Osimertinib for use in the treatment of non-small cell lung cancer

Abstract

This specification relates to an EGFR TKI for use in the treatment of EGFR tyrosine kinase inhibitor (TKI)-naive patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), wherein the EGFR TKI is administered in combination with pemetrexid and platinum chemotherapy.

Description

Technology Field

[0001] This specification describes EGFR TKIs for use in the treatment of EGFR tyrosine kinase inhibitor (TKI)-naive patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). In particular, this specification describes the combination of a second-generation or third-generation EGFR TKI with pemetrexid and platinum chemotherapy. Background Technology

[0002] Primary lung cancer is the most common form of cancer worldwide (approximately 13.5% of all new cancer cases in 2018) and remains the leading cause of cancer-related deaths globally (25.3% of all cancer-related deaths). Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 90% of all lung cancers [2019 NCCN (National Comprehensive Cancer Network) guidelines for NSCLC].

[0003] Despite recent advances in early detection, in 70 to 80 percent of patients, lung cancer is diagnosed at a locally advanced or metastatic stage where further surgical resection is impossible [NCI Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: lung and bronchus cancer. Available at https: / / seer.cancer.gov / statfacts / html / lungb.html. Accessed November 8, 2018]. Advanced NSCLC is an incurable disease. Despite the development of new therapies, the prognosis remains poor, with an average 5-year survival rate of approximately 5% for NSCLC patients with unknown EGFR status.

[0004] In current clinical practice, therapeutic decisions for patients with advanced NSCLC are made based on the molecular subtype of the tumor [2019 NCCN Guidelines for NSCLC]. Molecular profiling of patients with advanced NSCLC for biomarkers is standard clinical practice based on international guidelines and is performed to detect the presence of predictive and prognostic biomarkers for NSCLC [2019 NCCN Guidelines for NSCLC].

[0005] Numerous gene mutations or alterations have been identified as molecular therapeutic targets influencing therapy selection. Among these mutations, the presence of EGFR activating mutations, most commonly Ex19del and L858R, is associated with responsiveness to EGFR TKI therapies (e.g., erlotinib, gefitinib, afatinib, osimertinib, and dacomitinib). Other gene alterations detected in NSCLC include ALK fusion gene rearrangements associated with responsiveness to anaplastic lymphoma kinase (ALK)-TKIs; ROS1 gene rearrangements associated with responsiveness to ROS proto-oncogene 1 (ROS1)-TKIs; and BRAF point mutations, some (V600E), that respond to combination therapy with oral inhibitors of B-Raf proto-oncogene (BRAF) and MEK; and include KRAS proto-oncogene (KRAS) point mutations exhibiting poor survival and reduced response to EGFR-TKIs. Other evolving biomarkers include human epidermal growth factor receptor 2 (HER2), MET exon 14 mutations, and fusion genes associated with RET and neurogenic tropomyosin receptor kinase 1 (NTRK1) (Literature [ Annals Oncol.

[2018] , vol. 29(suppl_4):iv192-iv237]).

[0006] The established first-line therapy for patients with advanced NSCLC and tumors with activating EGFR mutations detected prior to first-line systemic therapy is one of the following EGFR-TKIs: osimertinib (labeled as preferred by the NCCN panel), erlotinib, afatinib, gefitinib, or dacomitinib (2019 NCCN guidelines for NSCLC). Survival of unselected patients who received platinum-based chemotherapy (approx. 12 months; literature[ J Clin Oncol. In contrast to

[2012] , vol. 30(27), 3417-20]), the median overall survival (OS) for patients with advanced mutation-positive EGFR NSCLC receiving EGFR-TKIs is greater than 2 years. In patients with activating EGFR mutations, response rates (RR) of 50% to 80% have been reported with first-line EGFR-TKI treatment, which compares to 15% to 34% in patients receiving platinum-double chemotherapy as first-line therapy or as second-line therapy following progression with first-line EGFR-TKI treatment (literature[ N. Engl. J. Med.

[2010] , vol. 362(25), 2380-8]; literature[ N. Engl. J. Med.

[2017] , vol. 376(7), 629-40]; literature[ Lancet Oncol.

[2012] , vol. 13(3), 239-46]; literature[ J. Clin. Oncol

[2013] , vol. 31(27), 3327-34]; [Lancet Oncol.

[2015] , vol. 16(8), 990-8]; [Lancet Oncol.

[2014] , vol. 15, 213-22]). In a Phase III study, dacomitinib, a second-generation EGFR TKI, extended progression-free survival (PFS) compared to gefitinib when administered as a first-line treatment in patients with EGFR mutation-positive NSCLC (median PFS 14.7 months (95% confidence interval (CI) 11.1 to 16.6) versus 9.2 months (9.1 to 11.0) (hazard ratio (HR) 0.59, 95% CI 0.47 to 0.74, p<0.0001) (Lancet [ Lancet Oncol.

[2017] , vol18(11), 1454-1466])).

[0007] Phase III FLAURA study comparing the efficacy and safety of osimertinib versus gefitinib or erlotinib administered as first-line therapy to patients with advanced mutation-positive EGFR (Ex19del or L858R) NSCLC (Literature[ N. Engl. J Med.

[2018] , vol. 378, 113-25]) demonstrated a significantly improved median progression-free survival (PFS) in the osimertinib arm (18.9 months [95% CI: 15.2, 21.4]) compared to erlotinib or gefitinib (10.2 months [95% CI: 9.6, 11.1]), with a hazard ratio (HR) of 0.46 (95% CI: 0.37, 0.57; p <0.0001). Based on the FLAURA study results, osimertinib is recommended by the NCCN panel as the preferred first-line therapy for these patients. Notably, in the FLAURA study, regardless of known or treated central nervous system (CNS) metastasis-related status at entry into the study, CNS progression events were observed in 6% of patients in the osimertinib group and 15% in the standard EGFR TKI group. Furthermore, in patients with CNS metastasis on baseline brain scans, osimertinib demonstrated a nominally statistically significant and clinically meaningful improvement in CNS PFS compared to standard EGFR-TKIs, with a 52% reduction in the risk of CNS progression (HR 0.48; 95% CI 0.26 to 0.86 p=0.014; median CNS PFS not reached (95% CI 16.5, NC (i.e., not calculable)) versus 13.9 months (95% CI 8.3 to NC); literature[ J Clin Oncol .

[2018] , vol. 36(33), 3290-7]).

[0008] Chemotherapy and 1st Generation EGFR TKI

[0009] The 2019 NCCN guidelines for NSCLC do not recommend adding EGFR-TKIs to current chemotherapy for patients with EGFR mutation-positive NSCLC. The guidelines are based on data from a subgroup of the randomized Phase II study CALGB 30406, which compared erlotinib monotherapy versus chemotherapy with erlotinib and carboplatin + paclitaxel as first-line treatment for patients with advanced EGFR mutation-positive NSCLC who were non-smoking or had a history of light smoking (Literature[ J Clin Oncol.

[2012] , vol. 30(17), 2063-9]). In the subgroup of patients with EGFR mutations, PFS and OS were similar in both arm subgroups of the study, and the combination was associated with more adverse effects than erlotinib monotherapy. Pemetrexid was not included in the chemotherapy regimen of this study.

[0010] However, a recent Phase III study (NEJ009) showed that adding carboplatin and pemetrexid to gefitinib as a first-line treatment for untreated advanced EGFR mutation-positive NSCLC patients improved progression-free survival (PFS) and overall survival (OS) and demonstrated an acceptable toxicity profile compared to gefitinib monotherapy (Literature[ J. Clin. Oncol.

[2018] , vol. 36 (15_suppl):abstr 9005]; literature[ Annals Oncol .

[2018] , vol. 29(suppl_8):viii493-viii547. 10.1093 / annonc / mdy292]). These data support the concept of adding chemotherapy to first-generation EGFR-TKI regimens in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. In other small clinical trials, the use of first-generation EGFR TKIs such as gefitinib and erlotinib in combination with chemotherapy as first-line treatment for EGFR mutation-positive NSCLC has been investigated, and these trials provide supporting data for first-generation EGFR TKI regimens in combination with chemotherapy (Literature [ J. Clin. Oncol.

[2018] , vol. 36 (15_suppl): abstr 9005; doi:10.1136 / esmoopen-2017-000313]; literature[ Annals Oncol.

[2015] , vol. 26(5), 888-94]; literature[ Int. J. Cancer.

[2017] , vol. 141(6), 1249-56]; literature[ J. Clin. Oncol.

[2016] , vol. 34(27), 3258-66]; literature[ Annals Oncol.

[2018] , vol. 29 (suppl_8):1381PD]; literature[ Lung Cancer ,

[2015] , vol. 90(1), 65-70]; literature[ Lancet Oncol.

[2013] , vol. 14(8), 777-86]; literature[ J. Clin. Oncol.

[2014] , vol. 32 (no.15_suppl):e19076]; Literature ["Is upfront combo therapy better than the sum of its parts?", Medscape , Aug 09, 2018]).

[0011] Combination of 2nd or 3rd generation EGFR TKIs with chemotherapy

[0012] It is not yet clear whether there is a role for chemotherapy provided in combination with second or third-generation EGFR TKIs (e.g., osimertinib) in these settings.

[0013] As mentioned above, the NEJ009 Phase III study showed that the combination of pemetrexid and platinum chemotherapy with gefitinib as first-line treatment for untreated advanced EGFR mutation-positive NSCLC patients improved patients' PFS and OS compared to gefitinib monotherapy. However, the clinical benefit of first-generation TKI monotherapy may be significantly lower than that of second- or third-generation EGFR TKI monotherapy. Furthermore, as mentioned above, this was demonstrated in the FLAURA Phase III clinical trial, where the median PFS for the osimertinib subarm was 18.9 months, compared to 10.2 months for the erlotinib / gefitinib subarm. Prior to the disclosure of this study, there was no information regarding whether the additional benefit of the pemetrexid and platinum chemotherapy combination compared to gefitinib monotherapy observed in the NEJ009 Phase III study would be observed for second- or third-generation EGFR TKIs.

[0014] A Phase II, non-blinded, randomized study comparing osimertinib monotherapy versus osimertinib + carboplatin / pemetrexid for patients with locally advanced or metastatic NSCLC whose disease has progressed despite previous EGFR TKI therapy and whose tumors possess the T790M mutation within the epidermal growth factor receptor gene is currently underway (UMIN000024438); however, the results are not yet known and it is not directly applicable to the first-line setting (i.e., EGFR TKI-naive patients). Furthermore, there have been no reported trials investigating the outcomes of the combination of second- or third-generation EGFR TKIs with pemetrexid and platinum chemotherapy in EGFR TKI-naive patients with EGFR mutation-positive NSCLC.

[0015] Locally advanced cancer and metastatic EGFR mutation-positive NSCLC, for which curative surgery or radiation therapy is impossible, are incurable diseases. Therefore, there is still a high unmet medical need for patients with these diseases.

[0016] The inventors have discovered that the combined use of osimertinib, pemetrexid, and platinum chemotherapy can lead to one or more improvements in prognosis, such as improved progression-free survival (PFS), improved duration of response (DoR), or improved overall survival (OS).

[0017] This specification describes an EGFR TKI for use in the treatment of EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with pemetrexid and platinum chemotherapy, and the EGFR TKI is a second-generation or third-generation EGFR TKI.

[0018] Such treatment is further described herein, and the treatment leads to one or more of improved progression-free survival (PFS); improved duration of response (DoR); or improved overall survival (OS). Specific details for implementing the invention

[0019] In the first aspect, an EGFR TKI is provided for use in the treatment of EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with pemetrexid and platinum chemotherapy, and the EGFR TKI is a second-generation or third-generation EGFR TKI.

[0020] In an additional embodiment, a method for treating locally advanced or metastatic EGFR mutation-positive NSCLC in a patient is provided, comprising the step of administering an EGFR TKI to an EGFR TKI-naive human patient, wherein the EGFR TKI is administered in combination with pemetrexid and platinum chemotherapy, and the EGFR TKI is a second-generation or third-generation EGFR TKI.

[0021] In an additional embodiment, an use of an EGFR TKI is provided for the manufacture of a medicine for the treatment of EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with pemetrexid and platinum chemotherapy, and the EGFR TKI is a second-generation or third-generation EGFR TKI.

[0022] When referring to any given value, the term "approximately" as used herein means within ±10% of that value.

[0023] EGFR Mutation-Positive NSCLC and Diagnostic Methods

[0024] In 2004, activating mutations in exons 18 to 21 of EGFR were reported to be correlated with the response to EGFR-TKI therapy in NSCLC (Literature[ Science

[2004] , vol. 304, 1497-1500]; literature[ New England Journal of Medicine

[2004] , vol. 350, 2129-2139]). These mutations are estimated to be prevalent in approximately 10% to 16% of NSCLC patients in the U.S. and Europe, and in approximately 30% to 50% of NSCLC patients in Asia. Two of the most significant EGFR-activating mutations are exon 19 deletions and missense mutations in exon 21. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven different mutations resulting in deletions of 3 to 7 amino acids were detected in exon 19, all concentrated in uniformly deleted codons at amino acids 747 through 749. The most significant exon 19 deletion is E746-A750. Missense mutations in exon 21 account for approximately 39% to 45% of known EGFR mutations, of which the substitution mutation L858R accounts for approximately 39% of total mutations in exon 21 (reference [J. Thorac. Oncol.

[2010] , 1551-1558]). Those skilled in the art will be aware of EGFR mutations associated with an improved response to EGFR-TKI therapy.

[0025] Accordingly, in an embodiment, the EGFR mutation-positive NSCLC comprises an activating mutation in the EGFR. In a further embodiment, the activating mutation in the EGFR comprises an activating mutation in exons 18 to 21. In a further embodiment, the activating mutation in the EGFR comprises an exon 19 deletion or a missense mutation in exon 21. In a further embodiment, the activating mutation in the EGFR comprises an exon 19 deletion or an L858R substitution mutation.

[0026] In an embodiment, the locally advanced or metastatic EGFR mutation-positive NSCLC is the locally advanced EGFR mutation-positive NSCLC.

[0027] In an embodiment, locally advanced or metastatic EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC.

[0028] In an embodiment, locally advanced or metastatic EGFR mutation-positive NSCLC is not curative surgery or radiation therapy.

[0029] There are numerous methods for detecting EGFR activating mutations, and those skilled in the art will be familiar with them. Several tests suitable for use with these methods have been approved by the U.S. Food and Drug Administration (FDA). These methods include both tumor tissue and plasma-based diagnostic methods. Generally, EGFR mutation status is first evaluated using tumor tissue biopsy samples derived from the patient. If tumor samples are unavailable or are negative, EGFR mutation status can be evaluated using plasma samples. Specific examples of diagnostic tests suitable for detecting EGFR activating mutations, particularly exon 19 deletion or L858R substitution mutations, include Cobas TM It is EGFR Mutation Test v2 (Roche Molecular System).

[0030] Accordingly, in an embodiment, EGFR mutation-positive NSCLC comprises an activating mutation in EGFR (e.g., an activating mutation in exons 18 to 21, e.g., an exon 19 deletion, or a missense mutation in exon 21, e.g., an exon 19 deletion, or an L858R substitution mutation), wherein the patient's EGFR mutation status was determined using an appropriate diagnostic test. In a further embodiment, the EGFR mutation status was determined using a tumor tissue sample. In a further embodiment, the EGFR mutation status was determined using a plasma sample. In a further embodiment, the diagnostic method uses an FDA-approved test. In a further embodiment, the diagnostic method uses Cobas TMUse the EGFR Mutation Test (v1 or v2).

[0031] EGFR TKI and T790M mutation

[0032] EGFR TKIs can be characterized as first-generation, second-generation, or third-generation EGFR TKIs as shown below.

[0033] First-generation EGFR TKIs are reversible inhibitors of EGFR with activating mutations that do not significantly inhibit EGFR with the T790M mutation. Examples of first-generation TKIs include gefitinib and erlotinib.

[0034] Second-generation EGFR TKIs are irreversible inhibitors of EGFR carrying activating mutations that do not significantly inhibit EGFR carrying the T790M mutation. Examples of second-generation TKIs include apatinib and dacomitinib.

[0035] Third-generation EGFR TKIs are inhibitors of EGFR carrying an activating mutation that significantly inhibits EGFR carrying the T790M mutation but does not significantly inhibit wild-type EGFR. Examples of third-generation TKIs include osimertinib, AZD3759, lazertinib, nazartinib, CO1686 (rociletinib), HM61713, ASP8273, EGF816, and PF-06747775 (mavelertinib).

[0036] In an embodiment, the EGFR TKI is a second-generation EGFR TKI. In a further embodiment, the second-generation EGFR TKI is dacomitinib or its pharmaceutically acceptable salt.

[0037] In an embodiment, the EGFR TKI is a third-generation EGFR TKI. In a further embodiment, the third-generation EGFR TKI is selected from the group consisting of osimertinib or its pharmaceutically acceptable salt, AZD3759 or its pharmaceutically acceptable salt, and lazertinib or its pharmaceutically acceptable salt. In a further embodiment, the third-generation EGFR TKI is osimertinib or its pharmaceutically acceptable salt.

[0038] Osimertinib and its pharmaceutical composition

[0039] Osimertinib has the following chemical structure:

[0040]

[0041] The free base of osimertinib is known by the following chemical names: N -(2-{2-dimethylamino ethyl-methylamino}-4-methoxy-5-{[4-(1-methylindole-3-yl)pyrimidine-2-yl]amino}phenyl)prop-2-enamide. Osimertinib is described in WO 2013 / 014448. Osimertinib is also known as AZD9291.

[0042] Osimertinib can be found in the following forms of mesylate salts: N -(2-{2-dimethylamino ethyl-methylamino}-4-methoxy-5-{[4-(1-methylindole-3-yl)pyrimidine-2-yl]amino}phenyl)prop-2-enamide mesylate salt. Osimertinib mesylate is TAGRISSO TM It is also known as...

[0043] Osimertinib mesylate is currently approved as an oral once-daily tablet formulation at a dose of 80 mg (equivalent to 95.4 mg of osimertinib mesylate, expressed as free base) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC. If dose adjustment is required, an oral once-daily tablet formulation of 40 mg (equivalent to 47.7 mg of osimertinib mesylate, expressed as free base) is available. The tablet core contains a pharmaceutical diluent (e.g., mannitol and microcrystalline cellulose), a disintegrant (e.g., low-substituted hydroxypropyl cellulose), and a lubricant (e.g., sodium stearyl fumarate). The tablet formulation is described in WO 2015 / 101791.

[0044] Accordingly, in the embodiment, osimertinib or its pharmaceutically acceptable salt is a mesylate salt, i.e., N -(2-{2-dimethylamino ethyl-methylamino}-4-methoxy-5-{[4-(1-methylindole-3-yl)pyrimidine-2-yl]amino}phenyl)prop-2-enamide mesylate salt form.

[0045] In an embodiment, osimertinib or its pharmaceutically acceptable salt is administered once daily. In a further embodiment, osimertinib mesylate is administered once daily.

[0046] In an embodiment, the total daily dose of osimertinib is about 80 mg. In an additional embodiment, the total daily dose of osimertinib mesylate is about 95.4 mg.

[0047] In an embodiment, the total daily dose of osimertinib is about 40 mg. In an additional embodiment, the total daily dose of osimertinib mesylate is about 47.7 mg.

[0048] In an embodiment, osimertinib or its pharmaceutically acceptable salt is in tablet form.

[0049] In an embodiment, osimertinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In a further embodiment, the composition comprises one or more pharmaceutical diluents (e.g., mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (e.g., low-substituted hydroxypropyl cellulose), or one or more pharmaceutical lubricants (e.g., sodium stearyl fumarate).

[0050] In an embodiment, the composition is in the form of a tablet, wherein the tablet core comprises (a) 2 to 70 parts of osimertinib or its pharmaceutically acceptable salt; (b) 5 to 96 parts of two or more pharmaceutical diluents; (c) 2 to 15 parts of one or more pharmaceutical disintegrants; and (d) 0.5 to 3 parts of one or more pharmaceutical lubricants; all parts are on a weight basis, and the sum of the parts (a)+(b)+(c)+(d) is 100.

[0051] In an embodiment, the composition is in the form of a tablet, wherein the tablet core comprises: (a) 7 to 25 parts of osimertinib or its pharmaceutically acceptable salt; (b) 55 to 85 parts of two or more pharmaceutical diluents (wherein the pharmaceutical diluents comprise microcrystalline cellulose and mannitol); (c) 2 to 8 parts of pharmaceutical disintegrant (wherein the pharmaceutical disintegrant comprises low-substituted hydroxypropyl cellulose); (d) 1.5 to 2.5 parts of pharmaceutical lubricant (wherein the pharmaceutical lubricant comprises sodium stearyl fumarate); all parts are on a weight basis, and the sum of the parts (a)+(b)+(c)+(d) is 100.

[0052] In an embodiment, the composition is in the form of a tablet, wherein the tablet core comprises (a) about 19 parts of osimertinib mesylate; (b) about 59 parts of mannitol; (c) about 15 parts of microcrystalline cellulose; (d) about 5 parts of low-substituted hydroxypropyl cellulose; and (e) about 2 parts of sodium stearyl fumarate; all parts are on a weight basis, and the sum of the parts (a)+(b)+(c)+(d)+(e) is 100.

[0053] AZD3759

[0054] AZD3759 has the following chemical structure:

[0055]

[0056] The free base of AZD3759 is known by the following chemical name: 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl(2 R )-2,4-dimethyl-1-piperazine carboxylate. AZD3759 is described in WO 2014 / 135876.

[0057] In an embodiment, AZD3759 or its pharmaceutically acceptable salt is administered twice daily. In a further embodiment, AZD3759 is administered twice daily.

[0058] In an embodiment, the total daily dose of AZD3759 is about 400 mg. In an additional embodiment, about 200 mg of AZD3759 is administered twice daily.

[0059] lazertinib

[0060] Lazertinib has the following chemical structure:

[0061]

[0062] The free base of lazertinib is the chemical name NIt is known as -{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazole-1-yl}-2-pyrimidinyl)amino]-4-methoxy-2-(4-mopolinyl)phenyl}acrylamide. Lazertinib is described in WO 2016 / 060443. Lazertinib is also known by the names YH25448 and GNS-1480.

[0063] In an embodiment, lazertinib or its pharmaceutically acceptable salt is administered once daily. In a further embodiment, lazertinib is administered once daily.

[0064] In the embodiment, the total daily dose of lazertinib is about 240 mg.

[0065] Dacomitinib

[0066] Dacomitinib has the following chemical structure:

[0067]

[0068] The free form of dacomitinib is known by the following chemical names: (2 E )- N -{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide. Dacomitinib is described in WO 2005 / 107758. Dacomitinib is also known by the name PF-00299804.

[0069] Dacomitinib can be found in the form of dacomitinib monohydrate, namely (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate.

[0070] In an embodiment, dacomitinib or its pharmaceutically acceptable salt is administered once daily. In a further embodiment, dacomitinib monohydrate is administered once daily.

[0071] In the embodiment, the total daily dose of dacomitinib monohydrate is about 45 mg.

[0072] In an embodiment, dacomitinib or its pharmaceutically acceptable salt is in tablet form.

[0073] In an embodiment, dacomitinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In a further embodiment, one or more pharmaceutically acceptable excipients comprise lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[0074] Platinum-based chemotherapy

[0075] In an embodiment, platinum chemotherapy includes the administration of cisplatin.

[0076] In an embodiment, platinum chemotherapy consists of the administration of cisplatin.

[0077] The total daily dose of cisplatin is generally calculated by referencing body surface area (BSA), and the daily dose is typically about 50 mg / m² 2 to about 120 mg / m² 2 It is within the range. Therefore, in the embodiment, the maximum daily dose of cisplatin is up to approximately 150 mg / m². 2 , for example, up to about 120 mg / m² 2 , for example, up to about 100 mg / m² 2 , for example, up to about 90 mg / m² 2 , for example, up to about 80 mg / m² 2 , for example, up to about 70 mg / m² 2 , for example, up to about 60 mg / m² 2 , for example, up to about 50 mg / m² 2 is. In the embodiment, the total daily dose of cisplatin is approximately 75 mg / m² 2 am.

[0078] Patients receiving chemotherapy with cisplatin generally do not receive cisplatin daily, and cisplatin is generally administered in treatment cycles. In an embodiment, the treatment cycle is up to 42 days, e.g., up to 35 days, e.g., up to 28 days, e.g., up to 21 days. In an embodiment, cisplatin is administered on day 1 of each treatment cycle. In an embodiment, cisplatin is administered only on day 1 of a treatment cycle lasting 21 days.

[0079] Alternatively, patients may receive cisplatin over a 5-day period. These patients typically receive approximately 15 mg / m² for 5 consecutive days. 2 to about 20 mg / m² 2 A maximum daily dose of is provided. In an embodiment, the treatment cycle is up to 42 days, e.g., up to 35 days, e.g., up to 28 days, e.g., up to 21 days. In an embodiment, cisplatin is administered only on days 1 through 5 of each treatment cycle. In an embodiment, cisplatin is administered only on days 1 through 5 of a treatment cycle lasting 21 days.

[0080] In an embodiment, platinum chemotherapy includes the administration of carboplatin.

[0081] In an embodiment, platinum chemotherapy is performed by administering carboplatin.

[0082] The total daily dose of carboplatin is calculated by referring to the area under the curve (AUC) for a given patient using a formula generally known to those skilled in the art (e.g., the Calvert formula). Typical daily doses are in the range of AUC 2 to AUC 7. In an embodiment, the maximum daily dose of carboplatin is a maximum AUC 7, e.g., a maximum AUC 6, e.g., a maximum AUC 5, e.g., a maximum AUC 4, e.g., a maximum AUC 3, e.g., a maximum AUC 2. In an embodiment, the total dose of carboplatin is approximately AUC 5.

[0083] Patients receiving chemotherapy with carboplatin generally do not receive carboplatin daily, and carboplatin is generally administered according to a treatment cycle. In an embodiment, the treatment cycle is up to 21 days, e.g., up to 14 days, e.g., up to 7 days. In an embodiment, carboplatin is administered on day 1 of each treatment cycle. In an embodiment, carboplatin is administered only on day 1 of a treatment cycle lasting 21 days.

[0084] Pemetrexid

[0085] In an embodiment, the total daily dose of pemetrexid is up to about 500 mg / m² 2 , for example, about 500 mg / m² 2 is. In an additional embodiment, pemetrexid is administered on day 1 of a treatment cycle lasting 21 days.

[0086] In an embodiment, pemetrexid is administered together with vitamin supplements, such as vitamin B12 and folic acid supplements.

[0087] In an embodiment, a 21-day cycle exists, wherein pemetrexid (approx. 500 mg / m²) 2 Total daily dose of (optional accompanied by vitamin supplementation) + cisplatin (approx. 75 mg / m²) 2 (total daily dose of) or carboplatin (total daily dose of approx. AUC 5 or approx. AUC 6) is administered only on Day 1 of the 21-day cycle. In additional embodiments, there are four sequential 21-day cycles. In other additional embodiments, pemetrexid maintenance therapy follows four sequential 21-day cycles, wherein pemetrexid maintenance therapy is administered once every 21 days (approx. 500 mg / m²) until disease progression or unacceptable toxicity occurs. 2 It includes the administration of a total daily dose of (optional accompanied by vitamin supplementation).

[0088] Clinical results

[0089] Patients with locally advanced or metastatic EGFR mutation-positive NSCLC who receive an EGFR TKI according to the present specification may benefit from an improved prognosis compared to existing standard treatment. In particular, these patients may benefit from one or more of improved progression-free survival (PFS); increased objective response rate; improved duration of response (DoR); or improved overall survival (OS).

[0090] Accordingly, in an embodiment, the patient benefits from progression-free survival of at least 16 months, e.g., at least 18 months, e.g., at least 20 months, e.g., at least 22 months, e.g., at least 24 months, e.g., at least 26 months, e.g., at least 28 months, e.g., at least 30 months, e.g., at least 32 months, e.g., at least 34 months, e.g., at least 36 months. In a further embodiment, the patient benefits from a duration of response of at least 14 months, e.g., at least 16 months, e.g., at least 18 months, e.g., at least 20 months, e.g., at least 25 months, e.g., at least 30 months, e.g., at least 70 months, e.g., at least 50 months, e.g., at least 55 months, e.g., at least 60 months, e.g., at least 65 months, e.g., at least 70 months.

[0091] Patients with advanced or metastatic EGFR mutation-positive NSCLC with CNS metastasis on baseline brain scans who receive an EGFR TKI according to the present specification may particularly benefit from an improved prognosis compared to existing standard treatment.

[0092] Accordingly, in an embodiment, a patient with CNS metastasis on a baseline brain scan benefits from progression-free survival of at least 12 months, e.g., at least 14 months, e.g., at least 16 months, e.g., at least 18 months, e.g., at least 20 months, e.g., at least 22 months, e.g., at least 24 months, e.g., at least 26 months, e.g., at least 28 months, e.g., at least 30 months, e.g., at least 32 months, e.g., at least 34 months, e.g., at least 36 months.

[0093] In the present disclosure, central nervous system progression-free survival (CNS PFS) refers to the time from the start of the study treatment until the progression of existing CNS lesions and / or new CNS lesions or death without CNS progression.

[0094] Patients with advanced or metastatic EGFR mutation-positive NSCLC with CNS metastasis on baseline brain scans who receive an EGFR TKI according to the present specification may particularly benefit from an improved prognosis compared to existing standard treatment based on (i) prevention / delay of the occurrence of new central nervous system metastases, particularly brain metastases and / or (ii) prevention / delay of the progression of existing CNS metastases, particularly brain metastases and / or (iii) improvement in CNS progression-free survival through prevention / delay of death without CNS progression.

[0095] Accordingly, in an embodiment, a patient with CNS metastasis on a baseline brain scan benefits from CNS progression-free survival of, for example, at least 14 months, for example, at least 16 months, for example, at least 18 months, for example, at least 20 months, for example, at least 22 months, for example, at least 24 months, for example, at least 26 months, for example, at least 28 months, for example, at least 30 months, for example, at least 32 months, for example, at least 34 months, for example, at least 36 months.

[0096] Accordingly, in an embodiment, the EGFR TKI provided according to the present specification is intended for use to improve either or both of duration of response (DoR) and overall survival (OS) in patients with CNS metastases on baseline brain scans.

[0097] Examples

[0098] A Phase III, randomized, double-blind, placebo-controlled, multicenter, international study on the combination of osimertinib and chemotherapy as first-line treatment for patients with locally advanced or metastatic EGFR mutation-positive NSCLC.

[0099] The study title is “A Phase III, Open-label, Randomized Study of Osimertinib with or without Platinum Plus Pemetrexed Chemotherapy, as First-line Treatment in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer.”

[0100] The following study is conducted to confirm the benefits of the combination of osimertinib, pemetrexid, and platinum chemotherapy in the treatment of locally advanced or metastatic EGFR mutation-positive NSCLC patients.

[0101] Overview of Research Design

[0102] This study will be a global Phase III, non-blinded, randomized study conducted in patients with locally advanced or metastatic EGFR mutation-positive (Ex19del and / or L858R) NSCLC who have not received any prior therapy for advanced disease and have a World Health Organization (WHO) performance status (PS) of 0 or 1. Approximately 556 patients will be enrolled from approximately 24 countries. Approximately 60% of the patients will be Asian and 40% will be non-Asian.

[0103] Before the start of the Phase III randomization phase of the study, up to 30 patients will be enrolled in a non-randomized safety run-in phase to evaluate the safety and tolerability of the combination of osimertinib, platinum chemotherapy (carboplatin or cisplatin), and pemetrexid.

[0104] The proposed study will allow the enrollment of only EGFR mutation-positive NSCLC patients having one of the following: (1) a positive existing tissue test (Ex19del or L858R) obtained from a CLIA-certified local laboratory (for U.S. locations) or an authorized local laboratory (for non-U.S. locations); or (2) a COBAS prospectively performed at a central laboratory. TM Tissue Ex19del or L858R EGFR mutation test based on EGFR Mutation Test v2 is positive.

[0105] During the safety run-in phase of the study, two patient cohorts (osimertinib + cisplatin / pemetrexid and osimertinib + carboplatin / pemetrexid) will be studied in a non-randomized manner. Up to 15 patients per cohort will receive osimertinib 80 mg along with cisplatin (75 mg / m²). 2 ) or carboplatin (AUC 5), and pemetrexid (500 mg / m² 2Administered once daily in combination with (both administered Q3W for 4 cycles), followed by maintenance of osimertinib 80 mg once daily + Q3W pemetrexed (500 mg / m²) until progression defined in RECIST v1.1 or other discontinuation criteria are met. 2 You will be provided with ).

[0106] For each cohort of the safety run-in, safety data from at least 12 evaluable patients who completed at least three cycles of platinum / pemetrexid dual therapy in combination with osimertinib will be reviewed by the Safety Review Committee (SMC). The SRC will recommend whether the data support the initiation of the randomization portion of the study.

[0107] Patients enrolled in the safety run-in will continue the treatment assigned per protocol. Safety and tolerability data from the safety run-in portion of the study will be reviewed for all patients who received at least one dose of osimertinib and initiated a chemotherapy cycle. Data will be evaluated by the SRC. Patients included in the safety run-in component of the study will be excluded from the analysis of the Phase III randomization component.

[0108] Following the completion of the safety run-in and subsequent consultation with the SRC, new patients will be randomized in a 1:1 ratio to receive osimertinib alone or in combination with pemetrexid and cisplatin or carboplatin. Patients will be stratified prior to randomization based on race (Chinese / Asian vs. non-Chinese / Asian vs. non-Asian, with approximately 60% Asian and 40% non-Asian), World Health Organization (WHO) activity level (PS) (0 or 1), and tissue testing method (central vs. local). Prior to randomization, the investigator will determine which chemotherapy regimen (carboplatin / pemetrexid or cisplatin / pemetrexid) a patient will receive if the patient is assigned to the osimertinib + chemotherapy subarm.

[0109] The two treatment regimens will be as follows:

[0110] a) 80 mg of osimertinib once daily; or

[0111] b) Osimertinib 80 mg once daily and pemetrexid (500 mg / m² 2 )(accompanied by vitamin supplementation) + Cisplatin (75 mg / m² 2 Q3W pemetrexid maintenance (500 mg / m²) following concomitant use of ) or carboplatin (AUC5) (both administered on Day 1 of the 21-day cycle for 4 cycles). 2 ).

[0112] Randomized treatment will continue until progression defined in RECIST v1.1 or until other discontinuation criteria are met.

[0113] After discontinuation of treatment, follow-up therapy will be at the investigator's discretion. Patients will be followed for secondary progression and survival in follow-up treatment as defined by local practice.

[0114] The management of safety and tolerability during the randomization phase of the study will be provided exclusively by the Independent Data Monitoring Committee (IDMC), composed of completely independent members.

[0115] The primary endpoint will be PFS based on investigator evaluation using RECIST v1.1. Sensitivity analysis based on a blinded independent central review (BICR) of efficacy data from all randomized patients will also be performed. Secondary endpoints will include OS, Landmark OS, PFS2, ORR, duration of response (DoR), DCR, safety and tolerability (based on AE, laboratory tests [clinical chemistry, hematology, urinalysis], vital signs [pulse and blood pressure], physical examination, body weight, electrocardiogram (ECG) parameters, left ventricular ejection fraction), pharmacokinetics, and patient-reported outcomes.

[0116] Key Inclusion Criteria

[0117] a) Pathologically confirmed non-squamous NSCLC

[0118] b) Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic NSCLC (clinical stage IVA or IVB) or recurrent NSCLC for which curative surgery or radiotherapy is not possible (according to Version 8 of the [IASLC (International Association for the Study of Lung Cancer)] Manual of Staging for Thoracic Oncology).

[0119] c) The tumor possesses one of two common activating EGFR mutations (Ex19del or L858R) known to be associated with EGFR-TKI sensitivity, alone, or in combination with another EGFR mutation evaluated by a CLIA-certified local laboratory (local in the U.S.) or an authorized local laboratory (local outside the U.S.) or by a central prospective test.

[0120] d) Mandatory provision of baseline plasma samples and unstained stored tumor tissue samples sufficient to enable central confirmation of EGFR mutation status. Refer to the laboratory manual for details.

[0121] e) The patient must have untreated advanced NSCLC for which curative surgery or radiotherapy is not possible. Definitive radiation / chemoradiation with or without prior adjuvant and neo-adjuvant therapy (chemotherapy, radiotherapy, immunotherapy, biological agent therapy, investigational agent), or therapy including immunotherapy, biological agent therapy, or investigational agent, is permitted if treatment was completed at least 12 months prior to the onset of recurrent disease.

[0122] f) WHO PS is 0 to 1 at screening without clinically significant deterioration within the last 2 weeks.

[0123] g) At least one previously unirradiated lesion suitable for accurate repeat measurements, with the longest diameter at baseline being accurately measured by CT or MRI to be 10 mm or more (excluding lymph nodes where the shortest must be 15 mm or more). If only one measurable lesion exists, this lesion may be permitted to be used (as a target lesion) provided that it has not been previously irradiated and a baseline tumor evaluation scan is not performed within 14 days of the lesion biopsy.

[0124] Major exclusion criteria

[0125] a) Spinal cord compression; symptomatic and unstable brain metastases, excluding patients who have completed definitive therapy, are not using steroids, or have a stable neurological status for at least 2 weeks after completion of definitive therapy and steroids. Patients with asymptomatic brain metastases may be enrolled if, in the investigator's opinion, immediate definitive treatment is not recommended.

[0126] b) A history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD.

[0127] c) Any evidence of severe or uncontrolled systemic disease, including uncontrolled hypertension and an active bleeding constitution, or any evidence of active infection, including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), that, in the investigator's opinion, would make it undesirable for the patient to participate in the study or compromise protocol compliance. Screening for chronic diseases is not required.

[0128] d) Any of the following heart criteria:

[0129] ● Screening Clinic ECG machine-derived QTcF values ​​obtained from three electrocardiograms (ECG), mean rest-corrected QT interval (QTc) of greater than 470 msec;

[0130] ● Clinically significant abnormalities in rhythm, conduction, or morphology of the resting ECG, e.g., complete left bundle branch block, third-degree atrioventricular block, second-degree atrioventricular block;

[0131] ● Any factor that increases the risk of QTc prolongation or arrhythmic events, e.g., electrolyte abnormalities including serum / plasma potassium*, magnesium*, and calcium* below the lower limit of normal (LLN), heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death of an immediate family member under the age of 40, or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes.

[0132] Correction of electrolyte abnormalities to within the normal range may be performed during screening.

[0133] e) Inadequate bone marrow reserve or organ function as evidenced by any of the following laboratory values:

[0134] ● Below the normal lower limit ( <LLN)의 절대 호중구 수*

[0135] ● Platelet count below LLN*

[0136] ● Hemoglobin* less than 90 g / L

[0137] The use of granulocyte colony-stimulating factor support, platelet transfusion, and blood transfusion to meet these criteria is not permitted.

[0138] ● ALT exceeding 2.5 times the Upper Limit of Normal (ULN) in the absence of verifiable liver metastasis, or exceeding 5 times the ULN in the presence of liver metastasis.

[0139] ● AST exceeding 2.5 times the ULN in the absence of verifiable liver metastasis, or exceeding 5 times the ULN in the presence of liver metastasis.

[0140] ● Total bilirubin exceeding 1.5 times the ULN in the absence of liver metastasis, or exceeding 3 times the ULN in the presence of documented Gilbert's syndrome (non-conjugated hyperbilirubinemia) or liver metastasis.

[0141] ● Creatinine clearance of less than 60 mL / min calculated by the Cockcroft-Gault equation.

[0142] f) Prior treatment with any systemic anticancer therapy for advanced NSCLC that is not curative surgery or radiation therapy, including chemotherapy, biological agent therapy, immunotherapy, or any investigational drug. If treatment was completed at least 12 months prior to the onset of relapsed disease, prior adjuvant and neo-adjuvant therapy (chemotherapy, radiation therapy, immunotherapy, biological agent therapy, investigational agent), or definitive radiation / chemoradiotherapy with or without therapy including immunotherapy, biological agent therapy, or investigational agent is permitted.

[0143] g) Pre-treatment with EGFR-TKI.

[0144] analyze

[0145] The Phase III component of the study will begin only after reviewing data from up to 30 patients included in the study's safety run-in component. Up to 15 patients (at least 12) will be treated with osimertinib in combination with each of the two chemotherapy regimens for at least 3 cycles.

[0146] Safety and tolerability data from the safety run-in portion of the study will be reviewed in all patients who have received at least one dose of osimertinib and started a chemotherapy cycle. Data will be evaluated by the SRC, which will be utilized only in the case of the safety run-in.

[0147] Patients included in the study's safety run-in component will be excluded from the analysis of the Phase III randomization component.

[0148] For the Phase III component, approximately 556 patients will be randomized globally in a 1:1 ratio to this study. The primary endpoint of the study is PFS based on investigator assessment (according to RECIST v1.1).

[0149] Progression-free survival will be defined as the time from randomization to the date of objective disease progression or death (of any cause in the absence of progression), regardless of whether the patient withdraws from the randomized regimen or receives another anticancer regimen prior to progression. Patients who have not progressed or died at the time of analysis will be screened on the latest evaluation date from their last evaluable RECIST assessment.

[0150] The primary analysis of PFS based on investigator assessment (according to RECIST 1.1) will occur when approximately 278 PFS events are observed in 556 randomized patients (approximately 50% maturity). This is expected to occur approximately 33 months after the first patient is randomized (under assumed exponential recruitment of 15 months). If the true PFS HR for the comparison of osimertinib and chemotherapy versus osimertinib monotherapy is 0.68, 280 progression events will provide 90% power to demonstrate a statistically significant difference in PFS at the 5% two-sided significance level. This translates to an improvement in the median PFS from 19 months to 28 months, assuming an exponential distribution and proportional hazards. The minimum threshold HR is 0.79, which translates to an improvement in the median PFS from approximately 19 months to 24 months.

[0151] Progression-free survival will be analyzed using log-rank tests stratified by race (Chinese / Asian vs. Non-Chinese / Asian vs. Non-Asian), WHO PS (0 vs. 1), and tissue testing methods (central vs. regional) for generating p-values, utilizing the Breslow approach for relationship handling. The assumption of proportionality will be evaluated. Sensitivity analysis of PFS will be performed based on data evaluated by a blinded independent central review (BICR) for all patients. COBAS used for study eligibility, or retrospectively to determine whether eligibility is based on regionally authorized testing, will be used. TM Organization or COBAS TM Pre-specified subgroup analyses will be performed in patients with a centrally confirmed EGFR mutation status by plasma testing.

[0152] The primary secondary endpoint of OS will be tested via a hierarchical procedure at the PFS analysis and after the primary PFS analysis when OS data reach approximately 60% maturity (approximately 334 death events across both subarms). Alpha will be controlled across two OS analyses, namely at the primary PFS analysis and the final OS analysis, and the total Type 1 error is strongly controlled at 5% (bilateral) for OS testing under the O'Brien and Fleming consumption rules. Under assumed medians of 40 and 52 months (HR = 0.77) for osimertinib monotherapy and osimertinib and chemotherapy, respectively, 170 observed events (information fraction 0.51) are expected at the primary PFS analysis with a bilateral alpha of 0.0034, and the remainder is allocated to the final OS analysis (0.0490).

[0153] Additional valid endpoints will be included, such as ORR and time to secondary progression or death (PFS2).

[0154] The investigator will determine the chemotherapy regimen to be used (cisplatin / pemetrexid or carboplatin / pemetrexid) if the patient is randomized to a combination subarm prior to randomization. The selection of the chemotherapy regimen will be made at the patient level. After progression, the selection of subsequent therapy will be at the investigator's discretion.

[0155] The IDMC, composed of completely independent members, will convene and meet periodically to review safety data and will recommend whether to continue, modify, or discontinue the study based on the findings of the investigation.

[0156] Severe AE, AE, and other safety data will be reviewed, and individual and aggregated safety data will be evaluated by the IDMC.

Claims

Claim 1 A pharmaceutical composition comprising an EGFR TKI for use in the treatment of EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with pemetrexid and platinum chemotherapy, the EGFR TKI is a third-generation EGFR TKI, and wherein the third-generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. Claim 2 A pharmaceutical composition according to claim 1, wherein the platinum chemotherapy comprises a platinum-based formulation selected from cisplatin or carboplatin. Claim 3 A pharmaceutical composition according to claim 1 or 2, wherein pemetrexid and platinum chemotherapy are administered only on day 1 of a treatment cycle lasting 21 days. Claim 4 A pharmaceutical composition according to claim 1 or 2, wherein pemetrexid and platinum chemotherapy are administered only on day 1 of a treatment cycle lasting 21 days for four sequential cycles, and subsequently, pemetrexid is administered once every 21 days until disease progression or unacceptable toxicity occurs. Claim 5 A pharmaceutical composition according to claim 1 or 2, wherein the EGFR mutation-positive NSCLC comprises an activating mutation in the EGFR selected from an exon 19 deletion or L858R substitution mutation. Claim 6 A pharmaceutical composition according to claim 1 or 2, wherein the locally advanced or metastatic EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC. Claim 7 A pharmaceutical composition according to claim 1 or 2, wherein osimertinib or its pharmaceutically acceptable salt is administered once daily. Claim 8 A pharmaceutical composition according to claim 1 or 2, wherein osimertinib or its pharmaceutically acceptable salt is administered in tablet form. Claim 9 A pharmaceutical composition according to claim 1 or 2, wherein osimertinib or its pharmaceutically acceptable salt is osimertinib mesylate salt. Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete

Images