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

Abstract

To provide an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for use in the treatment of EGFR TKI-naive patients having locally-advanced or metastatic EGFR mutation-positive non-small cell lung cancer (NSCLC).SOLUTION: Provided is an EGFR TKI, wherein the EGFR TKI is administered in combination with pemetrexed and platinum chemotherapy, and the EGFR TKI is either a second-generation or a third-generation EGFR TKI.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This document describes epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) inhibitors (EGFR TKIs) for use in the treatment of TKI-naive patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer (NSCLC). Specifically, this document describes the combination of either second- or third-generation EGFR TKIs with pemetrexed 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 the leading cause of cancer-related deaths worldwide (25.3% of all cancer deaths). Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 90% of all lung cancers [Non-Patent Document 1].

[0003] Despite recent advances in early detection, in 70% to 80% of patients, lung cancer is diagnosed at a locally advanced or metastatic stage, at which point surgical resection is no longer possible [Non-Patent Document 2, available at: https: / / seer.cancer.gov / statfacts / html / lungb.html. Accessed November 8, 2018]. Advanced NSCLC is incurable. Despite the development of novel therapies, the prognosis remains poor, with an average 5-year survival rate of approximately 5% for patients with NSCLC whose EGFR status is unknown.

[0004] In current clinical practice, treatment decisions for patients with advanced NSCLC are informed by the molecular subtype of the tumor [1]. 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 [1].

[0005] Numerous gene mutations or alterations have been identified as molecular therapeutic targets that influence therapy selection. Among these mutations, the presence of EGFR activating mutations (the most common of which are Ex19del and L858R) is associated with responsiveness to EGFR TKI therapy (e.g., erlotinib, gefitinib, afatinib, osimertinib, and dacomitinib). Other genetic alterations detected in NSCLC include anaplastic lymphoma kinase (ALK) fusion gene rearrangements (associated with responsiveness to ALK-TKIs); ROS proto-oncogene 1 (ROS1) gene rearrangements (associated with responsiveness to ROS1-TKIs); B-Raf proto-oncogene (BRAF) point mutations (some of which (V600E) respond to combination therapy with oral inhibitors of BRAF and MEK); and KRAS proto-oncogene (KRAS) point mutations (associated with poor survival and reduced response to EGFR-TKIs). Other progression biomarkers include human epidermal growth factor receptor 2 (HER2), MET exon 14 mutations, and fusion genes involving RET and neurotropic tropomyosin receptor kinase 1 (NTRK1) (Non-Patent Document 3).

[0006] The established first-line therapy for patients with advanced NSCLC and tumors harboring activating EGFR mutations detected before first-line systemic therapy is one of the following EGFR-TKIs: osimertinib (classified as preferred by the NCCN panel), erlotinib, afatinib, gefitinib, or dacomitinib (NPL 1). Patients with advanced mutation-positive EGFR NSCLC treated with an EGFR-TKI have a median overall survival (OS) of more than two years, which contrasts with the survival rate of patients receiving randomized platinum-based chemotherapy (approximately 12 months; NPL 4). In patients with activating EGFR mutations, response rates of 50% to 80% have been reported for first-line EGFR-TKI therapy, compared with 15% to 34% in patients receiving platinum-doublet chemotherapy as first-line or second-line therapy after progression of first-line therapy with an EGFR-TKI (NPL 5, NPL 6, NPL 7, NPL 8, NPL 9, NPL 10). In a phase III trial, dacomitinib, a second-generation EGFR TKI, extended progression-free survival (PFS) compared with gefitinib when given as first-line treatment in patients with EGFR-mutated NSCLC (median PFS 14.7 months (95% confidence interval (CI) 11.1-16.6) vs. 9.2 months (9.1-11.0) (hazard ratio (HR) 0.59, 95% CI: 0.47-0.74; p<0.0001)) [Non-Patent Document 11].

[0007] The phase III FLAURA trial (12), comparing the efficacy and safety of osimertinib with either gefitinib or erlotinib administered as first-line therapy for patients with advanced mutation-positive EGFR (Ex19del or L858R) NSCLC, demonstrated a significantly improved median progression-free survival (PFS) in the osimertinib treatment group (18.9 months (95% confidence interval (CI): 15.2, 21.4)) compared with erlotinib or gefitinib (10.2 months (95% CI: 9.6, 11.1)) (hazard ratio (HR) 0.46 (95% CI: 0.37, 0.57; p<0.0001)). Based on the results of the FLAURA trial, osimertinib has been recommended by the NCCN panel as the preferred first-line therapy in these patients. In particular, in the FLAURA trial, CNS progression events were observed in 6% of patients in the osimertinib group and 15% in the standard EGFR TKI group, regardless of the status of known or previously treated central nervous system (CNS) metastases at the time of enrollment. Furthermore, in patients with CNS metastases on baseline brain scans, osimertinib demonstrated a nominally statistically significant and clinically meaningful improvement in CNS progression-free survival (PFS) over standard EGFR-TKIs, reducing the risk of CNS progression by 52% (HR: 0.48; 95% CI: 0.26-0.86 p=0.014; median CNS PFS not reached (95% CI: 16.5, NC (i.e., not calculable)) vs. 13.9 months (95% CI: 8.3-NC) (Non-Patent Document 13).

[0008] Chemotherapy and first-generation EGFR TKI The 2019 NCCN guidelines for NSCLC do not recommend the addition of EGFR-TKIs to current chemotherapy for patients with EGFR mutation-positive NSCLC. These guidelines are based on data from CALGB30406, a subgroup of a randomized phase II trial comparing erlotinib alone with erlotinib in combination with carboplatin and paclitaxel chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive NSCLC who were never smokers or former light smokers (NPL 14). In the subgroup of patients with EGFR mutations, PFS and OS were similar in both arms of the trial, and the combination was associated with more side effects compared with erlotinib monotherapy. The chemotherapy regimen in this trial did not include pemetrexed.

[0009] However, in a recent phase III trial (NEJ009), the addition of carboplatin and pemetrexed to gefitinib as first-line treatment for patients with untreated advanced EGFR mutation-positive NSCLC improved progression-free survival (PFS) and overall survival (OS) with an acceptable toxicity profile compared with gefitinib monotherapy (Non-Patent Documents 15 and 16). These data support the concept of adding chemotherapy to first-generation EGFR-TKI therapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Other smaller clinical trials have investigated 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, which together provide data supporting first-generation EGFR TKI therapy in combination with chemotherapy (Non-Patent Document 17; Non-Patent Document 18; Non-Patent Document 19; Non-Patent Document 20; Non-Patent Document 21; Non-Patent Document 22; Non-Patent Document 23; Non-Patent Document 24; Non-Patent Document 25; Non-Patent Document 26).

[0010] Chemotherapy in combination with second- or third-generation EGFR TKIs Whether there is a role for chemotherapy given in combination with second- or third-generation EGFR TKIs (e.g., osimertinib) in this setting remains unclear.

[0011] As mentioned above, the NEJ009 phase III trial demonstrated that the combination of pemetrexed and platinum chemotherapy with gefitinib as first-line treatment for patients with previously untreated, advanced EGFR mutation-positive NSCLC improved patient PFS and OS compared with gefitinib monotherapy. However, the clinical benefit of first-generation TKI monotherapy can be significantly lower than that of second- or third-generation EGFR TKI monotherapy. As also mentioned above, this was demonstrated in the FLAURA phase III clinical trial, where the median PFS in the osimertinib treatment group was 18.9 months compared with 10.2 months in the erlotinib / gefitinib treatment group. Prior to this disclosure, there was no information available about whether the additional benefit of the combination of pemetrexed and platinum chemotherapy over monotherapy observed with gefitinib in the NEJ009 phase III trial would be observed with second- or third-generation EGFR TKIs.

[0012] A phase II, open-label, randomized trial of osimertinib alone versus osimertinib and carboplatin / pemetrexed in patients with locally advanced or metastatic NSCLC whose disease has progressed on prior EGFR TKI therapy and whose tumors harbor the T790M mutation in the epidermal growth factor receptor gene is currently underway (UMIN000024438), but the results are still unclear and cannot be directly applied to the first-line setting (i.e., EGFR TKI-naive patients). Furthermore, there are no reported clinical trials investigating the outcomes of either second- or third-generation EGFR TKIs in combination with pemetrexed and platinum chemotherapy in EGFR TKI-naive patients with EGFR mutation-positive NSCLC.

[0013] Locally advanced cancers that are not amenable to curative surgery or radiation therapy, and metastatic EGFR-mutated NSCLC, are incurable conditions, and therefore there remains a high unmet medical need for patients suffering from these conditions.

[0014] The inventors have discovered that the use of osimertinib in combination with pemetrexed and platinum chemotherapy can result in improved prognosis, for example an improvement in one or more of progression-free survival (PFS), or an improvement in duration of response (DoR), or an improvement in overall survival (OS). [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] National Comprehensive Cancer Network (NCCN) guidelines 2019 for NSCLC [Non-patent document 2] NCI Surveillance,Epidemiology,and End Results Program.Cancer Stat Facts:lung and bronchus cancer [Non-patent document 3] Annals Oncol.

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[2014] ,vol.32(no.15_suppl):e19076 [Non-Patent Document 26] “Is upfront combo therapy better than the sum of its parts?”,Medscape,Aug 09,2018 Summary of the Invention [Means for solving the problem]

[0016] This specification describes an EGFR TKI for use in treating EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with pemetrexed and platinum chemotherapy, and the EGFR TKI is either a second- or third-generation EGFR TKI.

[0017] This specification further describes treatments, wherein the treatment results in an improvement in one or more of: improved progression-free survival (PFS), improved duration of response (DoR), or improved overall survival (OS). DETAILED DESCRIPTION OF THE INVENTION

[0018] In a first aspect, there is provided an EGFR TKI for use in treating EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with pemetrexed and platinum chemotherapy, and the EGFR TKI is either a second- or third-generation EGFR TKI.

[0019] In a further aspect, there is provided a method of treating locally advanced or metastatic EGFR mutation-positive NSCLC in an EGFR TKI-naive human patient, the method comprising administering to the patient an EGFR TKI, wherein the EGFR TKI is administered in combination with pemetrexed and platinum chemotherapy, and the EGFR TKI is either a second-generation or third-generation EGFR TKI.

[0020] In a further aspect, there is provided the use of an EGFR TKI in the manufacture of a medicament 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 pemetrexed and platinum chemotherapy, and the EGFR TKI is either a second-generation or third-generation EGFR TKI.

[0021] As used herein, the term "about" when referring to any given numerical value means within ±10% of that value.

[0022] EGFR mutation-positive NSCLC and diagnostic methods In 2004, it was reported that activating mutations in EGFR exons 18–21 correlate with response to EGFR-TKI therapy in NSCLC (Science

[2004] , vol. 304, pp. 1497–1500; New England Journal of Medicine

[2004] , vol. 350, pp. 2129–2139). These mutations are estimated to occur in approximately 10–16% of NSCLC patients in the United States and Europe, and approximately 30–50% of NSCLC patients in Asia. Two of the most important EGFR activating mutations are exon 19 deletions and exon 21 missense mutations. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven different mutations resulting in deletions of 3–7 amino acids have been detected in exon 19, all of which are uniformly clustered at the codons corresponding to the deleted amino acids 747–749. The most important exon 19 deletion is E746-A750. Exon 21 missense mutations account for approximately 39-45% of known EGFR mutations, of which the substitution mutation L858R accounts for approximately 39% of all exon 21 mutations (J. Thorac. Oncol.

[2010] , 1551-1558). Those skilled in the art are aware of mutations in EGFR that correlate with improved response to EGFR-TKI therapy.

[0023] Thus, in an embodiment, the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR. In a further embodiment, the activating mutation in EGFR comprises an activating mutation in exons 18 to 21. In a further embodiment, the activating mutation in EGFR comprises a deletion of exon 19 or a missense mutation in exon 21. In a further embodiment, the activating mutation in EGFR comprises a deletion of exon 19 or an L858R substitution mutation.

[0024] In embodiments, the locally advanced or metastatic EGFR mutation-positive NSCLC is locally advanced EGFR mutation-positive NSCLC.

[0025] In embodiments, the locally advanced or metastatic EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC.

[0026] In embodiments, the locally advanced or metastatic EGFR mutation-positive NSCLC is not amenable to curative surgery or radiation therapy.

[0027] There are many methods for detecting activating mutations of EGFR, which are known to those skilled in the art. Many tests suitable for use in these methods have been approved by the U.S. Food and Drug Administration (FDA). These methods include diagnostic methods based on both tumor tissue and plasma. Generally, EGFR mutation status is first assessed using a tumor tissue biopsy sample from the patient. If a tumor sample is unavailable or negative, EGFR mutation status is assessed using a plasma sample. A specific example of a diagnostic test suitable for detecting EGFR activating mutations, particularly exon 19 deletions or L858R substitution mutations, is the Cobas™ EGFR Mutation Test v2 (Roche Molecular Diagnostics).

[0028] Thus, in embodiments, the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR (such as an activating mutation in exons 18-21, e.g., an exon 19 deletion or an exon 21 missense mutation, e.g., an exon 19 deletion or an L858R substitution mutation), and the patient's EGFR mutation status has been determined using an appropriate diagnostic test. In a further embodiment, the EGFR mutation status has been determined using a tumor tissue sample. In a further embodiment, the EGFR mutation status has been 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 the Cobas™ EGFR Mutation Test (v1 or v2).

[0029] EGFR TKI and T790M mutation The EGFR TKI may be characterized as any of the first, second, or third generation EGFR TKIs described below.

[0030] 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.

[0031] Second-generation EGFR TKIs are irreversible inhibitors of EGFR with activating mutations that do not significantly inhibit EGFR with the T790M mutation. Examples of second-generation TKIs include afatinib and dacomitinib.

[0032] Third-generation EGFR TKIs are inhibitors of EGFR with activating mutations that also significantly inhibit EGFR with T790M mutations but do not significantly inhibit wild-type EGFR. Examples of third-generation TKIs include osimertinib, AZD3759, lazertinib, nazartinib, CO1686 (rociletinib), HM61713, ASP8273, EGF816, and PF-06747775 (mavereltinib).

[0033] In an embodiment, the EGFR TKI is a second-generation EGFR TKI. In a further embodiment, the second-generation EGFR TKI is dacomitinib, or a pharmaceutically acceptable salt thereof.

[0034] 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 a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, and lazertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the third-generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

[0035] Osimertinib and its pharmaceutical composition Osimertinib has the following chemical structure: [ka]

[0036] The free base of osimertinib is known by the chemical name N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide. Osimertinib is described in WO 2013 / 014448. Osimertinib is also known as AZD9291.

[0037] Osimertinib can be found in the form of a mesylate salt: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate. Osimertinib mesylate is also known as TAGRISSO™.

[0038] Osimertinib mesylate is currently approved for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC at a dose of 80 mg (expressed as the free base, equivalent to 95.4 mg of osimertinib mesylate) in an oral, once-daily tablet formulation. If a dose adjustment is required, a 40 mg oral, once-daily tablet formulation (expressed as the free base, equivalent to 47.7 mg of osimertinib mesylate) is available. The tablet core contains pharmaceutical diluents (e.g., mannitol and microcrystalline cellulose), disintegrants (e.g., low-substituted hydroxypropyl cellulose), and lubricants (e.g., sodium stearyl fumarate). Tablet formulations are described in WO 2015 / 101791.

[0039] Thus, in embodiments, osimertinib, or a pharmaceutically acceptable salt thereof, is in the form of the mesylate salt, i.e., N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt.

[0040] In embodiments, osimertinib or a pharmaceutically acceptable salt thereof is administered once daily. In further embodiments, osimertinib mesylate is administered once daily.

[0041] In embodiments, the total daily dose of osimertinib is about 80 mg. In further embodiments, the total daily dose of osimertinib mesylate is about 95.4 mg.

[0042] In embodiments, the total daily dose of osimertinib is about 40 mg. In further embodiments, the total daily dose of osimertinib mesylate is about 47.7 mg.

[0043] In embodiments, the osimertinib or a pharmaceutically acceptable salt thereof is in tablet form.

[0044] In embodiments, osimertinib, or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In further embodiments, the composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low-substituted hydroxypropyl cellulose), or one or more pharmaceutical lubricants (such as sodium stearyl fumarate).

[0045] In embodiments, the composition is in the form of a tablet, and the tablet core comprises (a) 2-70 parts osimertinib or a pharmaceutically acceptable salt thereof, (b) 5-96 parts of two or more pharmaceutical diluents, (c) 2-15 parts of one or more pharmaceutical disintegrants, and (d) 0.5-3 parts of one or more pharmaceutical lubricants, where all parts are by weight and the total of the parts is (a)+(b)+(c)+(d)=100.

[0046] In embodiments, the composition is in the form of a tablet, wherein the tablet core comprises: (a) 7 to 25 parts osimertinib or a pharmaceutically acceptable salt thereof; (b) 55 to 85 parts of two or more pharmaceutical diluents comprising microcrystalline cellulose and mannitol; (c) 2 to 8 parts of a pharmaceutical disintegrant comprising low-substituted hydroxypropyl cellulose; and (d) 1.5 to 2.5 parts of a pharmaceutical lubricant comprising sodium stearyl fumarate, where all parts are by weight and the total of the parts is (a)+(b)+(c)+(d)=100.

[0047] In embodiments, the composition is in the form of a tablet, wherein the tablet core comprises (a) about 19 parts osimertinib mesylate, (b) about 59 parts mannitol, (c) about 15 parts microcrystalline cellulose, (d) about 5 parts low-substituted hydroxypropyl cellulose, and (e) about 2 parts sodium stearyl fumarate, where all parts are by weight and the sum of the parts is (a)+(b)+(c)+(d)+(e)=100.

[0048] AZD3759 AZD3759 has the following chemical structure: [ka]

[0049] The free base of AZD3759 is known by the chemical name 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl(2R)-2,4-dimethyl-1-piperazinecarboxylate. AZD3759 is described in WO 2014 / 135876.

[0050] In an embodiment, AZD3759 or a pharmaceutically acceptable salt thereof is administered twice daily. In a further embodiment, AZD3759 is administered twice daily.

[0051] In an embodiment, the total daily amount of AZD3759 is about 400 mg. In a further embodiment, about 200 mg of AZD3759 is administered twice daily.

[0052] Lazertinib Lazertinib has the following chemical structure: [ka]

[0053] The free base of lazertinib is known by the chemical name N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}-2-pyrimidinyl)amino]-4-methoxy-2-(4-morpholinyl)phenyl}acrylamide. Lazertinib is described in WO 2016 / 060443. Lazertinib is also known as YH25448 and GNS-1480.

[0054] In embodiments, lazertinib or a pharmaceutically acceptable salt thereof is administered once daily. In further embodiments, lazertinib is administered once daily.

[0055] In embodiments, the total daily dose of lazertinib is about 240 mg.

[0056] Dacomitinib Dacomitinib has the following chemical structure: [ka]

[0057] The free form of dacomitinib is known by the chemical name: (2E)-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 as PF-00299804.

[0058] Dacomitinib can be found in the form of dacomitinib monohydrate, i.e. (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate.

[0059] In embodiments, dacomitinib or a pharmaceutically acceptable salt thereof is administered once daily. In a further embodiment, dacomitinib monohydrate is administered once daily.

[0060] In embodiments, the total daily dose of dacomitinib monohydrate is about 45 mg.

[0061] In embodiments, the dacomitinib or a pharmaceutically acceptable salt thereof is in tablet form.

[0062] In embodiments, dacomitinib, or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, hi further embodiments, the one or more pharmaceutically acceptable excipients comprise lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[0063] Platinum-based chemotherapy In embodiments, the platinum chemotherapy comprises administration of cisplatin.

[0064] In embodiments, the platinum chemotherapy consists of administration of cisplatin.

[0065] The total daily dose of cisplatin is generally calculated based on body surface area (BSA), and the daily dose is usually about 50 mg / m 2 ~about 120mg / m 2 Thus, in embodiments, the maximum daily dose of cisplatin is about 150 mg / m 2 Below, for example, about 120 mg / m 2 Below, for example, about 100 mg / m 2 Below, for example, about 90 mg / m 2 Below, for example, about 80 mg / m 2Below, for example, about 70 mg / m 2 Below, for example, about 60 mg / m 2 Below, for example, about 50 mg / m 2 In embodiments, the total daily dose of cisplatin is about 75 mg / m 2 is.

[0066] Patients undergoing chemotherapy using cisplatin generally do not receive cisplatin every day, and cisplatin is generally administered in a treatment cycle.In an embodiment, the treatment cycle is 42 days or less, for example, 35 days or less, for example, 28 days or less, for example, 21 days or less.In an embodiment, cisplatin is administered on the first day of each treatment cycle.In an embodiment, cisplatin is administered only on the first day of a treatment cycle that lasts 21 days.

[0067] Alternatively, patients may receive cisplatin over a 5-day period. These patients usually receive about 15 mg / m 2 ~about 20mg / m 2 is administered for 5 consecutive days. In embodiments, the treatment cycle is 42 days or less, e.g., 35 days or less, e.g., 28 days or less, e.g., 21 days or less. In embodiments, cisplatin is administered only on days 1 through 5 of each treatment cycle. In embodiments, cisplatin is administered only on days 1 through 5 of a treatment cycle lasting 21 days.

[0068] In embodiments, the platinum chemotherapy comprises administration of carboplatin.

[0069] In embodiments, the platinum chemotherapy consists of administration of carboplatin.

[0070] The total daily dose of carboplatin is generally calculated for a given patient based on the area under the curve (AUC) using formulas known to those skilled in the art (e.g., the Calvert formula). Typical daily doses range from AUC2 to AUC7. In embodiments, the maximum daily dose of carboplatin is AUC7 or less, e.g., AUC6 or less, e.g., AUC5 or less, e.g., AUC4 or less, e.g., AUC3 or less, e.g., AUC2 or less. In embodiments, the total dose of carboplatin is about AUC5.

[0071] Patients undergoing chemotherapy using carboplatin generally do not receive carboplatin every day, and carboplatin is generally administered in a treatment cycle.In an embodiment, the treatment cycle is 21 days or less, for example, 14 days or less, for example, 7 days or less.In an embodiment, carboplatin is administered on the first day of each treatment cycle.In an embodiment, carboplatin is administered only on the first day of a treatment cycle that lasts 21 days.

[0072] Pemetrexed In embodiments, the total daily dose of pemetrexed is about 500 mg / m 2 Below, for example, about 500 mg / m 2 In a further embodiment, pemetrexed is administered on day 1 of a treatment cycle lasting 21 days.

[0073] In embodiments, pemetrexed is administered with vitamin supplementation, such as vitamin B12 and folic acid supplementation.

[0074] In embodiments, there is a 21-day cycle in which pemetrexed (total daily dose of about 500 mg / m 2 cisplatin (total daily dose of about 75 mg / m 2Either carboplatin (at a total daily dose of about AUC5 or about AUC6) is administered only on day 1 of a 21-day cycle. In a further embodiment, there are four consecutive 21-day cycles. In yet a further embodiment, the four consecutive 21-day cycles are followed by pemetrexed maintenance therapy, which consists of administration of pemetrexed (at a total daily dose of about 500 mg / m) once every 21 days until disease progression or unacceptable toxicity is reached. 2 and optionally with vitamin supplementation).

[0075] Clinical outcomes Patients with locally advanced or metastatic EGFR mutation-positive NSCLC who are administered an EGFR TKI herein may benefit from an improved prognosis compared to the current standard of care. In particular, such patients may benefit from one or more of improved progression-free survival (PFS), increased objective response rates, improved duration of response (DoR), or improved overall survival (OS).

[0076] Thus, in an embodiment the patient benefits from a progression free survival of at least 16 months, such as at least 18 months, for example at least 20 months, such as at least 22 months, for example at least 24 months, such as at least 26 months, for example at least 28 months, such as at least 30 months, for example at least 32 months, such as at least 34 months, for example at least 36 months. In a further embodiment the patient benefits from a response duration of at least 14 months, such as at least 16 months, for example at least 18 months, such as at least 20 months, for example at least 25 months, such as at least 30 months, for example at least 35 months. In a further embodiment the patient benefits from an overall survival of at least 30 months, such as at least 35 months, for example at least 40 months, such as at least 45 months, for example at least 50 months, for example at least 55 months, such as at least 60 months, for example at least 65 months, for example at least 70 months.

[0077] Patients with advanced or metastatic EGFR mutation-positive NSCLC with CNS metastases on baseline brain scan who receive an EGFR TKI herein may particularly benefit from an improved prognosis compared to the current standard of care.

[0078] Thus in an embodiment patients with CNS metastases on baseline brain scan will benefit from a progression free survival of at least 12 months, such as at least 14 months, for example at least 16 months, such as at least 18 months, for example at least 20 months, such as at least 22 months, for example at least 24 months, such as at least 26 months, for example at least 28 months, such as at least 30 months, for example at least 32 months, such as at least 34 months, for example at least 36 months.

[0079] Within this disclosure, central nervous system progression-free survival (CNS PFS) means the time from the start of study treatment to progression of pre-existing CNS lesions and / or new CNS lesions, or death in the absence of CNS progression.

[0080] Patients with advanced or metastatic EGFR mutation-positive NSCLC with CNS metastases on baseline brain scans who are administered an EGFR TKI herein may particularly benefit from improved prognosis compared to current standard of care based on improved CNS progression-free survival by (i) preventing / delaying the development of new central nervous system metastases, particularly brain metastases, and / or (ii) preventing / delaying the progression of existing CNS metastases, particularly brain metastases, and / or (iii) preventing / delaying death in the absence of CNS progression.

[0081] Thus in an embodiment patients with CNS metastases on baseline brain scan will benefit from a CNS progression free survival of, for example, at least 14 months, such as at least 16 months, for example at least 18 months, such as at least 20 months, for example at least 22 months, such as at least 24 months, for example at least 26 months, such as at least 28 months, for example at least 30 months, such as at least 32 months, for example at least 34 months, such as at least 36 months.

[0082] Thus, in embodiments, the EGFR TKIs provided herein are for use in improving either or both duration of response (DoR) or overall survival (OS) in patients with CNS metastases on a baseline brain scan. [Example]

[0083] A phase 3, randomized, double-blind, placebo-controlled, multicenter, international study of osimertinib in combination with chemotherapy as first-line treatment for patients with locally advanced or metastatic EGFR mutation-positive NSCLC.

[0084] The trial is titled "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."

[0085] The following study will be conducted to confirm the benefit of the combination of osimertinib, pemetrexed, and platinum chemotherapy in the treatment of patients with locally advanced or metastatic EGFR mutation-positive NSCLC.

[0086] Study design overview This will be a Phase 3, open-label, randomized, international trial conducted in patients with locally advanced or metastatic EGFR mutation-positive (Ex19del and / or L858R) NSCLC who have not received any prior progressive disease therapy and have a World Health Organization (WHO) performance status (PS) of 0 or 1. Approximately 556 patients will be enrolled in approximately 24 countries. The trial will enroll approximately 60% Asian patients and 40% non-Asian patients.

[0087] Prior to initiating the randomized phase 3 portion 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 osimertinib in combination with platinum chemotherapy (carboplatin or cisplatin) and pemetrexed.

[0088] The proposed study will allow enrollment only of patients with EGFR mutation-positive NSCLC who have either: (1) a pre-existing positive (Ex19del or L858R) tissue assay obtained from a Clinical Laboratory Improvement Amendments (CLIA)-certified local laboratory (for locations within the United States) or a certified local laboratory (for locations outside the United States), or (2) a positive tissue Ex19del or L858R EGFR mutation test based on the COBAS™ EGFR Mutation Test v2 previously performed in a central laboratory.

[0089] In the safety run-in portion of the trial, two cohorts of patients (osimertinib plus cisplatin / pemetrexed and osimertinib plus carboplatin / pemetrexed) will be studied in a non-randomized fashion. Up to 15 patients per cohort will receive cisplatin (75 mg / m²), both administered Q3W for four cycles. 2 ) or carboplatin (AUC5) and pemetrexed (500 mg / m 2), followed by osimertinib 80 mg once daily plus pemetrexed maintenance (500 mg / m 2 ) Q3W in combination with osimertinib 80 mg once daily until progression or another discontinuation criterion as defined by RECIST v1.1 is met.

[0090] For each safety run-in cohort, safety data from at least 12 evaluable patients who have completed at least three cycles of osimertinib in combination with platinum / pemetrexed doublet therapy will be reviewed by a Safety Review Committee (SMC), which will recommend whether the data support initiation of the randomized portion of the study.

[0091] Patients enrolled in the safety run-in will continue treatment assigned per protocol. 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 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 3 randomized component.

[0092] After completion of the safety run-in and discussion with the SRC, new patients will be randomized 1:1 to receive osimertinib alone or in combination with pemetrexed and either cisplatin or carboplatin. Patients will be stratified based on race (Chinese / Asian vs. non-Chinese / Asian vs. non-Asian, totaling approximately 60% Asian and 40% non-Asian), World Health Organization (WHO) performance status (PS) (0 or 1), and histology (central vs. regional). If patients are assigned to the osimertinib plus chemotherapy arm, the investigator will determine which chemotherapy regimen (carboplatin / pemetrexed or cisplatin / pemetrexed) they will receive prior to randomization.

[0093] The two treatment regimens are as follows: a) osimertinib 80 mg once daily; or b) Pemetrexed (500 mg / m), all administered on day 1 of a 21-day cycle for four cycles 2 ) (with vitamin supplementation), plus cisplatin (75 mg / m 2 ) or carboplatin (AUC5), followed by pemetrexed maintenance (500 mg / m 2 )Osimertinib 80mg once daily in combination with Q3W.

[0094] Randomized treatment will continue until progression or another discontinuation criterion as defined by RECIST v1.1 is met.

[0095] Following treatment discontinuation, subsequent therapy is at the discretion of the investigator. Patients will be followed for secondary progression on subsequent therapy as determined according to local practice, and for survival.

[0096] Safety and tolerability monitoring of the randomized phase of the study will be provided exclusively by an Independent Data Monitoring Committee (IDMC) with fully independent members.

[0097] The primary endpoint will be PFS based on investigator assessment using RECIST v1.1. A sensitivity analysis based on blinded independent central review (BICR) of efficacy data from all randomized patients will also be performed. Secondary endpoints include OS, landmark OS, PFS2, ORR, duration of response (DoR), DCR, safety and tolerability (based on AEs, laboratory tests (clinical chemistry, hematology, urinalysis), vital signs (pulse and blood pressure), physical examination, weight, electrocardiogram (ECG) parameters, and left ventricular ejection fraction), pharmacokinetics, and patient-reported outcomes.

[0098] Important inclusion criteria a) Pathologically confirmed non-squamous NSCLC. b) Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic NSCLC (clinical stage IVA or IVB) or recurrent NSCLC (based on the International Association for the Study of Lung Cancer (IASLC) Staging Manual in Thoracic Oncology, Version 8) not amenable to curative surgery or radiation therapy. c) Tumors harbor one of two common activating EGFR mutations (Ex19del or L858R) known to be associated with EGFR-TKI sensitivity, either alone or in combination with other EGFR mutations, as assessed by a CLIA-certified (for locations within the U.S.) or certified local laboratory (for locations outside the U.S.) or by central prospective testing. d) Mandatory provision of a baseline plasma sample and an unstained archival tumor tissue sample in sufficient quantity to allow central confirmation of EGFR mutation status. See laboratory manual for details. e) Patients must have previously untreated advanced NSCLC that is not amenable to curative surgery or radiation therapy. Prior adjuvant and neoadjuvant therapy (chemotherapy, radiation therapy, immunotherapy, biotherapy, investigational agents) or definitive radiation / chemoradiotherapy with or without regimens including immunotherapy, biotherapy, or investigational agents is permitted, as long as treatment is completed at least 12 months before the onset of recurrent disease. f) WHO PS 0-1 at screening and no clinically significant deterioration within the past 2 weeks. g) At least one previously unirradiated lesion that is accurately measurable at baseline as ≥10 mm in its longest diameter by CT or MRI (excluding lymph nodes, which must have a short axis of ≥15 mm) and amenable to accurate repeat measurement. If only one measurable lesion is present, its use is acceptable (as the target lesion) as long as it has not been previously irradiated and a baseline tumor assessment scan was performed within 14 days of the lesion biopsy.

[0099] Important exclusion criteria a) Spinal cord compression; symptomatic and unstable brain metastases, excluding patients who have completed definitive therapy, are steroid-naive, and have a stable neurological status for at least 2 weeks since completion of definitive therapy and steroids. Patients with asymptomatic brain metastases may be enrolled if, in the investigator's opinion, immediate definitive therapy is not indicated. b) History of steroid-treated ILD, drug-induced ILD, radiation pneumonitis, or evidence of clinically active ILD. c) Any evidence of serious or poorly controlled systemic disease, including poorly controlled hypertension and active bleeding diathesis, or active infections, including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), which in the investigator's opinion would make it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. Screening for chronic disease is not required. d) Any of the following cardiac criteria: ·A mean resting corrected QT interval (QTc) of >470 milliseconds obtained from three electrocardiograms (ECGs) with QTcF values ​​obtained by the screening clinic's ECG machine; Any clinically significant abnormality in rhythm, conduction, or morphology of the resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block; · Any factor that increases the risk of QTc prolongation or arrhythmia induction, such as 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 any concomitant medication known to cause torsades de pointes by prolonging the QT interval or causing sudden unexplained death before the age of 40 in first-degree relatives. * Correction of electrolyte abnormalities within the normal range may be performed during screening. e) Inadequate bone marrow reserve or organ function indicated by any of the following laboratory values: · Absolute neutrophil count* below the lower limit of normal (<LLN) · Platelet count* below LLN · Hemoglobin <90 g / L* * The use of granulocyte colony-stimulating factor support, platelet transfusions, and transfusions to meet these criteria is not permitted. · ALT >2.5 × upper limit of normal (ULN) if there is no demonstrable liver metastasis, or >5 × ULN if there is liver metastasis. · AST >2.5 × ULN if there is no demonstrable liver metastasis, or >5 × ULN if there is liver metastasis. · Total bilirubin >1.5 × ULN if there is no liver metastasis, or >3 × ULN in the presence of demonstrable Gilbert's syndrome (indirect hyperbilirubinemia) or liver metastasis. · Creatinine clearance calculated by the Cockcroft-Gault formula <60 mL / min. f) Past treatment with any systemic anti-cancer therapy for advanced NSCLC for which radical surgery or radiation is not possible, including chemotherapy, biological therapy, immunotherapy, or any investigational drug. Adjuvant and neoadjuvant therapy (chemotherapy, radiotherapy, immunotherapy, biological therapy, investigational drug) or radical radiotherapy / chemoradiotherapy with or without a regimen including immunotherapy, biological therapy, investigational drug is permitted provided that the treatment was completed at least 12 months before the onset of the recurrent disease. g) Past treatment with EGFR-TKI.

[0100] analysis The Phase 3 component of the study will begin only after review of data from up to 30 patients included in the safety run-in component of the study. Up to 15 patients (with a minimum of 12 patients) will be treated for at least three cycles with osimertinib in combination with each of the two chemotherapy regimens.

[0101] 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 initiated a chemotherapy cycle. Data will be evaluated by an SRC acting exclusively for the safety run-in.

[0102] Patients included in the safety run-in component of the study will be excluded from the analysis of the Phase 3 randomized component.

[0103] Approximately 556 patients worldwide will be randomized 1:1 into the study during the Phase 3 component. The primary endpoint of the study is PFS based on investigator assessment (per RECIST v1.1).

[0104] Progression-free survival is defined as the time from randomization to the date of objective disease progression or death (from any cause in the absence of progression), regardless of whether the patient drops out of randomized therapy before progression or receives another anticancer treatment. Patients who have not progressed or died at the time of analysis are censored at their last evaluable RECIST assessment as of the last assessment date.

[0105] The primary analysis of PFS based on investigator assessment (per RECIST 1.1) will occur when approximately 278 PFS events are observed among 556 randomized patients (approximately 50% maturity). This is expected to occur approximately 33 months after the first patient is randomized (under an assumed 15-month exponential recruitment). If the true PFS HR for osimertinib with chemotherapy versus osimertinib monotherapy is 0.68, 280 progression events would provide 90% power to demonstrate a statistically significant difference in PFS at the 5% two-sided significance level. This translates to an improvement in median PFS from approximately 19 to 28 months, assuming an exponential distribution and proportional hazards. The minimum critical HR is 0.79, which translates to an improvement in median PFS from approximately 19 to 24 months.

[0106] Progression-free survival will be analyzed using the log-rank test stratified by ethnicity (Chinese / Asian vs. non-Chinese / Asian vs. non-Asian), WHO PS (0 vs. 1), and histology (central vs. local) for generation of p-values ​​using the Breslow approach to account for ties. The assumption of proportionality will be assessed. Sensitivity analyses of PFS will be performed based on data assessed by blinded independent central review (BICR) for all patients. Prespecified subgroup analyses will be performed in patients with centrally confirmed EGFR mutation status by the COBAS™ tissue or COBAS™ plasma test, used for study eligibility or retrospectively if eligibility conforms to a locally approved test.

[0107] The key secondary endpoint of OS will be tested in a hierarchical manner at the time of the PFS analysis and after the primary PFS analysis, when OS data are approximately 60% mature (approximately 334 death events in both treatment groups). Alpha will be controlled across the two OS analyses, i.e., at the time of the primary PFS analysis and at the final OS analysis, with the overall type 1 error strongly controlled at 5% (two-sided) based on the O'Brien-Fleming spending rule for OS studies. For osimertinib monotherapy and osimertinib with chemotherapy, under assumed central values ​​of 40 and 52 months (HR = 0.77), respectively, 170 observed events (information fraction 0.51) are predicted at the time of the primary PFS analysis, resulting in a two-sided alpha of 0.0034, with the remaining alpha allocated to the final OS analysis (0.0490).

[0108] Additional efficacy endpoints such as ORR and time to secondary progression or death (PFS2) will be included.

[0109] If patients are randomized to the combination treatment arm prior to randomization, the investigator will specify the chemotherapy regimen to be used (cisplatin / pemetrexed or carboplatin / pemetrexed). The choice of chemotherapy regimen will be made at the patient level. After progression, the choice of subsequent therapy will be at the investigator's discretion.

[0110] An IDMC, composed of fully independent members, convenes and meets periodically to review safety data and make recommendations to continue, modify, or discontinue trials based on its findings.

[0111] Serious AEs, AEs, and other safety data will be reviewed, and individual and aggregate safety data will be evaluated by the IDMC.

Claims

1. 1. An EGFR TKI for use in the treatment of EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive NSCLC, wherein said EGFR TKI is administered in combination with pemetrexed and platinum chemotherapy, and said EGFR TKI is either a second or third generation EGFR TKI.

2. 2. The EGFR TKI for use according to claim 1, wherein said platinum chemotherapy comprises a platinum-based agent selected from cisplatin or carboplatin.

3. 3. The EGFR TKI for use according to claim 1 or 2, wherein the pemetrexed and platinum chemotherapy is administered only on day 1 of a treatment cycle lasting 21 days.

4. 3. The EGFR TKI for use according to claim 1 or 2, wherein the pemetrexed and platinum chemotherapy is administered only on day 1 of a treatment cycle lasting 21 days for four consecutive cycles, followed by administration of pemetrexed once every 21 days until disease progression or unacceptable toxicity is reached.

5. 5. The EGFR TKI for use according to any one of claims 1 to 4, wherein the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR selected from an exon 19 deletion or an L858R substitution mutation.

6. The EGFR TKI for use according to any one of claims 1 to 5, wherein the locally advanced or metastatic EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC.

7. The EGFR TKI for use according to any one of claims 1 to 6, wherein said EGFR TKI is a second generation EGFR TKI.

8. 8. The EGFR TKI for use according to claim 7, wherein the second generation EGFR TKI is dacomitinib or a pharmaceutically acceptable salt thereof.

9. The EGFR TKI for use according to any one of claims 1 to 6, wherein said EGFR TKI is a third generation EGFR TKI.

10. 10. The EGFR TKI for use according to claim 9, wherein said third generation EGFR TKI is selected from the group consisting of osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, and lazertinib or a pharmaceutically acceptable salt thereof.

11. 11. The EGFR TKI for use according to claim 10, wherein the third generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

12. 12. The EGFR TKI for use according to claim 11, wherein the osimertinib or a pharmaceutically acceptable salt thereof is administered once daily.

13. 13. The EGFR TKI for use according to claim 11 or 12, wherein the osimertinib or a pharmaceutically acceptable salt thereof is administered in tablet form.

14. The EGFR TKI for use according to any one of claims 11 to 13, wherein the osimertinib or a pharmaceutically acceptable salt thereof is osimertinib mesylate.

15. 1. A method of treating locally advanced or metastatic EGFR mutation-positive NSCLC in a human patient who has not been treated with an EGFR TKI, said method comprising administering to said patient an EGFR TKI, wherein said EGFR TKI is administered in combination with pemetrexed and platinum chemotherapy, and wherein said EGFR TKI is either a second-generation or third-generation EGFR TKI.

16. 1. Use of an EGFR TKI in the manufacture of a medicament 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 pemetrexed and platinum chemotherapy, and the EGFR TKI is either a second-generation or third-generation EGFR TKI.

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