Fused tetracyclic quinazoline derivative for use in the treatment of central nervous system (CNS) metastasis

Abstract

The present disclosure relates generally to methods for treating or preventing central nervous system (CNS) metastases with an ERBB2 inhibitor, and more specifically to treating CNS metastases with a fused tetracyclic quinazoline derivative.

Description

Docket No.: 18407-20027.40FUSED TETRACYCLIC QUINAZOLINE DERIVATIVE AND USES THEREOF FIELD OF THE INVENTION

[0001] The present disclosure relates generally to methods for treating or preventing central nervous system (CNS) metastases with an ERBB2 inhibitor, and more specifically to treating CNS metastases with a fused tetracyclic quinazoline derivative.BACKGROUND

[0002] Brain metastases represent a significant issue for patients with cancer, such as non-small cell lung cancer (NSCLC) and metastatic breast cancer (BRC). Up to 20% of patients with NSCLC have brain metastases at diagnosis, and up to 50% of patients with NSCLC and HER2-driven BRC have CNS involvement upon disease progression, which significantly impacts their longevity and quality of life. Unfortunately, approved large molecule HER-targeted drugs such as antibodies and antibody-drug conjugates (ADCs) do not cross the blood brain barrier (BBB) in sufficient levels to confer maximal activity in the CNS. The challenge with existing approved tyrosine kinase inhibitors (TKIs) is that they are substrates of efflux transporters, such as P-gp and BCRP, or have a narrow therapeutic index as exemplified by the dual EGFR / HER2 inhibitors, thereby limiting their ability to achieve sufficient drug exposures for activity in the CNS. Accordingly, what is needed is a compound useful in the treatment of CNS metastasis, and more particularly a compound useful in the treatment of CNS metastasis from a cancer comprising cells or cell tissue having increased ErbB2 kinase activity.SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein is a method of treating or preventing central nervous system (CNS) metastasis in a subject in need thereof, the method comprisingadministering Compoundpharmaceutically acceptable salt thereof, to the subject.1ny-2881318Docket No. : 18407-20027.40

[0004] In some embodiments, the method is for treating CNS metastasis. In some embodiments, the method is for preventing CNS metastasis.

[0005] In some embodiments, the CNS metastasis is brain metastasis. In some embodiments, the CNS metastasis is spinal metastasis.

[0006] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having increased ErbB2 kinase activity as compared to a control. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2 selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV, G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGC G776_V777insLeu, G776_V777insVGS, G778_S779InsCPG, V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, G778_S779insAVG, A775_G776insYVMA, S760del, L755S, G776VC, V777L, and G776delinsIC. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2 selected from the group consisting of A775_G776insYVMA, S760del, L755S, G776VC, V777L, G776delinsIC, and L755P.

[0007] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations selected from the group consisting of TP53 S94*, PTENR130Q, and GNAS R201C.

[0008] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having HER2 amplification or HER2 overexpression.

[0009] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more disease-associated point mutations in ErbB2. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more point mutations that introduce: (a) an 2ny-2881318Docket No. : 18407-20027.40amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, VI 1281, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R,Y803F, H878Y, R896G, and El 195G; or (b) a frameshift at A1232. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having, expressing, or over-expressing amino terminally truncated carboxyl-terminal fragments of HER2.

[0010] In some embodiments, the CNS metastasis is a CNS metastasis from lung, glioma, skin, head and neck, salivary gland, breast, esophageal, liver, stomach (gastric), uterine, cervical, biliary tract, pancreatic, colorectal, renal, bladder, or prostate cancer. In some embodiments, the CNS metastasis is a CNS metastasis from lung, head, or breast cancer. In some embodiments, the CNS metastasis is a CNS metastasis from non-small cell lung cancer.

[0011] In some embodiments, the patient has received at least one, at least two, or at least three prior therapies for the cancer. In some embodiments, the one or more of the prior therapies are selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib.

[0012] In some embodiments, the method further comprises administering one or more additional anti -cancer agents. In some embodiments, the method further comprises administering an anti-HER2 antibody or an anti-HER2 drug conjugate. In some embodiments, the method further comprises administering KADCYLA® (ado-trastuzumab emtansine), ENHERTU® (fam-trastuzumab deruxtecan-nxki), any biosimilar thereof, or any combination thereof.

[0013] In some embodiments, Compound 1 or the therapetuically acceptable salt thereof administered to the patient at a once daily dose of an amount equivalent to about 90 mg, about 180 mg, or about 270 mg of Compound 1 in the free baseform; or at a twice daily dose of an amount equivalent to about 45 mg each, about 90 mg each, about 135 mg each, or about 180 mg each of Compound 1 in the freebase form.

[0014] In some embodiments, Compound 1 or the therapetuically acceptable salt thereof administered to the patient at a once daily dose of an amount equivalent to about 270 mg of3ny-2881318Docket No. : 18407-20027.40Compound 1 in the freebase form; or at a twice daily dose of an amount equivalent to about 135 mg each of Compound 1 in the freebase form.

[0015] In some embodiments, the subject is human.DESCRIPTION OF THE FIGURES

[0016] The present application can be understood by reference to the following description taken in conjunction with the accompanying figure(s).

[0017] FIG. 1 depicts bioluminescence intensity over treatment days in NCI-N87 intracranial Human Tumor Xenograft Model.DETAILED DESCRIPTION

[0018] The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims. Where individual embodiments are disclosed, it should be appreciated that this disclosure is not limiting and that all embodiments may be combined. It should also be noted that references to methods of treatment herein should be read as equivalent to compounds and / or compositions for use in said methods of treatment.

[0019] The terms “individual”, “subject” and “patient” refer to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, subject refers to human.

[0020] As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0021] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration.4ny-2881318Docket No. : 18407-20027.40

[0022] As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0023] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such5ny-2881318Docket No. : 18407-20027.40as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0024] “Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment.

[0025] “Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease.

[0026] The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0027] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0028] In need of treatment” or “in need of prevention” as used herein means the subject is being treated by a physician or other caregiver after diagnoses of the disease, or a determination that the subject is at risk for developing the disease.6ny-2881318Docket No.: 18407-20027.40

[0029] “Administration”, “administer,” and the like, as they apply to, for example, a subject, refer to contact of, for example, Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, to the subject.

[0030] In one aspect, provided herein is a method of treating or preventing central nervous system (CNS) metastasis in a subject in need thereof, the method comprising administering (E)-l-((10S)-4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-2-fluoro-5-methylphenyl)amino)-7, 8, 10,11 -tetrahydro-9H-6, 10-methanopyrimido[4',5 ' : 5,6]pyrido[3 ,2-b][l,4,7]oxadiazonin-9-yl)-4-(dimethylamino)but-2-en-l-one (Compound 1;pharmaceutically acceptable salt thereof, to the subject. Compound 1 and pharmaceutically acceptable salts may be prepared by a variety of procedures known in the art. Compound 1 and an exemplary method of making Compound 1 are described in International Patent Application Publication No.WO2023081637, which is incorporated herein by reference in its entirety.

[0031] In some embodiments, the method is for treating CNS metastasis. In some embodiments, the method is for preventing CNS metastasis. In some embodiments, the CNS metastasis is brain metastasis. In some embodiments, the CNS metastasis is spinal metastasis. In some embodiments, the CNS metastasis is both brain metastasis and spinal metastasis.

[0032] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having increased ErbB2 kinase activity as compared to a control. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2 selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV,7ny-2881318Docket No. : 18407-20027.40G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGC G776_V777insLeu, G776_V777insVGS, G778_S779InsCPG, V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, G778_S779insAVG, A775_G776insYVMA, S760del, L755S, G776VC, V777L, and G776delinsIC. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2 selected from the group consisting of A775_G776insYVMA, S760del, L755S, G776VC, V777L, G776delinsIC, and L755P.

[0033] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations selected from the group consisting of TP53 S94*, PTENR130Q, and GNAS R201C.

[0034] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having HER2 amplification or HER2 overexpression. In some embodiments, HER2 amplification is HER2 gene amplification, and can be determined with a method known in the art. In some embodiments, HER2 overexpression can be determined with a method known in the art. In some embodiments, HER2 overexpression is defined as immunohistochemistry (IHC) score of IHC3+ or IHC2+ / ISH+.

[0035] In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more disease-associated point mutations in ErbB2. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more point mutations that introduce: (a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, VI 1281, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R,Y803F, H878Y, R896G, and El 195G; or (b) a frameshift at A1232. In some embodiments, the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having, expressing, or over-expressing amino terminally truncated carboxyl-terminal fragments of HER2.

[0036] In some embodiments, the CNS metastasis is a CNS metastasis from lung, glioma, skin, head and neck, salivary gland, breast, esophageal, liver, stomach (gastric), uterine,8ny-2881318Docket No. : 18407-20027.40cervical, biliary tract, pancreatic, colorectal, renal, bladder, or prostate cancer. In some embodiments, the CNS metastasis is a CNS metastasis from lung, head, or breast cancer. In some embodiments, the CNS metastasis is a CNS metastasis from non-small cell lung cancer.

[0037] In some embodiments, the patient has received at least one, at least two, or at least three prior therapies for the cancer. In some embodiments, the one or more of the prior therapies are selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib.

[0038] In some embodiments, the method further comprises administering one or more additional anti -cancer agents. In some embodiments, the method further comprises administering an anti-HER2 antibody or an anti-HER2 drug conjugate. In some embodiments, the method further comprises administering KADCYLA® (ado-trastuzumab emtansine), ENHERTU® (fam-trastuzumab deruxtecan-nxki), any biosimilar thereof, or any combination thereof.

[0039] In some embodiments, the subject is human.

[0040] In some embodiments, Compound 1 or the therapetuically acceptable salt thereof administered to the patient at a once daily dose of an amount equivalent to about 90 mg, about 180 mg, or about 270 mg of Compound 1 in the free baseform; or at a twice daily dose of an amount equivalent to about 45 mg each, about 90 mg each, about 135 mg each, or about 180 mg each of Compound 1 in the freebase form.

[0041] In some embodiments, Compound 1 or the therapetuically acceptable salt thereof administered to the patient at a once daily dose of an amount equivalent to about 270 mg of Compound 1 in the freebase form; or at a twice daily dose of an amount equivalent to about 135 mg each of Compound 1 in the freebase form.

[0042] In some embodiments, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and / or a therapeutically effective amount of one or more additional anti -cancer agents are administered. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and / or one or more additional anti-cancer agents are administered by any of the accepted modes of administration. In some embodiments, administration is oral, systemic (e.g. transdermal, intranasal, or by suppository), or parenteral9ny-2881318Docket No. : 18407-20027.40(e.g. intramuscular, intravenous, or subcutaneous). In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, is preferably oral.

[0043] In some embodiments, there is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% reduction in the CNS metastasis. In some embodiments, there is about 100% reduction in the CNS metastasis. In some embodiments, the CNS metastasis is completely eliminated.

[0044] In some embodiments, there is at least about about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% reduction in the size of the CNS metastasis. In some embodiments, there is about 100% reduction in the size of the CNS metastasis. In some embodiments, reduction in the size of the CNS metastasis is measured by a reduction in length, area, or volume of brain lesions. In some embodiments, the reduction in the size of the CNS metastasis is measured as the % change in the sum of the longest diameters of measurable brain lesions. In some embodiments, the reduction in the size of the CNS metastasis is measured as the % change in the sum of measurable brain lesion volume.

[0045] In some embodiments, the method reduces one or more symptoms of the CNS metastasis. In some embodiments, the one or more symptoms are selected from the group consisting of headache, mental changes, seizures, weakness or numbness on one side of the body, vision changes, difficulty speaking or understanding language, and loss of balance.

[0046] In some embodiments, the subject receiving the treatment has one or more symptoms associated with CNS metastasis. In some embodiments, the one or more symptoms are selected from the group consisting of headache, mental changes, seizures, weakness or numbness on one side of the body, vision changes, difficulty speaking or understanding language, and loss of balance.10ny-2881318Docket No. : 18407-20027.40EXAMPLES

[0047] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.Example 1: Anti-Tumor Activity of Compound 1 in the NCI-N87 intracranial Human Tumor Xenograft Model

[0048] Compound 1 was evaluated for in vivo activity in the human gastric carcinoma NCI-N87 (HER2WTamplified) intracranial model. BALBc / nude mice were each injected with 2* 105luciferase-expressing NCI-N87 cells into the right forebrain and tumor size was measured as a function of bioluminescent signal obtained from imaging (IVIS Lumina III). Mice were imaged approximately every 4 days to monitor tumor growth and randomized to the treatment groups (10 animals per group) when the luminescent signal had reached 8 photons / s *106. Compound 1 was administered via oral gavage in 5% TPGS in H2O (pH 4.0) at 10, 20, and 50 mg / kg once daily (i.e., QD). The comparator tucatinib was administered via oral gavage in 0.5% methylcelluose in water at 50 and 75 mg / kg twice daily (i.e., BID; achieving approximately 4.5 x and 12x its human exposure at its approved dose of 300 mg BID). Compound 1 treatment resulted in tumor suppression including regressions at all doses tested, whereas tucatinib only elicited moderate tumor growth inhibition but no regressions at both doses evaluated, as summarized in FIG. 1. Tucatinib exposures in this mouse model were 40- and 100-fold higher than exposures of Compound 1 at 10 mg / kg QD, and yet Compound 1 treatment at 10 mg / kg QD resulted in superior CNS anti-tumor activity.Example 2: Clinical study results

[0049] This Example summarizes the clinical study results for Compound 1 with respect to the treatment of brain metastasis in patients with HER2 mutant cancer. As of 14 February 2025, there were 14 patients enrolled with measurable brain metastasis at baseline per Investigator assessment. The baseline characteristics and dosage of Compound 1 administered of each patient are shown in Table 1. The primary solid tumor site for three patients was breast, for one patient was head and neck, and for ten patients was lung. All patients had at least one HER2 mutation, HER2 amplification, or HER2 overexpression.Table 1: Baseline patient characteristics and Compound 1 dosage11ny-2881318Docket No. : 18407-20027.40&*BID=twice daily; QD=once daily.

[0050] The efficacy results for these 14 patients with brain metastasis at baseline is shown in Table 2. Twelve of these 14 patients were evaluable for best percent change in brain lesion size. Nine of the evaluable patients (i.e., 9 / 12 or 75%) had either zero (i.e., indicating no change in brain lesion) or a negative (i.e., indicating a reduction in brain lesion) best percent change in brain lesion size. Among these 9 patients, 6 had a negative best percent change in brain lesion.

[0051] Thirteen of the 14 patients were evaluable for best objective response. Of the 13 patients, the best objective response for 2 patients was a partial response (1 confirmed, i.e., cPR, and 1 unconfirmed, i.e., unPR), and the best objective response for 7 patients was stable disease (SD). Among the patients with SD, one patient with lung cancer remains with stable disease and still on study at 12.9 months.Table 2: Efficacy results12ny-2881318Docket No. : 18407-20027.40*PD=progressive disease; SD=stable disease; cPR=confirmed partial response; unPR=unconfirmed partial response.

[0052] There were no significant safety signals of note specific to brain metastasis patients.13ny-2881318

Claims

Docket No.: 18407-20027.40CLAIMSWhat is claimed is:

1. A method of treating or preventing central nervous system (CNS) metastasis in a subject in need thereof, the method comprising administering Compound 1pharmaceutically acceptable salt thereof, to the subject.

2. The method of claim 1, wherein the method is for treating CNS metastasis.

3. The method of claim 1, wherein the method is for preventing CNS metastasis.

4. The method of any one of claims 1-3, wherein the CNS metastasis is brain metastasis.

5. The method of any one of claims 1-3, wherein the CNS metastasis is spinal metastasis.

6. The method of any one of claims 1-5, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having increased ErbB2 kinase activity as compared to a control.

7. The method of any one of claims 1-6, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2.

8. The method of any one of claims 1-7, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2 selected from the group consisting of A775_A776insYVMA, A775_A776insAYVM, A775_A776insYVMS, A775_A776insVVMA, A775_A776insMMAY, A775_A776insYVMA-R678Q, G778_P780insGSP, G776delinsVC, P780_Y781insGSP, M774delinsWLV, A775_G776insSVMA, A775_G776insI, G776delinsLC, G776delinsLV, G776delinsVV, G776insIC, G776delinsCVC, G776delinsAVGS, G776delinsAVGA, G776delinsAVGC G776_V777insLeu, G776_V777insVGS, G778_S779InsCPG, V777_G778insGSP, V777_G778insGC, V777_G778insCG, V777_G778insQ, V777_G778insG, G778_S779insLPS, G778_S779insAVG, A775_G776insYVMA, S760del, L755S, G776VC, V777L, and G776delinsIC.14ny-2881318Docket No. : 18407-20027.

409. The method of any one of claims 1-7, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations in Exon 20 of the ErbB2 selected from the group consisting of A775_G776insYVMA, S760del, L755S, G776VC, V777L, G776delinsIC, and L755P.

10. The method of any one of claims 1-9, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more mutations selected from the group consisting of TP53 S94*, PTENR130Q, and GNAS R201C.

11. The method of any one of claims 1-10, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having HER2 amplification or HER2 overexpression.

12. The method of any one of claims 1-11, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more disease-associated point mutations in ErbB2.

13. The method of any one of claims 1-12, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having one or more point mutations that introduce:(a) an amino acid substitution selected from the group consisting of P122L, R217C, I263T, A293T, S305C, S310F / Y / P, H470Q, I655V, V659E / D, L674F, G660D, R678Q / C, L755R / S / P / Y / M, I767M, D769H / N / Y, V777L / M, V842I, R868W, H878Y, E930K / D, E1021Q, F1030C, VI 1281, N1219S, G222C, A1057V, V842I, G776S / C / V / A, V773M, L869R,Y803F, H878Y, R896G, andE1195G; or(b) a frameshift at A1232.

14. The method of any one of claims 1-13, wherein the CNS metastasis is a CNS metastasis from a cancer comprising cells or cell tissue having, expressing, or over-expressing amino terminally truncated carboxyl -terminal fragments of HER2.

15. The method of any one of claims 1-14, wherein the CNS metastasis is a CNS metastasis from lung, glioma, skin, head and neck, salivary gland, breast, esophageal, liver, stomach (gastric), uterine, cervical, biliary tract, pancreatic, colorectal, renal, bladder, or prostate cancer.

16. The method of any one of claims 1-14, wherein the CNS metastasis is a CNS metastasis from lung, head, or breast cancer.

17. The method of any one of claims 1-14, wherein the CNS metastasis is a CNS metastasis from non-small cell lung cancer.15ny-2881318Docket No. : 18407-20027.4018. The method of any one of claims 1-17, wherein the patient has received at least one, at least two, or at least three prior therapies for the cancer.

19. The method of claim 18, wherein the one or more of the prior therapies are selected from the group consisting of lapatinib, neratinib, afatinib, pyrotinib, poziotinib, TAK-788, and tucatinib.

20. The method of any one of claims 1-19, wherein the method further comprises administering one or more additional anti-cancer agents.

21. The method of any one of claims 1-20, wherein the method further comprises administering an anti-HER2 antibody or an anti-HER2 drug conjugate.

22. The method of any one of claims 1-21, wherein the method further comprises administering KADCYLA® (ado-trastuzumab emtansine), ENHERTU® (fam-trastuzumab deruxtecan-nxki), any biosimilar thereof, or any combination thereof.

23. The method of any one of claims 1-22, wherein Compound 1 or the therapetuically acceptable salt thereof administered to the patient at a once daily dose of an amount equivalent to about 90 mg, about 180 mg, or about 270 mg of Compound 1 in the free baseform; or at a twice daily dose of an amount equivalent to about 45 mg each, about 90 mg each, about 135 mg each, or about 180 mg each of Compound 1 in the freebase form.

24. The method of any one of claims 1-22, wherein Compound 1 or the therapetuically acceptable salt thereof administered to the patient at a once daily dose of an amount equivalent to about 270 mg of Compound 1 in the freebase form; or at a twice daily dose of an amount equivalent to about 135 mg each of Compound 1 in the freebase form.

25. The method of any one of claims 1-24, wherein the subject is human.16ny-2881318

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