CN110652514A

CN110652514A - Pharmaceutical use of third generation EGFR inhibitor

Info

Publication number: CN110652514A
Application number: CN201910585852.4A
Authority: CN
Inventors: 孙长安; 杨勇; 史先胜; 王生斌
Original assignee: Jiangsu Hausen Pharmaceutical Group Co Ltd; Shanghai Hansen Biological Medicine Technology Co Ltd
Current assignee: Jiangsu Hausen Pharmaceutical Group Co Ltd; Shanghai Hansen Biological Medicine Technology Co Ltd
Priority date: 2018-06-29
Filing date: 2019-07-01
Publication date: 2020-01-07

Abstract

The present application relates to pharmaceutical uses of third generation EGFR inhibitors. In particular to application of a compound shown in a formula I or a pharmaceutically acceptable salt thereof in preparing a medicine for treating locally advanced or metastatic non-small cell lung cancer. The compound of the formula I or the pharmaceutically acceptable salt thereof has good curative effect on locally advanced or metastatic non-small cell lung cancer.

Description

Pharmaceutical use of third generation EGFR inhibitor

Technical Field

The invention relates to the field of clinical medicine and pharmacy; in particular to application of a third-generation EGFR inhibitor in preparing a medicament for treating non-small cell lung cancer.

Background

As first generation Tyrosine Kinase Inhibitors (TKIs), gefitinib and erlotinib were most effective in certain advanced non-small cell lung cancer (NSCLC) patients. These patients have frequent somatic activation mutations in the exon encoding the Epidermal Growth Factor Receptor (EGFR) domain. Tumor patients with these activating mutations (EGFRm +) account for approximately 10% to 17% in the western population and 30% to 50% in the asian population. EGFRm + patients typically show a good initial response to first generation TKIs. However, most patients develop Acquired Resistance (AR) after 9-14 months of treatment, resulting in worsening of the disease. In addition, these first generation TKIs were associated with side effects caused by inhibition of Wild Type (WT) EGFR in skin and gastrointestinal organs, including skin rash and diarrhea.

Various mechanisms of AR have been reported, such as HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, NF1 loss, and potential FGFR signaling. However, it is now well established that the threonine to methionine mutation of the "gatekeeper" amino acid at position 790 of EGFR (T790M) is the most common mechanism of resistance, and that this substitution is detected in tumor cells in more than 50% of patients with disease progression.

Second generation irreversible EGFR TKIs such as afatinib and dacatinib are effective in lung cancer without EGFR resistance mutations. However, in clinical applications the second generation EGFR TKI as a monotherapy fails to overcome EGFR T790M mediated resistance in patients. Although it shows potent inhibition of EGFR T790M in preclinical experiments, its clinical use is limited by the dose-limiting toxicity that can result from non-selective inhibition of wild-type EGFR.

Therefore, it is an unmet medical need to develop a new generation of high-selectivity small molecule inhibitors against EGFR T790M mutant to reduce toxic and side effects caused by EGFR wild-type inhibition. This has led to the development of "third generation" EGFR TKIs. WZ4002 is the first reported inhibitor. CO-168619 and HM171320 are in the clinical development phase. Oxitinib was recently approved for the treatment of metastatic EGFR T790M mutation positive NSCLC patients, applicable to patients treated with EGFR TKI or with disease progression after treatment.

Disclosure of Invention

The inventors have surprisingly found that a compound of formula I or a pharmaceutically acceptable salt thereof has a good therapeutic effect on the treatment of locally advanced or metastatic non-small cell lung cancer mediated by EGFR mutations associated with EGER-TKI sensitivity.

According to some embodiments, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of locally advanced or metastatic non-small cell lung cancer mediated by an EGFR mutation associated with EGER-TKI sensitivity,

in a specific embodiment, the locally advanced or metastatic non-small cell lung cancer mediated by EGFR mutation associated with EGER-TKI sensitivity is positive for the T790M mutation.

In specific embodiments, the locally advanced or metastatic non-small cell lung cancer patient mediated by an EGFR mutation associated with EGER-TKI sensitivity is a patient who has been treated with EGFR-TKI (especially who has been treated continuously), or who has progressed after receiving EGFR-TKI and receiving clinical benefit.

In a specific embodiment, the pharmaceutically acceptable salt is selected from the mesylate salts.

EGFR-TKI treatment, as used herein, refers to patients receiving treatment with first or second generation EGFR inhibitors. Wherein the first generation EGFR inhibitor is selected from one or a combination of: erlotinib, gefitinib or erlotinib. The second generation EGFR inhibitor is selected from one or a combination of: lapatinib, afatinib, dacatinib.

The EGFR mutations described herein are selected from one or a combination of: G719X mutation, L858R mutation, L861Q mutation, exon 19 deletion.

In a specific embodiment, the medicament comprises a compound of formula I as the active substance. In other specific embodiments, the medicament comprises a salt of a compound of formula I.

In some embodiments, the medicament further optionally comprises a pharmaceutically acceptable carrier.

A unit dose (e.g., without limitation, a daily unit dose) of a compound of formula I or a pharmaceutically acceptable salt thereof is 50mg to 300mg (inclusive of ± 10%) of the compound of formula I, such as, without limitation, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 310, 320, 330mg, and values between any two of the foregoing values (not expressly listed but considered to be stated); more specifically, 55mg, 110mg, 220mg or 260mg may be used. It can be prepared in unit dosage form in a daily dose, administered once daily, and should be avoided from eating within 1 hour before administration to 2 hours after administration.

A medicament prepared from a compound of formula I or a pharmaceutically acceptable salt thereof is suitable for oral administration.

In the most preferred embodiment of the present application, the compound of formula I or a pharmaceutically acceptable salt thereof is administered alone, i.e. without the need to be used in combination with other drugs having an anti-tumor effect, but without excluding the use of some adjunctive drugs which do not have an anti-tumor effect.

According to some embodiments, there is provided a method of treating locally advanced or metastatic non-small cell lung cancer comprising the steps of:

provides a compound shown as a formula I or a medicinal salt thereof

Administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in a therapeutically effective amount;

wherein the subject has locally advanced or metastatic non-small cell lung cancer; especially EGER-TKI sensitivity related EGFR mutation mediated locally advanced or metastatic non-small cell lung cancer. Wherein, the metastatic non-small cell lung cancer is preferably brain metastatic non-small cell lung cancer.

In some embodiments, the route of administration is selected from: intramuscular, intraperitoneal, intravenous, subcutaneous, transdermal, intradermal, intranasal, intraocular, oral, sublingual, intratumoral, peritumoral.

In some embodiments, the method of treatment administers a composition to a patient at a frequency selected from the group consisting of: unit doses of 3 times a month, 4 times a month, 5 times a month, 2 times a month, 1 time a week, 2 times a week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, 7 times a week, 1 time a day, 1 time two days, 2 times a day, 3 times a day.

In some embodiments, the pharmaceutically acceptable salt is selected from one or a combination of: mesylate, fumarate, maleate, acetate, hydrochloride, phosphate or sulfate.

Detailed description of the invention

Unless otherwise defined, terms in this application have the following meanings:

overall Survival (OS) refers to the date from random to death due to any cause. Subjects who survived the last visit had OS scored as data loss at the time of the last visit. Subjects who were missed their OS were data loss as the last confirmed survival time before the missed visit. The OS of data erasure is defined as the time from random grouping to erasure.

Objective Remission Rate (ORR) refers to the proportion of patients whose tumors have shrunk to a certain extent and for a certain period of time, including cases of CR and PR. Solid tumor remission evaluation criteria (RECIST 1.1 criteria) were used to assess objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline, and the criteria for efficacy assessment are divided into Complete Remission (CR), Partial Remission (PR), Stable (SD), Progression (PD) according to RECIST 1.1 criteria.

Disease Control Rate (DCR) refers to the percentage of confirmed cases of complete remission, partial remission, and stable Disease (> 8 weeks) among patients with evaluable efficacy.

The quality of life score QoL is referenced to EORTC QLQ-C30 (version 3, Chinese version). The evaluation method comprises the following steps: and (4) observing the related clinical symptoms of the tumor patients before and after treatment and the change of objective examination results, scoring, and recording the scoring results of all fields of the scale in an eCRF (electronic grade rf) table according to the requirements of a quality of life scale.

Complete Remission (CR): all target lesions disappeared and the short diameter of all pathological lymph nodes (including target and non-target nodes) had to be reduced to < 10 mm.

Partial Remission (PR): the sum of the target lesion diameters is reduced by at least 30% from baseline levels.

Disease Progression (PD): the diameter and relative increase is at least 20% with respect to the minimum of the sum of all measured target lesion diameters throughout the experimental study (baseline values are referenced if the baseline measurement is minimal); in addition to this, it must be satisfied that the absolute value of the sum of the diameters increases by at least 5mm (the appearance of one or more new lesions is also considered as disease progression).

Disease Stability (SD): the target lesion was decreased to a degree that did not reach PR and increased to a degree that did not reach PD levels, between which the minimum of the sum of the diameters was considered for the study.

In this specification, when numerical ranges are recited, the use of the expression "… to …", "within the range" or "between the ranges" is inclusive of the endpoints.

Drawings

Figure 1 represents the clinical study phase.

Detailed Description

Embodiments of the present application will be described in detail below with reference to specific examples. The following examples are merely illustrative of the present application and should not be construed as limiting the scope of the present application.

Examples

Example 1 EGFR enzyme assay study

1. EGFR mutant enzymology experiment:

preparation: compounds were dissolved in DMSO, with the highest concentration detected for compounds being 100nM, 3-fold dilution, for a total of ten concentrations.

The method comprises the following steps: in the experiment, the inhibition effect of the compound on T790M, Del, L858R, T790M/Del19 and T790M/L858R mutant EGFR enzymes is tested by adopting a fluorescence resonance energy transfer (TR-FRET) method, and the half inhibition concentration IC of the compound on the enzyme activity is obtained₅₀。

1) And adding 1-5 mu L of EGFR (epidermal growth factor receptor) mutant enzyme solution into a 384-well plate, wherein the final enzyme concentration is 0.1-1 nM.

2) Adding 1-5 mu L of the compound solution diluted in a gradient manner.

3) Incubate for 10 minutes at room temperature.

4) Adding 1-5 mu L of substrate mixed solution containing 5-50 nM of substrate polypeptide and 1-10 mu M of ATP.

5) And incubating for 0.5-2 hours at room temperature.

6) The reaction was stopped for 5 minutes by the addition of 5. mu.L of stop solution of LEDTA.

7) mu.L of the detection solution containing the labeled antibody was added thereto, and the mixture was incubated at room temperature for 1 hour.

8) The microplate reader measures the 665nm fluorescence signal value of each plate.

9) The inhibition rate was calculated from the fluorescence signal value.

10) Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀。

EGFR Wild Type (WT) enzymology experiment

This experiment used fluorescence resonance energy transfer (TR-FRET) to test the preparation of wild-type EGFR enzyme by compounds and to obtain the half inhibitory concentration IC of the compounds to the enzyme activity₅₀。

1) Adding 1-5 mu L of EGFR wild type enzyme solution into a 384-well plate, wherein the final enzyme concentration is 0.1-1 nM.

2) Adding 1-5 mu L of the compound solution diluted in a gradient manner.

3) Incubate for 10 minutes at room temperature.

4) Adding 1-5 mu L of substrate mixed solution containing 5-50 nM of substrate polypeptide and 0.1-5 mu M of ATP.

5) And incubating for 0.5-2 hours at room temperature.

6) The reaction was stopped for 5 minutes by adding 5. mu.L of EDTA stop buffer.

9) The inhibition rate was calculated from the fluorescence signal value.

The enzymatic Activity of the Compounds of the invention was determined by the above assay, the IC determined₅₀The values are given in the following table:

the results in the table show that the compound has stronger inhibition effect on the enzyme activities of EGFR drug-resistant mutant enzymes T790M, Del, L858R, T790M/Del19 and T790M/L858R, but has weaker inhibition effect on the activity of wild-type enzymes, so the compound has better selectivity on the EGFR mutant enzymes.

EXAMPLE 2 study of the inhibitory Effect of Compounds on the proliferation of mutant and wild type cells

Preparation: compounds were dissolved in DMSO and the highest concentration tested for compounds was 1000nM, 3-fold dilution, for a total of 9 concentrations.

The method comprises the following steps: the experiment adopts a method of CellTiter-Glo to test the inhibition effect of the compound on cell proliferation of HCC827(Del19), PC9(Del19), NCI-H1975(T790M/L858R), PC9-GR (T790M/Del19) and a wild-type human epidermal cell cancer cell line A431, and obtains the compoundHalf inhibitory concentration IC of substance for inhibiting cell proliferation activity₅₀。

1) Inoculating 90 mu L of cell suspension in a 96-well cell culture plate, wherein the density is 1-5 multiplied by 10³Cells/ml, plates were incubated in an incubator for 16-24 hours (37 ℃, 5% CO 2).

2) To the plate cells were added solutions of the test compounds at different concentrations diluted in a gradient and the plates were incubated in an incubator for 72 hours (37 ℃, 5% CO 2).

3) 50-100. mu.L of CellTiter-Glo reagent was added to each well, shaken for 10 minutes, and allowed to stand at room temperature for 10 minutes.

4) The microplate reader measures the chemiluminescence signal value of each plate.

5) The inhibition rate was calculated from the chemiluminescence signal value.

6) Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀。

Inhibition of cell proliferation by Compounds of the invention IC was determined by the above assay₅₀The values are given in the following table.

As is clear from the results in the table above, the compound can significantly inhibit the proliferation inhibitory effect of EGFR-activated mutant cells, but the inhibitory activity against EGFR wild-type human epidermal cell carcinoma cell line a431 is low, and therefore the compound exhibits good selectivity.

Example 3 clinical trials in animal models

In a nude mouse tumor model, the compound of formula I potently inhibited the tumor growth of EGFR T790M mutant NSCLC H1975 and LU1868 cell lines, and also inhibited the tumor growth of EGFR sensitive mutant NSCLC HCC827 cell line.

In the high dose 20mg/kg group, the compound of formula I or a pharmaceutically acceptable salt thereof can cause almost complete regression of EGFR mutated tumors. The compounds of formula I have a weak inhibitory effect on WT EGFR a431 cell line, suggesting a better safety profile than other EGFR inhibitors (data not shown). The compound in the formula I can effectively and specifically inhibit EGFR T790 drug resistance mutation, has weak effect on WT EGFR, and fully embodies the characteristics of a new generation of EGFR inhibitors.

Purpose of the experiment:

in vivo efficacy experiments prove that the compound has good therapeutic effect on locally advanced or metastatic non-small cell lung cancer.

Experimental main instruments and materials:

the instrument comprises the following steps:

1. biological safety cabinet (BSC-1300II A2, Shanghai Bocheng industry Co., Ltd.)

2. Clean bench (CJ-2F, Suzhou city Von shi laboratory animal facilities Co., Ltd.)

3、CO₂Incubator (Thermo-311)

4. Centrifuge (Centrifuge 5702R, Eppendorf)

5. Full-automatic cell counter (Countess II, Life)

6. Pipettor (10-20 μ L, Eppendorf)

7. Microscope (TS2, Nikang)

8. Slide measure (CD-6' AX, Japan Sanfeng)

9. Cell culture bottle (T75/T225, Corning)

10. Electronic balance (CPA2202S Saedolisi)

Reagent:

1. RPMI-1640 medium (22400-089, Gibco)

2. Fetal Bovine Serum (FBS) (10091-148, Gibco)

3. 0.25% trypsin (25200-056, Gibco)

4. Penicillin streptomycin double antibody (15140-122, Gibco)

5. Phosphate Buffered Saline (PBS) (10010-023, Gibco)

6. Matrigel Matrix (356234, Corning)

Animals:

BALB/c nude mice, 6-8 weeks old, purchased from Shanghai Sphall-Biky laboratory animals, Inc.

Experimental procedure

Cell culture and cell suspension preparation

a, taking H1975, LU1868, HCC827 or A431 cells from a cell bank, resuscitating the cells by using RPMI-1640 medium (RPMI-1640+ 10% FBS + 1% SP), placing the resuscitated cells in a cell culture flask (marking the cell types, dates, cultured human names and the like on the flask wall) in CO₂Culturing in incubator (incubator temperature 37 deg.C, CO)₂Concentration 5%).

b, after the cells are paved at 80-90% of the bottom of the culture flask, carrying out passage, and continuously placing the cells in CO after passage₂Culturing in an incubator. This process is repeated until the number of cells meets the in vivo pharmacodynamic requirements.

c, collecting cultured cells, counting by using a full-automatic cell counting instrument, and re-suspending the cells by using PBS and matrigel according to the counting result to prepare cell suspension (the density is 10 multiplied by 10)⁷mL), and placing in an ice box for standby.

Cell seeding

a, marking the nude mice with disposable universal big and small mouse ear tags before inoculation

And b, uniformly mixing the cell suspension during inoculation, pumping 0.1-1 mL of the cell suspension by using a 1mL syringe, removing bubbles, and then placing the syringe on an ice bag for later use.

And c, holding the nude mouse with the left hand, disinfecting the position (inoculation position) close to the right shoulder of the right back of the nude mouse by using 75% alcohol, and starting inoculation 30 seconds later.

d, test nude mice were sequentially inoculated (0.1 mL cell suspension per mouse).

Tumor-bearing mice are used for measuring, grouping and administering:

and a, measuring tumors at 45-60 days after inoculation according to the growth condition of the tumors, and calculating the sizes of the tumors. Calculating the tumor volume: tumor volume (mm)³) When the tumor volume reaches a certain degree, observing the mental state and eating condition of the nude mice, randomly drawing one nude mouse to dissect when the nude mouse is listened or has low eating, slicing the tumor, brain, heart, liver, kidney and lung tissues and performing HE staining to observe the tumor metastasis and progression, and confirming that the tumor-bearing mouse model is in the late stage or has metastasis.

And b, grouping by adopting a random grouping method according to the weight and the tumor size of the tumor-bearing mice.

And c, according to grouping results, starting to administer the test medicament (administration mode: oral administration; administration dosage: 5, 10 and 20 mg/kg; administration volume: 10 mL/kg; administration frequency: 1 time/day; administration period: 14 or 21 days; solvent: pH4.1 acetic acid buffer solution).

d, tumor is measured and weighed twice a week after the test drug administration is started.

e, euthanizing the animals after the experiment is finished.

f, processing the data by software such as Excel and the like. Calculation of tumor inhibition rate TGI (%) of compound: when there was no regression of the tumor, TGI (%) [ (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment of the solvent control group-average tumor volume at the start of treatment of the solvent control group) ] × 100%. When there was regression of the tumor, TGI (%) [1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group)/average tumor volume at the start of administration of the treatment group ] × 100%.

The test data are as follows:

the results in the table show that the compound can effectively inhibit the growth of transplanted tumors of EGFR drug-resistant mutant lung cancers H1975, LU1868 and activating mutant lung cancer HCC827 nude mice and cause the regression of the transplanted tumors of the nude mice, and the activity of the compound is dose-dependent; however, the compound has little inhibition effect on EGFR wild-type epidermal cell carcinoma A431 transplanted tumor, so the compound shows good selectivity.

Example 4 multicenter clinical trial

In an open, multicenter clinical trial evaluating once daily oral compound mesylate of formula I in locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with disease progression after previous treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), patients in this study received once daily oral drug containing compound mesylate of formula I evaluated for safety, tolerability, Pharmacokinetics (PK) and anti-tumor activity.

1. The whole study contained 3 phases:

(1) dose escalation cohort, (2) dose extension cohort and (3) dose extension cohort, as shown in figure 1 below.

2. The test population:

patients eligible for dose escalation, 18 years of age or older, with locally advanced or metastatic NSCLC, histologically or cytologically confirmed. The patient is refractory or resistant to previous EGFR TKI follow-up treatments (e.g., gefitinib or erlotinib).

Phase I dose extension, advanced NSCLC subjects who had received EGFR TKI treatment and developed disease progression, and patients confirmed T790M + status prior to enrollment.

Phase II dose extension, subjects who had received EGFR TKI treatment and developed disease progression and confirmed the T790M + status will be enrolled for further safety, tolerability and efficacy evaluations of the compound of formula I.

3. Duration of treatment:

a study treatment cycle was defined as 21 days of continuous administration. Patients continue to receive treatment until the disease worsens or termination criteria are met.

4. Preparation of the medicament:

formula I Compound mesylate 55mg tablet.

Prescription: 64.9mg of mesylate of the compound of the formula I, 15.3mg of anhydrous lactose, 21.0mg of carboxymethyl starch sodium, 2.7mg of sodium stearyl fumarate and 1.5mg of magnesium stearate. Wherein, the compound contains 55mg of the compound in the formula I.

The prescription process comprises the following steps: mixing the raw materials and the auxiliary materials uniformly, and then performing dry granulation, tabletting and coating to obtain the mesylate tablet of the compound of the formula I.

The mesylate of the compound of the formula I is prepared by amplifying 110mg, 220mg or 260mg tablets according to 55mg specification in equal proportion, and the preparation process is the same.

5. Dosage and usage of the drug:

the initial dose was 55mg, orally, once a day; patients fasted for 1 hour before administration and 2 hours after administration.

6. Subject demographic data:

TABLE 1 subject demographic data

TABLE 2 curative effect at dose escalation phase

TABLE 3 Effect of dose extension phase

TABLE 4 Effect of increasing dose + expanding phase

The clinical curative effect trend shows that the product has good development value: the T790M + patients in each dose group were pooled and calculated to have an ORR of about 52.4% and a DCR of 91.4%.

The curative effect of the compound in EGFR T790M mutation positive locally advanced and metastatic NSCLC patients with the prior EGFR TKI treatment progress is as follows: phase II dose extension results indicated 65.6% ORR (95% CI: 59.2% -71.5%) and 93.4% DCR (95% CI: 89.6% -96.2%) in all subjects.

Is effective for patients with brain metastasis (91 cases) whose ORR (overall efficacy) is 59.3% (95% CI: 48.5% -69.5%).

The compound has better response rate or treatment effect on L861Q or G719X gene mutation patients and Exon 19 or L858R gene mutation patients, the ORR of 19 Exon deletion patients (155 cases) is 69.0 percent (95 percent CI: 61.1 to 76.2 percent), the ORR of L858R patients (85 cases) is 60.0 percent (95 percent CI: 48.8 to 70.5 percent), and the DCR of G719X positive and L861Q positive patients can reach more than 95 percent.

Claims

1. The application of the compound of the formula I or the medicinal salt thereof in preparing the medicament for treating the locally advanced or metastatic non-small cell lung cancer,

wherein the locally advanced or metastatic non-small cell lung cancer is EGFR-TKI sensitivity-associated EGFR mutation-mediated locally advanced or metastatic non-small cell lung cancer;

wherein the pharmaceutically acceptable salt is selected from one or a combination of the following: mesylate, fumarate, maleate, acetate, hydrochloride, phosphate or sulfate.

2. The use of claim 1, wherein the non-small cell lung cancer is positive for the T790M mutation.

3. The use of claim 1, wherein the EGFR mutation is selected from one or a combination of: G719X mutation, L858R mutation, L861Q mutation, exon 19 deletion.

4. The use of claim 1, wherein the patient with non-small cell lung cancer is a patient that was previously treated with EGFR-TKI.

5. The use of claim 4, wherein the non-small cell lung cancer patient is a patient whose condition has progressed prior to treatment with an EGFR-TKI.

6. The use of any one of claims 4 or 5, wherein the EGFR-TKI treatment comprises use of a first generation EGFR inhibitor or a second generation EGFR inhibitor; or

The patient with non-small cell lung cancer is a patient resistant to treatment with a first generation EGFR inhibitor, or a patient resistant to treatment with a second generation EGFR inhibitor.

7. Use according to claim 6, wherein:

the first generation EGFR inhibitor is selected from one or a combination of: erlotinib, gefitinib or erlotinib;

the second generation EGFR inhibitor is selected from one or a combination of: lapatinib, afatinib, or dacatinib.

8. The use of claim 1, wherein a unit dose of the medicament comprises: 50mg to 300mg of a compound of formula I, preferably 55mg to 260mg of a compound of formula I, more preferably 55mg, 110mg, 220mg or 260mg of a compound of formula I.

9. The use of claim 1, wherein the medicament is suitable for oral administration.

10. The use of claim 1, wherein the medicament is administered once daily.

11. The use of claim 1, wherein the metastatic non-small cell lung cancer is brain metastatic non-small cell lung cancer.