RU2795089C2 - Nazartinib for use in the treatment of cns metastasis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: oncology, intended for the treatment of metastases in a patient with non-small cell lung cancer (NSCLC). Nazartinib or a pharmaceutically acceptable salt thereof is used to treat or prevent metastasis in a patient that is central nervous system (CNS) metastasis, brain metastasis, or leptomeningeal metastasis resulting from a primary lesion such as non-small cell lung cancer (NSCLC) and where NSCLC is characterized by the presence of an EGFR mutation (deletion in exon 19 or substitution (L858R) in exon 21). In other embodiments, methods are provided for treating metastases in a patient with NSCLC, wherein the metastases are selected from central nervous system (CNS) metastases, brain metastases, and leptomeningeal metastases, comprising administering a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof to the patient.

EFFECT: improving the efficiency of treatment or prevention of malignant neoplasms in the central nervous system and in relation to brain lesions in patients with NSCLC with EGFR mutation, including patients with initial brain metastases, and also provides a good quality of life for patients suffering from NSCLC.

22 cl, 1 dwg, 9 tbl, 3 ex

Description

The present invention provides nazartinib or a pharmaceutically acceptable salt thereof, preferably its mesylate salt, for use in the treatment or prevention of a metastasis selected from central nervous system (CNS) metastasis, brain metastasis, and leptomeningeal metastasis. In particular, the present invention contemplates uses in which the metastasis is the result of a primary lesion, such as non-small cell lung cancer (NSCLC), in particular NSCLC, which is characterized by the presence of an EGFR mutation (deletion in exon 19 or substitution (L858R) in exon 21 ). The present invention may be particularly applicable to the first line treatment of patients suffering from NSCLC, including locally advanced or metastatic NSCLC, which is characterized by the presence of an EGFR mutation (deletion in exon 19 or substitution (L858R) in exon 21).

State of the art

Lung cancer is the most common and deadly type of cancer in the world, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of lung cancers. In Western countries, 10-15% of patients with non-small cell lung cancer (NSCLC) express mutant forms of the epidermal growth factor receptor (EGFR) in their tumors, while in Asian countries in such patients the incidence reaches up to 30-40%. The dominant oncogenic EGFR mutations (L858R and ex19del) account for approximately 85% of EGFR-mutated NSCLC cases.

Patients with an EGFR mutation receive an EGFR inhibitor as first-line therapy. However, most patients develop acquired resistance, usually within 10-14 months. No more than 50% of NSCLC patients with a primary EGFR mutation who are treated with first-generation reversible EGFR tyrosine kinase inhibitors (TKIs), also called first-generation TKIs, such as erlotinib, gefitinib, and icotinib, develop a secondary gatekeeper gene mutation T790M.

Second-generation EGFR TKIs (such as afatinib and dacomitinib) have been developed to eliminate the development of this resistance mechanism. They are agents that are capable of irreversibly covalently binding to cysteine 797 in the ATP region of EGFR. In preclinical TKI models, second-generation EGFRs are active against both activating [L858R, ex19del] and acquired T790M mutations. However, their clinical efficacy has been shown to be limited, probably due to severe side effects caused by concomitant wild-type (WT) EGFR inhibition. Resistance to second-generation inhibitors also develops quite rapidly, with nearly all patients receiving first- and second-generation TKIs developing resistance to any of the first- or second-generation TKIs in about 9-13 months.

This has led to the development of third-generation EGFR TKIs such as nazartinib (EGF816), rociletinib, ASP8273, and osimertinib (Tagrisso®). Third-generation EGFR TKIs are sparing on wild-type EGFR and also have the same inhibitory activity against activating EGFR mutations [L858R, ex19del] and acquired T790M mutations. Osimertinib has recently been approved in the US for the treatment of patients with advanced NSCLC due to EGFR T790M+ whose disease progressed after or during TKI EGFR therapy. Osimertinib shows some inhibition of wild-type EGFR.

Patients with tumors characterized by EGFR mutations often experience disease progression during TKI treatment due to the growth of secondary brain metastases (Porta et al. Eur Respir J 2011;37:624-31). In addition, CNS metastases and brain metastases are common in patients with advanced NSCLC. More than 30% of patients with NSCLC experience disease progression during treatment with established EGFR TKIs due to the growth of synchronous or metachronous brain metastases (Ballard et al. 2016, Clin Cancer Res . 2016, 22(20):5130-5140 ). In addition, there is a cumulative increase in brain metastases over time in EGFR-mutated NSCLC patients (Rangachari et al. Lung Cancer 2015;88:108-11). Treatments for CNS metastases and brain metastases in NSCLC include surgical resection, stereotactic radiosurgery, and whole brain irradiation (WBRT). Although many patients die from systemic tumor progression rather than brain damage progression, their quality of life is significantly impaired both directly and as a result of whole brain irradiation (WBRT), which causes cognitive degradation (Li et al. Int J Radiat Oncol Biol Phys 2008;71:64-70). Therefore, there is a clinical need for new EGFR tyrosine kinase inhibitors (EGFR TKIs) with improved efficacy against central nervous system malignancies and brain lesions, while still eliciting effective and sustained responses in patients with EGFR-mutated NSCLC, including patients with initial brain metastases. It is also necessary to ensure a good quality of life for patients suffering from NSCLC, especially those patients who are at risk of developing brain metastases.

Brief description of the invention

Nazartinib is a compound of formula I, which is given below

(I)

which has the chemical name (R, E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazole-2 -yl)-2-methylisonicotinamide.

Nazartinib was shown to be clinically effective with good brain penetration in the treatment of patients with NSCLC, despite minimal brain distribution of nazartinib in a preclinical model. Therefore, patients treated with nazartinib may achieve a state of disease stabilization and slower disease progression than with standard therapies such as erlotinib or gefitinib. Thus, nazartinib may be of clinical benefit in NSCLC patients. The present invention provides an improved therapy for patients with NSCLC, for example, with locally advanced or metastatic NSCLC, who have been treated or not, and whose tumors are characterized by the presence of an activating EGFR mutation (L858R or ex19del). The present therapy may also be useful for preventing central nervous system (CNS) metastasis, brain metastasis, and leptomeningeal metastasis in patients suffering from NSCLC.

Thus, the present invention provides the following:

- a method of treating a patient with NSCLC, comprising selectively administering a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof to a patient who has previously been determined to have an EGFR mutation that is a deletion in exon 19 or a substitution (L858R) in exon 21;

- a method of treating a patient with NSCLC, comprising: (a) the process of determining or already carried out the determination of whether the patient has an EGFR mutation, which is a deletion in exon 19 or a substitution (L858R) in exon 21; and (b) administering a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof to said patient;

- a method of treating a patient with NSCLC, comprising selecting a patient for treatment based on the fact that the patient has previously been determined to have an EGFR mutation, which is a deletion in exon 19 or a substitution (L858R) in exon 21, and administration of a therapeutically effective amount of nazartinib or its pharmaceutical acceptable salt to the specified patient.

The patient may be an NSCLC patient whose cancer has progressed to a metastasis selected from central nervous system (CNS) metastasis, brain metastasis, and leptomeningeal metastasis. The metastasis is preferably a brain metastasis.

Thus, the present invention provides nazartinib or a pharmaceutically acceptable salt thereof, preferably a mesylate salt thereof, or a pharmaceutical composition containing such a compound, for use in the treatment or prevention of CNS metastasis, brain metastasis and/or prevention of leptomeningeal metastasis. In one embodiment, CNS metastasis, brain metastasis, or leptomeningeal metastasis is observed in a patient suffering from locally advanced or metastatic NSCLC. In a preferred embodiment, the patient suffers from metastatic NSCLC, where the NSCLC is optionally characterized by the presence of an EGFR mutation (deletions in exon 19 or substitution type mutations (L858R) in exon 21). Such a patient may also have progressed to CNS metastasis, brain metastasis, and/or leptomeningeal metastasis.

The present invention provides a compound that is nazartinib, or a pharmaceutically acceptable salt thereof, for use in treating or preventing metastasis in a patient, the metastasis being selected from central nervous system (CNS) metastasis, brain metastasis, and leptomeningeal metastasis, optionally metastasis is the result of a primary lesion, such as non-small cell lung cancer (NSCLC) in particular, in which the patient had a predetermined NSCLC, which is characterized by the presence of an EGFR mutation (deletion in exon 19 or replacement (L858R) in exon 21).

The present invention provides nazartinib, or a pharmaceutically acceptable salt thereof, for use in the treatment of NSCLC or for the prevention of NSCLC, wherein the patient has a metastasis, the metastasis being selected from central nervous system (CNS) metastasis, brain metastasis, and leptomeningeal metastasis, wherein the patient has NSCLC was predetermined, which is characterized by the presence of an EGFR mutation (deletion in exon 19 or substitution (L858R) in exon 21).

The present invention provides nazartinib, or a pharmaceutically acceptable salt thereof, preferably its mesylate salt, for use in the treatment of NSCLC, optionally locally advanced or metastatic NSCLC with activating EGFR mutations (e.g., L858R or ex19del) in a patient, for example, wherein:

there is an improvement in progression-free survival (PFS) of the patient, for example, compared with PFS, which was obtained after treatment with erlotinib or gefitinib; or

there is an improvement in the overall survival (OS) of the patient, for example, compared with OS, which was obtained after treatment with erlotinib, erlotinib or gefitinib; or

there is an improvement in the overall response rate (ORR) of the patient compared to the ORR obtained after treatment with erlotinib, erlotinib, or gefitinib; or

increased time to tumor progression (TPS) in the CNS or brain; or

increased CNS ORR or cerebral ORR; or

increases the duration of response to therapy (DoR) in the CNS or DoR in the brain;

including any combination of indicators (a)-(f)

As disclosed herein, nazartinib may provide a therapeutically beneficial effect selected from the group consisting of effects (a)-(f) above and any combination thereof.

In one preferred embodiment, nazartinib is used as monotherapy for the treatment of EGFR-mutated NSCLC. In another preferred embodiment, nazartinib is used in combination therapy for the treatment of EGFR-mutated NSCLC, e.g., for the treatment of patients with advanced EFGR-mutated NSCLC, including patients with brain metastases, where the patients have not previously received treatment.

In particular, nazartinib as monotherapy may be useful for

providing long-term benefit to patients suffering from NSCLC, for example, previously untreated patients with locally advanced or metastatic tumors of NSCLC, which is characterized by the presence of activating mutations in EGFR;

providing an increase in time to tumor progression in the CNS or brain, ORR in the CNS or brain, and DoR in the CNS or brain, as determined by the central neuroradiological BIRC according to modified RECIST 1.1 for patients with CNS disease or brain lesions on baseline;

improvement in patient-rated outcomes (PRO), including disease-related symptoms and health-related quality of life (HRQoL), especially when compared with erlotinib or gefitinib, improved safety profile and tolerability of nazartinib monotherapy, e.g. compared to erlotinib or gefitinib;

or any combination of the above benefits.

In another embodiment, nazartinib is used in combination with another anticancer drug.

Thus, it is an object of the present invention to provide a therapeutic agent for improving the treatment of cancer, in particular non-small cell lung cancer (NSCLC), more specifically EGFR-mutated NSCLC. In particular, it is an object of the present invention to provide a safe and tolerable treatment that prevents or delays the onset or progression of CNS metastasis, more specifically brain metastasis. As described herein, nazartinib was tolerable with an acceptable safety profile in EGFR-mutated NSCLC patients with increased time to tumor progression in the CNS or brain, increased ORR in the CNS or brain, and increased DoR in the CNS or brain. brain as determined by the central neuroradiological BIRC according to modified RECIST 1.1 for patients with CNS disease at baseline.

Detailed description of graphic materials

Figure 1: Phase I Study Design

Detailed description of the invention

In one aspect, the present invention provides a pharmaceutical composition comprising nazartinib, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a metastasis selected from CNS metastasis, brain metastasis, and leptomeningeal metastasis.

In one embodiment, nazartinib is in the form of a mesylate salt.

In a preferred embodiment, CNS metastasis or leptomeningeal metastasis is present in a patient suffering from locally advanced or metastatic NSCLC.

In one embodiment, the tumor is characterized by the presence of an activating EGFR mutation, preferably an L858R mutation and/or an ex19del mutation.

In one embodiment, the patient is an NSCLC patient with a T790M EGFR mutation who has experienced progression of CNS metastasis and/or leptomeningeal metastasis.

In another aspect, the present invention provides nazartinib, or a pharmaceutically acceptable salt thereof, preferably its mesylate salt, for use in the treatment of NSCLC, optionally locally advanced or metastatic NSCLC with activating EGFR mutations (e.g., L858R or ex19del) in a patient, wherein:

there is an improvement in the patient's progression-free survival (PFS), for example, compared to the PFS that was obtained after treatment with erlotinib or gefitinib, or it is comparable to the PFS that was obtained after treatment with erlotinib or gefitinib. PFS can be measured using a Central Blind Independent Rating Committee (BIRC) according to the Criteria for Response Evaluation in Solid Tumors (RECIST 1.1)

there is an improvement in the overall survival (OS) of the patient, for example, compared to OS that was obtained after treatment with erlotinib or gefitinib, or it is comparable to the PFS that was obtained after treatment with erlotinib or gefitinib, or

there is an improvement in the overall response rate (ORR as measured by the central BIRC) of the patient compared to the ORR that was obtained after treatment with erlotinib or gefitinib, or it was comparable to the ORR that was obtained after treatment with erlotinib or gefitinib, or

there is an increase in time to tumor progression in the central nervous system (CNS) (for example, compared with standard of care or after treatment with erlotinib, gefitinib, or osimertinib), or

there is an increase in CNS ORR (CNS ORR can be measured by central neuroradiological BIRC), for example, in patients with brain metastases who have a measurable brain tumor at baseline according to modified RECIST 1.1, or

there is an increase in the duration of CNS response to therapy (DoR) (eg, as assessed by the central neuroradiological BIRC; for example, DoR in the CNS in patients with brain metastases who have a measurable tumor in the brain at baseline according to modified RECIST 1.1).

As disclosed herein, nazartinib as monotherapy may provide a therapeutically beneficial effect selected from the group consisting of effects (a)-(f) above and any combination thereof. In addition, nazartinib may provide an improved treatment option with fewer side effects compared to treatment with gefitinib, erlotinib, or osimertinib.

In one embodiment, nazartinib is used as monotherapy. In another embodiment, nazartinib is used in combination with another anticancer drug.

Nazartinib

Nazartinib and its pharmaceutically acceptable salts are described in WO2013/184757.

Nazartinib is also known under the code name “EGF816”. As used herein, the terms "nazartinib" or "EGF816" refer to a compound of formula (I) or a pharmaceutically acceptable salt thereof, unless otherwise indicated herein or where there is a clear conflict of context.

Nazartinib is a targeted, covalent, irreversible epidermal growth factor receptor (EGFR) inhibitor that selectively inhibits activating and acquired resistance mutations (L858R, ex19del, and T790M) while being sparing of wild-type (WT) EGFR (Jia et al, Cancer Res October 1, 2014 74; 1734). Nazartinib has shown significant efficacy in EGFR mutant cancer models (L858R, ex19del and T790M) (in vitro and in vivo) with no inhibition of WT EGFR at clinically significant effective concentrations. Dose-dependent antitumor efficacy was observed in several xenograft models, and nazartinib was well tolerated without the body weight loss seen at effective doses.

Nazartinib was found to exhibit long-term antitumor activity in a clinical trial in patients with advanced non-small cell lung cancer (NSCLC) carrying the T790M mutation (Tan et al, Journal of Clinical Oncology 34, no. 15_suppl (May 2016)).

Pharmaceutical compositions containing nazartinib or a pharmaceutically acceptable salt thereof are described in WO2013/184757, which are incorporated herein by reference in their entirety. Nazartinib, or a pharmaceutically acceptable salt thereof, may be administered as an oral pharmaceutical composition in the form of a capsule or tablet formulation. Pharmaceutically acceptable salts of nazartinib include the mesylate salt and its hydrochloride salt. The preferred pharmaceutically acceptable salt is the mesylate salt.

It is contemplated that nazartinib may be particularly useful for patients who have not previously received treatment, ie. patients who have not received any prior NSCLC therapy, such as advanced NSCLC. Patients “previously untreated” include patients who have not previously received any systemic anticancer therapy for advanced disease, including chemotherapy, biologic therapy, immunotherapy, or any experimental therapy. The term also describes patients who have previously received neoadjuvant or adjuvant systemic therapy who relapsed more than 12 months after the end of neoadjuvant or adjuvant systemic therapy, whichever was later. It is also assumed that such patients include patients who have not been treated with third generation TKI EGFR.

Thus, the present invention also provides a compound for use and a composition as described herein for use in the treatment of first line non-small cell lung cancer, including NSCLC with an EGFR mutation (eg, NSCLC with a deletion in exon 19 or with an L858R mutation).

The present invention also provides for the use of nazartinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the first line treatment of non-small cell lung cancer, including non-small cell lung cancer with an EGFR mutation (e.g., exon 19 deletion NSCLC or L858R mutation).

Patients who may benefit from the uses, pharmaceutical compositions, and therapeutic regimens provided herein also include pretreated patients, for example, patients who have received prior treatment with first generation TKI EGFR and/or second generation TKI EGFR.

Patients who may benefit from the present invention also include patients who have been screened for HBV and HCV infections and found to be free of such infections, or who are treated concomitantly with antiviral treatment. For example, patients who test positive for HBsAg or who test positive for HBV DNA can take antiviral therapy (eg, entecavir or tenofovir) for at least 1 week prior to the first dose of nazartinib treatment and continue antiviral therapy. therapy for at least 4 weeks after the last dose of nazartinib.

Tumor burden (also called “tumor mass”) refers to the number of cancer cells, the size of the tumor, or the extent of the cancer in the body. A subject suffering from cancer is defined as having disease progression or cessation of response to therapy with one or more agents, or intolerance to one or more agents, while the cancer he or she suffers from has progressed, i.e., tumor burden has increased. Progression of a cancer, such as NSCLC, or tumors, may be indicated by the detection of new tumors, or the detection of metastases, or the cessation of tumor shrinkage. Cancer progression and assessment of increase or decrease in tumor burden can be monitored by methods well known in the art. For example, progression can be monitored by imaging the cancer, such as by X-ray, CT scan, or MRI, or by detecting tumor biomarkers. Increased cancer growth may indicate cancer progression. The tumor burden score can be determined by the percentage change from baseline in the sum of target lesion diameters. The assessment of tumor burden, which determines the decrease or increase in tumor burden, is usually carried out at various time intervals, for example, in successive assessments carried out at least 1, 2, 3 months, preferably with an interval of one month.

Tumor examinations and assessment of tumor burden can be performed based on the RECIST criteria (Therasse et al 2000), New Guidelines to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European Journal of Cancer; 45:228-247.

The pharmaceutical composition disclosed herein is particularly useful in the treatment of non-small cell lung cancer (NSCLC). The most common types of NSCLC are squamous cell lung cancer, large cell carcinoma, and adenocarcinoma of the lung. Less common types of NSCLC include pleomorphic carcinoid tumor, salivary gland sarcoma, and unclassified sarcoma. NSCLC, and in particular lung adenocarcinoma, can be characterized by abnormal EGFR activation, in particular EGFR amplification or somatic mutation of EGFR.

Thus, lung cancers to be treated include EGFR-mutated NSCLCs. Nazartinib or a pharmaceutical composition containing nazartinib or a pharmaceutically acceptable salt thereof is expected to be useful in the treatment of late stage NSCLC with EGFR mutation. Late stage NSCLC is mentioned in relation to patients with either locally advanced or metastatic NSCLC. Locally advanced NSCLC is defined as stage IIIB NSCLC that is not amenable to complex treatment, including surgery. Metastatic NSCLC refers to stage IV NSCLC.

EGFR mutation status can be determined using tests available in the art, such as the QIAGEN therascreen® EGFR test, or other FDA-approved tests. The therascreen RGQ EGFR PCR Assay Kit is an FDA-approved qualitative real-time PCR assay for the detection of specific mutations in the EGFR oncogene. Evidence of an EGFR mutation can be obtained from available local data and testing of tumor samples. EGFR mutation status can be determined using any available tumor tissue.

Nazartinib may be particularly useful for the treatment of NSCLC that contains an EGFR L858R mutation, a deletion in EGFR exon 19, or both. The NSCLC to be treated may also contain an additional T790M EGFR mutation, which may be a de novo mutation or an acquired mutation.

In one embodiment, the T790M EGFR mutation is a de novo mutation. The term “ de novo mutation” as used herein refers to a change in a gene that is detectable or detected in an individual prior to initiation of any treatment with an EGFR inhibitor. A de novo mutation is a mutation that usually results from an error in copying genetic material or an error in cell division, for example, a de novo mutation may result from a mutation in the germ cell (egg or sperm) of one of the parents or in the fertilized egg itself, or the result of a mutation occurring in a somatic cell.

A de novo T790M mutation is defined as the presence of a T790M EGFR mutation in NSCLC patients who have not previously been treated with any therapy known to inhibit EGFR.

In another aspect, the present invention provides a pharmaceutical composition comprising nazartinib and at least one pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterials, antifungals), isotonics, absorption delay agents, salts. , preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavors, colors, buffering agents (for example, maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc. . p.), etc., as well as combinations thereof, which are known to specialists in the art (see, for example, Remington's Pharmaceutical Sciences). Unless any conventional carrier is incompatible with nazartinib, its use in pharmaceutical compositions or medicaments is contemplated.

Examples of pharmaceutical compositions containing nazartinib or a pharmaceutically acceptable salt thereof are described in WO2013/184757.

Dosages

The dosages or doses given herein, unless expressly stated otherwise, refer to the amount of nazartinib present in the drug product, based on the free base.

When nazartinib is administered as monotherapy or as part of a combination therapy, the dose of nazartinib may be selected from the range of about 50 to about 200 mg, more preferably from the range of about 50 to about 150 mg. Nazartinib can be administered at a dose of about 25, about 50, about 75, about 100, or about 150 mg once daily. Thus, nazartinib can be administered at a dose of about 50, about 75, about 100, or about 150 mg once daily; more preferably about 50, about 75 or about 100 mg once a day. Doses of about 50, about 75, or about 100 mg may be better tolerated without loss of efficacy. In a preferred embodiment, nazartinib may be administered at a dose of about 100 mg or about 150 mg once daily. Hepatitis reactivation is not expected to occur at a dose of approximately 150 mg or less daily.

The term "effective amount" or "therapeutically effective amount" of a therapeutic agent is defined herein to mean an amount sufficient to provide a marked improvement over baseline clinically observable signs and symptoms of cancer treated with that therapeutic agent.

The definition of achieving a stable disease response state can be determined using criteria for evaluating the response of solid tumors to therapy (RECIST 1.1) or WHO criteria. Stabilized disease response (SD) can be defined as a response in which the target lesions show neither sufficient volume loss consistent with partial response (PR) nor sufficient expansion consistent with progressive disease (PD), with the reference being the smallest sum of the longest diameter (LD) of the target lesions since the start of treatment. Other response criteria can be defined as follows.

Complete response (CR): disappearance of all target lesions.

Partial Response (PR): At least a 30% reduction in the sum LD of the target lesions, with the original sum LD taken as a reference.

Progressive disease (PD): an increase of at least 20% in the sum of LD of the target lesions, with the lowest sum of LD recorded since the start of treatment or the appearance of one or more new lesions as a reference.

Thus, a person skilled in the art can easily determine the period of treatment during which an EGFR inhibitor should be administered as monotherapy or as part of a combination therapy. The treatment period may consist of one, two, three, four, five, six or more 14-day, 21-day, 28-day or 35-day cycles, preferably two or three cycles. The cycles are preferably 21 day or 28 day cycles.

Definitions

The term “pharmaceutically acceptable salt” refers to a salt that retains the biological efficacy and properties of the compound and that is generally not biologically or otherwise undesirable. The compound may be capable of forming acid addition salts due to the presence of an amino group.

Singular forms and like forms in the context of the description of the present invention (in particular, in the context of the following claims), should be construed to cover both the singular form and the plural form, unless otherwise indicated in this document or there is no clear conflict of context. . If the plural form is used for compounds, salts, etc., it also means one compound, salt, or the like.

The term “approximately” refers to the statistically acceptable variation in a given value and is typically +/- 5% or 10%. On the other hand, when a numerical value is given that is not accompanied by the term "approximately", it will be understood that the numerical value will include variation of that value that is statistically acceptable in the art.

The terms "treat", "treatment", and "treatment" are defined herein to mean treatment that provides relief, reduction in intensity or weakening of at least one symptom in a subject or delays the progression of a disease. For example, the treatment may be the reduction of the intensity of one or more symptoms of the disease or the complete elimination of the disease, such as cancer. In the context of the present invention, the terms “treat”, “treatment”, and “optimized treatment” also mean one or more of the following: improvement in PFS, improvement in OS, ORR, increase in time to tumor progression in the CNS or in the brain, increase in ORR, and/ or DoR in the CNS or in the brain, especially when compared with treatment with gefitinib and/or erlotinib.

The term "subject" or "patient" as used herein refers to a human suffering from cancer, preferably lung cancer, such as NSCLC, in particular EGFR-mutated NSCLC.

As used herein, the terms “select”, “selection”, and “selected”, when used in relation to a patient, mean that a particular patient is specifically selected from a larger group of patients based on (due to) that a particular patient meets predetermined criteria. Similarly, "selective treatment" refers to providing treatment to a patient having a particular disease, where that patient is specifically selected from a larger group of patients based on the fact that the particular patient meets a predetermined criterion. Similarly, "selective administration" refers to the administration of a drug to a patient that is specifically selected from a larger group of patients based on (due to) that the particular patient meets a predetermined criterion. By selection, selective treatment, and selective administration, it is meant that a patient is provided with personalized therapy based on the patient's personal history (e.g., previous therapeutic interventions, e.g., previous treatment with biologics), biology (e.g., specific genetic markers), and/or manifestation (for example, non-compliance with certain diagnostic criteria), instead of using a standard treatment regimen based solely on the patient's belonging to a larger group. Selection, in relation to a method of treatment in the context of this document, does not refer to the occasional treatment of a patient meeting a particular criterion, but rather refers to an informed decision regarding the administration of a drug to a patient based on the fact that the patient meets a particular criterion. Thus, selective treatment/administration differs from standard treatment/administration, which delivers a particular drug to all patients with a particular disease, regardless of their personal history, disease manifestations, and/or biology.

The term “determining” refers to performing a test, procedure, experiment, study, assay, etc. to determine the presence (or absence) of a present marker, such as a biomarker or genetic mutation, such as an EGFR mutation that is T790M, a deletion in exon 19 or a substitution (L858R) in exon 21, in a biological sample (eg, a sample from a tumor metastasis) taken from a patient.

The phrase “making a determination” refers to fulfilling a request from a third party (e.g., laboratory, hospital, nurse, doctor) to perform or provide the results of a test, procedure, experiment, study, analysis, etc. that determines the presence (or absence) of a given a marker, such as a biomarker or a genetic mutation, such as an EGFR mutation, which is a T790M mutation, a deletion in exon 19, or a substitution (L858R) in exon 21, in a biological sample (for example, a sample from a tumor metastasis) taken from a patient.

The expression “has been previously determined” refers to the status (eg, genetic status, patient characteristics, biomarker status, etc.) of a given patient that has already been established in the past by some party (third party or otherwise).

The term "monotherapy" as used herein refers to the use of nazartinib (as the free base or a pharmaceutically acceptable salt thereof) as the sole drug for the treatment of a disease or condition. Thus, the term "monotherapy" as used herein does not include the use of nazartinib with another therapeutic agent.

The terms "combination therapy" or "combination" and the like are not intended to imply that the therapy or therapeutic agents must be physically mixed or administered at the same time and/or formulated for co-delivery, although these delivery methods are within scope described in this document. The therapeutic agent in these combinations can be administered simultaneously with, before or after one or more additional therapies or therapeutic agents. Therapeutic agents or therapeutic protocol can be applied in any order. Typically, each agent will be administered at a dose and/or time schedule that is determined for that agent. It should also be understood that the additional therapeutic agent used in this combination may be administered together in the same composition or administered separately in different compositions. In general, it is expected that additional therapeutic agents used in combination will be used at levels that do not exceed the levels at which they are used separately. In some embodiments, the levels used in combination will be below the levels used for monotherapy drugs.

PFS is defined as the time from the date of randomization to the date of first documented disease progression or death from any cause, whichever comes first. PFS is usually assessed through local verification in accordance with RECIST 1.1.

Locally validated PFS can be analyzed using a stratified Cox model with the same analysis rules as in the primary effectiveness analysis. The PFS distribution is usually estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals of the medians will be presented for each treatment group. The hazard ratio for PFS will be calculated along with a 95% confidence interval using a stratified Cox model. An analysis of the correspondence of PFS between local validation and centralized BICR validation can be done by treatment group.

PFS obtained after treatment with erlotinib, gefitinib, or osimertinib can be between 9 and 10 months, such as 9.7, 9.5 months, and 10.2 months, respectively.

ORR is defined as the proportion of patients with BOR (best overall response to therapy) from groups with CR (complete response) or PR (partial response), according to the BIRC central review and according to RECIST 1.1. The ORR is calculated based on the FAS and according to the ITT (Treatment Intended Population) principle.

The BOR for each patient is determined from a sequence of overall responses (lesions) according to the following rules:

CR = at least two CR determinations at least 4 weeks apart before disease progression.

PR=at least two PR measurements or better at least 4 weeks apart before progression (and does not meet criteria for CR).

SD = at least one SD score (or better) > 6 weeks after randomization (and does not meet CR or PR criteria).

PD=progression ≤ 12 weeks after randomization (and does not meet CR, PR, or SD criteria). The ORR and its 95% confidence interval can be presented by treatment group.

As a supporting analysis, the above analysis can be performed using investigators' estimates. An analysis of the BOR correspondence between the local check and the central BICR check can be done by treatment group.

CNS ORR or brain ORR refers only to patients with measurable brain disease at baseline as assessed by the central neuroradiological BIRC according to modified RECIST 1.1. CNS ORR or Brain ORR is defined as the proportion of patients with the best overall response, which is either CR or PR in the brain.

DCR (disease control rate) is defined as the proportion of patients with a confirmed best overall response (BOR), which is CR, PR or SD. CR, PR and SD are determined according to the BIRC central check, according to RECIST 1.1. DCR can be calculated based on FAS and according to the ITT principle. The DCR and its 95% confidence interval can be presented by treatment group.

As a supporting analysis, the above analysis can be performed using investigators' estimates.

TTR (Time to Response Development) is defined as the time from the date of patient randomization to the first documented response (CR or PR to be subsequently confirmed). CR and PR are based on tumor response data according to the BIRC central review, according to RECIST 1.1. All patients included in the FAS (Full Analysis Population) are included in the TTR calculations. Data from patients without confirmed CR or PR will be censored during the maximum follow-up period (i.e. LPLV-FPFV) for patients with PFS event (i.e. disease progression or death from any cause) or relative to the date of the last adequate tumor evaluation for patients without PFS phenomenon. TTRs can be listed and summarized by treatment group. The TTR distribution is estimated using the Kaplan-Meier method. For each treatment group, medians and 95% confidence intervals of the medians can be presented.

Time to tumor progression (TTP) is the time from the date of randomization/treatment initiation to the date of the event, defined as the first documented disease progression or death from underlying disease, i.e. cancer. If the patient did not have the specified event, the time to tumor progression is estimated relative to the date of the last adequate tumor evaluation. Time to tumor progression in the CNS or brain is defined as the time from the date of randomization to the date of the first documented progression of brain metastases as assessed by the central neuroradiological BIRC according to modified RECIST 1.1 in FAS patients with at least one unmeasurable and/or measurable brain tumor at baseline.

Analysis of time to disease progression in the CNS or in the brain, ORR in the CNS, ORR in the brain, DoR in the brain, and DoR in the CNS is performed in the same manner as described above for PFS, ORR, and DoR, respectively. Stratification can be based on stratification randomization factors, ie race (Asian versus non-Asian) and EGFR activating mutation type (L858R versus ex19del).

DoR (Duration of Response to Therapy) is only applicable to patients whose best overall response is CR or PR according to RECIST 1.1 based on BIRC centralized tumor response data. The start date is the date of the first documented response (CR or PR) and the end date is defined as the date of the first documented progression or death from the underlying disease, i.e. cancer, whichever occurs first. Patients who have not experienced disease progression or death due to underlying cancer are censored for the date of their last adequate tumor evaluation. DoRs can be listed and summarized by treatment group for all FAS patients with confirmed BOR, which is CR or PR.

The DoR distribution can be estimated using the Kaplan-Meier method. For each treatment group, medians and 95% confidence intervals of the medians can be presented.

DoR in the CNS or DoR in the brain applies only to patients with measurable brain disease at baseline and whose best overall response in the CNS or brain was a CR or PR according to modified RECIST 1.1 based on tumor response data according to centralized verification of neuroradiological BIRC. The start date is the date of the first documented response (CR or PR) in the brain, and the end date is defined as the date of the first documented tumor progression in the brain. Data from patients who have not experienced tumor progression in the brain are censored for the date of their last adequate tumor evaluation.

The Clinical Benefit Rate (CBR) is the proportion of patients with the best overall response, which is CR or PR, or an overall response associated with SD or Non-CR/Non-PD lesions, lasting a minimum period of time (default in studies breast cancer, a period of at least 24 weeks is used). This endpoint measures the signs of disease activity given its duration of disease stabilization.

PFS2: A recent EMA guideline (EMA 2012) recommends using an alternative endpoint intermediate between PFS and OS, called “PFS2”, a surrogate for OS, when OS cannot be measured reliably, allowing the impact of experimental therapy on next line treatment to be assessed . The main purpose of this endpoint is to evaluate long-term maintenance strategies, in particular with the use of re-sensitizing agents, and also in cases where it is necessary to study the overall “field of influence”.

PFS2, which may be referred to as “delayed PFS”, “delayed PFS”, “tandem PFS”, or “PFS version 2.0”, is the time from the date of randomization/treatment initiation to the date of the event defined as the first documented disease progression on the next line of treatment or death from any cause. The rules for censoring this endpoint include the same principles as for PFS.

Determine the response of target lesions

Complete response (CR) is defined as the disappearance of all non-nodular target lesions. In addition, any pathological lymph nodes designated as target lesions should have short-axis reduction to < 10 mm. SOD at CR may be non-zero if nodular lesions are part of the target lesions.

Partial response (PR) is defined as a reduction of at least 30% in the sum of diameters of all target lesions, with the original sum of diameters taken as a reference.

Progressive disease (PD) is defined as an increase of at least 20% in the sum of the diameters of all measured target lesions, with the minimum sum of the diameters of all target lesions recorded before or after the patient entered the study as a reference. In addition to a relative increase of 20%, the sum must also show an absolute increase of at least 5 mm. After baseline CR, PD cannot be established if all nonnodular target lesions are still absent and all nodular lesions are <10 mm in size. In this case, the response of the target lesions is CR.

Stable disease (SD) is defined as the absence of sufficient volume loss consistent with PR or CR, and no enlargement of lesions that would be consistent with PD.

Unknown (UNK) is defined as a situation in which no progression has been documented and none or more of the target lesions have been assessed using any method other than baseline. In exceptional cases, a UNK response due to a method change may be rejected by the investigator or the central reviewer using peer review based on available information.

Determining the response of non-target lesions

CR is defined as D=disappearance of all non-target lesions. In addition, all lymph nodes with non-target lesions should be non-pathologic in size (short axis < 10 mm).

PD is defined as the unambiguous development of existing non-target lesions. Estimation of PD based solely on the change in non-target lesions given the target lesion's response to CR, PR, or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer shall prevail.

Unknown (UNK) is defined as a situation in which no progression has been documented and none or more of the non-target lesions have been assessed using any method other than baseline. It is recommended that the investigator and/or the central reviewer use peer review to assign a response other than UNK whenever possible (see the notes section for more details).

Disease progression in the brain can be defined as a new brain lesion, worsening of the original non-target brain lesion, or an increase of ≥20% in the sum of the longest diameters of the original target brain lesion.

The following examples illustrate the present invention as described above, but are not intended to limit the scope of the present invention in any way. With the help of other test models known to the person skilled in the art, it is also possible to determine the beneficial effects of the claimed invention.

Examples

Example 1: Phase I, Multicentre, Open-Label Trial of Nazartinib (EGF816) in Adult Patients with NSCLC with EGFR Mutation

Acquired resistance to tyrosine kinase inhibitors (TKIs) of the first-generation epidermal growth factor receptor (EGFR) T790M due to a gatekeeper gene mutation occurs in 50-60% of treated non-small cell lung cancer (NSCLC) patients. Nazartinib (EGF816), a third-generation TKI EGFR that is selective for both activating and T790M mutations while being sparing of wild-type EGFR, was evaluated in patients with advanced NSCLC characterized by the presence of an EGFR mutation. .

Patients had stage IIIB/IV NSCLC with EGFR mutation, ≥1 measurable lesion, and Eastern Joint Cancer Group General Condition ≤2. Patients were screened for study eligibility with six subgroups according to EGFR mutation status and prior therapy, and were treated with nazartinib 75-350 mg (capsule or tablet) orally once a day (QD), on a continuous basis. 28 day dosing schedule. The main goal of phase I, which is part of the study, was to determine the maximum tolerated dose and/or the recommended phase II dose (RP2D).

By August 2017, 180 patients were treated with nazartinib through seven dose levels. Nazartinib appeared to be tolerable with an acceptable safety profile in EGFR-mutated NSCLC patients. The best overall dose response rate, based on 162 evaluable T790M EGFR positive tumor patients who were not treated with third-generation TKI EGFR, was 51% (95% CI: 43-59) with a median duration of response to therapy amounting to 11.0 months. The median progression-free survival (PFS) was 9.1 months (95% CI: 7.3-11.1). Clinical benefit was seen in the majority of patients treated with nazartinib, with an overall disease control rate of 89% in patients with T790M EGFR positive tumors who were not treated with third-generation TKI EGFR. Of 162 such patients, 45 patients (28%) had brain metastases reported as non-target lesions at baseline, and seven (16%) of these patients experienced regression of brain lesions while taking study drug. These data demonstrate the clinically significant antitumor activity of nazartinib, including in the brain, in EGFR-mutated NSCLC patients.

Therefore, given the limited treatment options available for patients with advanced NSCLC with an EGFR mutation, nazartinib may provide an effective treatment option in these conditions.

Ways

Study plan

A multicentre, open-label phase I/II study of nazartinib was conducted in patients with locally advanced/metastatic EGFR-mutated NSCLC.

Nazartinib was administered orally once daily (QD) on a continuous 28-day cycle schedule. The starting dose for the Phase I part of the study was 75 mg in encapsulated form. Nazartinib tablet formulation was also administered during phase I. Patients were treated in the following QD dosage groups: 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, 300 mg, and 350 mg. Initial cohorts consisted of 1-6 patients.

Statistical analyzes

Patients receiving capsules or tablets at the same dose level were pooled into a single group for safety and efficacy analysis. The complete analysis population (FAS) consists of all patients who received ≥1 dose of study drug. Efficacy analyzes were performed in all patients in the FAS for whom baseline and post-baseline tumor assessment data were available, or in those patients who discontinued treatment prior to post-baseline tumor assessment and patients with wild-type T790 EGFR tumors were excluded. type or who have received prior treatment with third-generation TKI EGFR, unless otherwise noted.

Duration of response to therapy (DoR) and PFS were described using the Kaplan-Meier method. This study presents data from 180 patients who were included in the dose escalation phase of the Phase I trial.

results

At the end date of data collection 31 August 2017, 180 patients were enrolled in the study and were treated with nazartinib at seven QD dose levels in tablet or capsule formulation (75 mg [n=17], 100 mg [n =38], 150 mg [n=73], 200 mg [n=8], 225 mg [n=28], 300 mg [n=5], and 350 mg [n=11]).

Recommended dose

The 150 mg QD (once daily) dose level was well tolerated and demonstrated good antitumor efficacy, with an ORR of 46%. Based on these observations, a dose of 150 mg QD was selected as the recommended dose for phase II (RP2D).

Other doses of nazartinib, as described above, may also be applicable in the present invention.

Discussion

In this study, nazartinib demonstrated clinical activity in NSCLC patients with the T790M EGFR mutation, with clinical benefit achieved in the majority of patients at all dose levels. Nearly half of all evaluable patients achieved an objective response, and the DCR was 87%. The median duration of response to therapy was 11.0 months, which is comparable to the 9.7 months average duration of response to therapy that was reported in NSCLC patients with T790M ⁺ EGFR who were treated with osimertinib in the phase III AURA3 study (Mok et al. , N Engl J Med 2017;376:629-40). A median PFS of 9.1 months with nazartinib was also similar to a median PFS of 10.1 months with osimertinib AURA3 (Mok et al. N Engl J Med 2017; 376: 629-40 ).

Similar responses were observed in patients regardless of whether their last prior systemic therapy was EGFR TKI therapy, suggesting that the observed efficacy could hardly be attributed to a "retreatment effect". Clinical activity in patients with T790M ⁺ , ex19del EGFR mutations was higher than in patients with T790M ⁺ , L858R EGFR mutations for both ORR and PFS, although in the latter case the difference was not statistically significant. Differential activity of EGFR TKIs with respect to ex19del and L858R mutations has been previously reported, albeit inconsistently (Zhang et al. PLoS One 2014;9:e107161; Yu et al. Chin J Cancer 2016; 35:30,016-0086-2; Lin et al. Eur Respir J 2016;48: PA4837). Other concomitant changes found had little effect on the quality of response to nazartinib.

The AURA3 study reported efficacy of osimertinib in patients with CNS metastases, with a hazard ratio for PFS comparable to the general population (0.32 [95% CI, 0.21-0.49] vs. 0.30 [ 95% CI, 0.23-0.41] respectively) (Mok et al. N Engl J Med 2017; 376: 629-40). The lack of CNS activity with rociletinib may have contributed to the reduction in confirmed response rates reported in the full Phase I/II study data. Rociletinib demonstrated an initial ORR of 59% in NSCLC patients with the T790M EGFR mutation who had disease progression in response to prior EGFR TKI treatment (Sequist et al. N Engl J Med 2015; 372 : 1700-9 ); however, a later analysis of the full data showed a 28-45% reduction in confirmed response rates (Sequist et al. N Engl J Med 2016; 374: 2296-7; Business Wire. Clovis Oncology announces regulatory update for rociletinib NDA filing. November 16, 2015: world wide web.

businesswire.com/news/home/20151116005513/en/). The authors suggested that early brain metastases may underlie the failure to confirm initial responses to therapy (Sequist et al. N Engl J Med 2016; 374: 2296-7). Following this suggestion, Clovis Oncology discontinued clinical development of rociletinib (OncLive. Clovis Ends Development of Rociletinib in Lung Cancer. May 06, 2016: world wide web

://global.onclive.com/web-exclusives/clovis-ends-development-of-rociletinib-in-lung-cancer). In contrast, none of the T790M ⁺ EGFR mutated NSCLC patients treated with nazartinib in this study experienced tumor progression in the brain alone, and 14% of patients with baseline brain lesions experienced regression of these lesions during time of treatment with nazartinib. These data suggest that nazartinib has a clinically significant antitumor effect on lesions in the brain.

Nazartinib was generally well tolerated; most drug-related adverse events were of mild or moderate severity. Six patients experienced DLT at doses of 150 mg QD and above. The most common adverse events were rash, diarrhea, and itching; similar to those seen with other third-generation EGFR TKIs such as osimertinib and olmutinib (Mok et al.N Engl J Med 2017; 376:629-40; Park et al.J Thorac Oncol 2016; 11(4 Suppl): S113.0864(16)30243-X. Epub 2016 Apr 15). Rash was the most common adverse event thought to be drug-related. The rash that occurs after nazartinib treatment is distinct from the acne/pustular rash that is often associated with EGFR TKI treatments that target EGFRwt. The rash following nazartinib treatment was predominantly a finely dispersed maculopapular rash, usually acute and self-limiting, occurring within the first 4-6 weeks of treatment. This type of rash responded to systemic antiallergic treatment and/or dose interruption or dose reduction and rarely recurred.

Two patients treated with nazartinib experienced HBV reactivation, both of whom were treated with 225 mg QD, resulting in liver failure and death in one patient. The exact mechanism of viral reactivation in these patients is not known, but may be due to the inhibitory effect of nazartinib on Tec family kinases such as Bruton's tyrosine kinase (BTK). Reactivation of viral hepatitis has been reported in combination with other antitumor therapies. Since the introduction of screening, monitoring, and treatment algorithms for HBV and HCV, no additional cases of HBV reactivation have been reported in this study.

In addition, the observed favorable safety profile, efficacy achieved at all dose levels tested, and the selectivity of nazartinib for mutant EGFR over wild-type EGFR also indicate that there may be a sufficient therapeutic window to allow nazartinib to be combined with other anticancer agents. with acceptable tolerance. Such combined approaches are likely to be needed to overcome TKI resistance such as MET amplification, a common mechanism for first and third generation TKI EGFR resistance (Squist et al. Sci Transl Med 2011; 3:75ra26; Piotrowska et al. J Clin Oncol 2017; 35: (suppl; abstr 9020); Oxnard et al. AACR Annual Meeting 2017; (abstr. 4112/22)). A separate study of nazartinib in combination with the MET inhibitor capmatinib (Phase I/II; NCT02335944) is currently ongoing in EGFR-mutated NSCLC patients. Additional combinations may also be investigated clinically to prevent or delay the onset of treatment resistance in patients with advanced NSCLC with an EGFR mutation.

Clinical activity in patients with brain metastases at baseline

Patients with asymptomatic and/or previously treated stable brain metastases were allowed to participate in this study. Of 162 T790M EGFR positive NSCLC patients who were not treated with third-generation TKI EGFR, 46 (28%) had brain metastases at baseline. In 45 (98%) of these patients, brain lesions were recorded only as non-target lesions. In seven of these 45 patients (16%), non-target brain lesions became radiologically undetectable during treatment (1/9, 3/23, and 3/9 patients in the nazartinib 100 mg, 150 mg, and 225 mg groups, respectively ). One such case was a 69-year-old Asian male with NSCLC with ex19del/T790M EGFR mutations, who had previously been treated with gefitinib and afatinib. At baseline, he had numerous small brain metastases and had not previously received topical brain-targeting therapy. After treatment with nazartinib, the patient achieved an overall partial response lasting 11.1 months, and brain metastases were no longer detected radiographically at the first evaluation after baseline.

After a median follow-up of 29.6 months (all patients) and 29.2 months (patients with brain metastases at baseline), 118/162 of all patients (73%) and 33/46 (72%) of patients with brain metastases at baseline, disease progression was observed. Of the 118 patients who experienced disease progression, only 19 (16%) had tumor progression in the brain, and only 12 (10%) had tumor progression in the brain without documented simultaneous progression outside the brain (five of these patients, brain metastases were at baseline).

Tables: Brain Metastasis Summary-Population for Complete Analysis

75 mg EGF816 QD N=12 n= (%) 100 mg EGF816 QD N=34 n= (%) 150 mg EGF816 QD N=68 n= (%) Number of patients with brain metastases at baseline 1 (8.3) 10 ( 29.4) 23 ( 33.8) Number of patients with brain metastases in non-target lesions noted only at baseline 1 (100.0) 9 (90.0) 23 (100.0) Number of patients with brain metastases in target lesions noted only at baseline 0 (0.0) 1 ( 10.0) 0 (0.0) Number of patients with brain metastases in both non-target and target lesions at baseline 0 (0.0) 0 (0.0) 0 (0.0) Number of patients with brain metastases at baseline who developed new brain metastases 0 (0.0) 1 ( 10.0) 1 (4.3) Best Response of Non-Targeted Brain Lesions# Missing/Normalized 0 (0.0) 1 ( 11.1) 3 ( 13.0) Present 1 (100.0) 8 (88.9) 16 (69.6) Deterioration 0 (0.0) 0 (0.0) 3 ( 13.0) unknown 0 (0.0) 0 (0.0) 1 (4.3) No data 0 (0.0) 0 (0.0) 0 (0.0) Best % change from baseline in target brain lesions$ >= -30 0 (0.0) 0 (0.0) 0 (0.0) -30 to < 20 0 (0.0) 0 (0.0) 0 (0.0) >= 20 0 (0.0) 1 (100.0) 0 (0.0) Number of patients without brain metastases at baseline 11 (91.7) 24 (70.6) 45 (66.2) Number of patients without brain metastases at baseline who developed a new brain metastasis 2 ( 18.2) 2 (8.3) 5 ( 11.1) 200 mg EGF816 QD N=8 n= (%) 225 mg EGF816 QD N=24 n= (%) 300 mg EGF816 QD N=5 n= (%) Number of patients with brain metastases at baseline 1 ( 12.5) 9 (37.5) 1 (20.0) Number of patients with brain metastases in non-target lesions noted only at baseline 1 (100.0) 9 (100.0) 1 (100.0) Number of patients with brain metastases in target lesions noted only at baseline 0 (0.0) 0 (0.0) 0 (0.0) Number of patients with brain metastases in both non-target and target lesions at baseline 0 (0.0) 0 (0.0) 0 (0.0) Number of patients with brain metastases at baseline who developed new brain metastases 0 (0.0) 0 (0.0) 0 (0.0) Best Response of Non-Targeted Brain Lesions# Missing/Normalized 0 (0.0) 3 (33.3) 0 (0.0) Present 1 (100.0) 6 (66.7) 1 (100.0) Deterioration 0 (0.0) 0 (0.0) 0 (0.0) unknown 0 (0.0) 0 (0.0) 0 (0.0) No data 0 (0.0) 0 (0.0) 0 (0.0) Best % change from baseline in target brain lesions$ >= -30 0 (0.0) 0 (0.0) 0 (0.0) -30 to < 20 0 (0.0) 0 (0.0) 0 (0.0) >= 20 0 (0.0) 0 (0.0) 0 (0.0) Number of patients without brain metastases at baseline 7 (87.5) 15 (62.5) 4 (80.0) Number of patients without brain metastases at baseline who developed a new brain metastasis 0 (0.0) 0 (0.0) 0 (0.0)

350 mg EGF816 QD N=11 n= (%) All patients N=162 n= (%) Number of patients with brain metastases at baseline 1 (9.1) 46 ( 28.4) Number of patients with brain metastases in non-target lesions noted only at baseline 1 (100.0) 45 (97.8) Number of patients with brain metastases in target lesions noted only at baseline 0 (0.0) 1 ( 2.2) Number of patients with brain metastases in both non-target and target lesions at baseline 0 (0.0) 0 (0.0) Number of patients with brain metastases at baseline who developed new brain metastases 0 (0.0) 2 (4.3) Best Response of Non-Targeted Brain Lesions# Missing/Normalized 0 (0.0) 7 ( 15.6) Present 1 (100.0) 34 (75.6) Deterioration 0 (0.0) 3 (6.7) unknown 0 (0.0) 1 ( 2.2) No data 0 (0.0) 0 (0.0) Best % change from baseline in target brain lesions$ >= -30 0 (0.0) 0 (0.0) -30 to < 20 0 (0.0) 0 (0.0) >= 20 0 (0.0) 1 (100.0) Number of patients without brain metastases at baseline 10 (90.9) 116 (71.6) Number of patients without brain metastases at baseline who developed a new brain metastasis 0 (0.0) 9 ( 7.8)

- N: Total number of patients in the treatment group. This is the denominator for calculating percentages (%).

- n: Number of patients belonging to the corresponding category.

- #The number of patients with non-target brain lesions at baseline is used as the denominator.

- $The number of patients with target brain lesions at baseline is used as the denominator.

- excluded patients with T790M-EGFR status or patients previously treated with third-generation TKIs.

Summary data on the status of brain metastases during disease progression

75 mg EGF816 QD N=12 n= (%) 100 mg EGF816 QD N=34 n= (%) 150 mg EGF816 QD N=68 n= (%) 200 mg EGF816 QD N=8 n= (%) 225 mg EGF816 QD N=24 n= (%) All patients Progression was observed 7 (58.3) 22 (64.7) 55 ( 80.9) 7 (87.5) 17 (70.8) Progression was not observed 5 (41.7) 12 (35.3) 13 ( 19.1) 1 ( 12.5) 7 (29.2) Among patients who have experienced disease progression A: New brain metastases were noted at first PD, or worsening of non-target brain metastases was observed at first PD, or there was an increase in the sum of diameters of target brain lesions by at least 20% at first PD 2 (28.6) 5 ( 22.7) 9 ( 16.4) 1 (14.3) 1 (5.9) B: There is at least a 20% increase in the sum of diameters of non-target lesions outside the brain at first PD, or deterioration in the response of non-target lesions outside the brain at first PD, or formation of a new non-brain lesion at first PD 6 (85.7) 19 (86.4) 49 ( 89.1) 6 (85.7) 16 (94.1) Only A, not B 1 (14.3) 3 ( 13.6) 5 (9.1) 1 (14.3) 1 (5.9) Only B, not A 5 (71.4) 17 (77.3) 45 (81.8) 6 (85.7) 16 (94.1) Both A and B 1 (14.3) 2 (9.1) 4 (7.3) 0 (0.0) 0 (0.0) Among patients with brain metastases at baseline Progression was observed 1 (100.0) 7 (70.0) 16 (69.6) 1 (100.0) 7 (77.8) Progression was not observed 0 (0.0) 3 (30.0) 7 (30.4) 0 (0.0) 2 (22.2) Among patients with brain metastases at baseline who have experienced disease progression A: New brain metastases were noted at first PD, or worsening of non-target brain metastases was observed at first PD, or there was an increase in the sum of diameters of target brain lesions by at least 20% at first PD 0 (0.0) 3 (42.9) 4 (25.0) 1 (100.0) 1 (14.3) B: There is at least a 20% increase in the sum of non-brain target lesion diameters at first PD, or worsening response of non-target non-brain lesions at first PD, or formation of a new extra-brain lesion at first PD. 1 (100.0) 6 (85.7) 15 (93.8) 0 (0.0) 6 (85.7) Only A, not B 0 (0.0) 1 (14.3) 1 (6.3) 1 (100.0) 1 (14.3) Only B, not A 1 (100.0) 4 (57.1) 12 (75.0) 0 (0.0) 6 (85.7) Both A and B 0 (0.0) 2 (28.6) 3 ( 18.8) 0 (0.0) 0 (0.0)

300 mg EGF816 QD N=5 n= (%) 350 mg EGF816 QD N=11 n= (%) All patients N=162 n= (%) All patients Progression was observed 4 (80.0) 6 (54.5) 118 ( 72.8) Progression was not observed 1 (20.0) 5 (45.5) 44 ( 27.2) Among patients who have experienced disease progression A: New brain metastases were noted at first PD, or worsening of non-target brain metastases was observed at first PD, or there was an increase in the sum of diameters of target brain lesions by at least 20% at first PD 1 (25.0) 0 (0.0) 19 ( 16.1) B: There is at least a 20% increase in the sum of diameters of non-target lesions outside the brain at first PD, or deterioration in the response of non-target lesions outside the brain at first PD, or formation of a new non-brain lesion at first PD 3 (75.0) 6 (100.0) 105 ( 89.0) Only A, not B 1 (25.0) 0 (0.0) 12 ( 10.2) Only B, not A 3 (75.0) 6 (100.0) 98 ( 83.1) Both A and B 0 (0.0) 0 (0.0) 7 (5.9) Among patients with brain metastases at baseline Progression was observed 1 (100.0) 0 (0.0) 33 (71.7) Progression was not observed 0 (0.0) 1 (100.0) 13 ( 28.3) Among patients with brain metastases at baseline who have experienced disease progression A: New brain metastases were noted at first PD, or worsening of non-target brain metastases was observed at first PD, or there was an increase in the sum of diameters of target brain lesions by at least 20% at first PD 1 (100.0) 0 (0.0) 10 ( 30.3) B: There is at least a 20% increase in the sum of non-brain target lesion diameters at first PD, or worsening response of non-target non-brain lesions at first PD, or formation of a new extra-brain lesion at first PD. 0 (0.0) 0 (0.0) 28 ( 84.8) Only A, not B 1 (100.0) 0 (0.0) 5 ( 15.2) Only B, not A 0 (0.0) 0 (0.0) 23 (69.7) Both A and B 0 (0.0) 0 (0.0) 5 ( 15.2)

- N: Total number of patients in the treatment group. This is the denominator for calculating percentages (%).

- n: Number of patients belonging to the corresponding category.

- excluded patients with T790M-EGFR status or patients previously treated with third-generation TKIs.

In conclusion, these results demonstrate the promising clinical activity of nazartinib in EGFR-mutated NSCLC patients. In particular, the results show that nazartinib has the potential to be effective in treating or preventing the development of CNS metastasis, brain metastasis, and leptomeningeal metastasis, especially in patients suffering from EGFR-mutated NSCLC.

Example 2: A phase II clinical trial of nazartinib as the only available agent in adult patients with EGFR-mutated non-small cell lung cancer (NSCLC) who have not received prior treatment

This phase I/II multicenter study of nazartinib was conducted in previously untreated patients with advanced NSCLC mutated EGFR carrying activating EGFR mutations, namely L858R and/or ex19del.

All 45 patients received the recommended phase II oral dose of 150 mg once daily on a continuous schedule. Antitumor activity, including overall response rate (ORR) according to RECIST v1.1, as assessed by independent, centrally blinded assessment (BICR), was the main study objective, and secondary objectives included drug safety, tolerability, and pharmacokinetics. The median age was 64 years, women accounted for 60% of patients participating in the clinical study, and 62% of patients were Asian. Fifty-eight percent had an ECOG General Condition Score of 1, and 18 (45%) patients had brain metastases at baseline. EGFR mutations were ex19del in 56% of patients, L858R in 40%, and 4% of patients had other EGFR mutations. Twenty-nine of 45 patients demonstrated a response to nazartinib, with an ORR of 64% (95% confidence interval [CI], 49%-78%). One patient achieved a complete response.

At the end of data collection on March 22, 2018, responses were ongoing in 27 of 29 patients who were responding to therapy. The 6-month duration of response to therapy (DoR) rate was 91%, and the median DoR has not been estimated (NE) and is not yet available. The disease control rate was 93%.

With nazartinib, the 6-month progression-free survival rate was 83% (median NE) and the 6-month overall survival rate was 95% (median NE).

An evaluation of 17 patients with brain metastases in non-target lesions at baseline showed that 9 (53%) patients had regression of brain metastasis. One of 27 patients without brain metastasis at baseline developed a new brain metastasis during the study. At the end of data collection on March 22, 2018, responses were ongoing in 27 of 29 patients who were responding to therapy. The 6-month duration of response to therapy (DoR) rate was 91%, and the mean DoR was not assessed (NE). The disease control rate was 93%.

With nazartinib, the 6-month progression-free survival rate was 83% (median NE) and the 6-month overall survival rate was 95% (median NE).

The data point to the efficacy of third-generation EGFR TKI with good brain penetration. Nazartinib has demonstrated encouraging efficacy and sustained responses in previously untreated patients with EGFR-mutated advanced NSCLC, including patients with baseline brain metastases.

Preliminary data on patients included in the study 15 weeks before the end date of data collection

The following set of data, based on evaluable patients enrolled in the study 15 weeks prior to the end date of data collection, further indicates that nazartinib may be particularly useful for the treatment or prevention of metastasis, which is central nervous system (CNS) metastasis. brain metastasis and leptomeningeal metastasis.

Brain metastases at baseline were assessed by computed tomography (CT)/magnetic resonance imaging (MRI). Ten of 24 (42%) evaluable patients had brain metastases at baseline.

Nazartinib was effective in both patients with and without brain metastasis at baseline (see table below). Complete and/or partial responses were achieved in 5/10 (ORR 50%) and 11/14 (ORR 79%) patients with or without baseline brain metastases as assessed by BIRC, respectively. DCR (stable disease, partial response and complete response) was similar in patients with (90%) and without (100%) brain metastases as assessed by BIRC. This suggests that nazartinib penetrates the brain and is effective in the treatment of brain tumors.

Table: Best Overall Response Rate Assessed for Brain Metastases at Baseline According to BIRC According to RECIST v1.1

BIRC (FAS)
n=24 Metastases to the brain are present No brain metastases Patients to be evaluated, n (%)* 10 (41.7) 14 (58.3) Best overall response rate, n (%) Complete response (CR) 0 1 (7.1) Partial Response (PR) 5 (50.0) 10 (71.4) Stable disease (SD) 4 (40.0) 2 (14.3) Disease Progression (PD) 1 (10.0) 0 Non-CR/non-PD (NCRNPD) 0 1 (7.1) Disease control rate, n (%) ^†
[95% CI] 9 (90.0)
[55.5-99.7] 14 (100)
[76.8-100] Overall response rate, n (%)
[95% CI] 5 (50.0)
[18.7-81.3] 11 (78.6)
[49.2-95.3] *Eligible Patients: Patients enrolled in the study 15 weeks prior to the data collection end date. This amount is used to calculate interest.
^† CR+PR+SD+NCRNPD.

BIRC, Blind Independent Review Committee; CT, computed tomography; FAS, population for complete analysis;

MRI, magnetic resonance imaging; RECIST, Response Evaluation Criteria for Solid Tumors.

Brain metastases at baseline were assessed by CT/MRI.

In addition, a 49-year-old patient with lung adenocarcinoma with EGFR mutation (ex19del, G719S/A/C), stage IV AJCC (brain, bone, liver) had PR as the best overall response rate. Brain scans after the initial scan performed on day 1 to cycle 5 (day 113 of the study) showed complete normalization of the brain lesion compared to the lesion at baseline as assessed by BIRC. The patient had not previously been treated for brain metastases, suggesting that this result was due to nazartinib and not to a delayed response to radiological treatment or other treatment.

Example 3: Randomized, open-label phase III study of nazartinib as the sole agent used versus the investigator's choice of drug (erlotinib or gefitinib) as first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer with activating EGFR mutations.

The aim of this study is to evaluate the superiority of EGF816 as the only used agent assessed by central BIRC PFS compared with the investigator's choice of drug (erlotinib or gefitinib) in previously untreated patients with locally advanced or metastatic NSCLC with tumors patients were characterized by the presence of activating EGFR mutations (L858R or ex19del).

The primary aim of this study is to compare the efficacy of EGF816 as the sole agent used versus the investigator's choice of drug (erlotinib or gefitinib) as measured by PFS as assessed by the central BIRC and according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). A key secondary objective of this study is to compare overall survival (OS) of patients treated with EGF816 as the only treatment used versus the investigator's choice of drug (erlotinib or gefitinib). Other secondary goals are the following:

To further evaluate the efficacy of EGF816 as the sole agent used versus the investigator's choice of drug (erlotinib or gefitinib) in terms of PFS as determined by the investigators, ORR, DoR, disease control rate (DCR) and time to response (TTR), which are determined by the central BIRC.

Evaluate long-term beneficial effects of EGF816

Evaluate the antitumor activity of EGF816 in the central nervous system (CNS) compared to the investigator's choice of drug (erlotinib or gefitinib) as measured by time to tumor progression in the CNS, ORR in the CNS, and DoR in the CNS as determined by the central neuroradiological BIRC according to with modified RECIST 1.1 for patients with CNS disease at baseline.

Characterize the pharmacokinetics (PK) of EGF816 as the only agent used.

Evaluate the effect of EGF816 as the sole agent used versus the investigator's choice of drug (erlotinib or gefitinib) on patient-reviewed outcomes (PRO), including patients' disease-related symptoms and patient health-related quality of life (HRQoL). ).

Evaluate the profile of EGF816 as the only agent used compared to the investigator's choice of drug (erlotinib or gefitinib).

The study population includes adult patients with locally advanced or metastatic NSCLC with activating EGFR mutations (L858R or ex19del) who have not previously received treatment.

Patients were randomized in a 1:1 ratio: Arm A (Investigator's choice of drug): erlotinib 150 mg QD taken without food or gefitinib 250 mg QD taken with or without food, or Arm B: EGF816 at 50 mg QD or 75 mg QD or 100 mg QD or 150 mg QD taken with or without food.

State of the art

Osimertinib (Tagrisso®), a third-generation EGFR inhibitor, is indicated for T790M EGFR mutation-positive metastatic NSCLC in patients who experience disease progression during or after TKI EGFR therapy (Jänne et al. 2015, N Engl J Med ., vol.372 (18), pp. 1689-1699).

The FLAURA study (NCT02296125) reported positive results with osimertinib as a first-line treatment for EGFR-mutated NSCLC: the investigator reported that median progression-free survival was significantly longer with osimertinib compared with standard EGFR TKIs (18.9 months versus 10.2 months; HR for disease progression or death, confidence interval [CI] 0.46; 95%, 0.37–0.57; P<0.001). The objective response rate (ORR) was similar between the two arms: 80% with osimertinib and 76% with standard EGFR TKIs (odds ratio, 1.27; 95% CI, 0.85-1.90; P =0.24). The median duration of response to therapy was 17.2 months (95% CI, 13.8–22.0) with osimertinib compared to 8.5 months (95% CI, 7.3–9.8) with using standard TKI EGFR. Overall survival data were incomplete at the interim analysis (25% completion). Survival rates at 18 months were 83% (95% CI, 78-87) with osimertinib and 71% (95% CI, 65-76) with standard EGFR TKIs (hazard ratio of death 0.63; 95 % CI, 0.45-0.88, P=0.007 [not significant in interim analysis]). The most frequently reported adverse events (AE) from any cause were rash or acne (58% in the osimertinib group and 78% in the standard EGFR TKI group), diarrhea (58% and 57%, respectively), and dry skin (36 % in each group). Grade 3 or higher AEs were less common with osimertinib than with standard EGFR TKIs (34% vs. 45%) (Soria et al. 2018, N Engl J Med , vol. 378(2), pp 113-125).

Erlotinib (Tarceva®) is an orally active, potent, selective TK EGFR inhibitor. Erlotinib has been approved in most countries as a first-line treatment for patients with metastatic NSCLC whose tumors are characterized by the presence of EGFR mutations, which are either ex19del or L858R substitution mutations. For more information, see your local prescribing information for erlotinib (Tarceva®).

The safety and efficacy of erlotinib as monotherapy in the first-line treatment of patients with metastatic NSCLC with EGFR mutations representing ex19del or L858R substitution mutations was demonstrated in a randomized, open-label clinical trial conducted in Europe (the EURTAC study), in which 174 patients were were randomized 1:1 to receive erlotinib 150 mg once daily or receive platinum-based doublet chemotherapy (n=88). The median investigator-assessed PFS was 9.7 months for erlotinib versus 5.2 months for platinum-based chemotherapy, with no improvement in OS (Rosell et al. 2012, Lancet Oncol. vol. 13(3), pp. 239- 246).

The most common adverse reactions (≥ 20%) with erlotinib in the pooled analysis were rash (mostly acneiform), diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. ILD occurred in 1.1% of patients.

Gefitinib (Iressa®) is a potent and selective reversible TK EGFR inhibitor. Gefitinib has been approved in most countries as a first-line treatment for patients with NSCLC whose tumors were characterized by the presence of EGFR mutations, which are either ex19del or L858R substitution mutations.

A randomized, first-line, phase III IPASS trial was conducted in Asian patients with advanced NSCLC (stage IIIB or IV) with histological examination of adenocarcinoma, former non-heavy smokers. Patients were randomized 1,217 (1:1) to receive gefitinib or carboplatin/paclitaxel. In patients with activating EGFR mutations, gefitinib demonstrated a higher PFS of 9.5 months vs. 6.3 months ORR (71.2% vs. 47.3%), with no significant difference in overall survival vs. carboplatin/paclitaxel.

The most frequently reported adverse drug reactions (occurring in more than 20% of patients) among 2463 patients treated with gefitinib were diarrhea and skin reactions (including rash (mostly acneiform), acne, dry skin and itching) . Adverse drug reactions usually occur within the first month of therapy and are usually reversible. Approximately 8% of patients experienced a severe adverse drug reaction (grade 3 or 4). Approximately 3% of patients discontinued therapy due to an adverse drug reaction. ILD occurred in 1.3% of patients, often in a severe form (CTC grade 3-4). Cases of death have been reported.

Rationale for the study plan

This study is a global, open-label, multicentre, active-controlled, randomized, 2-arm, phase III trial designed to compare the efficacy and safety of EGF816 as a single agent versus the investigator's choice of drug (erlotinib or gefitinib) in previously untreated patients with locally advanced or metastatic stage IIIB/IIIC (not suitable for definitive multimodal therapy) or stage IV NSCLC (Detterbeck et al. 2017, Chest, vol. 151 (1), pp. 193-203) characterized by the presence of an activating EGFR mutation (L858R or ex19del).

The primary objective of this study is to evaluate the efficacy of EGF816 as the sole agent used compared with the investigator's choice of drug (erlotinib or gefitinib) as measured by PFS as assessed by the central BIRC and according to criteria for evaluating response in solid tumors (RECIST 1.1).

Patients are randomized in a 1:1 ratio to one of two treatment groups:

group A: control group (investigator's choice): erlotinib 150 mg QD or gefitinib 250 mg QD;

group B: EGF816 at 50, 75, 100, or 150 mg QD.

Rationale for the choice of dose and treatment regimen

The overall benefit/risk assessment of EGF816 is considered favorable for the treatment of previously untreated patients with locally advanced or metastatic NSCLC, which is characterized by the presence of previously untreated EGFR activating mutations. Based on the results of the CEGF816X2101 study, the 150 mg QD dose of EGF816 was selected as RP2D because it was well tolerated and showed antitumor activity in ^2nd line NSCLC patients with T790M positive EGFR mutations and in ^1st line NSCLC patients. with EGFR mutations that were included in the study in phase I (part of the dose escalation study) and phase II (part of the application of the previously established maximum tolerated dose in an expanded population). The discontinuation rate was low, namely 7.5% (n=3) of phase II discontinuations (part of the previously established maximum tolerated dose in the extended population) (2.5% due to an adverse event).

In addition, an exploratory dose-response analysis was also performed using efficacy data (confirmed response) and safety data (rash) from phase I (dose escalation part) of the CEGF816X2101 study, confirming 150 mg QD as the optimal dose for monotherapy using EGF816.

Overall, based on phase I (dose escalation study) and phase II (use of the previously established maximum tolerated dose in the extended population) efficacy and safety data and dose-response analysis, 150 mg QD was selected as the dose for this phase III study, which should provide a favorable benefit/risk ratio for previously untreated patients with locally advanced or metastatic NSCLC with activating EGFR mutations.

In conclusion, nazartinib at 150 mg QD was effective in patients with advanced NSCLC with an EGFR mutation with a controlled safety profile in both pre-treatment and naive patients at the 150 mg QD dose used in this study. phase III study in the treatment of EGFR-mutated NSCLC.

Ways

Description of the study plan

This study is an open-label, multicentre, active-controlled, randomized, phase III, 2-arm study to evaluate the efficacy and safety of EGF816 compared with the investigator's choice of drug (erlotinib or gefitinib) in previously untreated adult patients with locally advanced or metastatic stage NSCLC. IIIB/IIIC (not suitable for definitive multimodal therapy, including surgery) or stage IV, which is characterized by the presence of an activating EGFR mutation (L858R or ex19del).

Patients are randomized in a 1:1 ratio:

Group A (Investigator's choice): erlotinib 150 mg QD taken without food or gefitinib 250 mg QD taken with or without food, or

Group B: EGF816 at 50, 75, 100, or 150mg QD taken with or without food.

Transfer from one treatment group to another is allowed; in Arm A (Investigator's Choice), no change to another drug (erlotinib or gefitinib) is permitted during the study.

This study includes the following steps:

pre-screening period based on molecular analysis

screening period (after signing the Basic Informed Consent Form (ICF) 28 days prior to randomization)

period of treatment until disease progression, unacceptable toxicity, or discontinuation of study drug for any other reason

follow-up period for drug safety (30 days after last dose of study drug)

• post-treatment follow-up for patients who discontinue investigational drug for reasons other than withdrawal of consent, advanced disease, pregnancy, initiation of new cancer therapy, loss of follow-up contact, termination of study by sponsor, or patient death

follow-up to assess survival, including PFS2.

Inclusion Criteria

Patients eligible for inclusion in this study must meet all of the following criteria:

- Written informed consent obtained prior to any screening procedures

Histologically documented stage IIIB/IIIC or stage IV locally advanced or metastatic NSCLC with documented EGFR activating mutation (L858R or ex19del)

- provision of a tumor tissue sample for retrospective analysis of EGFR mutation status

- lack of previous treatment with any systemic anticancer therapy at a late stage

- the patient got rid of all the toxic effects associated with the previous treatment

- presence of at least one measurable lesion according to RECIST 1.1

- index of general condition according to the scale of the Eastern United Oncology Group (ECOG) ≤1

- at the screening visit, they must meet the following laboratory parameters:

absolute neutrophil count ≥1.5×109/l

platelet count ≥75×109/l

hemoglobin (Hgb) ≥9 g/dl

creatinine clearance ≥ 45 ml/min calculated using the Cockcroft-Gault formula

total bilirubin ≤1.5 x ULN

aspartate aminotransferase (AST) activity ≤ 3.0 x ULN, except for patients with liver metastasis, who can only be included in the study if AST ≤ 5.0 x ULN

alanine aminotransferase (ALT) activity ≤ 3.0 x ULN, except for patients with liver metastasis, who can only be included in the study if ALT ≤ 5.0 x ULN

Exclusion Criteria

- prior treatment with TKI EGFR

- established positive status of the T790M mutation. Presence of other known activating EGFR mutations other than L858R or ex19del. Patients whose tumors contain other EGFR mutations at the same time as L858R or ex19del EGFR mutations are eligible to participate in the study.

- symptomatic brain metastases

- history of interstitial lung disease or interstitial pneumonitis

- any disease for which, in the opinion of the investigator, the patient cannot participate in the study for reasons of safety, adherence to clinical study procedures, or interpretation of study results

- Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required treatment within the past 3 years

- the presence of clinically significant ophthalmic abnormalities

- bullous and exfoliative skin diseases of any severity

- Presence or history of microangiopathic hemolytic anemia with thrombocytopenia

- known history of positive human immunodeficiency virus (HIV) test results

- violation of cardiac activity or cardiac repolarization

Major surgery: ≤4 weeks prior to study treatment, or patients who have not recovered from the side effects of such a procedure

- inability or unwillingness to swallow tablets or capsules

- pregnant or lactating female patients

Women of childbearing age who refuse or are unable to use a highly effective method of contraception as defined in the study protocol

- Sexually active men, if they do not use a condom during intercourse while taking the drug and within 3 months after taking the last dose of study drug.

Dosing regimen

EGF816, erlotinib, or gefitinib is administered orally once a day on a continuous dosing schedule. A complete treatment cycle is defined as 21 days of daily dosing (Table 8).

Table 8. Dose and treatment schedule.

Table 9. Other doses provided for EGF816, erlotinib and gefitinib.

Starting dose level Dose level - 1 Dose level - 2 EGF816 150 mg QD 100 mg QD 75 mg QD Erlotinib 150 mg QD 100 mg QD 50 mg QD Gefitinib 250 mg QD But But *Dose reduction should be based on the worst case toxicity of the last dose.

Claims (24)

1. The use of nazartinib, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of metastasis in a patient, the metastasis being selected from central nervous system (CNS) metastasis, brain metastasis, and leptomeningeal metastasis, the metastasis being the result of a primary lesion such as non-small cell lung cancer (NSCLC) and, where NSCLC is characterized by the presence of an EGFR mutation (deletion in exon 19 or substitution (L858R) in exon 21). 2. Use according to claim 1 wherein nazartinib is in the form of the mesylate salt. 3. Use according to claim 1 or 2, wherein the patient is a patient with locally advanced or metastatic non-small cell lung cancer (NSCLC). 4. Application according to any one of paragraphs. 1-3, where NSCLC is characterized by the presence of an activating EGFR mutation. 5. Use according to claim 4, wherein the activating EGFR mutation is an L858R mutation. 6. Use according to claim 4 or 5, wherein the EGFR activating mutation is an ex19del mutation. 7. Application according to any one of paragraphs. 1-6, wherein the patient is an NSCLC patient who has progressed to brain metastasis, CNS metastasis, and/or leptomeningeal metastasis. 8. Application according to any one of paragraphs. 1-7, where the patient's progression-free survival (PFS) is improved compared to PFS obtained after treatment with erlotinib or gefitinib. 9. Application according to any one of paragraphs. 1-8, where the overall survival (OS) of the patient is improved compared to OS obtained after treatment with erlotinib or gefitinib. 10. Application according to any one of paragraphs. 1-9, where the overall response rate (ORR) of the patient is improved compared to the ORR obtained after treatment with erlotinib or gefitinib. 11. Application according to any one of paragraphs. 1-10 wherein time to tumor progression (TPP) in the CNS or brain is increased compared to TPP in the CNS or brain when administered/treated with erlotinib, gefitinib, or osimertinib. 12. Application according to any one of paragraphs. 1-11, where the ORR in the CNS or in the brain is increased compared to the ORR in the CNS when treated with erlotinib, gefitinib, or osimertinib. 13. Application according to any one of paragraphs. 1-12, where the duration of response to therapy (DoR) in the CNS or brain is increased compared to the DoR in the CNS or brain when treated with erlotinib, gefitinib, or osimertinib. 14. Application according to any one of paragraphs. 1-13, where nazartinib is used as monotherapy. 15. The use of nazartinib or a pharmaceutically acceptable salt thereof for the treatment or prevention of central nervous system (CNS) metastases, including brain metastases, in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), where the cancer is characterized by the presence of an EGFR mutation (deletions in exon 19 or a replacement (L858R) in exon 21). 16. Use according to claim 15, wherein nazartinib is used as monotherapy (the only treatment for NSCLC) or as part of combination therapy for the treatment of NSCLC. 17. Use according to any one of the preceding claims, wherein nazartinib is administered at a total dose that is selected from the range of about 50 to about 200 mg daily, administered once daily. 18. A method of treating metastases in a patient with NSCLC, wherein the metastases are selected from central nervous system (CNS) metastases, brain metastases, and leptomeningeal metastases, comprising selectively administering a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof to a patient who has previously been diagnosed the presence of an EGFR mutation, which is a deletion in exon 19 or a substitution (L858R) in exon 21. 19. A method of treating metastases in a patient with NSCLC, wherein the metastases are selected from central nervous system (CNS) metastases, brain metastases, and leptomeningeal metastases, comprising: (a) determining or having already determined whether the patient has an EGFR mutation that is a deletion in exon 19 or a substitution (L858R) in exon 21; And (b) administering a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof to said patient. 20. A method of treating metastases in a patient with NSCLC, wherein the metastases are selected from central nervous system (CNS) metastases, brain metastases, and leptomeningeal metastases, comprising selecting a patient for treatment based on the patient previously having an EGFR mutation, representing a deletion in exon 19 or a substitution (L858R) in exon 21, and administering a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof to said patient. 21. The method according to any one of paragraphs. 18-20, wherein the therapeutically effective amount is selected from the range of about 50 to about 200 mg administered once daily. 22. Use of nazartinib or a pharmaceutically acceptable salt thereof for the treatment or prevention of metastasis in a patient, where the metastasis is selected from central nervous system (CNS) metastasis, brain metastasis, and leptomeningeal metastasis, where the metastasis is the result of a primary lesion such as non-small cell lung cancer (NSCLC) and where the patient had a predetermined NSCLC, which is characterized by the presence of an EGFR mutation (deletion in exon 19 or substitution (L858R) in exon 21).

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