodiments, the cancer being treated is metastatic. In some embodiments, the patient's cancer has bone metastases.

[0041] The methods of the present disclosure comprise administering a therapeutically effective amount of NX-019, wherein the patient exhibits regression of systemic tumors.

[0042] In some embodiments, the patient's cancer is NSCLC with at least one EGFRm (eg, as described herein).

[0043] 4.1.2. Patients with CNS lesions

[0044] Many patients develop central nervous system (CNS) lesions during their illness. CNS lesions can be identified as abnormalities on imaging tests, such as magnetic resonance imaging (MRI) or computed tomography (CT).

[0045] In some embodiments, the CNS lesion comprises at least one EGFRm (eg, as described herein).

[0046] In some embodiments, the patient has a CNS lesion that is a metastatic brain tumor.

[0047] In some embodiments, the patient has a CNS lesion that is a brain metastasis of NSCLC.

[0048] The methods of the present disclosure comprise administering a therapeutically effective amount of NX-019 to provide adequate penetration of the compound and regression of NSCLC brain metastases in the patient.

[0049] In some embodiments, the patient's cancer has a NSCLC brain metastasis carrying at least one EGFRm (eg, as described herein).

[0050] 4.2. EGFR inhibitor compounds and compositions

[0051] The EGFR inhibitor compounds described herein and compositions comprising such compounds can be used in the methods of the present disclosure, wherein the compounds and compositions act to inhibit the activity of EGFR (eg, EGFR mutants).

[0052] In some embodiments, the EGFR inhibitor compound has the formula:

[0053]

[0054] or a single enantiomer, a racemic mixture, a diastereomeric mixture, or an isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof.

[0055] The phrase "a single enantiomer, racemic mixture, diastereomeric mixture, or isotopic variation thereof; or a pharmaceutically acceptable salt or solvate thereof" has the same meaning as the following phrases: "(i) wherein a single enantiomer, racemic mixture, diastereomeric mixture, or isotopic variation of said compound; (ii) wherein a pharmaceutically acceptable salt or solvate of said compound; or (iii) wherein a pharmaceutically acceptable salt or solvate of a single enantiomer, racemic mixture, diastereomeric mixture, or isotopic variation of said compound".

[0056] EGFR inhibitor compounds containing nitrogen-containing heteroaryls can have alkalinity and can react with a variety of inorganic acids and organic acids to form corresponding pharmaceutically acceptable salts. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions. Inorganic acids commonly used to form such salts include hydrochloric acid and related inorganic acids. Organic acids commonly used to form such salts include acetic acid, formic acid, and related organic acids. Therefore, such pharmaceutically acceptable salts include chlorides, acetates, formates, and related salts.

[0057] In some embodiments, the EGFR inhibitor compound is NX-019, a compound having the following structure:

[0058]

[0059] The synthesis and EGFR inhibitor activity of NX-019 and related compounds are described, for example, in U.S. Pat. No. 10,005,765, the disclosure of which is incorporated herein by reference.

[0060] In some embodiments of the disclosed methods, compound NX-019 is provided and administered as a free base. In some embodiments of the disclosed methods, compound NX-019 is provided and administered as a pharmaceutically acceptable salt.

[0061] The EGFR inhibitor compounds described herein may exist in a variety of forms, including crystalline, powder and amorphous forms of the compounds, pharmaceutically acceptable salts, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[0062] The compounds described herein may exist as solvates, particularly hydrates, and unless otherwise stated, all such solvates and hydrates are encompassed. Hydrates may be formed during the manufacture of a compound or a composition comprising the compound, or hydrates may be formed over time due to the hygroscopic properties of the compound. The compounds of the present technology may also exist in the form of organic solvates, including alcohol solvates. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. The identification and preparation of any particular solvate are within the capabilities of those of ordinary skill in the field of synthetic organic chemistry or medicinal chemistry.

[0063] In some embodiments, the compounds described herein exist as solvates. In some embodiments, when the solvent component of the solvate is water, the compounds described herein exist as hydrates.

[0064] In some embodiments of the method, the EGFR inhibitor compound is an isotopically labeled compound (also referred to as an isotopologue of a compound) that is identical to a compound described herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example, respectively. 2 H("D"), 3 H. 13 C. 14 C. 15 N. 18 O. 17 O and 36 Cl. For example, the compounds described herein may have one or more H atoms replaced by deuterium. Unless otherwise indicated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures but with hydrogen replaced by deuterium or tritium or with a carbon enriched 13 C- or 14 Compounds substituted at least one of the carbon atoms of C- are within the scope of the invention. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0065] 4.2.1. Pharmaceutical compositions

[0066] In some embodiments of the method for treating cancer, the EGFR inhibitor compound of the present disclosure administered to the subject may constitute a pharmaceutical composition. The pharmaceutical composition may include a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0067] The term "pharmaceutical composition" is intended to encompass compositions suitable for administration to a subject, such as a mammal, particularly a human. In general, a "pharmaceutical composition" is sterile and preferably does not contain contaminants that can cause adverse reactions in a subject (i.e., the compound in the pharmaceutical composition is pharmaceutical grade). The pharmaceutical composition can be designed to be administered to a subject or patient in need thereof via an oral administration route.

[0068] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable diluent", "pharmaceutically acceptable carrier" and "pharmaceutically acceptable adjuvant" are used interchangeably and refer to any ingredient other than the EGFR inhibitor compounds described herein (e.g., a solvent capable of suspending or dissolving the active compound, or any other convenient pharmaceutically acceptable carrier, excipient, diluent, adjuvant or additive) that is substantially non-toxic and non-inflammatory to the patient. The phrase "pharmaceutically acceptable excipient" includes one or more than one such excipient, diluent, carrier and / or adjuvant. Excipients may include, for example: anti-adhesives, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), emollients, emulsifiers, fillers (diluents), film formers or coating agents, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, formulation or dispersing agents, sweeteners and water for hydration.

[0069] The pharmaceutical composition can be formulated according to any convenient method and can be prepared into various forms for oral administration, such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions.

[0070] 4.3. Method of administration

[0071] One aspect of the disclosed method of treating cancer is to orally deliver an EGFR inhibitor compound or composition to a patient. The compound can be combined with a pharmaceutically acceptable carrier (eg, an inert diluent or an absorbable carrier) to form a pharmaceutical composition for systemic administration, for example, orally.

[0072] The term "patient" refers to a human subject.

[0073] The phrase "therapeutically effective amount" refers to an amount sufficient to effectively treat a disease, condition or disorder when a compound is administered to a patient for treating the disease, condition or disorder. The "therapeutically effective amount" may vary depending on the disease and its severity, as well as the age, weight, etc., of the subject to be treated.

[0074] The terms "treat" and "treating" refer to partially or completely alleviating, ameliorating, improving, relieving, delaying the onset of, inhibiting the progression of, lessening the severity of, and / or reducing the incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not show signs of the disease, disorder, and / or condition and / or to subjects who show only early signs of the disease, disorder, and / or condition to reduce the risk of developing pathology associated with the disease, disorder, and / or condition. Thus, these terms do not require a cure or complete alleviation of the disease, but rather encompass obtaining any clinically desired pharmacological and / or physiological effect.

[0075] It will be understood by those skilled in the art that the methods disclosed herein are also disclosed in their corresponding "Swiss-type" or "EPC2000" equivalent forms. Therefore, the following methods: a method of treating a patient's cancer, wherein the patient's cancer has at least one mutation in the epidermal growth factor receptor (EGR) gene, the method comprising orally administering to the patient a daily dose of NX-019 or a pharmaceutically acceptable salt thereof; or a method of treating a patient's cancer with CNS metastasis, the method comprising orally administering to the patient a daily dose of NX-019 or a pharmaceutically acceptable salt thereof, should be understood to also disclose: the use of NX-019 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient's cancer, wherein the patient's cancer has at least one mutation in the epidermal growth factor receptor (EGR) gene; or the use of NX-019 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient's cancer with CNS metastasis. Likewise, the disclosure of the above methods should be understood as disclosing: NX-019 or a pharmaceutically acceptable salt thereof for use in a method of treating a patient's cancer, wherein the patient's cancer has at least one mutation in the epidermal growth factor receptor (EGR) gene, the method comprising orally administering to the patient a daily dose of NX-019 or a pharmaceutically acceptable salt thereof; or a method of treating a patient's cancer with CNS metastases, the method comprising orally administering to the patient a daily dose of NX-019 or a pharmaceutically acceptable salt thereof.

[0076] 4.3.1. Dosage

[0077] In some embodiments of the method, the effective amount of the compound is achieved by oral administration of a dosing regimen comprising a daily dose of 37.5 to 450 mg of NX-019 or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the dose is administered as a single daily dose (QD).

[0079] In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 75 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 150 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 300 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 375 mg.

[0080] In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75-150 mg.

[0081] In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150-300 mg.

[0082] In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 37.5 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 300 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 375 mg. In some embodiments, the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 450 mg.

[0083] In some embodiments, NX-019 is administered in the free base form combined in the pharmaceutical composition.

[0084] In some embodiments, NX-019 or a pharmaceutically acceptable salt thereof is administered in combination in a pharmaceutical composition.

[0085] In some embodiments of the method, the daily dose is orally administered to the patient as needed. In some embodiments, the daily dose is administered for one week or longer, such as two weeks or longer, three weeks or longer, or four weeks or longer. In some embodiments, the daily dose is administered for 28 days. In some embodiments, the course of treatment can be repeated as needed. In some embodiments, the daily dose is administered for up to 3 months, up to 6 months, up to 1 year, up to 2 years, up to 3 years, up to 4 years, or up to 5 years.

[0086] The compounds of the present disclosure may also be co-administered with one or more additional therapeutic compounds. "Co-administration" of a compound includes administration of one or more compounds substantially simultaneously with the EGFR inhibitor compounds of the present disclosure, whether or not in the same pharmaceutical composition, or sequentially. In some embodiments of the disclosed methods, the EGFR inhibitor compounds disclosed herein are administered or combined with other anticancer therapies (e.g., internal or external radiation, surgery, and chemotherapy).

[0087] 4.3.2. Patient selection / condition

[0088] One aspect of the present disclosure is to treat an EGFR-mediated cancer in a patient. The present disclosure provides methods of treating a cancer having at least one mutation in the epidermal growth factor receptor (EGFR) gene.

[0089] In some embodiments, the patient suffers from an EGFR-mediated cancer selected from lung cancer, head and neck cancer, and colon cancer. In some embodiments, the patient suffers from lung cancer. In some embodiments, the lung cancer is NSCLC.

[0090] In some embodiments, the patient's cancer is locally advanced. In some embodiments, the patient's cancer is metastatic. In some embodiments, the patient has systemic NSCLC.

[0091] The experimental part of the present disclosure describes several inclusion and exclusion criteria for clinical studies, which can be used to select patients for treatment according to the methods of the present disclosure. In some embodiments, the inclusion criteria include: patients with histologically confirmed, locally advanced or metastatic EGFR mutation cancer, and the cancer has progressed or is intolerant to all standard therapies; patients with non-small cell lung cancer (NSCLC) carrying mutations sensitive to osimertinib must have received osimertinib treatment; patients with measurable disease; baseline brain MRI is required; patients with adequate organ and bone marrow function; patients with Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2; and patients aged ≥ 18 years. In some embodiments, exclusion criteria apply to patients with any of the following: a known C797X EGFR mutation or a known second disease driver; a serious or unstable medical condition, including heart disease, uncontrolled diabetes, or an unstable psychiatric condition; a history of interstitial lung disease, radiation pneumonitis, or other serious lung disease requiring systemic steroid therapy; a known infection requiring systemic therapy, including HIV, HBV, HCV; active gastrointestinal disease that may affect drug absorption; use of strong CYP3A inhibitors or inducers; or any disease, including severe skin or nail disease, that, in the investigator's opinion, would place the patient at unacceptable risk or would not allow the patient to comply with the protocol.

[0092] In some embodiments, the patient's cancer has asymptomatic leptomeningeal disease. In some embodiments, the patient's cancer is human epidermal growth factor receptor 2 positive (HER2 + ). In some embodiments, the patient has previously received EGFR targeted therapy. In some embodiments, the patient has previously received osimertinib treatment.

[0093] In some embodiments, the patient exhibits improvement in one or more primary or secondary outcome measures of efficacy (e.g., as described herein) after receiving treatment according to the methods of the present disclosure. In some embodiments, the patient exhibits systemic tumor regression after receiving treatment.

[0094] In some embodiments, treatment according to the methods of the present disclosure increases overall survival (OS) time in a patient population compared to a control patient population not administered.

[0095] In some embodiments, treatment according to the methods of the present disclosure increases progression-free survival (PFS) time in a patient population compared to a control patient population not administered.

[0096] 4.3.2.1 Patients with CNS metastases

[0097] Aspects of the present disclosure include treating cancer in a patient having central nervous system (CNS) metastases and at least one mutation in the epidermal growth factor receptor (EGFR) gene.

[0098] In some embodiments, the patient is identified as having, for example, EGFRm cancer with CNS disease, for example, with CNS lesions, such as brain metastases. In some embodiments, the patient has a measurable CNS lesion with a diameter of >5 mm, as determined by MRI (e.g., as described herein). In some embodiments, the cancer is NSCLC with CNS disease.

[0099] In some embodiments, the cancer of the patient with the CNS disease is identified as having an EGFR ex20ins mutation (ie, an exon 20 insertion mutation).

[0100] In some embodiments, the patient with the CNS disease has a cancer identified with an EGFR mutation that excludes an ex20ins mutation.

[0101] In some embodiments, the cancer in the patient with the CNS disease comprises one or more mutations in an epidermal growth factor receptor (EGFR) gene, e.g., as described herein.

[0102] In some embodiments, compared with a control patient population not administered, treatment according to the methods of the present disclosure increases the overall survival (OS) time of the patient population. In some embodiments, compared with a control patient population not administered, treatment according to the methods of the present disclosure increases the progression-free survival (PFS) time of the patient population.

[0103] In some embodiments, treatment according to the methods of the present disclosure reduces CNS metastasis of cancer in patients. In some embodiments, treatment according to the methods of the present disclosure reduces the progression of existing CNS lesions (e.g., brain metastases). In some embodiments, treatment according to the methods of the present disclosure reduces the size of existing CNS lesions (e.g., brain metastases). In some embodiments, treatment according to the methods of the present disclosure reduces the risk of new CNS lesions developing.

[0104] The effectiveness of the disclosed treatment methods can be determined using any convenient patient assessment methods and outcome measures, for example, by comparing pre-treatment or baseline assessments or measurements with assessments or measurements taken after treatment as described herein in the Experimental Section.

[0105] 4.4. Definitions

[0106] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. It should be understood that the definitions provided herein are not intended to be mutually exclusive.

[0107] Range: Throughout this disclosure, various aspects of the invention are presented in a range format. The ranges include the stated endpoints. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the invention. Therefore, the description of a range should be considered to have explicitly disclosed all possible subranges and individual values ​​within the range. For example, a description of a range from 1 to 6 should be considered to have specifically disclosed subranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within the range, such as 1, 2, 3, 4, 5, 5.3, and 6. This applies no matter how broad the range is.

[0108] In this disclosure, "comprises," "includes," "contains," "has," "encompasses," "including," "comprising," and variations thereof have the meanings ascribed to them in U.S. patent law, allowing for the presence of additional elements other than those explicitly recited.

[0109] Unless otherwise specified or obvious from the context, the terms "a", "an", and "the" as used herein shall be understood to be singular or plural. That is, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. For example, "an element" refers to one element or more than one element.

[0110] Unless otherwise specified or obvious from the context, the term "about" as used herein shall be understood to be within the normal tolerances in the art, for example within 2 standard deviations of the mean, and is intended to cover variations of ±20% or ±10% of the stated value, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1%. When a percentage of the amount of a component or material in a composition is provided, the percentage shall be understood to be a weight-based percentage unless otherwise specified or understood from the context.

[0111] The term "pretreatment" refers to before the first administration of a DP1 receptor antagonist according to the methods described herein. Pretreatment does not exclude and generally includes prior use of treatments other than DP1 receptor antagonists.

[0112] The term "post-treatment" refers to after the administration of a DP1 receptor antagonist according to the methods described herein. Post-treatment includes after the administration of a DP1 receptor antagonist at any dose described herein. Post-treatment also includes after the bolus treatment phase of a DP1 receptor antagonist, and after continuous administration of a DP1 receptor antagonist at any dose described herein.

[0113] It should be understood that as long as the present disclosure remains operable, the order of steps or the order of performing certain actions is not important. In addition, two or more steps or actions can be performed simultaneously.

[0114] 5. Additional Embodiments

[0115] The present disclosure is further described by the following non-limiting numbered clauses:

[0116] 1. A method of treating cancer in a patient, wherein the cancer of the patient has at least one mutation in the epidermal growth factor receptor (EGFR) gene, the method comprising:

[0117] Orally administering to the patient a daily dose of 37.5 - 450 mg of NX-019 or a pharmaceutically acceptable salt thereof.

[0118] 2. The method according to clause 1 or 2, wherein the patient has lung cancer, head and neck cancer, or colon cancer.

[0119] 3. The method according to clause 1 or 2, wherein the patient has systemic non-small cell lung cancer (NSCLC).

[0120] 4. The method according to any one of clauses 1 to 3, wherein the patient exhibits systemic tumor regression following administration of NX-019.

[0121] 5. A method according to any one of clauses 1 to 4, wherein the patient's cancer is human epidermal growth factor receptor 2 positive (HER2 + )of.

[0122] 6. A method according to any one of clauses 1 to 5, wherein the at least one mutation comprises an insertion in the EGFR gene.

[0123] 7. The method according to clause 6, wherein the insertion is located in exon 20 of the EGFR gene.

[0124] 8. The method according to clause 6, wherein the insertion is not an insertion in exon 20 of the EGFR gene.

[0125] 9. The method according to clause 6, wherein the insertion is located in exon 19 of the EGFR gene.

[0126] 10. The method according to any one of clauses 1 to 9, wherein the at least one mutation comprises a deletion in the EGFR gene.

[0127] 11. The method according to clause 10, wherein the deletion is located in exon 19 of the EGFR gene.

[0128] 12. A method according to any one of clauses 1 to 11, wherein the at least one mutation comprises a point mutation in the EGFR gene.

[0129] 13. The method according to clause 12, wherein the at least one point mutation is located at one or more of amino acid positions L858, G719, L861, S768 and E709 of the EGFR gene.

[0130] 14. A method according to any one of clauses 1 to 13, wherein the at least one mutation comprises a frameshift mutation in the EGFR gene.

[0131] 15. The method according to any one of clauses 1 to 14, wherein the patient's cancer is locally advanced.

[0132] 16. The method according to any one of clauses 1 to 14, wherein the patient's cancer is metastatic.

[0133] 17. The method according to clause 16, wherein the patient's cancer has bone metastases.

[0134] 18. The method according to any one of clauses 1 to 17, wherein the patient has previously been treated with EGFR targeted therapy.

[0135] 19. The method according to clause 18, wherein the patient has previously been treated with osimertinib.

[0136] 20. The method according to any one of clauses 1 to 19, wherein the patient has not been previously treated with an EGFR targeted therapy targeting an insertion in exon 20.

[0137] 21. The method according to any one of clauses 1 to 20, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 75 mg.

[0138] 22. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 150 mg.

[0139] 23. The method according to clause 22, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 300 mg.

[0140] 24. The method according to clause 23, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 375 mg.

[0141] 25. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75-150 mg.

[0142] 26. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150-300 mg.

[0143] 27. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75 mg.

[0144] 28. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150 mg.

[0145] 29. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 300 mg.

[0146] 30. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 375 mg.

[0147] 31. The method according to clause 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 450 mg.

[0148] 32. The method according to any one of clauses 1 to 31, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases the overall survival (OS) time of a patient population compared to a control patient population without said administration.

[0149] 33. The method according to any one of clauses 1 to 32, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases progression-free survival (PFS) time in a patient population compared to a control patient population without said administration.

[0150] 34. A method of treating cancer in a patient with CNS metastases, the method comprising:

[0151] orally administering to the patient a daily dose of 37.5-450 mg of NX-019 or a pharmaceutically acceptable salt thereof,

[0152] wherein the patient's cancer has central nervous system (CNS) metastasis and at least one mutation in the epidermal growth factor receptor (EGFR) gene.

[0153] 35. The method of clause 34, wherein the patient's cancer does not have an insertion in exon 20 of the EGFR gene.

[0154] 36. The method of clause 34, wherein the patient's cancer has an insertion in exon 20 of the EGFR gene.

[0155] 37. The method according to clause 36, wherein the patient has not been previously treated with an EGFR targeted therapy targeting an insertion in exon 20 of the EGFR gene.

[0156] 38. A method according to any one of clauses 34 to 37, wherein the patient's cancer is human epidermal growth factor receptor 2 positive (HER2 + )of.

[0157] 39. A method according to any one of clauses 34 to 38, wherein the at least one mutation comprises an insertion in exon 19 of the EGFR gene.

[0158] 40. The method according to any one of clauses 34 to 38, wherein the at least one mutation comprises a deletion in the EGFR gene.

[0159] 41. The method according to clause 40, wherein the deletion is located in exon 19 of the EGFR gene.

[0160] 42. The method of any one of clauses 34 to 41, wherein the at least one mutation comprises a point mutation in the EGFR gene.

[0161] 43. A method according to clause 42, wherein the at least one point mutation is located at one or more of amino acid positions L858, G719, L861, S768 and E709 of the EGFR gene.

[0162] 44. The method of any one of clauses 34 to 43, wherein the at least one mutation comprises a frameshift mutation in the EGFR gene.

[0163] 45. The method of any one of clauses 34 to 37, wherein the patient's cancer has brain metastases.

[0164] 46. ​​The method of any one of clauses 34 to 38, wherein the patient has lung cancer, head and neck cancer, or colon cancer.

[0165] 47. The method according to any one of clauses 34 to 39, wherein the patient has metastatic non-small cell lung cancer (NSCLC).

[0166] 48. The method of any one of clauses 34 to 37, wherein the patient's cancer has asymptomatic leptomeningeal disease.

[0167] 49. The method according to any one of clauses 34 to 48, wherein the patient has previously been treated with an EGFR targeted therapy.

[0168] 50. The method according to clause 49, wherein the patient has previously been treated with osimertinib.

[0169] 51. The method of any one of clauses 34 to 50, wherein the patient has not been previously treated with an EGFR targeted therapy targeting an insertion in exon 20.

[0170] 52. The method according to any one of clauses 34 to 51, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 75 mg.

[0171] 53. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 150 mg.

[0172] 54. The method according to clause 53, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 300 mg.

[0173] 55. The method according to clause 54, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 375 mg.

[0174] 56. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75-150 mg.

[0175] 57. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150-300 mg.

[0176] 58. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75 mg.

[0177] 59. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150 mg.

[0178] 60. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 300 mg.

[0179] 61. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 375 mg.

[0180] 62. The method according to clause 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 450 mg.

[0181] 63. The method according to any one of clauses 34 to 62, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases the overall survival (OS) time of a patient population compared to a control patient population without said administration.

[0182] 64. The method of any one of clauses 34 to 62, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases progression-free survival (PFS) time in a patient population compared to a control patient population without said administration.

[0183] 65. The method of any one of clauses 34 to 64, wherein the administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof reduces CNS metastasis of the patient's cancer.

[0184] 66. The method according to any one of clauses 34 to 64, wherein the administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof reduces the progression of an existing CNS pathology.

[0185] 67. The method according to any one of clauses 34 to 64, wherein the administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof reduces the size of an existing CNS lesion.

[0186] 68. The method according to any one of clauses 34 to 64, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof reduces the risk of development of new CNS lesions.

[0187] 6. Examples

[0188] The following examples are provided to illustrate the present disclosure, but should not be interpreted as limiting the scope of the present technology in any way. Any functionally equivalent method belongs to the scope of the present technology. According to the above description and the accompanying drawings, it will be clear to those skilled in the art that various modifications of the present technology other than those described herein. Such modifications fall within the scope of the appended claims. Unless otherwise stated, all temperatures are degrees Celsius. We have tried our best to ensure the accuracy of the numbers used (such as amounts, temperatures, etc.), but some experimental errors and deviations should be allowed. In the following examples, if an abbreviation is not defined, it has its generally accepted meaning.

[0189] 6.1. Preclinical studies of NX-019

[0190] Approved targeted EGFR therapies have limited efficacy against many common EGFR driver mutations (e.g., L7858R, exon 19 mutations, and exon 20 insertion mutations). Approximately 20%-50% of NSCLC patients develop brain metastases (BM) during the course of the disease, but current tyrosine kinase inhibitors (TKIs) are still not well treated for BM. NX-019 is a potent, orally bioavailable, CNS-penetrant, mutation-selective EGFR inhibitor that targets a broad range of EGFR mutations, including common activating mutations (e.g., exon 19 deletions and L858R), T790M, exon 20 insertions, and other rare mutations.

[0191] NX-019 is selective for mutant EGFR but not wild-type EGFR and is generally effective against a wide range of mutations and mutation types of EGFR. The mutation selectivity of the mutant L858R (T1975) EGFR cancer cell line is >110-fold compared to the wild-type (Lovo) cancer cell line. This selectivity has also been validated in vitro in a large number of cell lines with various EGFR mutations that lead to EGFR activation or resistance to EGFR. Table 3 shows the in vitro cellular efficacy of NX-019 in wild-type and various EGFR mutations. The results are also shown in Figure 3In this study, Ba / F3 (engineered to have specific EGFR mutations using standard protocols) or cancer cell lines expressing wild-type or mutant EGFR were treated with titrated concentrations of NX-019 and cell viability was measured after 3 days. NX-019 showed enhanced potency in cell lines expressing all types of EGFR mutations (e.g., classic, exon 20 insertions, rare, complex) compared to wild-type EGFR cell lines. These data demonstrate the broad potency and mutation selectivity of NX-019, suggesting that NX-019 has the potential to treat patients with mutations that are unresolved or resistant to current EGFR TKI therapies.

[0192] Table 3: In vitro efficacy validation of NX-019 against EGFR mutant cells.

[0193]

[0194] 6.1.1. Evaluation of NX-019 in mouse cancer models

[0195] The efficacy of NX-019 has been demonstrated in a variety of mouse subcutaneous xenograft models, including a lung orthotopic model and a bone metastasis model. In all xenograft models, NX-019 was well tolerated, with no or minimal weight loss during treatment (Figure 5, subfigure B). In both in vitro and in vivo (Figure 1, subfigures AC; Figure 5 subfigure A) models, NX-019 showed sustained downregulation of phosphorylated EGFR in both treated cells and tumors. Referring to Figure 5, PDX model exon 20ins (LU0387-H773_V774insNPH) cells were subcutaneously implanted into BALB / c nude mice. When the tumor reached an average of 160mm 3 NX-019 was orally administered to mice at a dose of 75 mg / kg and 125 mg / kg, twice a day (PO BID). The tumor volume and body weight of the mice were measured and graphed (Figure 5). NX-019 showed tumor regression and cure at both test doses (sub-figure A), and had no effect on body weight (sub-figure B). The efficacy of NX-019 on CNS lesions in these xenograft brain models showed tumor regression and prolonged pharmacodynamic (PD) effects. NX-019 treatment resulted in tumor regression and cure at both test doses, and had no effect on body weight.

[0196] NX-019 has broad activity against EGFR mutations, is selective for mutant EGFR, and has in vitro and in vivo activity in mutation-driven EGFR models across mutation types and tumor locations.

[0197] 6.1.2. Evaluation of NX-019 on mutant EGFR and wild-type EGFR

[0198] Compared with wild-type EGFR, NX-019 showed selective inhibition of mutant EGFR. Cells expressing Ba / F3EGFR exon 20ins (D770_N771insSVD) were subcutaneously implanted into BALB / c nude mice. When the tumor reached an average of 310 mm 3 Mice were dosed with 25-125 mg / kg NX-019PO BIDx1. Tumor and skin samples were collected 2 hours after dosing and analyzed by western blotting to detect levels of phosphorylated EGFR and β-actin. NX-019 reduced tumor and skin phosphorylated EGFR expression at all doses tested (25 mg / kg, 50 mg / kg, 75 mg / kg, 125 mg / kg) (Figure 4, subfigure A). In contrast, β-actin levels remained unchanged after dose increases. Phosphorylated EGFR levels were quantified and normalized to total EGFR and β-actin levels. As low as 25 mg / kg NX-019 significantly reduced tumor EGFR levels (Figure 4, subfigure B). NX-019 showed enhanced inhibition and selectivity against mutant EGFR in tumors compared to wild-type EGFR in skin samples.

[0199] Cell lines expressing wild-type EGFR or specific EGFR exon 20 insertion mutants were treated with titrated concentrations of NX-019 or other EGFR inhibitors, and cell viability was measured (Figure 4, panel C). NX-019 showed better selectivity for EGFR exon 20 insertion mutants than other tested compounds.

[0200] These data demonstrate that NX-019 is selective for mutant EGFR over wild-type EGFR and exhibits increased potency in cell lines harboring classic, exon 20 insertions, and other rare EGFR mutations compared to cells expressing wild-type EGFR. Notably, no classic EGFR dermatologic adverse events were observed in preclinical animal models, consistent with the improved selectivity profile of NX-019.

[0201] NX-019 is a broad-spectrum EGFR inhibitor with potent mutant EGFR inhibitory activity, superior wild-type EGFR selectivity and excellent CNS penetration in animal models. NX-019 is a broad-spectrum EGFR inhibitor targeting common and rare mutations, including EGFR ex20ins, G719S and L861Q. In preclinical studies, NX-019 showed selective activity against mutants relative to wild-type EGFR.

[0202] 6.1.3. Brain Penetration Activity of NX-019

[0203] NX-019 has brain penetrant properties. Studies were conducted to demonstrate and characterize the ability of NX-019 to penetrate the CNS. In a pharmacokinetic (PK) experiment to formally evaluate the distribution of NX 019 in the CNS compartment, mice were orally administered a 100 mg / kg dose of NX-019. Calculated NX-019 free fraction levels in the cerebral cortex exceeded 1 μM within 15 minutes and remained above 100 nm for approximately 4 hours. Progressive disease (PD) confirmation evaluated the effect on phosphorylated EGFR in the intracranial PC9 (exon 19del) model after 175 mg / kg NX-019 (oral, QDx3), and the results showed a robust downregulation of phosphorylated EGFR within 12 to 18 hours after the last dose (Figure 1, sub-figure C).

[0204] In dogs, cerebrospinal fluid (CSF) levels of NX-019 were assessed following a single oral dose of 40 mg / kg. max The values ​​are in the range of 2μm to 3μm (total NX-019). Estimated C max The plasma free fraction is ∼140 nm and is similar to CSF ​​C max This indicates that there is an almost 1:1 relationship between the plasma free fraction and CSF levels in dogs within 1 hour. Under these conditions, CSF levels greater than 40 nM can be maintained for nearly 4 hours.

[0205] A similar relationship between plasma free fraction and CSF levels was also demonstrated in rats. Taken together, these data suggest that NX-019 enters the CNS and that CSF levels are closely correlated with plasma free fraction levels. max The CSF concentration at 50 μg / mL would be the same as that of the plasma free fraction and consistent with the overall exposure / time profile of NX-019 in plasma, suggesting that its exposure may be able to inhibit EGFRm in brain metastases.

[0206] Animal models have demonstrated substantial CNS exposure, potent antitumor activity against intracranial xenografts, and long-term inhibition of EGFR signaling. Drug levels measured in the brain of rats and mice were similar to those in plasma. NX-109 was readily detected in the CSF of cynomolgus monkeys, dogs, and rats at concentrations similar to the estimated plasma free fraction.

[0207] 6.1.4. Activity of NX-019 in a mouse model of brain cancer

[0208] The efficacy of NX-019 has also been demonstrated in a NSCLC brain metastasis tumor model. Figure 1 shows the efficacy of NX-019 in a brain cancer mouse model (PC9-GFP) carrying an EGFR exon 19 insertion mutation (DelE746-A750) in the brain of NCrnu / nu mice. The oral dose of NX-019 was 75, 125 or 150 mg / kg PO BID. Tumor volume was measured over time and a graph was drawn. The weight of the mice was measured over time and a graph was drawn. NX-019 treatment resulted in complete tumor regression, as shown in the tumor reduction graph (sub-graph A), GFP fluorescent tumor photos of control mice and 75 mg / kg treated mice 22 days after administration (sub-graph B), and downregulation of phosphorylated EGFR in the tumor (sub-graph C) (Figure 1). Figure 2 shows additional photos of GFP fluorescent tumors in treated mice at a higher dose (125 mg / kg), which reduced tumor volume (GFP fluorescence) (sub-graph A). NX-019 treatment resulted in tumor regression and cure at both doses tested, with no effect on body weight.

[0209] NX-019 was well tolerated, with no or only mild weight loss during treatment (Figure 2, sub-figure B). A companion study has been completed to observe the PD effect of NX-019 in PC-9 CNS. NX-019 showed sustained downregulation of phosphorylated EGFR in tumors, demonstrating targeted pharmacodynamic inhibition of mutant EGFR (Figure 1, sub-figure C). Tumor lysates were analyzed by Western blotting using EGFR, phosphorylated EGFR, and tubulin antibodies. In the Western blot images of tumors probed with EGFR, P-EGFR, and tubulin antibodies, NX-019 showed sustained inhibition of EGFR phosphorylation at time points after dosing (175 mg / kg) (Figure 1, sub-figure C).

[0210] Thus, NX-019 is broadly active against EGFR mutations, selective for mutant EGFR, and has in vivo activity in EGFR models of mutation-driven central nervous system (CNS) disease. NX-019 demonstrated tumor regression and cure at both doses tested, with no effect on body weight.

[0211] 6.1.5. CNS / brain and plasma exposure of NX-019 in animal models

[0212] The significance of the ratio of NX-019 brain and plasma exposure was investigated. The pharmacokinetic exposure levels of NX-019 in plasma and brain were measured (Figure 6, subfigure A). The ratio of rat brain / plasma AUC, the ratio of rat brain / plasma Cmax, and the Cmax of mouse brain / plasma had a NX-019 brain / plasma ratio greater than 1 (vertical dashed line, Figure 6, subfigure A). The Kp,uu values ​​of NX-019 brain exposure levels in mice and rats were calculated (Figure 6, subfigure B). The Kp,uu values ​​of NX-019 brain exposure levels in rats, dogs, and cynomolgus monkeys were calculated. CSF Value (Fig. 6 panel D). Kp,uu of NX-019 compared with osimertinib (Colclough N, et al. Clin Cancer Res, 2021; 27: 189-2021) is shown. CSF (Figure 6, subfigure E). The results showed that Kp,uu was close to 1, indicating excellent CNS exposure. The NX-019 free fractions in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, dogs, and rats were measured (Figure 6, subfigure C). The results showed that the exposure levels of NX-019 in the CNS and plasma were similar, indicating that NX-019 is brain-penetrating and has excellent CNS exposure levels. In addition, NX-019 was easily detected in the cerebrospinal fluid of rats, dogs, and cynomolgus monkeys.

[0213] Conclusion

[0214] The data showed that NX-019 is a potent and selective inhibitor of mutant EGFR, including classic, resistant and rare mutations such as exon 20 insertions ( Figure 8 ). Orally administered NX-019 is highly brain penetrant, works in an orthotopic model of CNS metastasis at a well-tolerated dose, and demonstrates long-term inhibition of phosphorylated EGFR in implanted brain tumors. In addition, NX-019 demonstrated selective inhibitory effects against mutant EGFR both in vitro and in vivo while preserving the function of wild-type EGFR. NX-019 demonstrated high potency in multiple mutant EGFR models. NX-019 has been optimized for enhanced CNS penetration and potency against a broad range of EGFR mutations. NX-019 is currently being evaluated in a Phase 1 clinical trial (NCT05514496).

[0215] Preclinical in vitro and in vivo studies have shown that NX-019 has high efficacy in a wide range of mutant EGFR models, indicating that NX-019 has the potential to treat patients who are currently not covered or resistant to current EGFR TKI therapies. NX-019 is selective for mutant EGFR relative to wild-type EGFR, and exhibits higher potency (7.3-200+ times) in cell lines with classic mutations, exon 20 insertions, and other rare mutations compared to cells expressing wild-type EGFR. This improved mutant selectivity should help improve tolerance at higher dose levels and greater systemic exposure. Studies in preclinical animal models (mice, rats, dogs) did not show classic EGFR dermatological findings, which is consistent with the improved NX-019 selectivity profile. Studies measuring the CNS efficacy of NX-019 in xenograft brain models (e.g., PC9 brain orthotopic models) showed tumor regression and prolonged PD effects (e.g., inhibition of phosphorylated EGFR). CNS exposure studies conducted in multiple preclinical species showed that Kp,uu was approximately 1, indicating excellent CNS exposure.

[0216] 6.2. Preparation of NX-019 formulation

[0217] N-(1-(R)-1-acryloylazepan-3-yl)-7-chloro-6-(((S)-tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (NX019) can be synthesized according to the synthesis method described in Example 20 of U.S. Patent No. US10,005,765. NX-019 free base can be isolated by crystallization in DCM and tert-butyl methyl ether (MTBE). The NX019 free base product is recrystallized in ethanol / water to obtain crystalline Form I material. This study used NX-019 free base Form I formulated in hydroxypropyl methylcellulose (HPMC) capsules.

[0218] 6.3. Study of NX-019 in Patients with Advanced Epidermal Growth Factor Receptor (EGFR) Mutated Cancers

[0219] 6.3.1. Study description and objectives

[0220] Clinical trial NCT05514496. This is a two-part, first-in-human, open-label study designed to determine the safety and tolerability of NX-019 and preliminary efficacy in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) mutant cancers.

[0221] Dose Escalation (Part 1): The primary objectives of Part 1 of this study are to evaluate the safety and tolerability of NX-019 and to determine the maximum tolerated dose (MTD) / recommended Phase 2 dose (RP2D).

[0222] Dose escalation (Part 1): The secondary objectives of Part 2 of this study are to:

[0223] 1. Evaluate the pharmacokinetic (PK) properties of NX-019.

[0224] 2. Determine the anti-tumor activity of NX-019 according to RECIST 1.1:

[0225] a. Objective response rate (ORR) (ORR = complete response [CR] + partial response [PR]);

[0226] b. Reaction time (TTR);

[0227] c. Duration of response (DOR);

[0228] d. Disease control rate (DCR) (DCR = CR + PR + stable disease [SD]);

[0229] e. Overall survival (OS) after starting NX-019 treatment.

[0230] 3. Determine the anti-tumor activity of NX-019 for central nervous system (CNS) diseases according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) guidelines:

[0231] a. ORR CNS metastasis;

[0232] b. TTR CNS metastases; and

[0233] c.DOR CNS metastasis.

[0234] Dose Expansion (Part 2): The primary objectives of Part 2 of this study are to confirm the safety and tolerability of NX-019 at the MTD / RP2D and to obtain preliminary evidence of efficacy as measured by objective response rate (ORR) for each expansion cohort.

[0235] Dose Expansion (Part 2): The secondary objectives of Part 2 of this study are to:

[0236] 1. Further evaluate the PK properties of NX 019.

[0237] 2. Determine the anti-tumor activity of NX019 (as defined by RECIST 1.1):

[0238] a.TTR;

[0239] b.DOR;

[0240] c. DCR (DCR = CR + PR + SD); and

[0241] d. OS after starting NX-019 treatment.

[0242] 3. Determine the anti-tumor activity of NX-019 for CNS diseases according to the RANO-BM guidelines:

[0243] a. ORR CNS metastasis;

[0244] b. TTR CNS metastases; and

[0245] c.DOR CNS metastasis.

[0246] Exploratory - Dose escalation (Part 1) and dose expansion (Part 2): Characterize the mutational profile of each tumor and assess ORR based on patient EGFR mutation type.

[0247] Study design

[0248] This is a two-part, first-in-human, open-label, dose-escalation and expansion study of oral administration of NX-019 in patients with advanced EGFR-mutated cancer: Study Type: Interventional, Estimated Enrollment: 178 Participants, Allocation: Non-randomized, Intervention Mode: Continuous Allocation, Primary Objective: Treatment.

[0249] Figure 7 and Figure 9 Flowchart showing the study design. The study determines the safety and tolerability of NX-019 and preliminary efficacy in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) mutant cancer. The study will include a dose escalation portion and a dose expansion portion. NX-019 is initially administered orally once daily (QD) in a 28-day cycle. If the first 3 patients experience a DLT within the first 28 days of continuous dosing, the treatment cohort is expanded to 6 patients. If at least two patients in each cohort experience a DLT, the MTD is reached. The safety and tolerability of NX-019 were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 5.0. All patients were evaluated for response using RECIST1.1 and underwent computed tomography (CT) or magnetic resonance (MR) imaging at 28 days and every 8 weeks (±7 days) within 8 weeks after day 1 (D) of cycle 1. Serial blood samples for PK and pharmacodynamics and circulating tumor DNA (ctDNA) were collected. An optional CSF sample was collected on C1D15 4 hours after dosing to assess the levels of NX-019 and any metabolites.

[0250] The dose escalation and dose expansion parts each consisted of a screening period, a treatment period (continuous 28-day cycles), an end-of-treatment (EOT) visit, a safety follow-up visit, and a long-term follow-up (LTFU). Continuous safety and disease assessments, disease status, survival, and subsequent anticancer treatment were evaluated during the LTFU period.

[0251] 6.3.3. Grouping and intervention

[0252] Experimental: Part 1: NX-019 dose escalation. Patients were treated with NX-019 in multiple escalation cohorts. NX-019 was administered orally.

[0253] Experimental: Part 2: NX-019 dose escalation. Patients were treated at the MTD / RP2D of NX-019 in multiple escalation cohorts. NX-019 was administered orally.

[0254] 6.3.4. Outcome measurement

[0255] Primary outcome measures included the frequency, severity, and relevance of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs):

[0256] 1. Part 1 and Part 2: Incidence of TEAEs [Time frame: up to 4.5 years].

[0257] 2. Part 1 and Part 2: Incidence of AESI [Time frame: up to 4.5 years].

[0258] 3. Part 1 and Part 2: Incidence of SAEs [Time frame: up to 4.5 years].

[0259] 4. Part 2: Objective response rate (ORR) [time frame: up to 4.5 years].

[0260] Secondary outcome measures included plasma and cerebrospinal fluid (CSF) concentrations and calculated PK parameters of NX-019, as well as parameters of antitumor activity / clinical benefit:

[0261] 1. Part 1: Objective response rate of NX-019 [time frame: up to 4.5 years].

[0262] 2. Part 1 and Part 2: Plasma concentrations of NX-019 [Time frame: up to 43 days].

[0263] 3. Part 1 and Part 2: Cerebrospinal fluid (CSF) concentrations of NX-019 [Time frame:

[0264] Up to 43 days].

[0265] 4. Part 1 and Part 2: Maximum observed serum concentration (Cmax) of NX-019 [Time frame: up to 43 days].

[0266] 5. Part 1 and Part 2: Area under the concentration versus time curve (AUCtau) of NX-019 during the dosing interval [Time range: up to 43 days].

[0267] 6. Part 1 and Part 2: AUC of NX-019 from time 0 to the last quantifiable plasma concentration (AUC0-t) [time range: up to 43 days].

[0268] 7. Part 1 and Part 2: AUC of NX-019 from time 0 to infinity (AUC0-inf) [Time range: up to 43 days].

[0269] 8. Part 1 and Part 2: AUC% extrapolation percentage (AUC%extrap) of NX-019 [Time frame: up to 43 days].

[0270] 9. Part 1 and Part 2: Terminal phase elimination half-life of NX-019 (t 1 / 2 )[Time frame: up to 43 days].

[0271] 10. Part 1 and Part 2: Terminal phase elimination rate constant (λz) of NX-019 [Time frame: up to 43 days].

[0272] 11. Part 1 and Part 2: Apparent plasma clearance (CL / F) of NX-019 [Time frame: up to 43 days].

[0273] 12. Part 1 and Part 2: Apparent volume of distribution (Vd / F) of NX-019 [Time frame: up to 43 days].

[0274] 13. Part 1 and Part 2: Cumulative index using Cmax (AICmax) and cumulative index using AUC of NX-019 (AIAUC0-inf) [Time frame: up to 43 days].

[0275] 14. Part 1 and Part 2: Time to Response (TTR) [Time Frame: Up to 4.5 years].

[0276] 15. Part 1 and Part 2: Duration of Response (DOR) [Time frame: up to 4.5 years].

[0277] 16. Part 1 and Part 2: Disease Control Rate (DCR) [Time Frame: Up to 4.5 years].

[0278] 17. Part 1 and Part 2: Overall Survival (OS) [Time Frame: Up to 4.5 years].

[0279] 18. Part 1 and Part 2: Objective Response Rate for CNS (Central Nervous System) Metastases [Time Frame: Up to 4.5 years].

[0280] 19. Part 1 and Part 2: TTR for CNS (Central Nervous System) Metastases [Time Frame: Up to 4.5 years].

[0281] 20. Part 1 and Part 2: DOR for CNS (Central Nervous System) Metastases [Time Frame: Up to 4.5 years].

[0282] 6.3.5. Eligibility Criteria:

[0283] Age suitable for the study: 18 years and older

[0284] Gender suitable for the study: All

[0285] Based on gender: No

[0286] Accept healthy volunteers: No

[0287] Inclusion criteria:

[0288] 1. Histologically confirmed locally advanced or metastatic EGFR-mutated cancer that has progressed or is intolerant to all standard therapies.

[0289] 2. Patients with non-small cell lung cancer (NSCLC) carrying a mutation sensitive to osimertinib must have received osimertinib treatment prior to enrollment. Patients who refuse platinum-based therapy can be enrolled. For patients with mutations for which no inhibitor is available, prior EGFR inhibitor therapy is not required, but they must receive an alternative first-line therapy.

[0290] 3. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (evaluable disease in the dose escalation part of the study is acceptable).

[0291] 4. ≥ 18 years old.

[0292] 5. Life expectancy ≥ 3 months.

[0293] 6. Adequate organ and bone marrow function, as defined by the following:

[0294] a. Absolute neutrophil count ≥ 1.5 × 10 9 / L (≥ 1500 / mm 3 );

[0295] b. Platelet count ≥ 100 × 10 9 / L(≥100,000 / mm 3 );

[0296] c. Total bilirubin ≤1.5×ULN; unless a known Gilbert syndrome has been diagnosed;

[0297] d. For patients with known liver metastases, AST and ALT ≤ 2.5 × ULN or

[0298] ≤5×ULN;

[0299] e. Measured (or calculated) creatinine clearance (glomerular filtration rate) ≥ 60 mL / min;

[0300] f. International normalized ratio or prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. If the patient is receiving anticoagulant therapy, PT

[0301] Or the aPTT must be within the therapeutic range for the intended use of the anticoagulant.

[0302] 7. All patients underwent baseline brain magnetic resonance imaging (MRI) (or computed tomography [CT] with contrast if contraindicated), which was permitted if newly discovered metastases were smaller than 1 cm, asymptomatic, without neurological changes or requiring steroids, and no immediate treatment was required at the discretion of the investigator. Patients with previously treated stable CNS metastases (including leptomeningeal carcinomatosis) could be treated if they had no signs of progression after receiving CNS-directed therapy for at least 2 weeks as determined by clinical examination and brain imaging, and if the patient was receiving no more than 4 mg of dexamethasone per day.

[0303] Note: This does not apply to patients in expansion cohorts 1 and 2, which specifically allowed for the inclusion of patients with CNS progression to evaluate patients with CNS disease;

[0304] See Extended Queues 1 and 2 below.

[0305] 8. Any clinically significant toxic effects of previous therapy have resolved to Grade 0 or 1 (except alopecia and Grade 2 peripheral neuropathy) according to the National Cancer Institute CTCAE v5.0.

[0306] 9. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

[0307] 10. Males and females of reproductive potential are willing to comply with traditional effective contraceptive methods with a failure rate of <1% during treatment and within 3 months after the last dose of study treatment.

[0308] 11. The serum pregnancy test result is negative at screening, and the pregnancy test (serum or urine) result is negative within 72 hours before the first dose of study drug (only for female patients of childbearing age).

[0309] 12. Willing and able to give informed consent and comply with protocol requirements during the duration of the study.

[0310] Specific inclusion criteria for the expansion cohort:

[0311] To be eligible in the extension portion of the study, patients must meet the inclusion criteria above as well as the criteria for one of the following cohorts:

[0312] Expansion cohort 1:

[0313] 1. Patients with EGFR-mutant NSCLC (excluding ex20ins mutation) with CNS lesions, including asymptomatic leptomeningeal disease, that have progressed or been detected after previous treatment.

[0314] 2. The treatment regimen immediately before study registration must include 80 mg osimertinib combination therapy or single drug therapy;

[0315] 3. Patients must have measurable CNS disease with a diameter of

[0316] ≥5 mg, with appropriate slice thickness (response will be assessed according to RECIST using the two-compartment model defined in the RANO-BM guidelines);

[0317] 4. No patients suffering from diseases requiring immediate surgery or radiotherapy;

[0318] 5. Patients who are not using steroids or are using stable or reduced doses of steroids (maximum allowed daily dose is 4 mg dexamethasone or equivalent).

[0319] Expansion cohort 2:

[0320] 1. Patients with EGFR ex20ins mutant NSCLC and CNS lesions (including asymptomatic leptomeningeal disease that has progressed or been detected after prior therapy).

[0321] 2. Patients must have measurable CNS disease, as measured by MRI with a diameter ≥5 mm and appropriate slice thickness (response will be assessed according to RECIST using the two-compartment model defined in the RANO-BM guidelines);

[0322] 3. Patients who do not have diseases that require immediate surgery or radiotherapy;

[0323] 4. Patients who are not using steroids or are using stable or reduced doses of steroids (maximum allowed daily dose is 4 mg dexamethasone or equivalent).

[0324] Expansion cohort 3: Patients with NSCLC and EGFR ex20ins mutation who have not received ex20ins mutation-targeted therapy.

[0325] Expansion cohort 4: Patients with NSCLC and rare EGFR mutations for which there are currently no targeted therapies, excluding exon 19, exon 21 L858R or L861Q, and ex20ins mutations.

[0326] Expansion cohort 5: Patients with EGFR-mutant NSCLC who met inclusion criterion #1 and did not meet the specific requirements of expansion cohorts 1 to 4 after discussion with the sponsor.

[0327] Exclusion criteria:

[0328] Patients meeting any of the following criteria will be excluded from the study:

[0329] 1. Known C797X EGFR mutation or known second disease driver.

[0330] 2. Patients have received systemic anticancer chemotherapy, targeted drugs, cancer antibody therapy, cancer immunotherapy, hormone therapy, or investigational drugs within 2 weeks or 5 half-lives (whichever is shorter) before starting study drug treatment.

[0331] 3. Underwent major surgery within 3 weeks before starting study drug treatment.

[0332] 4. Received radiotherapy within 4 weeks before starting study drug treatment.

[0333] 5. Severe or unstable heart condition within 6 months before starting study drug treatment.

[0334] 6. Serious or unstable medical conditions, including uncontrolled diabetes or unstable mental conditions.

[0335] 7. Dependence on contact lenses (unable to wear glasses) or inability to follow ophthalmologist instructions.

[0336] 8. History of interstitial lung disease, radiation pneumonitis requiring systemic steroid therapy, or other severe lung disease.

[0337] 9. A history of another active malignancy (second cancer).

[0338] 10. Active infection requiring systemic treatment.

[0339] 11. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) (i.e., positive hepatitis B surface antigen), or hepatitis C virus (HCV) (i.e., detectable HCV ribonucleic acid [RNA]).

[0340] 12. Active gastrointestinal diseases (such as Crohn's disease, ulcerative colitis, or short bowel syndrome) or diseases that may affect drug absorption.

[0341] 13. Pregnant or breastfeeding.

[0342] 14. Currently using strong CYP3A inhibitors or inducers.

[0343] 15. Any other condition, including severe skin or nail disease, that, in the opinion of the investigator, would expose the patient to unacceptable risk or render the patient unlikely to fully participate in or comply with study procedures.

[0344] 6.3.6. Procedure

[0345] Study procedures followed the planned evaluation of patients during the study. The procedures for selected tests are listed below.

[0346] 6.3.6.1 Tumor Measurement

[0347] Tumors were assessed based on RECIST 1.1. CNS disease was assessed by RECIST using a two-compartment model (CNS and non-CNS) according to RANO-BM guidelines. Baseline disease assessment was performed within 28 days after C1D1 using radiologic tumor measurements of the chest, abdomen, and pelvis or any other area of ​​suspected disease using CT or MR imaging. All patients were required to undergo brain imaging during screening (MR imaging was preferred, CT with contrast was acceptable if MRI was contraindicated). For each modality, intravenous (IV) and oral contrast agents should be used (IV contrast is not required for chest CT) unless there are clear contraindications (e.g., decreased renal function or allergies that cannot be resolved with standard preventive therapy). In-study scans should be performed every 8 weeks (±7 days) during the first year after C1D1 and every 12 weeks (±6 days) thereafter, including imaging of the chest, abdomen, pelvis, and brain or any other known area of ​​disease at baseline, using the same modality as baseline imaging assessments until PD, withdrawal of consent, or initiation of new anticancer therapy.

[0348] 6.3.7. Study treatment

[0349] NX-019 is available as 37.5 mg and 75 mg capsules in bottles of 35. The pharmacist dispenses the capsules or bottles to patients in outpatient quantities at the designated dose level. Dosages are fixed (i.e., not based on body weight or BSA).

[0350] Capsules are stored at controlled room temperature (between 15°C and 30°C [59°F and 86°F]. Currently available data support a 12-month retest period for packaged drug products and this may be extended with additional stability data.

[0351] 6.3.7.1 NX-019 Administration: General Dosing Instructions

[0352] NX-019 was initially administered orally QD for 28 consecutive days. Patients fasted 2 hours before and 1 hour after administration of NX-019. NX-019 was administered with about 8 ounces (about 236 mL) of water. Each person's daily dosing was at a fixed time. NX-019 was swallowed whole and taken in a consistent manner.

[0353] Cycle 1:

[0354] Patients begin dosing on C1D1 according to their assigned cohort. Serial blood samples for PK monitoring are collected and patients are monitored for safety. An optional CSF sample is collected on C1D15 4 hours after dosing to assess levels of NX-019 and any metabolites. The cycle length for both the dose escalation and dose expansion parts is 28 days; the DLT period during Part 1 will consist of Days 1-28 of C1.

[0355] Cycle 2 and above:

[0356] Each patient received NX-019 QD in 28-day cycles, based on the assigned dose level (or RP2D in Part 2), until disease progression (PD), unacceptable toxicity, or other reasons for discontinuation of treatment. Patients with documented PD were allowed to continue NX-019 if they were able to tolerate treatment and if they derive clinical benefit from continuing study treatment and continuing treatment.

[0357] Administration delay / modification

[0358] Cycles were 28 days with or without dose interruptions, unless the dose interruption included D1 of the next cycle, in which case the next cycle would begin with resumption of study drug. In this case, disease assessments continued as originally planned.

[0359] Toxic effects associated with the above symptoms, such as nausea, vomiting, diarrhea, dizziness, or dehydration, can be managed with enhanced supportive care, including rehydration of water, electrolytes, and, as appropriate, the use of antiemetics (e.g., serotonin antagonists) and / or antidiarrheals (e.g., loperamide).

[0360] Patients who experience a clinically significant adverse event (i.e., >Grade 2 or a change of more than 1 grade from baseline if baseline was Grade 2 or higher) may have NX-019 dosing interrupted for up to 28 days to assess the adverse event and allow for recovery (to Grade 1 or baseline level). Following recovery, patients may restart treatment if continued treatment is in the best interest of the patient. Upon restarting, the patient's dose may be reduced by at least 1 dose level (Table). If the adverse event does not recover to Grade 1 or lower (or baseline) within 28 days, the patient's treatment will be permanently discontinued unless there is a compelling clinical reason for a further dose reduction as presented by the investigator and approved by the sponsor. A maximum of 2 dose reductions will be permitted for each patient unless there is a compelling clinical reason for an additional dose reduction.

[0361] Table 2: Recommended toxicity management

[0362]

[0363] 6.3.8. Security Assessment

[0364] An adverse event is defined as any untoward medical occurrence that occurs when a drug is administered to a patient in a clinical investigational setting and that does not necessarily have a causal relationship to that treatment. Thus, an adverse event can be any unfavorable and / or unexpected sign (including abnormal laboratory results), symptom, or illness temporally associated with the use of an investigational drug, whether or not related to the investigational drug. Record all adverse events, including problems, complaints, or symptoms that are observed or volunteered.

[0365] The safety profile is based on adverse events (including DLTs, AESIs, and SAEs), physical examination findings (including ECOG performance status), ophthalmologic examinations, vital sign measurements, clinical laboratory measurements, and ECG recordings. Safety analyses are typically descriptive and presented in tables with appropriate summary statistics. Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).

[0366] 7. Equivalents and References

[0367] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and details may be made therein without departing from the spirit and scope of the invention.

[0368] All publications, patents, patent applications, and other documents cited in this application, including U.S. Provisional Application No. 63 / 398,192, U.S. Provisional Application No. 63 / 385,388, U.S. Provisional Application No. 63 / 484,791, and U.S. Provisional Application No. 63 / 504,416, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference herein for all purposes.

Claims

1. A method of treating cancer in a patient, wherein the patient's cancer has at least one mutation in an epidermal growth factor receptor (EGFR) gene, wherein the method include: The patient is orally administered a daily dose of 37.5-450 mg of NX-019 or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 or 2, wherein the patient has lung cancer, head and neck cancer, or colon cancer.

3. The method of claim 1 or 2, wherein the patient has systemic non-small cell lung cancer (NSCLC).

4. The method of any one of claims 1 to 3, wherein the patient exhibits systemic tumor regression following administration of NX-019.

5. The method according to any one of claims 1 to 4, wherein the patient's cancer is human epidermal growth factor receptor 2 positive (HER2 + )of.

6. The method of any one of claims 1 to 5, wherein the at least one mutation comprises an insertion in the EGFR gene.

7. The method of claim 6, wherein the insertion is located in exon 20 of the EGFR gene.

8. The method of claim 6, wherein the insertion is not an insertion in exon 20 of the EGFR gene.

9. The method of claim 6, wherein the insertion is located in exon 19 of the EGFR gene.

10. The method of any one of claims 1 to 9, wherein the at least one mutation comprises a deletion in the EGFR gene.

11. The method of claim 10, wherein the deletion is located in exon 19 of the EGFR gene.

12. The method of any one of claims 1 to 11, wherein the at least one mutation comprises a point mutation in the EGFR gene.

13. The method of claim 12, wherein the at least one point mutation is located at one or more of amino acid positions L858, G719, L861, S768, and E709 of the EGFR gene.

14. The method of any one of claims 1 to 13, wherein the at least one mutation comprises a frameshift mutation in the EGFR gene.

15. The method of any one of claims 1 to 14, wherein the patient's cancer is locally advanced.

16. The method of any one of claims 1 to 14, wherein the patient's cancer is metastatic.

17. The method of claim 16, wherein the patient's cancer has bone metastases.

18. The method according to any one of claims 1 to 17, wherein the patient has previously been treated with EGFR targeted therapy.

19. The method of claim 18, wherein the patient has previously been treated with osimertinib.

20. The method of any one of claims 1 to 19, wherein the patient has not been previously treated with an EGFR targeted therapy targeting an insertion in exon 20.

21. The method of any one of claims 1 to 20, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 75 mg.

22. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 150 mg.

23. The method of claim 22, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 300 mg.

24. The method of claim 23, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 375 mg.

25. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75-150 mg.

26. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150-300 mg.

27. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75 mg.

28. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150 mg.

29. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 300 mg.

30. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 375 mg.

31. The method of claim 21, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 450 mg.

32. The method of any one of claims 1 to 31, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases the overall survival (OS) time of a patient population compared to a control patient population without said administration.

33. The method according to any one of claims 1 to 32, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases progression-free survival (PFS) time in a patient population compared to a control patient population without said administration.

34. A method of treating cancer in a patient with CNS metastases, the method include: orally administering to the patient a daily dose of 37.5-450 mg of NX-019 or a pharmaceutically acceptable salt thereof, wherein the patient's cancer has central nervous system (CNS) metastasis and at least one mutation in the epidermal growth factor receptor (EGFR) gene.

35. The method of claim 34, wherein the patient's cancer does not have an insertion in exon 20 of the EGFR gene.

36. The method of claim 34, wherein the patient's cancer has an insertion in exon 20 of the EGFR gene.

37. The method of claim 36, wherein the patient has not been previously treated with an EGFR targeted therapy targeting an insertion in exon 20 of the EGFR gene.

38. The method of any one of claims 34 to 37, wherein the patient's cancer is human epidermal growth factor receptor 2 positive (HER2 + )of.

39. The method of any one of claims 34 to 38, wherein the at least one mutation comprises an insertion in exon 19 of the EGFR gene.

40. The method of any one of claims 34 to 38, wherein the at least one mutation comprises a deletion in the EGFR gene.

41. The method of claim 40, wherein the deletion is located in exon 19 of the EGFR gene.

42. The method of any one of claims 34 to 41, wherein the at least one mutation comprises a point mutation in the EGFR gene.

43. The method of claim 42, wherein the at least one point mutation is located at one or more of amino acid positions L858, G719, L861, S768, and E709 of the EGFR gene.

44. The method of any one of claims 34 to 43, wherein the at least one mutation comprises a frameshift mutation in the EGFR gene.

45. The method of any one of claims 34 to 37, wherein the patient's cancer has brain metastases.

46. ​​The method of any one of claims 34 to 38, wherein the patient has lung cancer, head and neck cancer, or colon cancer.

47. The method of any one of claims 34 to 39, wherein the patient has metastatic non-small cell lung cancer (NSCLC).

48. The method of any one of claims 34 to 37, wherein the patient's cancer has asymptomatic leptomeningeal disease.

49. The method of any one of claims 34 to 48, wherein the patient has previously been treated with EGFR targeted therapy.

50. The method of claim 49, wherein the patient has previously been treated with osimertinib.

51. The method of any one of claims 34 to 50, wherein the patient has not been previously treated with an EGFR targeted therapy targeting an insertion in exon 20.

52. The method of any one of claims 34 to 51, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 75 mg.

53. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 150 mg.

54. The method of claim 53, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 300 mg.

55. The method of claim 54, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is at least 375 mg.

56. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75-150 mg.

57. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150-300 mg.

58. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 75 mg.

59. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 150 mg.

60. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 300 mg.

61. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 375 mg.

62. The method of claim 52, wherein the daily oral dose of NX-019 or a pharmaceutically acceptable salt thereof is 450 mg.

63. The method of any one of claims 34 to 62, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases the overall survival (OS) time of a patient population compared to a control patient population without said administration.

64. The method of any one of claims 34 to 62, wherein said administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof increases progression-free survival (PFS) time in a patient population compared to a control patient population without said administration.

65. The method of any one of claims 34 to 64, wherein the administration of an effective amount of NX-019, or a pharmaceutically acceptable salt thereof, reduces CNS metastasis of the patient's cancer.

66. The method of any one of claims 34 to 64, wherein the administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof reduces progression of an existing CNS pathology.

67. The method of any one of claims 34 to 64, wherein the administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof reduces the size of an existing CNS lesion.

68. The method of any one of claims 34 to 64, wherein the administration of an effective amount of NX-019 or a pharmaceutically acceptable salt thereof reduces the risk of development of new CNS lesions.

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