Combination of BLU-945 and osimertinib for treating non-small cell lung cancer

Abstract

The present disclosure provides an improved method of treating non-small cell lung cancer using N-(2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl) pyrimidin-4-yl)-5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) methyl) azetidin-1-yl) isoquinolin-3-amine represented by the following structure: # imgabs 0 #, or a pharmaceutically acceptable salt thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 322,371, filed on March 22, 2022, U.S. Provisional Application Serial No. 63 / 417,489, filed on October 19, 2022, and U.S. Provisional Application Serial No. 63 / 421,516, filed on November 1, 2022. The entire contents of the above applications are incorporated herein by reference. Background Art

[0003] As the most common oncogenic driver of non-small cell lung cancer (NSCLC), epidermal growth factor receptor mutation (EGFRm) is present in approximately 17% of Caucasians and up to 50% of Asian patients (Zhang YL et al. Oncotarget. 2016; 7:78985-78993; Shi Y et al. J Thorac Oncol. 2014; 9:154-162), among which the most common are exon 19 deletion (ex19del) and L858R (Leonetti A et al. Br J Cancer. 2019; 121:725-737).

[0004] The use of tyrosine kinase inhibitors (TKIs) such as osimertinib has prolonged survival, but resistance eventually develops through multiple on-target and off-target mutations that are often present simultaneously in different clones within individual patients. The most common resistance mutations during treatment are EGFR T790M (after the first [1G] and second [2G] generation TKIs) and EGFR C797S (after the third [3G] generation TKIs) (Niederst MJ et al. Clin Cancer Res. 2015; 21: 3924-3933). Currently, there are no approved targeted therapies after progression on 3G TKIs, including those that simultaneously target C797S and T790M (Park S et al. Cancer Res Treat. 2020; 52: 1288-1290).

[0005] An additional advance in the treatment paradigm for EGFRm NSCLC is to prevent the emergence of multiple resistance mutations in the absence of treatment (Planchard D et al. ESMO Open. 2021; 6:100271; Cho BC et al. Future Oncol. 2022; 18:639-647), and multiple combination studies are currently underway to address this heterogeneity (Yu H et al. Ann Oncol. 2021; 32(Suppl 5):S978-979; Miura S et al. J Thorac Oncol. 2021; 16(Suppl 1):S890-891; Bauml J et al. J Clin Oncol. 2021; 39(Suppl 15):9006).

[0006] International Application Publication No. WO 2021 / 133809 (the entire contents of which are incorporated herein by reference) discloses N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (also referred to herein as "BLU-945" or N-{2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl}-8-[(2R,3S)-3-(methylsulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinolin-3-amine) as shown below.

[0007]

[0008] BLU-945 is an investigational, oral, next-generation EGFR TKI designed to target clones carrying EGFR T790M (regardless of whether it is a driver mutation), including clones carrying C797S (Schalm SS et al. Annals of Oncology. 2020; 31: S839). In addition, it inhibits L858R regardless of the presence of T790M and C797S mutations at clinically relevant exposure levels. BLU-945 targets common EGFR activating mutations (such as ex19del and L858R) as well as T790M and C797X resistance mutations, while being selective for EGFR wild-type (WT).

[0009] The high selectivity of BLU-945 allows mutation targeting without inhibiting wild-type (WT) EGFR, which can be combined with other TKIs to address multiple resistance mechanisms without increasing toxicity. BLU-945 demonstrated in vivo antitumor monotherapy activity in both untreated EGFRm xenografts and osimertinib-resistant EGFRm models carrying C797S (Miura S et al. J Thorac Oncol. 2021; 16(Suppl): S890-891), regardless of the presence of T790M (Lim SM et al. Cancer Res. 2021; 81: 1467-1467; Tavera L et al. AACR 2022 presentation; poster #3328).

[0010] In osimertinib-resistant tumor models, BLU-945 showed enhanced anti-tumor activity when combined with complementary EGFR TKIs such as osimertinib (Tavera L et al. Lung Cancer. 2022; 165(Suppl 1):S78) and next-generation EGFR TKI BLU-701 (Tavera L et al. AACR 2022 presentation; poster #3328). Summary of the invention

[0011] Disclosed herein are improved methods for treating subjects with non-small cell lung cancer using N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof. The present disclosure provides a dosing regimen of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine for treating non-small cell lung cancer. More specifically, provided herein is a method of treating a subject with non-small cell lung cancer (NSCLC) by orally administering to the patient an amount of 200 mg to 1000 mg of N-(2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine daily. Alternatively, an amount of 100 mg to 1000 mg of N-(2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is orally administered daily. It is an object of the present disclosure to provide new methods for treating subjects with non-small cell lung cancer using a safe and effective daily dose.

[0012] In one aspect, the present disclosure provides a method of treating a subject having NSCLC, comprising orally administering to a subject in need thereof an effective amount of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, and concurrently administering an effective amount of osimertinib.

[0013] In some embodiments, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine represented by the following structure is administered daily in an amount of 200 mg to 1000 mg:

[0014] or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine. Alternatively, an amount of 100 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine per day is administered.

[0015] The present disclosure also provides the use of 200 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine in the preparation of a daily oral medicament for the treatment of non-small cell lung cancer (NSCLC). Alternatively, 100 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is used daily. In certain embodiments, the drug is used in combination with an effective amount of osimertinib.

[0016] In another aspect, provided herein is 200 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine for daily oral treatment of a subject with NSCLC, optionally in combination with an effective amount of osimertinib. Alternatively, provided herein is 100 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine for daily oral treatment of a subject with NSCLC, optionally in combination with an effective amount of osimertinib. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The study design of the ongoing Phase 1 / 2, open-label, first-in-human study (NCT04862780) is presented. ctDNA, circulating tumor DNA; DUSP6, dual-specificity phosphatase 6; ECG, electrocardiogram; ECOGPS, Eastern Cooperative Oncology Group performance status; EGFRm, mutant epidermal growth factor receptor gene; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; QD, once daily; RP2D, recommended phase 2 dose; SPRY4, antagonist of sprouted RTK signaling 4; TKI, tyrosine kinase inhibitor.

[0018] a Based on Bayesian Optimal Interval (BOIN) ramp-up design; b BID dosing will also be evaluated; c Part 1B and Phase 2 have not yet started and are dependent on the results of Part 1A.

[0019] Figure 2AShown is a reduction in EGFR T790M ctDNA levels after BLU-945 treatment*. Figure 2B Shown is a reduction in EGFR C797S ctDNA levels after BLU-945 treatment*.

[0020] * Patient has two different DNA mutations in C797S. Note: Decreases in fraction of a single variant allele are shown; therefore, patients with multiple mutations may be represented in both graphs. All T790M and C797S allele fractions with available baseline and C1D15 data are shown. Increases greater than 100% are truncated at 100%.

[0021] Figure 3 Shows dose-dependent tumor shrinkage after BLU-945 treatment a,b . a Patients with measurable target lesions at baseline and scans after baseline; b The data deadline is March 9, 2022.

[0022] Figure 4 Longitudinal ctDNA analysis of two patients is presented.

[0023] Figure 5 The dose escalation data of BLU-945 monotherapy are presented, showing the reduction of EGFR C797SctDNA levels (left) and tumor shrinkage (right) after BLU-945 treatment. BID = twice daily; C1D1 = cycle 1 day 1; C1D15 = cycle 1 day 15; PD = progressive disease; PR = partial response; SD = stable disease; VAF = variant allele fraction.

[0024] Figure 6is a bar graph showing the change in EGFR variant allele fraction in ctDNA from baseline to C1D15 while receiving BLU-945 monotherapy. Abbreviations: BID = twice daily; EGFR = epidermal growth factor receptor; FMI = functional math index; QD = once daily; VAF = variant allele fraction. The change in EGFR-T790M and EGFR-C797S variant allele fraction (VAF) at C1D15 was calculated using each patient's pre-treatment baseline (C1D1) VAF. The identity of the baseline (C1D1) EGFR mutation detected (using the FMI F1LCDx assay) is detailed below each graph. *Indicates that the patient was detected to have two different DNA molecules that result in the same protein alteration. In this case, the VAF change for each corresponding DNA molecule is plotted separately, so multiple bars on each graph may belong to the same patient. ^Indicates that the patient's C2D1 sample was used for analysis instead of C1D15, and in addition, the LR mutation was not detected at baseline (C1D1).

[0025] Figure 7 is a bar graph showing the sum of target lesion diameters by initial dose level for patients receiving BLU-945 monotherapy ≥ 400 mg / day. Abbreviations: BID = twice daily; QD = once daily. Maximum percent reduction was calculated before disease progression.

[0026] Figure 8 is a bar graph showing the change in EGFR variant allele fraction in ctDNA from baseline to C1D15 with the combination of BLU-945 and osimertinib. Abbreviations: BID = twice daily; EGFR = epidermal growth factor receptor; FMI = functional math index; osi = osimertinib; QD = once daily; VAF = variant allele fraction. The change in EGFR variant allele fraction (VAF) at C1D15 was calculated using the VAF at pre-treatment baseline (C1D1) for each patient. The identity of the baseline (C1D1) EGFR mutation detected (using the FMI F1LCDx assay) is detailed in each graph. *Indicates that the patient was detected to have two different DNA molecules that result in the same protein alteration. In this case, the change in VAF for each corresponding DNA molecule is plotted separately, so multiple bars on each graph may belong to the same patient.

[0027] Fig. 9 is a bar graph showing the sum of target lesion diameters grouped by initial dose level for patients receiving BLU-945 (all doses) in combination with osimertinib 80 mg QD. Abbreviations: BID = twice daily; osi = osimertinib; QD = once daily. Maximum percent reduction was calculated before disease progression. DETAILED DESCRIPTION

[0028] Treatment

[0029] Despite significant advances, including three generations of EGFR tyrosine kinase inhibitors (TKIs), patients with advanced EGFR-mutated NSCLC will eventually deteriorate. The median PFS with first-line osimertinib treatment was 18.8 months overall, and was even shorter in poor prognostic subgroups, such as patients with EGFR L858R (14.4 months), patients with detectable ctDNA at baseline (11.1 months), or patients with detectable ctDNA after 3 weeks of treatment (9.5 months) (Zhou C, Imamura F, Cheng Y, Okamoto I, Cho BC, Lin MC, et al. Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial. J Clin Oncol. 2019; 37(15 Suppl) ASCO Annual Meeting Abstract 9020). Although post-osimifida treatment is an area of ​​significant unmet medical need, patients often experience multiple on-target and off-target escape mechanisms that may require simultaneous inhibition of EGFR and non-EGFR pathways to address.

[0030] On the other hand, deepening and broadening responses in the first-line setting before complex heterogeneous resistance mechanisms emerge is an important opportunity to improve patient outcomes. Several combinations of strategies aimed at delaying or preventing resistance and prolonging first-line responses are currently being investigated, including the use of osimertinib in combination with platinum-based chemotherapy and ervantumab and lazertinib in all patients with EGFR mutations and in subgroups with poor prognosis (e.g., L858R patients with ramucirumab and erlotinib, patients with detectable ctDNA after 3 weeks with osimertinib and chemotherapy). Each of these strategies involves IV therapy or combinations with significant toxicity.

[0031] Although the combination of two EGFR TKIs is expected to improve outcomes by more strongly inhibiting primary EGFR driver mutations and covering a wider range of EGFR resistance mutations, previous combinations were limited by increased adverse events (AEs) in wild-type (WT) EGFR, which is dose-limiting.

[0032] BLU-945 is an investigational next-generation EGFR TKI that covers common on-target resistance mutations T790M and C797S and is highly selective for WT EGFR, resulting in minimal WT EGFR AEs. Preclinical data showed that BLU-945 had antitumor activity in osimertinib-resistant models and enhanced activity when combined with osimertinib in treatment-naïve L858R models, with improved response duration and survival compared with BLU-945 or osimertinib alone. (See "BLU-945 or BLU-701 as single agents versus their combination with osimertinib in EGFR L858R-driven tumor model", Tavera-Mendoza, LE, AACR-NCI-EORTC 2022, Barcelona, ​​Spain, October 26–28, 2022)

[0033] As of January 6, 2023, 108 patients have been treated with BLU-945 monotherapy and 25 patients have been treated with BLU-945 in combination with osimertinib. In a large population of patients who have received prior treatment, BLU-945 monotherapy was generally well tolerated, with a variable safety profile, few patients discontinued due to related AEs, minimal WT EGFR AEs, and demonstrated strong on-target activity at EGFR, reducing and eliminating EGFR resistance mutations, and confirming responses in patients with genomic heterogeneity with multiple oncogene drivers. For example, BLU-945 doses of 400mg QD, 500mg QD, 200mg BID, and 250mg BID can be used to treat NSCLC, while BLU-945 doses of 600mg QD and 300mg BID were not tolerated by patients.

[0034] During the dose escalation process, BLU-945 combined with osimertinib was generally well tolerated, with few patients discontinuing due to related AEs, consistent with the safety profile of both drugs, and there was no evidence that the combination increased the frequency of WTAEs compared with osimertinib, and there were no new safety signals. While awaiting confirmation, responses also occurred in patients who had progressed after prior use of osimertinib, and the dose of BLU-945 was lower than that observed with monotherapy.

[0035] Given the need for new treatment options to improve outcomes in first-line NSCLC, the preclinical activity of BLU-945 and osimertinib in first-line models demonstrating prolonged anti-tumor responses, the tolerability of BLU-945 monotherapy and BLU-945 in combination with osimertinib, and the promising activity in advanced-line patients, the available data support an acceptable risk / benefit ratio for continued clinical development of BLU-945, including the addition of BLU-945 to standard osimertinib therapy in first-line patients with advanced EGFR-mutant NSCLC.

[0036] The present disclosure provides a method for treating a patient with non-small cell lung cancer (NSCLC), comprising orally administering to a patient in need thereof an amount of 200 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, or administering a pharmaceutical composition comprising the same drug daily.

[0037] "Pharmaceutically acceptable salts" means pharmaceutical salts that are suitable for use in contact with the tissues of humans and lower animals without causing excessive toxicity, irritation or allergic reaction, and are commensurate with a reasonable risk / benefit ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmacologically acceptable salts described by SM Berge et al. in J. Pharm. Sci., 1977, 66, 1-19.

[0038] N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine disclosed herein can be used in the form of a free base or a salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrosulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptanoate, lactobionate, and laurylsulfonate, among others. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0039] In some embodiments, in the treatment methods disclosed herein, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered as a free base. In some embodiments, in the treatment methods disclosed herein, a pharmaceutically acceptable salt of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered.

[0040] When the stereochemical configuration of a chiral center in N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is indicated by its chemical name (e.g., when the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., when the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. The "enrichment of the indicated configuration relative to the opposite configuration" is a molar percentage determined by dividing the number of compounds having the indicated stereochemical configuration of the chiral center by the total number of all compounds in the mixture having the same or opposite stereochemical configuration.

[0041] In some embodiments, the non-small cell lung cancer in the subject in need thereof has metastasized (eg, to the brain).

[0042] In some embodiments, the NSCLC is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology.

[0043] In some embodiments, non-small cell lung cancer is characterized by epidermal growth factor receptor (EGFR) L858R mutation. In some embodiments, non-small cell lung cancer is characterized by epidermal growth factor receptor (EGFR) exon 19 deletion mutation. In some embodiments, NSCLC is characterized by EGFR L858R / T790M mutation or EGFR exon 19 deletion / T790M mutation. In some embodiments, NSCLC is characterized by EGFR L858R / C797X mutation or EGFR exon 19 deletion / C797X mutation (wherein "X" can be "S" or "G" or "N" or "Y" or "T" or "D"). In some embodiments, NSCLC is characterized by EGFR L858R / T790M / C797X mutation or EGFR exon 19 deletion / T790M / C797X mutation. In a specific embodiment, the C797X mutation is a C797S mutation.

[0044] In another embodiment, NSCLC is associated with or regulated by a mutant EGFR, characterized by an EGFR genotype selected from genotypes 1-76 listed in the table below (del18 = exon 18 deletion, specifically, for example, del E709_T710insD; and del19 = exon 19 deletion, specifically, for example, delE746_A750 (most common), delE746_S752insV, del747_A750insP, delL747_P753insS, and delS752_I759; ex20ins - exon 20 insertion, specifically, for example, D761-E762insX, A763-Y764insX, Y764-V765insX, V765-M766insX, A767-S768insX, S768-D769insX, V769-D770insX, N771-P772insX, P772-H773insX, H773-V774insX, and V774-C775insX): EGFR genotype

[0045]

[0046]

[0047]

[0048] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19.

[0049] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 T790M.

[0050] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 C797S.

[0051] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 C797X (C797G or C797N).

[0052] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 T790M C797S.

[0053] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 T790M C797X (C797G or C797N).

[0054] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 L792X (L792F, L792H or L792Y).

[0055] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 T790M L792X (L792F, L792H or L792Y).

[0056] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 G796R (G796S).

[0057] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 L792R (L792V or L792P).

[0058] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRdel19 L718Q (L718V).

[0059] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRdel19 T790M G796R (G796S).

[0060] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRdel19 T790M L792R (L792V or L792P).

[0061] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRdel19 T790M L718Q (L718V).

[0062] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRL858R.

[0063] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRL858R T790M.

[0064] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRL858R C797S.

[0065] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRL858R C797X (C797G or C797N).

[0066] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is characterized in that its EGFR comprises EGFRL858R T790M C797S.

[0067] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRL858R T790M C797X (C797G or C797N).

[0068] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRL858R L792X (L792F, L792H or L792Y).

[0069] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRL858R L790M L792X (L792F, L792H or L792Y).

[0070] In another embodiment, NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRL858R G796R (G796S).

[0071] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRL858R L792R (L792V or L792P).

[0072] In another embodiment, NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRL858R L718Q(L718V).

[0073] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRL858R T790M G796R (G796S).

[0074] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRL858R T790M L792R (L792V or L792P).

[0075] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRL858R T790M L718Q(L718V).

[0076] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRdel18.

[0077] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein is characterized in that its EGFR comprises EGFRG719X (G719A, G719S, G719C, G719R, G719D or G719V).

[0078] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRE709X (E709K, E709H or E709A).

[0079] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRE709X (E709K, E709H or E709A) (G719A, G719S, G719C, G719D, G719R or G719V).

[0080] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRG719X(G719A, G719S, G719C, G719D, G719R or G719V)S768I.

[0081] In another embodiment, NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRex20ins.

[0082] In another embodiment, NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRex20ins L718Q.

[0083] In another embodiment, NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRex20ins T790M.

[0084] In another embodiment, NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRex20ins C797S.

[0085] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFRS7681I.

[0086] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFR T790M.

[0087] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR comprises EGFR T790M C797S / G L792X (L792F, L792H, L792R or L792Y).

[0088] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR genotype is selected from genotypes 1-76.

[0089] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to osimertinib, gefitinib, erlotinib, lazertinib, ametinib (formerly known as almonertinib), omotinib or nazartinib.

[0090] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to osimertinib.

[0091] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to gefitinib.

[0092] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to erlotinib.

[0093] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to lazertinib.

[0094] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR is mutated and these mutations confer resistance to ametinib (formerly known as almonertinib).

[0095] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to omotinib.

[0096] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to nazartinib.

[0097] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to afatinib, dacomitinib or avitinib.

[0098] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to afatinib.

[0099] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to dacomitinib.

[0100] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to Avitinib.

[0101] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to ivanovich.

[0102] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to osimertinib and afatinib.

[0103] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to osimertinib and dacomitinib.

[0104] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to osimertinib and gefitinib.

[0105] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to osimertinib and erlotinib.

[0106] In another embodiment, the NSCLC treated with N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, is characterized in that its EGFR has mutations that confer resistance to ivanovich and lazertinib.

[0107] Another embodiment is treating a subject with metastatic NSCLC whose tumor carries an activating exon 19 deletion or L858R EGFR mutation, as well as G719X (A, S, C, D, R, V), S768I, and L861Q mutations, and a resistance mutation disclosed herein as detected by an approved molecular test.

[0108] Another embodiment is treating a subject with metastatic NSCLC whose tumor carries an activating exon 19 deletion or an L858R EGFR mutation and a resistance mutation disclosed herein as detected by an approved molecular test.

[0109] Another embodiment is a disclosed compound for use in combination with a first or third generation TKI indicated for the treatment of a subject with metastatic NSCLC whose tumor carries T790M and C797S mutations as detected by an approved test and whose disease has progressed after at least 2 prior EGFR TKI treatments.

[0110] Another embodiment is a disclosed compound for use in combination with a second or third generation TKI indicated for the treatment of a subject with metastatic NSCLC whose tumor carries a C797X mutation as detected by an approved test and whose disease has progressed after 1 or 2 prior EGFR TKI therapies.

[0111] Another embodiment is a disclosed compound for use in treating a subject with metastatic NSCLC whose disease has on-target EGFR resistance that progresses on or after any EGFR TKI treatment. In a specific embodiment, the compounds disclosed herein are used in combination with a second or third generation TKI suitable for treating a subject with NSCLC (e.g., metastatic NSCLC).

[0112] Another embodiment is a disclosed compound for use in treating a subject with metastatic EGFR C797X mutation-positive NSCLC detected by an approved molecular test whose disease has progressed after first-line or second-line osimertinib treatment. In a specific embodiment, the compounds disclosed herein are used in combination with a second or third generation TKI suitable for treating a subject with metastatic NSCLC.

[0113] In certain embodiments, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.

[0114] One skilled in the art can readily determine the specific EGFR alterations present in a subject's cells, cancer, gene or gene product, for example, by determining whether the subject has one or more mutations or deletions described herein using a detection method selected from detection methods known in the art, including hybridization-based methods, amplification-based methods, microarray analysis, flow cytometric analysis, DNA sequencing, next generation sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot hybridization, and Southern blot.

[0115] To detect one or more EGFR deletions and / or mutations, primary tumor samples, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and / or circulating exosomes can be collected from a subject. The sample is processed to isolate nucleic acids using techniques well known in the art, and then the nucleic acids are sequenced using methods well known in the art. The sequences are then mapped to individual exons and measures of transcriptional expression are quantified (e.g., RPKM, or reads per kilobase mapped per million reads). Raw sequence and exon array data are available from sources such as TCGA, ICGC, and the NCBI Gene Expression Omnibus (GEO). For a given sample, individual exon coordinates are annotated with gene identifier information, and exons belonging to the kinase domain are labeled. Exon levels are then z-scored across all tumor samples. ctDNA is increasingly being adopted in clinical practice as a method to monitor treatment response and the emergence of drug resistance. Clearance of ctDNA after 6-8 weeks of treatment predicts the beneficial effects of TKIs, while increase in ctDNA or the emergence of new mutations is associated with disease progression (Ku BM et al. Oncology. 2022; Epub ahead of print. PMID: 35196661; Ma L. et al. Front Oncol. 2021; 11: 643199; Fernandes et al. Cells. 2021; 10: 1912.).

[0116] N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be used to treat a subject who has developed resistance to one or more other EGFR inhibitors. "Resistant" means that the subject's cancer previously responded to the drug, but then responded poorly or not at all. In some embodiments, the subject has developed resistance to one or more first-generation EGFR inhibitors, such as erlotinib, gefitinib, icotinib, or lapatinib. In some embodiments, the subject has developed resistance to one or more second-generation EGFR inhibitors, such as afatinib, dacomitinib, pocitinib, or neratinib. In some embodiments, the subject has developed resistance to one or more first-generation inhibitors and one or more second-generation inhibitors. In some embodiments, the subject has developed resistance to one or more third-generation inhibitors, such as osimertinib, nazartinib, or avitinib. In one embodiment, the subject has developed resistance to one or more first-generation EGFR inhibitors and one or more third-generation EGFR inhibitors. In some embodiments, the subject has developed resistance to one or more second-generation EGFR inhibitors and one or more third-generation EGFR inhibitors. In some embodiments, the subject has developed resistance to one or more first-generation inhibitors and one or more third-generation EGFR inhibitors.

[0117] Pharmaceutical composition

[0118] The pharmaceutical compositions of the present disclosure (also referred to as "the disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carriers and / or diluents, and N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, or a pharmaceutically acceptable salt thereof.

[0119] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to a substance that helps the preparation and / or administration of active pharmaceutical ingredients and / or absorption by subjects, and can be included in the pharmaceutical composition of the present disclosure without producing significant harmful toxicological effects on subjects. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include NaCl, lactated Ringer's solution, normal sucrose, normal glucose, adhesives, fillers, decomposing agents, lubricants, coating agents, sweeteners, spices, alcohol, oils, gelatin, carbohydrates (e.g., lactose, straight-chain starch or starch), hydroxymethyl cellulose, fatty acid esters, polyvinyl pyrrolidone and colorants, etc. These preparations can be sterilized and mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants and / or aromatic substances, etc., when necessary, which do not react adversely or interfere with the activity of the compounds provided herein. Those of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with the compounds disclosed herein or their pharmaceutically acceptable salts.

[0120] The pharmaceutical compositions of the present disclosure optionally include one or more pharmaceutically acceptable carriers and / or diluents, such as lactose, starch, cellulose and glucose. Other excipients may also be included, such as flavorings, sweeteners and preservatives (e.g., methyl, ethyl, propyl and butyl parabens). A more complete list of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). Those skilled in the art know how to prepare formulations suitable for various routes of administration. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24NF19) (published in 1999). Carriers, diluents and / or excipients are "acceptable" in the sense that they are compatible with the other ingredients in the pharmaceutical composition and are not harmful to the recipient.

[0121] Combination therapy

[0122] N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be used in combination with one or more additional pharmacologically active substances. For example, the present disclosure includes methods of treating NSCLC comprising administering to a subject in need thereof a combination of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (or a pharmaceutically acceptable salt thereof) disclosed herein and an EGFR (or EGFR mutation) inhibitor, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, pocitinib, neratinib, gefitinib JBJ-04-125-02, afatinib (ASTR-04-125-02), or selenistatinib. 2818), ametinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib, PCC-0208027, rizitinib (BPI-7711), TQB3804, zolitinib (AZ-3759), or DZD9008; EGFR antibodies, such as cetuximab, panitumumab, nesituzumab, HLX07, JMT101; or bispecific EGFR and MET antibodies, such as ervantumab (JNJ-61186372, JNJ-372). For the treatment of cancer, such as NSCLC, the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein in combination with a first-line treatment, such as a first, second or third generation EGFR inhibitor (i.e., as an initial treatment before the cancer becomes refractory), can prevent or delay the cancer from becoming refractory. Typically, the cancer is characterized by one of the EGFR genotypes described in the present disclosure.

[0123] In some embodiments, in the methods disclosed herein, effective amounts of afatinib, dacomitinib, or avitinib are administered concurrently to a patient in need thereof.

[0124] In some embodiments, in the methods disclosed herein, an effective amount of osimertinib, gefitinib, erlotinib, lazertinib, ametinib (formerly almonertinib), omotinib or nazartinib is administered to a patient in need thereof simultaneously. In a specific embodiment, an effective amount of osimertinib (e.g., 80 mg) is administered to a patient in need thereof simultaneously.

[0125] It should be understood that, unless otherwise specified, the administration described herein includes administering N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof before, simultaneously with, or after another pharmacologically active substance disclosed herein (e.g., osimertinib) or a pharmaceutically acceptable salt thereof described herein. However, in one embodiment, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof is administered simultaneously with another pharmacologically active substance (e.g., osimertinib) or a pharmaceutically acceptable salt thereof. In another embodiment, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof is administered sequentially with another pharmacologically active substance (e.g., osimertinib) or a pharmaceutically acceptable salt thereof. For example, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof is administered after administration of another pharmacologically active substance (e.g., osimertinib) or a pharmaceutically acceptable salt thereof.

[0126] Administration and dosage form

[0127] The exact amount of compound administered to provide an "effective dose" to a subject will depend on the type and severity of NSCLC, as well as the characteristics of the subject, such as general health, age, sex, weight, and drug tolerance. One skilled in the art will be able to determine an appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, such as anticancer drugs, the "effective dose" of any additional therapeutic agent will depend on the type of drug used. Appropriate doses of approved therapeutic agents are known, and one skilled in the art can adjust the amount of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine used, for example, based on doses reported in the literature or recommended in the Physician's Desk Reference (57th Ed., 2003).

[0128] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of a disease, disorder, or cancer; alleviating or improving clinical symptoms or indicators associated with a disease, disorder, or cancer; delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or cancer; or reducing the likelihood of recurrence of a disease, disorder, or cancer.

[0129] "Effective dose" refers to an amount that produces a beneficial or desired result when administered to a subject, including a clinical result, for example, inhibiting, suppressing or reducing the symptoms of a condition in the treated subject compared to a control group. For example, a therapeutically effective dose can be administered in a unit dosage form (e.g., 0.1 mg to about 50 g per day).

[0130] As used herein, the term "patient" or "subject" refers to an organism to be treated by the disclosed methods. Non-limiting examples include mammals, e.g., mice, monkeys, horses, cows, pigs, dogs, cats, etc. In certain embodiments, the organism is a human.

[0131] In some embodiments, a total daily dose of 100 mg to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 100 mg to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0132] In some embodiments, 50 mg to 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 50 mg to 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily is administered to a subject in need thereof.

[0133] In some embodiments, an amount of 200 to 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 200 to 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0134] In some embodiments, an amount of 400 to 600 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 400 to 600 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0135] In some embodiments, an amount of 400 to 800 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 400 to 800 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0136] In some embodiments, an amount of 800 to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 800 to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0137] In some embodiments, an amount of 600 mg to 800 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 600 mg to 800 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0138] In some embodiments, an amount of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-1-ol is administered to a subject in need thereof. 3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, 600 mg to 800 mg, 700 mg to 900 mg or 800 mg to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

[0139] In some embodiments, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 ... 0 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg or 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3- -amine or the equivalent of 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg or 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine in an amount of a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, an amount of 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0141] In some embodiments, an amount of 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0142] In some embodiments, an amount of 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0143] In some embodiments, an amount of 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0144] In some embodiments, an amount of 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0145] In some embodiments, an amount of 600 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 600 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0146] In some embodiments, an amount of 700 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 700 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0147] In some embodiments, an amount of 800 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 800 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0148] In some embodiments, an amount of 900 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 900 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0149] In some embodiments, an amount of 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof.

[0150] In some embodiments, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof is orally administered once daily (QD) to a subject in need thereof in an amount as above.

[0151] In some embodiments, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof is orally administered twice daily (BID) to a subject in need thereof in an amount as described above.

[0152] In some embodiments, an amount of 50 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 50 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0153] In some embodiments, an amount of 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0154] In some embodiments, an amount of 150 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 150 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0155] In some embodiments, an amount of 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0156] In some embodiments, an amount of 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0157] In some embodiments, an amount of 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0158] In some embodiments, an amount of 350 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 350 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0159] In some embodiments, an amount of 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0160] In some embodiments, an amount of 450 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 450 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0161] In some embodiments, an amount of 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or an amount of a pharmaceutically acceptable salt thereof equivalent to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID).

[0162] In some embodiments, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in combination with an effective amount (e.g., 80 mg) of osimertinib in an amount as described in any of the embodiments above (e.g., any of the first thirty-first paragraphs). In one embodiment, osimertinib is administered once daily.

[0163] In some embodiments, an amount of 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof once daily (QD) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered simultaneously QD.

[0164] In some embodiments, an amount of 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof once daily (QD) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered simultaneously QD.

[0165] In some embodiments, an amount of 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof once daily (QD) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently QD.

[0166] In some embodiments, an amount of 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof once daily (QD) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently QD.

[0167] In some embodiments, an amount of 50 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 50 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently once daily.

[0168] In some embodiments, an amount of 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently once daily.

[0169] In some embodiments, an amount of 150 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 150 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently once daily.

[0170] In some embodiments, an amount of 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently once daily.

[0171] In some embodiments, an amount of 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently once daily.

[0172] In some embodiments, an amount of 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof equivalent to 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered to a subject in need thereof twice daily (BID) in combination with 80 mg of osimertinib. In one embodiment, osimertinib is administered concurrently once daily.

[0173] The pharmaceutical compositions of the present disclosure are formulated into formulations that are compatible with their intended route of administration. In one embodiment, the composition is formulated in accordance with routine procedures into a pharmaceutical composition suitable for oral administration to humans.

[0174] Typically, for oral therapeutic administration, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be combined with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0175] The following examples are intended to be illustrative and are not intended to limit the scope of the present disclosure in any way.

[0176] Example

[0177] Example 1: Phase 1 / 2 study targeting acquired resistance mechanisms in patients with EGFR mutant non-small cell lung cancer

[0178] Part 1A: BLU-945 monotherapy

[0179] Study Design

[0180] This is an ongoing Phase 1 / 2, open-label, first-in-human study (NCT04862780) evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity ( ) of BLU-945 as monotherapy and in combination with osimertinib in patients with metastatic EGFRm NSCLC in the United States and Japan. Figure 1 ).

[0181] The study consists of a preliminary Phase 1 portion to determine the maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D) of BLU-945 as monotherapy (initially using a QD (once daily) dosing schedule, with the option to evaluate BID (twice daily) dosing if supported by emerging pharmacokinetic and safety data), and an additional dose-escalation portion to determine the RP2D of BLU-945 in combination with osimertinib.

[0182] The Phase 1 dose escalation portion of the study used a Bayesian optimal interval (BOIN) design, with a maximum of 12 patients evaluable for dose-limiting toxicities (DLTs) at any given dose level, and dose escalation was considered complete when 12 patients were evaluable for DLT at a dose level. In the Phase 1 dose escalation, patients (age ≥18 years; metastatic EGFRm NSCLC; ECOGPS 0-1; received ≥1 EGFR TKI treatment) received BLU-945 monotherapy at a starting dose of 25 mg QD. Patients who progressed after osimertinib treatment could receive BLU-945 combined with 80 mg osimertinib starting at 50% of the highest safe BLU-945 monotherapy dose. Each dose escalation followed a Bayesian optimal interval design. Safety, including dose-limiting toxicity (DLT), PK, and circulating tumor DNA (ctDNA) mutation status, was evaluated.

[0183] BLU-945 is administered orally in 4-week cycles. The DLT assessment period is the first 28 days (Cycle 1 of each cohort in Phase 1 dose escalation). Patients who experience a DLT or receive at least 75% of the prescribed BLU-945 doses (i.e., ≥21 days) and complete the 28-day DLT assessment period are evaluable for DLT assessment. Intra-patient dose escalation is allowed. If sustained clinical benefit is observed (assessed by the investigator and approved by the sponsor), patients can continue study treatment after disease progression.

[0184] In addition, a twice-daily (BID) dosing schedule was explored using the same BOIN dose escalation design as described for the QD dosing schedule. The starting total daily dose level for the BID dose escalation will be determined by the Safety Review Committee (SRC), and the total daily dose will not exceed the highest dose level in the QD schedule approved by the SRC for further dose escalation. For example, if BID dosing is started after QD dosing of 100 mg is considered safe for further escalation, the maximum BID dose will be 50 mg BID (equivalent to a total daily dose of 100 mg).

[0185] The BLU-945 and osimertinib combination treatment escalation will begin at 50% of the recommended Phase 2 dose (RP2D) or 50% of the highest safe dose in the ongoing Phase 1 BLU-945 monotherapy study.

[0186] Dose level 1 will evaluate BLU-945 at 50% of the recommended Phase 2 dose (RP2D) for monotherapy (or 50% of the highest dose deemed safe in Part 1A if the monotherapy RP2D has not been established) in combination with full dose osimertinib (80 mg QD). Dose escalation or reduction will be performed according to BOIN-designed rules based on dose-limiting toxicities (DLTs) and pharmacokinetic (PK) results observed within the first 28-day treatment cycle, as follows: Dose level 1 (25% RP2D of BLU-945 + osimertinib 80 mg); Dose level 2 (50% RP2D of BLU-945 + osimertinib 80 mg); Dose level 3 (75% RP2D of BLU-945 + osimertinib 80 mg); Dose level 4 (100% RP2D of BLU-945 + osimertinib 80 mg). In cohorts following Cohort 1, dose level escalation should be <100% BLU-945, and the next dose of BLU-945 will be selected such that the predicted area under the curve (AUC) for BLU-945 in combination with osimertinib will not exceed the AUC for BLU-945 monotherapy at the MTD or the highest dose deemed safe in combination escalation in Part 1A. Dose escalation will not exceed the RP2D for BLU-945 monotherapy or the osimertinib dose of 80 mg.

[0187] Critical Assessment (Phase 1)

[0188] The maximum tolerated dose (MTD) will be determined based on the safety profile within the first 28-day treatment cycle.

[0189] The RP2D will be determined based on DLT, PK, PD, and preliminary safety and antitumor activity data.

[0190] Real-time assessment of ctDNA will be performed using the FoundationOneLiquid CDx assay at Cycle 1 (C), Day 1 (D), C1D15, and end of treatment / disease progression.

[0191] The treatment effect was assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1, with the first two scans assessed every 28 days, then every 8 weeks during the first year, and then every 12 weeks.

[0192] result

[0193] Patients (data cutoff: March 9, 2022)

[0194] In the first 5 cohorts, 33 patients were treated with BLU-945 at doses of 25-400 mg once daily (QD). (Data cutoff: March 9, 2022)

[0195] The baseline characteristics of these patients are shown in Table 1 .

[0196] The majority of patients were nonsmokers, and the majority (n = 26 [79%]) had received ≥ 3 prior lines of systemic therapy.

[0197] Table 1

[0198]

[0199]

[0200] C, cycle; ctDNA NGS, circulating tumor DNA next-generation sequencing; D, day; EGFRm, primary EGFR activating mutation, exon 19 deletion, or L858R.

[0201] a The original study protocol allowed for an ECOGPS of 0-2, but this was later amended to allow an ECOGPS of 0-1.

[0202] b Patients with EGFR mutation-positive NSCLC were enrolled based on positional mutation assessment of tumor biopsy or blood ctDNA and followed up with central ctDNA assessment at C1D1.

[0203] c At the time of data cutoff, results were not available for all patients.

[0204] Security

[0205] Safety data are summarized in Table 2. No grade 4 or 5 adverse events (AEs) were reported. One DLT occurred in the 400 mg QD cohort, which was grade 3 transaminase elevation, which improved with dose interruption and the patient continued treatment. AEs commonly associated with EGFR wild-type inhibition were rare (rash 3%, grade 1; dry skin 3%, grade 1; diarrhea 9%, grade 1; paronychia not reported; interstitial lung disease not reported; QT prolongation not reported). Overall, there were 8 (24%) serious AEs, of which only 2 (6%) were considered related to study drug: 1 case of grade 3 vomiting and 1 case of grade 3 transaminase elevation. No treatment discontinuations due to AEs were reported.

[0206] Table 2: Most common AEs by preferred term in ≥10% of patients

[0207]

[0208]

[0209] Antitumor activity

[0210] After 14 days of treatment in each dose cohort tested, BLU-945 treatment was active as assessed by ctDNA in EGFR T790M and C797S variant allele fractions. After treatment with BLU-945, 83% (10 / 12) of EGFR T790M ( Figure 2A ) and 81% (9 / 11) of EGFR C797S ( Figure 2B ) variant alleles decreased. In the 400 mg cohort, all detectable T790M and C797S alleles showed a decrease, including 3 that fell below the limit of detection (clearance). Increasing BLU-945 doses were associated with enhanced antitumor activity ( Figure 3 ), tumor shrinkage was observed at doses of 200 mg QD and above, including an unconfirmed partial response observed on C2D1 in a patient with documented ex19del / T790M / C797S who was treated with 400 mg QD. Tumor growth stabilized in two patients who started treatment at 100 mg QD when the dose was increased to 200 mg on C3D1.

[0211] BLU-945 treatment with a twice-daily (BID) dosing regimen also demonstrated EGFR C797S ctDNA clearance and tumor shrinkage ( Figure 5 ).

[0212] Patient Cases

[0213] Patient 1 is a 69-year-old white female, never smoker, diagnosed with stage IV NSCLC with ex19del, T790M, and C797S mutations detected by ctDNA. The patient had previously been treated with platinum-based chemotherapy, erlotinib, and osimertinib, with the best response to all previous treatments being stable disease (SD). The patient had two target lesions in the liver and multiple non-target lesions in the brain, bones, liver, retroperitoneum, and mediastinal lymph nodes. Patient 1 started treatment at a dose of 400 mg QD, and on C1D15, all three detectable EGFR mutations were reduced, C797S was cleared, and then on C2D1, the tumor shrank by 30%, an unconfirmed partial response. See Figure 4 The patient continued to receive treatment and tolerated it well.

[0214] Patient 2 is a 70-year-old Asian female, never smoker, diagnosed with EGFR L858R-positive stage IVB NSCLC with L858R, T790M, and C797S mutations. The patient had previously been treated with osimertinib and sirolimus with partial responses and had disease progression on platinum-based chemotherapy with bevacizumab. There were two target lesions in the right lung and multiple non-target lesions in the lung and left femoral head. Patient 2 started treatment at a dose of 200 mg QD and had a reduction in all three detectable EGFR mutations on C1D15, with a 21% and 28% tumor reduction on C2D1 and C3D1, respectively. See Figure 4 .

[0215] As of the data cut-off date of March 9, 2022 in conclusion :BLU-945 is a highly potent and selective oral EGFR inhibitor that is generally well tolerated at clinically effective doses in heavily pretreated EGFRm NSCLC, with only a few adverse events (AEs) related to wild-type EGFR toxicity observed at daily doses up to 400 mg.

[0216] Despite the presence of EGFR mutations conferring resistance to osimertinib, treatment with BLU-945 resulted in a rapid and dose-dependent reduction in ctDNA, consistent with preclinical data.

[0217] Increasing doses of BLU-945 were associated with enhanced anti-tumor activity, with tumor shrinkage observed at doses of 200 mg QD and above, including an unconfirmed partial response at the 400 mg dose.

[0218] The clonal evolution of EGFR-driven NSCLC tumor cells and the resulting mutational complexity suggest that combination therapy with precision medicine is needed to improve clinical outcomes.

[0219] Preliminary safety and clinical activity results from the Phase 1 SYMPHONY trial support further expansion of clinical development of BLU-945 in combination with osimertinib and other adjunctive agents. Part 1B: BLU-945 in combination with osimertinib

[0220] The dose-escalation study of BLU-945 in combination with osimertinib will include patients who have experienced disease progression while receiving osimertinib. During Part 1B, enrollment of NSCLC patients with EGFR T790M / C797S resistance mutations is encouraged, and may be reserved for patients with EGFR T790M / C797S resistance mutations or other clinically relevant mutational features based on discussions between the sponsor and study investigators.

[0221] Dose level 1 will evaluate BLU-945 at 50% of the monotherapy RP2D (or 50% of the highest dose deemed safe in Part 1A if the monotherapy RP2D has not yet been established) in combination with full dose osimertinib (80 mg QD). Based on the DLTs and PK data observed within the first 28-day treatment cycle, dose escalation or reduction was performed according to the BOIN design rules (Section 7.2.1.2), and a dose escalation plan was proposed, such as Figure 1 In cohorts following Cohort 1, dose level escalation should be <100% BLU-945, and the next BLU-945 dose will be selected such that the predicted AUC of BLU-945 in combination with osimertinib does not exceed the AUC of BLU-945 monotherapy at the MTD or the highest dose considered safe in combination escalation in Part 1A. Dose escalation will not exceed the RP2D of BLU-945 monotherapy nor the osimertinib dose of 80 mg.

[0222] Patients who experience DLT, or who receive at least 75% (i.e., ≥21 days) of the prescribed dose of BLU-945 and osimertinib and complete the 28-day DLT evaluation period, will be included in the DLT evaluation. For any given dose level, the total number of patients who can be evaluated for DLT shall not exceed 12, and the dose escalation is considered complete when 12 patients at a dose level are evaluable for DLT. The MTD will be determined based on the isotonic regression method, and the selection of the RP2D (which will not exceed the MTD) will take into account all clinical data, including safety, PK, PD, and anti-tumor activity.

[0223] Part 2: Extension Period

[0224] 2.1. BLU-945 monotherapy (Groups 1, 2, and 3)

[0225] Once the RP2D for BLU-945 monotherapy is determined in Part 1A, a Phase 2 extension study will be initiated to further evaluate the activity, safety, PK, and PD of the BLU-945 RP2D in specific patient populations. All patients enrolled in these expansion groups will receive BLU-945 monotherapy at the RP2D and schedule selected in Part 1A and will be enrolled in one of the following 3 expansion groups based on EGFR mutational signature:

[0226] ● Group 1 will consist of approximately 37 evaluable NSCLC patients with EGFR T790M and C797S mutations and will be conducted according to a Simon optimal two-stage design (17 patients in stage 1 and 20 patients in stage 2).

[0227] ●Cohort 2 will include approximately 12 evaluable patients with EGFR T790M but not C797S mutations.

[0228] ●Cohort 3 will include approximately 12 evaluable patients with EGFR C797S but not T790M mutations.

[0229] 2.2.BLU-945 combined with osimertinib (Group 4)

[0230] All patients enrolled in the BLU-945 plus osimertinib expansion cohort (Cohort 4) will receive BLU-945 and osimertinib at the RP2D and schedule selected in Part 1B. Cohort 4 will enroll approximately 24 evaluable patients, with a minimum of 12 reserved for patients harboring EGFR T790M and C797S mutations.

[0231] BLU-945 monotherapy (data cutoff: January 6, 2023)

[0232] As of January 6, 2023, 108 patients have received BLU-945 monotherapy in the dose escalation phase (Part 1A), of which 68 patients received a dose range of 25 to 600 mg once daily (QD) and 40 patients received a dose range of 100 to 300 mg twice daily (BID). As of data cutoff, monotherapy dose escalation is still ongoing, and the RP2D and maximum tolerated dose (MTD) have not yet been determined.

[0233] Safety of BLU-945 monotherapy

[0234] Across all monotherapy doses, 99 of 108 patients (91.7%) experienced at least one treatment-related AE (TEAE), and 35 (32.4%) experienced grade 3 or higher AEs. Only 4.6% of patients discontinued due to related AEs. Wild-type EGFR-related AEs were uncommon and included rash (10.2%; 0%), diarrhea (9.3%; 0%), and paronychia (1.9%; 0%). A total of 12 patients experienced dose-limiting toxicity (DLT) at doses of 400mg, 500mg, 600mg, 200mg BID, 250mg BID, and 300mg BID. Based on available data, the 600mg QD and 300mg BID doses were considered poorly tolerated and were not further explored.

[0235] BLU-945 Monotherapy Biomarker Efficacy

[0236] In the setting of progression after osimertinib treatment, multiple different off-target and on-target resistance mechanisms can occur simultaneously (Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019; 121(9): 725-37. https: / / doi.org / 10.1038 / s41416-019-0573-8), which may limit the ability to assess the on-target activity of EGFR inhibitors by simply measuring tumor shrinkage. Therefore, ctDNA was evaluated at baseline (C1D1), during treatment (C1D15), and at the end of treatment.

[0237] Between baseline and C1D15, robust dose-dependent on-target activity was observed against common EGFR resistance mutations T790M and C797S, including clearance of these mutations in several patients ( Figure 6 ).

[0238] BLU-945 monotherapy clinical activity

[0239] Confirmed responses have been achieved at doses of 400 mg QD, 200 mg BID, and higher according to RECIST 1.1. Tumor shrinkage was observed in 10 (37%) of 27 patients treated at ≥400 mg QD, including 1 confirmed partial response (PR); and in 15 (60%) of 25 patients treated at ≥200 mg BID, including 2 confirmed PR. Four additional patients had unconfirmed reductions in target lesions of 30% or more, usually due to the emergence of new lesions, which were often located in the CNS. This mixed response may be consistent with the genomic heterogeneity documented at baseline in this population, with some lesions amplified by non-EGFR pathways, while others remained EGFR-dependent and shrank after BLU-945 treatment. Limited analysis of ctDNA at the end of treatment suggested the emergence of new drivers in some samples. A first-line patient population with less genetic complexity may benefit more from EGFR inhibition than later-line patients.

[0240] In conclusion, BLU-945 monotherapy showed promising biomarker and clinical activity in this heavily pretreated and genomically heterogeneous population and was generally well tolerated with few discontinuations due to AEs. Importantly, BLU-945 has a different safety profile than other EGFR TKIs, with minimal WT EGFR AEs, making it a good candidate for combination with other EGFR TKIs, such as the standard of care osimertinib.

[0241] BLU-945 combined with osimertinib 80 mg QD

[0242] A total of 25 patients received BLU-945 (200 to 400 mg QD; 100 to 200 mg BID) combined with 80 mg osimertinib.

[0243] Safety of BLU-945 combined with osimertinib

[0244] Across all combination doses, 21 of 25 patients (84.0%) experienced at least one TEAE, of which 4 (16%) were grade 3 or higher. The frequency of WT EGFR AEs was consistent with the addition of osimertinib, and there has been no evidence of increased WT EGFR toxicity to date. To date, only one patient has discontinued due to a treatment-related AE. Pneumonitis was a grade 4 SAE considered related to osimertinib and the only DLT in the combination to date, occurring in the 300 mg QD and osimertinib 80 mg QD groups. As of data cutoff, no AEs of QT prolongation (QTc) occurred.

[0245] Blood samples were collected in this study to assess the plasma pharmacokinetics (PK) of BLU-945 and osimertinib. Preliminary PK data comparing patients treated with BLU-945 alone with those treated with BLU-945 and osimertinib showed that osimertinib had no significant effect on the PK of BLU-945 in patients. Similarly, comparison of the PK of the combination of osimertinib and BLU-945 with the PK of osimertinib alone reported in the literature showed that BLU-945 had no significant effect on the PK of osimertinib, indicating the lack of clinically significant drug-drug interactions.

[0246] Biomarker efficacy of BLU-945 combined with osimertinib

[0247] As with BLU-945 monotherapy, combination therapy with osimertinib also demonstrated rapid and robust reduction and clearance of EGFR ctDNA mutant alleles, consistent with on-target EGFR inhibition (see Figure 8 ).

[0248] Clinical efficacy of BLU-945 in combination with osimertinib

[0249] Dose escalation of BLU-945 at doses of 400 mg QD and 200 mg BID (which previously resulted in a first confirmed response as monotherapy) in combination with osimertinib 80 mg QD (the approved dose) is currently being explored. Of note, unconfirmed responses were seen in the 300 mg QD and 150 mg BID arms, and confirmatory scan data are pending (see Fig. 9 ).

[0250] In summary, BLU-945 in combination with osimertinib showed promising biomarker and clinical activity in patients who had progressed on osimertinib. The combination was generally well tolerated, with few discontinuations due to related AEs and no evidence of increased WT EGFR AEs or other combination toxicities. Responses with osimertinib occurred at a lower dose than the first observed response with BLU-945 monotherapy, which may be evidence of an additive benefit of the two agents, consistent with preclinical data. This encouraging activity and tolerability supports expansion of this combination into first-line therapy once the combination RP2D is established.

[0251] BLU-945 Food Effect

[0252] BLU-945-0102 is a Phase 1, open-label, single-dose, 3-group crossover study designed to evaluate the effect of food on BLU-945 PK in healthy adult subjects (N=9). The 9 subjects took 100 mg BLU-945 on an empty stomach, after a high-fat meal, or after a snack. Overall, the results of the BLU-945-0102 study support dosing without regard to food effects in the Phase 2 portion of BLU-945-1101.

Claims

1. A method of treating a subject having non-small cell lung cancer, comprising orally administering to the subject an effective amount of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine represented by the following structure: or a pharmaceutically acceptable salt thereof, and wherein an effective amount of osimertinib is co-administered to the subject.

2. The method of claim 1, wherein the subject is administered an amount of 200 to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 to 1000 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine daily.

3. The method of claim 1, wherein the subject is administered a total daily dose of 100 mg to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 100 mg to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.

4. The method of claim 1, 2 or 3, wherein the subject is administered N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine or a pharmaceutically acceptable salt thereof twice daily.

5. The method of claim 3, wherein the subject is administered an amount of 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily, or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily.

6. The method of claim 3, wherein the subject is administered 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily, or an amount of a pharmaceutically acceptable salt thereof equivalent to 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily.

7. The method of claim 3, wherein the subject is administered 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily, or an amount of a pharmaceutically acceptable salt thereof equivalent to 300 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily.

8. The method of claim 3, wherein the subject is administered 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily, or an amount of a pharmaceutically acceptable salt thereof equivalent to 400 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily.

9. The method of claim 3, wherein the subject is administered 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily, or an amount of a pharmaceutically acceptable salt thereof equivalent to 500 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine once daily.

10. The method of claim 3, wherein the subject in need thereof is administered 50 mg to 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily (BID), or an amount equivalent to 50 mg to 250 mg of a pharmaceutically acceptable salt thereof.

11. The method of claim 3, wherein the subject in need thereof is administered 50 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily (BID).

12. The method of claim 3, wherein the subject in need thereof is administered 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily (BID).

13. The method of claim 3, wherein the subject in need thereof is administered 150 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily or a pharmaceutically acceptable salt thereof in an amount equivalent to 150 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily (BID).

14. The method of claim 3, wherein the subject in need thereof is administered 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily (BID).

15. The method of claim 3, wherein the subject in need thereof is administered 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily or a pharmaceutically acceptable salt thereof in an amount equivalent to 250 mg of N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine twice daily (BID).

16. The method of any one of claims 1 to 15, wherein the non-small cell lung cancer in the subject in need thereof has metastasized.

17. The method of any one of claims 1 to 16, wherein the non-small cell lung cancer is characterized by an epidermal growth factor receptor (EGFR) L858R mutation.

18. The method of any one of claims 1 to 16, wherein the non-small cell lung cancer is characterized by epidermal growth factor receptor (EGFR) exon 19 deletion.

19. The method of any one of claims 1 to 16, wherein the non-small cell lung cancer is characterized by EGFR L858R / T790M mutation or EGFR exon 19 deletion / T790M mutation.

20. The method of any one of claims 1 to 16, wherein the non-small cell lung cancer is characterized by EGFR L858R / C797X mutation or EGFR exon 19 deletion / C797X mutation.

21. The method of any one of claims 1 to 16, wherein the non-small cell lung cancer is characterized by EGFR L858R / T790M / C797X mutation or EGFR exon 19 deletion / T790M / C797X mutation.

22. The method of claim 20 or 21, wherein the C797X mutation is a C797S mutation.

23. The method of any one of claims 1 to 22, wherein N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered as the free base.

24. The method of any one of claims 1 to 23, wherein N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered concurrently with osimertinib.

25. The method of any one of claims 1 to 23, wherein N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine is administered sequentially with osimertinib.

26. The method of any one of claims 1 to 25, wherein 80 mg of osimertinib is co-administered once daily to the subject in need thereof.

Images