WO2024046405A1 - Use of egfr kinase inhibitor - Google Patents

Abstract

Provided is use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in treating advanced or metastatic NSCLC.

Description

Use of an EGFR kinase inhibitor Technical field

The present disclosure relates to the field of biomedicine, specifically the use of a compound represented by formula (I) and its pharmaceutically acceptable salts in advanced or metastatic NSCLC.

Background technique

Lung cancer is currently the most common malignant tumor with the highest fatality rate in the world. In 2020, the number of global lung cancer cases was about 2.2 million (accounting for 11.4% of the total new cancer cases), and the global number of lung cancer deaths was about 1.8 million. The Global Cancer Observatory predicts that new lung cancer cases and deaths will continue to rise, with approximately 2.5 million new lung cancer cases and 2.1 million deaths by 2025. In China, the number of lung cancer deaths is as high as 715,000, with a mortality rate of 23.8%. Regardless of tumor incidence or mortality, lung cancer occupies the first place, seriously threatening people's health.

Among lung cancer patients, non-small cell lung cancer (NSCLC) accounts for approximately 85%. Non-squamous cell NSCLC accounts for approximately 60% of NSCLC, of which lung adenocarcinoma is the most common type, accounting for approximately 40% of NSCLC. In lung adenocarcinoma, approximately 10% of Caucasian patients and up to 50% of Asian patients carry EGFR-sensitizing mutations, mainly including deletions in EGFR exon 19 and L858R mutations in exon 21. In the past few decades, the discovery of oncogenic driver genes, including EGFR mutations and anaplastic lymphoma kinase rearrangements, and the development of specific molecularly targeted drugs have fundamentally changed the treatment prospects for patients with advanced NSCLC.

After first-generation (gefitinib and erlotinib) and second-generation (afatinib) EGFR-TKIs are used to treat patients with advanced NSCLC harboring EGFR activating mutations, the ORR is significantly higher (60-70%), with an average The PFS range is 9 to 15 months. However, most patients will develop EGFR-dependent resistance soon after taking the drug. Among them, the most common resistance mutation is the T790M mutation. Because residue 790 is at a critical position at the entrance to the ATP-binding hydrophobic pocket, the T790M mutation is also known as the "gatekeeper mutation." In addition to affecting the binding of EGFR-TKI to the ATP kinase pocket, the T790M mutation can also mediate drug resistance by reducing the effectiveness of competitive inhibitors.

The third generation EGFR-TKI has good efficacy against T790M mutation, but acquired resistance inevitably occurs. Among patients treated with first-line osimertinib, about 10-15% show EGFR-dependent resistance; among patients treated with second-line therapy, about 20% show EGFR-dependent resistance. EGFR-dependent resistance mechanisms include: C797X mutation (C797X mutation has become the most common osimertinib resistance mechanism), EGFR exon 20 mutations, G796X, L792X, L718Q mutations and other EGFR tertiary mutations (G719X, G724S and S768I) etc. EGFR-independent resistance mechanisms include: acquired amplification (MET amplification, HER2 amplification, PIK3CA amplification), acquired oncogenic fusion (FGFR3 fusion, NTRK fusion, RET fusion, ALK fusion, BRAF fusion), acquired MAPK-PI3K mutations, acquired cell cycle gene alterations, histological and phenotypic switches, and unknown mutations.

When osimertinib is used as first-line treatment, the frequency of C797S mutation is 7%, which is the second resistance mechanism after MET amplification; when patients who progressed after second-line treatment with osimertinib were tested, it was found that C797S Mutation frequency ranks first among drug resistance mechanisms, accounting for 14%. EGFR C797S The mutation occurs in exon 20, where the cysteine at codon 797 within the ATP-binding site is replaced by serine, resulting in the loss of the covalent bond between osimertinib and mutant EGFR. The C797S mutation also confers cross-resistance to other irreversible third-generation TKIs by preventing their binding to the EGFR active site. Recent findings indicate that 6% of patients have a C797S single mutation without T790M, and 2% of patients have two coexisting C797S clones (one cis and one trans) containing T790M.

In summary, NSCLC patients with EGFR-dependent mutations such as C797S who progress after treatment need more effective treatment.

Patent WO2021208918A1 discloses a small molecule EGFR inhibitor targeting the C797S mutation. Its structure is shown in formula (I), and its chemical name is N-(6-((5-bromo-2-((6-isopropyl) -8-Methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)-pyrimidine-4 -yl)amino)-quinoxalin-5-yl)methanesulfonamide. This small molecule inhibitor has good kinase inhibitory activity and cell anti-proliferation activity. At the same time, the molecule has demonstrated good anti-tumor activity and tolerance in mouse models, and is expected to be developed into a clinical drug.

Contents of the invention

The present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in advanced or metastatic NSCLC.

specific,

The present disclosure provides a method of treating advanced or metastatic NSCLC, characterized by administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

In some aspects of the present disclosure, the advanced or metastatic NSCLC described in the above treatment methods refers to advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI.

In some aspects of the present disclosure, the EGFR-TKI treatment described in the above treatment methods refers to first-generation, second-generation or third-generation EGFR-TKI. Anti-tumor therapy with TKIs.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above treatment methods is an advanced NSCLC that progresses after EGFR-TKI treatment and carries the EGFR C797S mutation.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above treatment methods is advanced NSCLC that progresses after standard treatment and has no other additional driver gene mutations.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above treatment method is an advanced NSCLC that carries the EGFR T790M mutation after EGFR-TKI treatment.

In some aspects of the present disclosure, the advanced or metastatic NSCLC described in the above treatment methods refers to advanced or metastatic NSCLC that progresses without EGFR-TKI treatment.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that has not progressed after EGFR-TKI treatment described in the above treatment methods is localized NSCLC carrying an EGFR mutation-sensitive mutation (19del or 21L858R) that has not been treated with EGFR-TKI. Progression of inoperable or recurrent metastatic NSCLC.

In some schemes of the present disclosure, the advanced or metastatic NSCLC described in the above treatment methods is after treatment with EGFR-TKI and carries EGFR L792X and/or EGFR G796X and/or EGFR L718Q and/or EGFR 20 exon. Mutated advanced NSCLC.

In some aspects of the present disclosure, the advanced or metastatic NSCLC described in the above treatment method is an advanced or metastatic NSCLC carrying a rare mutation of EGFR after treatment with EGFR-TKI.

In some schemes of the present disclosure, the advanced or metastatic NSCLC described in the above treatment method is an advanced or metastatic NSCLC carrying EGFR L861Q, EGFR G719X, and EGFR S768I mutations after treatment with EGFR-TKI.

In some schemes of the present disclosure, the advanced or metastatic NSCLC described in the above treatment methods is the advanced or metastatic NSCLC that carries the EGFR L861Q mutation after treatment with EGFR-TKI.

In some aspects of the present disclosure, the advanced or metastatic NSCLC described in the above treatment methods is NSCLC with brain metastasis.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 5 mg to 400 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 5 mg to 300 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 10 mg-300 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 10 mg-240 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 20 mg-200 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 20 mg-160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 40 mg-160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 80 mg-160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 100 mg- 200mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 120 mg-160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt in the above treatment method is 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 120 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 160 mg.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in the above treatment method.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day in the above treatment method.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is suitable for oral administration.

In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) in the above treatment method is the hydrochloride.

In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) in the above treatment method is a hydrochloride salt.

The present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of advanced or metastatic NSCLC.

In some aspects of the present disclosure, the advanced or metastatic NSCLC described in the above uses refers to advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI.

In some aspects of the present disclosure, the EGFR-TKI treatment described in the above uses refers to anti-tumor treatment of first-, second- or third-generation EGFR-TKI.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above uses is an advanced NSCLC that progresses after EGFR-TKI treatment and carries the EGFR C797S mutation.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above uses is advanced NSCLC that progresses after standard treatment and has no other additional driver gene mutations.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI described in the above uses is an advanced NSCLC that carries the EGFR T790M mutation after treatment with EGFR-TKI.

In some aspects of the present disclosure, the advanced or metastatic NSCLC described in the above uses refers to advanced or metastatic NSCLC that has not progressed after EGFR-TKI treatment.

In some aspects of the present disclosure, the advanced or metastatic NSCLC that has not progressed after EGFR-TKI treatment as described in the above uses is locally advanced and carries an EGFR mutation-sensitive mutation (19del or 21L858R) that has not been treated with EGFR-TKI. Inoperable or recurrent metastatic NSCLC.

In some embodiments of the present disclosure, the advanced or metastatic NSCLC described in the above uses is after treatment with EGFR-TKI and carries EGFR L792X and/or EGFR G796X and/or EGFR L718Q and/or EGFR exon 20 mutations. of advanced NSCLC.

In some aspects of the present disclosure, the advanced or metastatic NSCLC described in the above uses is an advanced or metastatic NSCLC carrying a rare mutation of EGFR after treatment with EGFR-TKI.

In some embodiments of the present disclosure, the advanced or metastatic NSCLC described in the above uses is an advanced or metastatic NSCLC carrying EGFR L861Q, EGFR G719X, and EGFR S768I mutations after EGFR-TKI treatment.

In some embodiments of the present disclosure, the advanced or metastatic NSCLC described in the above uses is an advanced or metastatic NSCLC carrying the EGFR L861Q mutation after treatment with EGFR-TKI.

In some embodiments of the present disclosure, the advanced or metastatic NSCLC in the above uses is NSCLC with brain metastasis.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 5 mg to 400 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 5 mg to 300 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 10 mg to 300 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 10 mg to 240 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 20 mg to 200 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 20 mg to 160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 40 mg to 160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 80 mg to 160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 100 mg to 200 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 120 mg to 160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt for the above-mentioned uses is 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above-mentioned uses is 120 mg.

In some embodiments of the present disclosure, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 160 mg.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for the above-mentioned uses.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily for the above-mentioned uses.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is suitable for oral administration in the above-mentioned uses.

In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) in the above-mentioned uses is the hydrochloride.

In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) for the above-mentioned uses is a hydrochloride salt.

Technical effect

The compound of formula (I) provided by the present disclosure has better safety and tolerability.

The compound of formula (I) provided by the present disclosure has a good curative effect on advanced or metastatic NSCLC that progresses after EGFR-TKI treatment. It is effective for advanced NSCLC carrying EGFR C797S mutation, advanced NSCLC carrying EGFR T790M mutation, and advanced NSCLC carrying EGFR TKI. NSCLC with mutation-sensitive mutations (19del or 21L858R) all have good curative effects; especially late-stage NSCLC carrying EGFR C797S mutations, such as 19del/T790M/C797S mutations, have good curative effects; in addition, NSCLC with rare NSCLC with mutated genes such as L861Q mutation also have better efficacy.

Definition and Description

Unless otherwise stated, the following terms and phrases used in this disclosure are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present disclosure prepared from compounds having specific substituents discovered in the present disclosure and relatively non-toxic acids or bases. When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.

The term "therapeutically effective amount" refers to a sufficient amount of a compound or pharmaceutically acceptable salt of the present disclosure to treat a disorder with a reasonable effect/risk ratio suitable for any medical treatment and/or prevention. However, it should be recognized that the total daily dosage of pharmaceutically acceptable salts and compositions of the compound represented by Formula I of the present disclosure must be determined by the attending physician within the scope of reliable medical judgment. For any particular patient, the specific therapeutically effective dosage level will be determined by a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; The patient's age, weight, general health, sex, and diet; the timing, route of administration, and excretion rate of the specific compound employed; the duration of treatment; medications used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical field. For example, this The practice in the field is to start dosages of compounds at levels lower than those required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.

The term "administering" means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration include oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalational, vaginal, intraocular, topical (e.g., via catheter or stent), subcutaneous, intrafatal, intraarticular, intraperitoneal and intrathecal, etc. In certain embodiments of the present disclosure, "administering" means delivering to a subject via the oral route.

The term "subject" includes any human or non-human animal. The term "non-human animals" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject" and "patient" and "subject" are used interchangeably in certain contexts in this disclosure, and in certain embodiments of the disclosure, the "subject" is a human.

In this disclosure, the EGFR-TKI refers to an epidermal growth factor receptor tyrosine kinase inhibitor, which currently includes first-, second- or third-generation epidermal growth factor receptor tyrosine kinase inhibitors.

In the present disclosure, the EGFR mutation-mediated tumors or cancers refer to cancer driver mutations (driver mutations) of EGFR that can be detected in these tumors or cancer patients, including but not limited to Del19 mutation, L858R mutation, T790M mutation , 20 exon insertion mutations (Exon 20 ins), C797S and other mutations. Among them, the Del19 mutation refers to the mutation caused by the deletion of the amino acid in exon 19; L858R refers to the missense mutation of the base that causes the 858th amino acid to change from L to R; T790M refers to the change of the base in the gene. The missense mutation at the base causes amino acid 790 to change from T to M; Exon 20 ins insertion mutation refers to the in-frame duplication/insertion mutation that occurs in exon 20 of EGFR; C797S mutation is Refers to the mutation of the cysteine residue at position 797 to serine. In the present disclosure, the EGFR mutations include not only the above-mentioned single mutants of EGFR, but also compound mutants of T790M, Del19, L858R, Exon 20 ins, C797S and other sites freely combined, including but not limited to L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, etc.

“Standard treatment” in this disclosure refers to the treatment recommended by the Chinese Society of Clinical Oncology (CSCO) or the National Comprehensive Cancer Network (NCCN) non-small cell lung cancer treatment guidelines.

In specific embodiments, the medicament contains a compound represented by formula (I) as an active substance; in certain embodiments, the medicament contains a salt of a compound represented by formula (I); in others In embodiments, the medicament optionally includes a pharmaceutically acceptable carrier, and Compound I or a pharmaceutically acceptable salt thereof can be formulated in various pharmaceutically acceptable pharmaceutical compositions, including oral forms (e.g., tablets). capsules, powders, granules, pills, pastes, powders), injectable forms (e.g. subcutaneous, intravenous, intramuscular and intraperitoneal injections), infusions, topical forms (e.g. nasal sprays, transdermal preparations, ointments, etc.) and suppositories (such as rectal and vaginal suppositories). These different pharmaceutically acceptable pharmaceutical compositions can be manufactured using known techniques commonly used in the pharmaceutical industry, using pharmaceutically acceptable carriers commonly used in the pharmaceutical industry.

The term "pharmaceutically acceptable carrier" refers to a carrier generally accepted in the art for delivering biologically active agents to animals, particularly mammals. The medium of the substance, depending on the mode of administration and the nature of the dosage form, includes, for example, adjuvants, excipients or excipients, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, Suspending agents, sweeteners, flavorings, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants. The formulation of pharmaceutically acceptable carriers depends on a number of factors within the purview of one of ordinary skill in the art. This includes, but is not limited to: the type and nature of the formulated active agent, the subjects to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients are well known to those of ordinary skill in the art to be included in the formulation for a variety of reasons (e.g., to stabilize the active agent, binders, etc.) .

The unit dosage (for example, but not limited to, the daily unit dosage) of the compound of formula (I) or its pharmaceutically acceptable salt is calculated based on the free form of the compound of formula I. Although the value between any two numerical values is not listed one by one, it shall be regarded as To clarify, for example, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5 mg to 300 mg, including but not limited to 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 240 mg, 300 mg, etc.

In the clinical protocols recorded in the specific embodiments of the present disclosure, the compound of formula (I) may refer to the free base form of the compound represented by formula (I); it may also refer to the pharmaceutically acceptable salt of the compound represented by formula (I) form, such as hydrochloride, preferably monohydrochloride; it can also refer to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound represented by formula (I) or Its pharmaceutically acceptable salts are formulated in various pharmaceutically acceptable pharmaceutical compositions, such as oral tablets, capsules, powders, granules, dropping pills, pastes, powders, etc. These different pharmaceutically acceptable pharmaceutical compositions can be manufactured using known techniques commonly used in the pharmaceutical industry, using pharmaceutically acceptable carriers commonly used in the pharmaceutical industry. Tumor progression refers to the evaluation of tumor efficacy of subjects according to RECIST 1.0 or RECIST 1.1, and the evaluation result is disease progression.

Advanced tumors generally refer to solid tumors that have metastasized to distant sites. According to the TNM staging standard for lung cancer, lung cancer is divided into stages I, II, III, and IV. Lung cancer patients in stages IIIb and IV are usually defined as late-stage lung cancer.

Metastatic lung cancer refers to malignant tumors in any location that metastasize to the lungs through various metastasis methods.

"No other additional driver gene mutations" described in this disclosure means that the mutation is not a currently known clear mutation (such as EGFR, MET mutation, etc.), and the mutation type is unknown.

The "EGFR rare mutation types" mentioned in this disclosure refer to mutation types such as L861Q, G719X, S768I, etc.

Some common abbreviations and their meanings in this disclosure are as follows:

Detailed ways

The present disclosure is described in detail below through examples, but these examples are only for illustration and do not limit any scope of the present disclosure. Likewise, this disclosure is not limited to any specific preferred embodiments described herein. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the technical features of the present disclosure still fall within the protection scope of the present disclosure.

Example 1: Phase I clinical study to evaluate the safety, tolerability, pharmacokinetics and efficacy of the compound of formula (I) in patients with advanced or metastatic NSCLC that progressed after EGFR-TKI treatment

1. Experimental purpose

(1) Evaluation of the compound of formula (I) in advanced or metastatic non-small cell lung cancer (Non-small cell lung cancer) that progresses after epidermal growth factor receptor tyrosine kinase inhibitor (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, EGFR-TKI) treatment. Safety and tolerability, Dose-limiting Toxicity (DLT), Maximum Tolerated Dose (MTD, if possible) or Maximum administered dose (MTD) in patients with Cell Lung Cancer (NSCLC) Allowable Dose, MAD) and Phase II clinical study recommended dose (Recommended Phase 2 Dose, RP2D);

(2) To evaluate the efficacy of the compound of formula (I) in patients with advanced or metastatic NSCLC that progressed after EGFR-TKI treatment.

2. Selection criteria

Each subject participating in the study must meet all of the following inclusion criteria.

1. Subjects voluntarily participate, sign the Informed Consent Form (ICF), and be able to comply with the research process;

2. Age ≥18 years old;

3. Histologically or cytologically confirmed EGFR mutation, and inoperable locally advanced or recurrent/metastatic non-small cell lung cancer;

4. EGFR mutation requirements:

●Dose escalation phase (Phase Ia): NSCLC subjects who have progressed after standard EGFR-TKI treatment, or are intolerant to standard treatment or refuse to accept standard treatment;

Table 1 Phase Ia dose escalation table

Note: QD: once daily.

●Queue expansion phase (Phase Ib):

a) Cohort 1: advanced NSCLC patients who have progressed after third-generation EGFR-TKI treatment and carry EGFR C797S mutation

b) Cohort 2: advanced NSCLC patients who have progressed after standard EGFR-TKI therapy and have no additional driver gene mutations

c) Cohort 3: advanced NSCLC patients who progressed after EGFR-TKI treatment and carried T790M mutation

d) Cohort 4: Patients with locally advanced inoperable or recurrent metastatic NSCLC carrying EGFR mutation-sensitive mutations (19del or 21L858R) who have not received EGFR-TKI treatment

Table 2 Phase Ib queue expansion table

Note: EGFR-TKI: epidermal growth factor receptor tyrosine kinase inhibitor; NSCLC: non-small cell lung cancer

5. Agree to provide tumor samples (fresh tissue or archived samples) for EGFR gene analysis.

Dose escalation phase: Tumor samples from sites of disease progression during or after the last TKI treatment should be provided for new genetic testing. If it cannot be provided, you can communicate with the sponsor and negotiate for inclusion.

Queue expansion phase:

Cohort 1: Tumor samples from the site of disease progression during or after the last TKI treatment must be provided for central laboratory genetic testing.

Cohort 2 and Cohort 3: Tumor samples from the site of disease progression during or after the last TKI treatment must be provided for genetic testing. If there are test results that meet the above requirements before enrollment, re-testing is not required.

Cohort 4: Tumor samples during or after disease progression after the last treatment must be provided (if there has been no previous treatment, tumor samples are required to be provided during the screening period) for genetic testing (EGFR mutation). If there are test results that meet the above requirements before enrollment, re-testing is not required.

6.ECOG≤1 point;

7. Life expectancy ≥12 weeks;

8. Only subjects with measurable lesions confirmed according to RECIST version 1.1 standards and recorded by computed tomography (CT) and/or magnetic resonance imaging (MRI) can be enrolled in this study. (Note: Phase Ia allows subjects without measurable lesions to be enrolled). Note: Measurable lesions that can be used for efficacy evaluation must meet the following conditions: a) not within areas that have previously received radiotherapy, or b) have obvious radiographic evidence of progression after completion of radiotherapy and before study enrollment;

9. To have adequate organ function, the following standards must be met:

a) Blood:

Absolute neutrophil count ≥1.5×10 ⁹ /L; platelet count ≥100×10 ⁹ /L; hemoglobin ≥90g/L (no blood transfusion, no use of granulocyte colony-stimulating factor within 14 days before screening);

b) Coagulation function:

For those who do not receive anticoagulant therapy, the international normalized ratio of prothrombin time and partial thromboplastin time are ≤1.5 times the upper limit of normal (ULN);

c) Liver:

Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤ 3.0 × ULN; ALT and AST ≤ 5 × ULN in subjects with liver metastasis; total bilirubin ≤ 1.5 ×ULN; except for subjects with Gilbert syndrome, who can be enrolled if their conjugated bilirubin is within the normal range;

d)Kidney:

Serum creatinine ≤1.5×ULN, or creatinine clearance ≥50mL/min (calculated according to the Cockcroft-Gault formula).

10. All acute toxic reactions from previous anti-tumor treatments or surgeries are alleviated to baseline, or the severity is reduced to NCI CTCAE V5.0 version ≤ grade 1 (except for alopecia or other toxicities that the researcher deems to have no safety risk);

11. Subjects (including females and males) agree to take effective contraceptive measures from the time of signing the informed consent form to 6 months after the last use of study drugs. Women of childbearing potential must have a negative serum pregnancy test within 7 days before starting treatment.

3. Exclusion criteria

Those who meet any of the following conditions will not be enrolled in this study.

1) Received systemic anti-cancer treatment within 2 weeks before the first dose of study treatment: chemotherapy, molecular targeted therapy, radiotherapy, biological therapy, hormone therapy, vaccine treatment, or anti-tumor traditional Chinese medicine treatment; or received within 4 weeks Immune checkpoint inhibitor treatment;

2) Received radical radiotherapy (including more than 25% bone marrow radiotherapy) within 4 weeks before the first dose, or received local palliative radiotherapy for bone metastases within 1 week;

3) Have received strong or moderate CYP3A or P-gp inhibitors within 1 week before the first dose, or have used the drug within 5 half-lives (whichever is longer), or need to continue to receive these during the study Subjects undergoing drug treatment; those who have received strong or moderate CYP2B6, CYP1A2, and CYP3A inducers within 4 weeks before the first dose;

4) Those who are in the treatment period of other interventional clinical studies within 4 weeks before the first dose; if they are participating in non-interventional clinical studies (such as epidemiological studies), they can be selected for this study; if they are already in the treatment period of interventional clinical studies During the follow-up period, you can also be enrolled in this study;

5) Within 1 week before the first dose, there is an active bacterial, fungal or viral infection that requires systemic treatment;

6) Subjects who have undergone major surgery (for example, inpatient surgery with local or general anesthesia) within 3 weeks before the start of study treatment;

7) Have a history of diseases that cause chronic diarrhea, including but not limited to Crohn's disease, irritable bowel syndrome, etc.;

8) Persistent diarrhea >CTCAE grade 1 within 1 week before the first dose;

9) Severe respiratory diseases, such as interstitial lung disease, radiation pneumonitis, drug-induced pneumonia, etc. (Those who have been stable for 3 months or more after recovery are allowed to be included);

10) Subjects with symptomatic central nervous system (CNS) metastasis and/or cancerous meningitis.

Note: Subjects with brain metastases who have been treated and are clinically stable can participate in the study, provided they demonstrate radiological stability (defined as 2 brain images acquired after treatment of brain metastases using the same imaging modality) . These imaging scans should be at least 4 weeks apart and not demonstrate intracranial progression. In addition, neurological symptoms induced by brain metastases or their treatment must return to baseline levels or resolve. All steroid treatment given as part of this treatment must be completed ≥3 days before study treatment administration.

11) Clinically significant cardiovascular and cerebrovascular diseases, including but not limited to:

a) Myocardial infarction or unstable angina within 6 months before the first dose;

b) Stroke or transient ischemic attack occurred within 6 months before the first dose;

c) There are any clinically significant abnormalities in the rhythm, heart rate, conduction or morphology of the resting ECG, such as complete left bundle branch block, III degree conduction block, II degree conduction block, PR interval >250 ms, etc.;

d) Hypertension that cannot be controlled after active treatment: systolic blood pressure >180mmHg or diastolic blood pressure >100mmHg;

e) Congestive heart failure (New York Heart Association cardiac function class III-IV);

f) Pericarditis or clinically significant pericardial effusion;

g) Myocarditis;

h) Before using the test drug for the first time, the 12-lead ECG shows that the mean QT interval (QTcF) is >450ms (males) or >470ms (females);

i) Subjects who use drugs that may cause QTc interval prolongation or torsade de pointes (such as antiarrhythmic drugs) cannot be interrupted during the study.

12) Clinically uncontrollable serosal effusion (such as pleural effusion that cannot be controlled by drainage or other methods).

13) There are active gastrointestinal diseases or other conditions that seriously interfere with drug absorption.

14) Any situation that affects swallowing of drugs and seriously affects the absorption or pharmacokinetic parameters of test drugs;

15) Known to be severely allergic to the study drug or any excipient;

16) Subjects who are known to have positive human immunodeficiency virus (HIV) test results and those who are positive for Treponema pallidum antibodies (except those who are cured after treatment).

17) Hepatitis B virus surface antigen (HBsAg) positive and viral deoxyribonucleic acid (HBV DNA) >2000IU/mL or 10 ⁴ copies/mL (centers that can only conduct qualitative testing, HBV DNA test results are positive or high below the lower limit of detection); those who are hepatitis C virus antibody positive and viral ribonucleic acid (HCV RNA) positive.

18) Other malignant tumors occurred within 2 years before study enrollment (except: Bowen's disease; cured basal cell or squamous cell skin cancer; prostate cancer with Gleason score 6; treated cervical carcinoma in situ).

19) Pregnant or lactating women. Lactating female subjects must stop breastfeeding before the first dose of study treatment and must not breastfeed throughout the treatment period and for 6 months after the last dose of study treatment.

20) Any serious or unstable disease (except for the above-mentioned malignant tumors), mental illness, or any disease or medical condition that the researcher believes may interfere with subject safety, obtaining informed consent, or compliance with research procedures.

Also participate in clinical studies of other experimental therapies.

4.Experimental design

Oral compound of formula (I) (provided by Qilu Pharmaceutical Co., Ltd.), once daily (QD), 10mg-240mg, every 21 days as a cycle.

5. Treatment duration and follow-up period

After the subject starts receiving treatment, there will be one treatment cycle every 3 weeks (the first treatment cycle of Phase Ia starts from C1D1) until disease progression occurs (unless the investigator believes that there is sustained clinical benefit, until the study is discontinued) drug), intolerable toxicity, voluntary withdrawal, loss to follow-up, initiation of other anti-tumor treatments, death or the investigator's judgment that the treatment needs to be terminated, whichever occurs first. The anti-tumor efficacy will be evaluated every 6 weeks (±7 days) in the first year, and then every 12 weeks (±7 days) or as clinically necessary.

The last subject who received treatment experienced disease progression (until the study drug is discontinued unless the investigator believes there is sustained clinical benefit), intolerable toxicity, voluntary withdrawal, loss to follow-up, initiation of other anti-tumor treatments, The clinical study will end in the event of death, the investigator's judgment that treatment needs to be terminated, or the maximum medication time from the first medication being 2 years, whichever occurs first.

All subjects will be followed for survival assessment after receiving the last dose of study drug until the end of the study, or for up to 1 year, whichever occurs first. During this period, subjects will be followed up for overall survival by telephone or other electronic contact methods every 3 months.

6.Evaluation criteria

Security assessment:

The clinical safety of study treatments should be evaluated according to NCI CTCAE version 5.0 throughout the study period. Subjects' AEs need to be assessed at each clinical visit. The eCRF should record the start and end time of the AE, severity classification, correlation with the study drug and its therapeutic impact on the study drug, the presence or absence of concomitant treatments, and outcome status, etc.

Effectiveness assessment:

Wrong use will be made! Reference source not found. Specify and evaluate target and non-target lesions. ORR = Complete Response (CR) + Partial Response (PR), Disease Control Rate (Disease Control Rate, DCR) = CR + PR + Stable Disease (SD). Subjects in remission (CR or PR) need to be re-evaluated 4 weeks (+7 days) after the first evaluation of CR or PR for efficacy confirmation.

For study participants, radiographic evaluation results (including screening studies) will need to be collected for center review and will be detailed in a separate radiology charter.

7. Study endpoints

Primary endpoint:

1) Safety parameters: AE, SAE, abnormal laboratory results, ECG changes and vital signs, etc.;

2) ORR (blinded independent center imaging evaluation based on RECIST v1.1 for NSCLC patients carrying EGFR-C797S mutation).

secondary endpoint

1) PK parameters of compounds of formula (I) in patients with advanced EGFR mutation NSCLC;

2) Effectiveness:

●ORR (according to RECIST v1.1);

●DoR (according to RECIST v1.1);

●DCR (according to RECIST v1.1);

●PFS (according to RECIST v1.1);

●OS.

3) Safety parameters: AE, SAE, abnormal laboratory results, ECG changes and vital signs, etc.;

exploratory endpoint

1) Factors that may affect the development of NSCLC and/or biomarkers for the efficacy, tolerability or safety of compounds of formula (I);

2) The relationship between blood drug concentration and QTcF;

3) PK characteristics of QLH11811 and its metabolites in cerebrospinal fluid;

4) Intracranial objective response rate (CORR).

8.Experimental results

8.1 Security assessment

As of August 16, 2023, a total of 30 subjects had been enrolled in the 10-160 mg dose group of the compound of formula (I). As of August 18, 2023, a total of 250 TEAEs had occurred in 26 subjects, with an incidence rate of 86.7%. TEAEs related to compounds of formula (I) occurred in 26 subjects, with an incidence rate of 86.7%. TRAEs with higher incidence rates include diarrhea (70.4%), increased AST (29.6%), increased ALT (25.9%), Weight loss (29.6%), etc. During the treatment period, a total of 7 SAEs occurred in 5 subjects, including disease progression (4 cases), dyspnea (1 case), general fatigue (1 case) and pulmonary infection (1 case), of which systemic Fatigue may be related to the study drug. The other 6 SAE cases may be related to underlying diseases and may/definitely not be related to the study drug. A total of 3 DLT events occurred in 3 subjects: 07003 (80 mg) grade 3 hypokalemia, which returned to normal after 1 day of drug treatment; 01008 (160 mg) missed ≥20% of the planned dosage during the DLT observation period due to AE ;07007 (160mg) Grade 3 nausea, vomiting, and loss of appetite, which were relieved to Grade 1 after treatment. The overall safety information is shown in Table 3. From the safety assessment results, it can be concluded that the compound of formula (I) is safe and well tolerated.

8.2 Effectiveness evaluation

As of August 29, 2023, a total of 23 subjects in the 10-160mg dosage group had completed at least one treatment evaluation (6 weeks). The BOR results were 1 PR, 18 SD, 4 PD, and DCR 82.6%.

Among them, the gene mutation types of subjects with PR efficacy are 19del/T790M/C797S mutation, and the gene mutation types of subjects with SD efficacy include L858R mutation, 19del mutation, 19del/C797S mutation, and 19del/T790M/C797S. L861Q mutation, 19del/T790M/C797S mutation, L858R/C797S mutation, 19del/T790M mutation.

Table 4 Efficacy evaluation results

Among the above treatment evaluation results, a total of 9 subjects with C797S mutation completed at least one treatment evaluation. The results are as follows:

Table 5 Efficacy evaluation results of subjects with C797S mutation

Among the subjects whose curative effect is PR, the gene mutation type is 19del/T790M/C797S mutation, and the subjects whose curative effect is SD have gene mutation types including 19del/T790M/C797S mutation, 19del/C797S mutation, and 19del/T790M/C797S. L861Q mutation, L858R mutation, L858R/C797S mutation, 19del/T790M mutation.

The above therapeutic evaluation results show that the compound of formula (I) provided by the present disclosure has a good curative effect on advanced or metastatic NSCLC that progresses after EGFR-TKI treatment. Advanced NSCLC and NSCLC carrying EGFR mutation-sensitive mutations (19del or 21L858R) all have good curative effects; especially late-stage NSCLC carrying EGFR C797S mutations, such as NSCLC with 19del/T790M/C797S mutations, have good curative effects; in addition In addition, it also has good curative effect on NSCLC carrying rare mutated genes such as L861Q mutation.

Claims (40)

1. A method of treating advanced or metastatic NSCLC, characterized by administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
   
2. The treatment method according to claim 1, wherein the advanced or metastatic NSCLC refers to advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI.
3. The treatment method according to claim 2, characterized in that said EGFR-TKI treatment refers to anti-tumor treatment of first generation, second generation or third generation EGFR-TKI.
4. The treatment method according to claim 2, characterized in that the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment is an advanced NSCLC that progresses after EGFR-TKI treatment and carries the EGFR C797S mutation.
5. The treatment method according to claim 2, characterized in that the advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI is advanced NSCLC that progresses after standard treatment and has no other additional driver gene mutations.
6. The treatment method according to claim 2, characterized in that the advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI is an advanced NSCLC that carries the EGFR T790M mutation after treatment with EGFR-TKI.
7. The treatment method according to claim 1, wherein the advanced or metastatic NSCLC refers to advanced or metastatic NSCLC that has progressed without EGFR-TKI treatment.
8. The treatment method according to claim 7, characterized in that the advanced or metastatic NSCLC that has progressed without EGFR-TKI treatment is an EGFR mutation-sensitive mutation (19del or 21L858R) that has not been treated with EGFR-TKI. of locally advanced inoperable or recurrent metastatic NSCLC.
9. The treatment method according to claim 1, wherein the advanced or metastatic NSCLC is an advanced or metastatic NSCLC carrying a rare mutation of EGFR after treatment with EGFR-TKI.
10. The treatment method of claim 9, characterized in that the rare EGFR mutations are EGFR L861Q, EGFR S768I, and EGFR G719X mutations.
11. The treatment method according to any one of claims 1 to 10, wherein the late-stage or metastatic NSCLC is NSCLC with brain metastasis.
12. The treatment method according to any one of claims 1 to 11, wherein the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 40 mg to 160 mg.
13. The treatment method according to any one of claims 1 to 12, wherein the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 80 mg to 160 mg.
14. The treatment method according to any one of claims 1 to 13, wherein the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 120 mg to 160 mg.
15. The treatment method according to any one of claims 1 to 14, wherein the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.
16. The treatment method according to any one of claims 1 to 15, wherein the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 120 mg.
17. The treatment method according to any one of claims 1 to 16, wherein the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 160 mg.
18. The treatment method according to any one of claims 1 to 17, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
19. The treatment method according to any one of claims 1 to 18, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is suitable for oral administration.
20. The treatment method according to any one of claims 1 to 19, wherein the pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride.
21. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of advanced or metastatic NSCLC:
    
22. The use according to claim 21, wherein the advanced or metastatic NSCLC refers to advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI.
23. The use according to claim 22, characterized in that the EGFR-TKI treatment refers to the anti-tumor treatment of first generation, second generation or third generation EGFR-TKI.
24. The use according to claim 22, characterized in that the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment is an advanced NSCLC that progresses after EGFR-TKI treatment and carries the EGFR C797S mutation.
25. The use according to claim 22, characterized in that the advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI is an advanced NSCLC that progresses after standard treatment and has no other additional driver gene mutations.
26. The use according to claim 22, characterized in that the advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI is an advanced NSCLC that carries the EGFR T790M mutation after treatment with EGFR-TKI.
27. The use according to claim 20, wherein the advanced or metastatic NSCLC refers to advanced or metastatic NSCLC that has progressed without EGFR-TKI treatment.
28. The use according to claim 27, characterized in that the advanced or metastatic NSCLC that has not progressed after EGFR-TKI treatment is an EGFR mutation-sensitive mutation (19del or 21L858R) that has not been treated with EGFR-TKI. Locally advanced inoperable or recurrent metastatic NSCLC.
29. The use according to claim 20, characterized in that the late-stage or metastatic NSCLC refers to late-stage or metastatic NSCLC carrying rare mutations of EGFR after treatment with EGFR-TKI.
30. The use according to claim 29, characterized in that the rare EGFR mutations are EGFR L861Q, EGFR S768I, and EGFR G719X mutations.
31. The use according to any one of claims 20 to 30, characterized in that the late-stage or metastatic NSCLC is NSCLC with brain metastasis.
32. The use according to any one of claims 20 to 31, wherein the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 40 mg to 160 mg.
33. The use according to any one of claims 20 to 32, characterized in that the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 80 mg to 160 mg.
34. The use according to any one of claims 20 to 33, wherein the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 120 mg to 160 mg.
35. The use according to any one of claims 20 to 34, characterized in that the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.
36. The use according to any one of claims 20 to 35, characterized in that the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 120 mg.
37. The use according to any one of claims 20 to 36, characterized in that the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 160 mg.
38. The use according to any one of claims 20 to 37, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
39. The use according to any one of claims 20 to 38, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is suitable for oral administration.
40. The drug according to any one of claims 20 to 39, characterized in that the pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride.