OSIMERTINIB FOR USE IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER

Abstract

The descriptive memorandum refers to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for use in the treatment of previously EGFR TKI-naïve patients with metastatic or locally advanced EGFR mutation-positive non-small cell lung cancer (NSCLC), wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed.

Description

OSIMERTINIB FOR USE IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER FIELD OF INVENTION This product description describes epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for use in the treatment of EGFR-TKI-naïve patients with metastatic or locally advanced EGFR-mutant non-small cell lung cancer (NSCLC). In particular, this product description describes the combination of either a second-generation or a third-generation EGFR TKI with platinum-based chemotherapy and pemetrexed. BACKGROUND OF THE INVENTION 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 death globally (25.3% of all cancer deaths). Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 90% of all lung cancers [2019 National Network of Comprehensive Cancer Centers (NCCN) guidelines for NSCLC]. Despite recent advances in early detection, 70% to 80% of patients are diagnosed with lung cancer at a metastatic or locally advanced stage when it is no longer amenable to surgical resection [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 condition. Despite the development of new therapies, the prognosis remains poor, with a median 5-year survival rate of approximately 5% in patients with NSCLC whose EGFR status is unknown. In current clinical practice, treatment decisions for patients with advanced NSCLC are informed by molecular tumor subtypes [2019 NCCN guidelines for NSCLC]. Molecular biomarker profiling of patients with advanced NSCLC is a 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]. Numerous gene mutations or alterations have been identified as molecular therapeutic targets that impact 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 gene alterations detected in olol Ln / Lznz / E / Yi NSCLC include anaplastic lymphoma kinase (ALK) fusion gene transpositions, associated with responsiveness to ALK-TKIs; proto-oncogene ROS1 (ROS1) gene transpositions, associated with responsiveness to ROS1-TKIs; proto-oncogene B-Raf (BRAF) point mutations, some of which (V600E) respond to combination therapy with oral BRAF and MEK inhibitors; and proto-oncogene KRAS (KRAS) point mutations, which are indicative of decreased survival and reduced response to EGFR-TKIs. Other biomarkers under development include the human epidermal growth factor receptor 2 (HER2), MET exon 14 mutations, and fusion genes involving RET and neurotropic tropomyosin receptor kinase 1 (NTRK1) (Annals Oncol.

[2018] , vol. 29(suppl_4):iv192-iv237). The established first-line therapy in patients with advanced NSCLC and a tumor harboring discovered activating EGFR mutations prior to first-line systemic therapy is one of the following EGFR-TKIs: osimertinib (marked as preferred by the NCCN panel), erlotinib, afatinib, gefitinib, or dacomitinib (2019 NCCN guidelines for NSCLC). Patients with advanced EGFR-mutant-positive NSCLC who received an EGFR-TKI have a median overall survival (OS) of more than 2 years, compared with the survival of unselected patients who received platinum-based chemotherapy (approximately 12 months; J Clin Oncol.

[2012] , vol. 30(27), 3417-20).In patients with activating EGFR mutations, response rates (RR) of 50% to 80% have been reported with first-line EGFR-TKI treatment, compared with 15% to 34% in patients receiving platinum doublet chemotherapy as first-line therapy or as second-line therapy following progression on first-line EGFR-TKI treatment (N. Engl. J. Med.

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[2014] , vol. 15, 213-22).In a phase III study, dacomitinib, a second-generation EGFR TKI, prolonged progression-free survival (PFS) compared with gefitinib when administered as first-line treatment in patients with EGFR mutation-positive NSCLC - median PFS of 14.7 months (95% confidence interval (CI) 111-16.6) vs 92 months (9-1-11.0) (risk ratio (RR) 0.59, 95% CI 0.47-0.74; p<0.0001) [Lancet Oncol.

[2017] , voh 8(11), 14541466]. The phase III FLAURA study (N. Engl. J Med.

[2018] , vol. 378, 113-25) comparing the efficacy and safety of osimertinib administered as first-line therapy to patients with EGFR mutation-positive NSCLC (Ex19del or L858R) versus (vs.) either gefitinib or erlotinib showed a significant improvement in median progression-free survival (PFS) in the osimertinib arm (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]), with a risk ratio (RR) of 0.46 (95% CI: 0.37, 0.46). 0.57; p <0.0001). Based on the results of the FLAURA study, osimertinib is recommended by the NCCN panel as the preferred first-line therapy in these patients.It is worth noting that in the FLAURA study, regardless of the status with respect to known or treated central nervous system (CNS) metastases at the start of the study, CNS progression events were observed in 6% of patients in the osimertinib group and 15% in the conventional EGFR TKI group. Furthermore, in patients with CNS metastases on baseline brain scan, osimertinib demonstrated a statistically significant and clinically useful nominal increase in CNS progression-free survival (RF 0.48; 95% CI 0.26-0.86 p=0.014; median CNS progression-free survival not achieved (95% CI 16.5, NC (i.e. could not be calculated)) vs 13.9 months (95% CI 8.3 to NC); J Clin Oncol.

[2018] , vol. 36(33), 3290-7). CHEMOTHERAPY AND FIRST-GENERATION EGFR TKI The 2019 NCCN guidelines for NSCLC do not recommend adding EGFR-TKIs to current chemotherapy for patients with EGFR-mutant NSCLC. These guidelines are based on data from a subgroup of the randomized phase II CALGB 30406 trial, which compared erlotinib alone versus erlotinib in combination with carboplatin plus paclitaxel chemotherapy as first-line treatment for patients with advanced EGFR-mutant NSCLC who were never smokers or former smokers (J Clin Oncol.

[2012] , vol. 30(17), 2063-9). In the EGFR-mutant subgroup, progression-free survival (PFS) and overall survival (OS) were similar in both arms of the study, and the combination was associated with more side effects than erlotinib monotherapy. The chemotherapy regimen in this study did not include pemetrexed. However, in a recent phase III study (NEJ009), the addition of carboplatin and pemetrexed to gefitinib as first-line treatment for previously untreated patients with advanced EGFR-mutant-positive NSCLC improved progression-free survival (PFS) and overall survival (OS) with an acceptable toxicity profile, compared to gefitinib monotherapy (J. Clin. Oncol.

[2018] , vol. 36 (15_suppl):abstr 9005; 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 therapy in the first-line treatment of patients with advanced EGFR-mutant-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 a first-line treatment for EGFR mutation-positive NSCLC and together provide supporting data for first-generation EGFR TKI therapy in combination with chemotherapy (J. Clin. Oncol.

[2018] , vol. 36 (15_suppl): abstr 9005; Do¡:10.1136 / esmoopen2017-000313; Annals Oncol.

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

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

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

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

[2014] , vol. 32 (no.15_suppl):e19076; Is upfront combo therapy betterthan the sum of its parts?, Medscape, August 9, 2018). Chemotherapy in combination with second or third combination EGFR TKI Whether there is a role for chemotherapy given in combination with second or third combination EGFR TKIs (e.g., osimertinib) in this setting remains uncertain. As previously observed, the phase III NEJ009 study showed that the combination of platinum-based chemotherapy and pemetrexed with gefitinib as first-line treatment for previously untreated patients with advanced EGFR-mutant-positive NSCLC improved progression-free survival (PFS) and overall survival (OS) compared to gefitinib monotherapy. However, the clinical benefit of first-generation TKI monotherapy may be significantly less than that of second- or third-generation EGFR TKI monotherapy. As also previously observed, this was demonstrated in the phase III FLAURA clinical trial, where the median PFS in the osimertinib arm was 18.9 months, compared to 10.2 months for the erlotinib / gefitinib arm.Prior to this description, there was no information on whether the additional benefit of combining platinum-based chemotherapy and pemetrexed versus monotherapy observed for gefitinib in the phase III NEJ009 study would be observed for second- or third-generation EGFR TKIs. A randomized, open-label, phase II study of osimertinib alone versus osimertinib plus carboplatin / pemetrexed in patients with metastatic or locally advanced NSCLC whose disease has progressed on prior EGFR TKI therapy and whose tumors harbor a T790M mutation within the epidermal growth factor receptor gene is currently underway (UMIN000024438), but the results are not yet known and may not be directly applicable to the first-line setting (i.e., EGFR TKI-naïve patients). Furthermore, no trials have been reported investigating the outcome of either a second- or third-generation EGFR TKI in combination with platinum-based chemotherapy and pemetrexed in EGFR TKI-naïve patients with EGFR-mutant-positive NSCLC. Locally advanced cancer that is not amenable to curative surgery or radiotherapy and metastatic EGFR-mutant NSCLC are incurable conditions. Therefore, a significant unmet medical need remains for patients with these conditions. The use of osimertinib in combination with platinum-based chemotherapy and pemetrexed has been found to result in an improved prognosis, for example, an improvement in one or more of the progression-free survival (PFS) or a better duration of response (DoR) or an improved overall survival (OS). íuol Ln / Lznz / E / Yi BRIEF DESCRIPTION OF THE INVENTION This descriptive report describes an EGFR TKI for use in the treatment of an EGFR TKI-naïve patient with metastatic or locally advanced EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed and wherein the EGFR TKI is either a second-generation or third-generation EGFR TKI. The descriptive report further describes such treatment in which the treatment results 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 In one aspect, an EGFR TKI is provided for use in the treatment of an EGFR TKI-naïve patient with metastatic or locally advanced EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed and wherein the EGFR TKI is either a second-generation or third-generation EGFR TKI. In an additional aspect, a method is provided for treating metastatic or locally advanced EGFR mutation-positive NSCLC in a previously EGFR TKI-naïve human patient comprising administering an EGFR TKI to the patient, wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed, and wherein the EGFR TKI is either a second-generation or third-generation EGFR TKI. In an additional aspect, the use of an EGFR TKI is provided in the manufacture of a drug for the treatment of an EGFR TKI-naïve patient with metastatic or locally advanced EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed and wherein the EGFR TKI is either a second-generation or third-generation EGFR TKI. As used herein, the term approximately when referring to any given numerical value means that it is within ± 10% of that value. EGFR-positive NSCLC and diagnostic methods In 2004, activating mutations in EGFR exons 18–21 were reported to correlate with a response to EGFR-TKI therapy in NSCLC (Science

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

[2004] , vol. 350, 2129–2139). These mutations are estimated to be prevalent in approximately 10–16% of NSCLC patients in the United States and Europe, and in approximately 30–50% of NSCLC patients in Asia. Two of the most significant activating EGFR mutations are exon 19 deletions and exon 21 missense mutations. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven different mutations have been detected, resulting in the deletion of three to seven amino acids in exon 19, and all are centered around the codons uniformly deleted for amino acids 747-749. The most important deletion of exon 19 is E746A750.Missense mutations in exon 21 account for approximately 39–45% of known EGFR mutations, of which the L858R substitution mutation represents approximately 39% of all mutations in exon 21 (J. Thorac. Oncol.

[2010] , 1551–1558). The expert will be aware of EGFR mutations that correlate with an enhanced response to EGFR-TKI therapy. In embodiments, therefore, EGFR-positive NSCLC comprises activating EGFR mutations. In further embodiments, the activating EGFR mutations comprise activating mutations in exons 18-21. In further embodiments, the activating EGFR mutations comprise exon 19 deletions or missense mutations in exon 21. In further embodiments, the activating EGFR mutations comprise exon 19 deletions or L858R substitution mutations. In realization, metastatic or locally advanced EGFR-positive NSCLC is locally advanced EGFR-positive NSCLC. In realization, metastatic or locally advanced EGFR-positive NSCLC is metastatic EGFR-positive NSCLC. In practice, metastatic or locally advanced EGFR-positive NSCLC is not amenable to curative surgery or radiotherapy. Numerous methods exist for detecting activating EGFR mutations, of which the expert will be aware. Several assays suitable for use with these methods have been approved by the U.S. Food and Drug Administration (FDA). These include diagnostic methods based on plasma and tumor tissue. Generally, EGFR mutation status is first assessed using a patient-derived tumor tissue biopsy sample. If a tumor sample is unavailable, or if the tumor sample is negative, EGFR mutation status can be assessed using a plasma sample. One example of a diagnostic assay suitable for detecting activating EGFR mutations, and specifically for detecting exon 19 deletions or L858R substitution mutations, is the Cobas™ v2 EGFR Mutation Test (Roche Molecular Diagnostics). In embodiments, therefore, EGFR-positive NSCLC comprises activating EGFR mutations (such as activating mutations in exons 18-21, e.g., exon 19 deletions or missense mutations in exon 21, e.g., exon 19 deletions or L858R substitution mutations), in which the patient's EGFR mutation status has been determined using an appropriate diagnostic assay. In further embodiments, the EGFR mutation status has been determined using a tumor tissue sample. In further embodiments, the EGFR mutation status has been determined using a plasma sample. In further embodiments, the diagnostic method uses an FDA-approved assay. In further embodiments, the diagnostic method uses the Cobas™ EGFR Mutation Assay (v1 or v2). EGFR TKI AND THE T790M MUTATION EGFR TKIs can be characterized as either first, second, or third generation EGFR TKIs, as explained below. First-generation EGFR TKIs are reversible inhibitors of EGFR carrying activating mutations that do not significantly inhibit EGFR carrying the T790M mutation. Examples of first-generation TKIs include gefitinib and erlotinib. 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 afatinib and dacomitinib. Third-generation EGFR TKIs are inhibitors of EGFR carrying activating mutations that also significantly inhibit EGFR carrying the T790M mutation and do not significantly inhibit natural-type EGFR. Examples of third-generation TKIs include osimertinib, AZD3759, lazertinib, nazartinib, 001686 (rociletinib), HM61713, ASP8273, EGF816, and PF-06747775 (mavelertinib). In one embodiment, the EGFR TKI is a second-generation EGFR TKI. In further embodiments, the second-generation EGFR TKI is dacomitinib or a pharmaceutically acceptable salt thereof. In one embodiment, the EGFR TKI is a third-generation EGFR TKI. In further embodiments, 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 further embodiments, the third-generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. OSIMERTINIB AND ITS PHARMACEUTICAL COMPOSITIONS Osimertinib has the following chemical structure: íilol Ln / Lznz / E / Yi The free base of osimertinib is known by the chemical name: A / -(2-{2-dimethylaminoethylmethylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidi n-2-yl]amino}f eni I) prop-2-enamide. Osimertinib is described in WO 2013 / 014448. Osimertinib is also known as AZD9291. Puede encontrarse osimertinib en forma de la sal de mesilato: sal de mesilato de N-(2{2-dimetilamino et¡l-met¡lam¡no}-4-metox¡-5-{[4-(1-met¡lindol-3-¡l)p¡r¡m¡d¡n-2-¡l]am¡no}fen¡l) prop2-enamida. También se conoce mesilato de osimertinib como TAGRISSO™. Osimertinib mesylate is currently approved as a once-daily oral tablet formulation at a dose of 80 mg (expressed as free base, equivalent to 95.4 mg of osimertinib mesylate) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC. A 40 mg once-daily oral tablet formulation (expressed as free base, equivalent to 47.7 mg of osimertinib mesylate) is available if dose modification is required. The tablet core comprises pharmaceutical diluents (such as mannitol and microcrystalline cellulose), disintegrants (such as low-substituted hydroxypropylcellulose), and lubricants (such as sodium stearyl fumarate). The tablet formulation is described in WO 2015 / 101791. In embodiments, therefore, osimertinib or an acceptable pharmaceutical salt thereof is in the form of the mesylate salt, i.e. mesylate salt of A / -(2-{2-dimethylaminoethylmethylamino}4-methoxy-5-{[4-(1-methylindole-3-1)pyrimidin-2-1]amino}phen)prop-2-enamide. In one embodiment, osimertinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In additional embodiments, osimertinib mesylate is administered once daily. In one implementation, the total daily dose of osimertinib is approximately 80 mg. In additional implementations, the total daily dose of osimertinib mesylate is approximately 95.4 mg. In one implementation, the total daily dose of osimertinib is approximately 40 mg. In additional implementations, the total daily dose of osimertinib mesylate is approximately 47.7 mg. In embodiments, osimertinib, or a pharmaceutically acceptable salt thereof, is in tablet form. In one 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 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 hydroxypropylcellulose), or one or more pharmaceutical lubricants (such as sodium stearyl fumarate). In embodiments, the composition is in the form of a tablet, wherein the tablet core comprises: (a) from 2 to 70 parts of osimertinib or a pharmaceutically acceptable salt thereof; (b) from 5 to 96 parts of two or more diluents ÍUOL Ln / Lznz / E / Yli pharmaceuticals; (c) from 2 to 15 parts of one or more pharmaceutical disintegrants; and (d) from 0.5 to 3 parts of one or more pharmaceutical lubricants; and where all parts are by weight and the sum of parts (a)+(b)+(c)+(d)=100. In embodiments, the composition is in the form of a tablet, wherein the tablet core comprises: (a) from 7 to 25 parts of osimertinib or a pharmaceutically acceptable salt thereof; (b) from 55 to 85 parts of two or more pharmaceutical diluents, wherein the pharmaceutical diluents comprise microcrystalline cellulose and mannitol; (c) from 2 to 8 parts of pharmaceutical disintegrant, wherein the pharmaceutical disintegrant comprises low-substituted hydroxypropylcellulose; (d) from 1.5 to 2.5 parts of pharmaceutical lubricant, wherein the pharmaceutical lubricant comprises sodium stearyl fumarate; and wherein all parts are by weight and the sum of parts (a)+(b)+(c)+(d)=100. In embodiments, the composition is in the form of a tablet, wherein the tablet core comprises: (a) approximately 19 parts of osimertinib mesylate; (b) approximately 59 parts of mannitol; (c) approximately 15 parts of microcrystalline cellulose; (d) approximately 5 parts of low-substituted hydroxypropylcellulose; and (e) approximately 2 parts of sodium stearyl fumarate; and wherein all parts are by weight and the sum of parts (a)+(b)+(c)+(d)+(e)=100. olol Ln / Lznz / E / Yi AZD3759 AZD3759 has the following chemical structure: HN V Cl The free base of AZD3759 is known by the chemical name: (2F?)-2,4-dimethyl-1-piperazincarboxylate of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl. AZD3759 is described in WO 2014 / 135876. In one embodiment, AZD3759, or a pharmaceutically acceptable salt thereof, is administered three times a day. In additional embodiments, AZD3759 is administered twice a day. In one embodiment, the total daily dose of AZD3759 is approximately 400 mg. In additional embodiments, approximately 200 mg of AZD3759 is administered twice daily. LAZERTINIB Lazertinib has the following chemical structure: > ai N The free base of lazertinib is known by the chemical name Λ / -{5-[(4-{4[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}-2-primidinyl)amino]-4-methoxy-2-(4-morpholinyl)phenyl}acrylamide. Lazertinib is described in WO 2016 / 060443. Lazertinib is also known by the names YH25448 and GNS-1480. In one embodiment, lazertinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In additional embodiments, lazertinib is administered once daily. In one embodiment, the total daily dose of lazertinib is approximately 240 mg. DACOMITINIB Dacomitinib has the following chemical structure: The free form of dacomitinib is known by the chemical name: (2E)-A / -{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-1}-4-(piperidin-1-1)but-2-enamide. Dacomitinib is described in WO 2005 / 107758. Dacomitinib is also known by the name PF00299804. Dacomitinib can be found in the form of dacomitinib monohydrate, i.e., (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-1l}-4-(piperidin-1yl)but-2-enamide monohydrate. In one embodiment, dacomitinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In additional embodiments, dacomitinib monohydrate is administered once daily. In practice, the total daily dose of dacomitinib monohydrate is approximately 45 mg. In embodiments, dacomitinib, or a pharmaceutically acceptable salt thereof, is in tablet form. In one 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 further embodiments, the one or more pharmaceutically acceptable excipients comprise lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. PLATINUM-BASED CHEMOTHERAPY In some cases, platinum-based chemotherapy involves the administration of cisplatin. The total daily dose of cisplatin is generally calculated by reference to body surface area (BSA), and the daily dose typically ranges from approximately 50 mg / m² to approximately 120 mg / m². In realizations, therefore, the maximum daily dose of cisplatin is up to approximately 150 mg / m², such as up to approximately 120 mg / m², such as up to approximately 100 mg / m², such as up to approximately 90 mg / m², such as up to approximately 80 mg / m², such as up to approximately 70 mg / m², such as up to approximately 60 mg / m², such as up to approximately 50 mg / m². In realizations, the total daily dose of cisplatin is approximately 75 mg / m². Patients undergoing cisplatin chemotherapy generally do not receive cisplatin daily; it is typically administered in treatment cycles. In some cases, the treatment cycle is up to 42 days, or up to 35 days, or up to 28 days, or up to 21 days. In some cases, cisplatin is administered on day 1 of each treatment cycle. In some cases, cisplatin is administered only on day 1 of a 21-day treatment cycle. Alternatively, patients may receive cisplatin over a 5-day period. These patients typically receive a maximum daily dose of between approximately 15 mg / m² and approximately 20 mg / m² for 5 consecutive days. In some implementations, the treatment cycle is up to 42 days, such as up to 35 days, such as up to 28 days, or up to 21 days. In some implementations, cisplatin is administered only on days 1 to 5 of each treatment cycle. In some implementations, cisplatin is administered only on days 1 to 5 of a 21-day treatment cycle. In practice, platinum chemotherapy involves the administration of platinum carboplatin. In practice, platinum chemotherapy involves the administration of platinum carboplatin. The total daily dose of carboplatin is generally calculated by reference to the area under the curve (AUC) for a given patient using a formula known to practitioners (such as the Calvert formula). The typical daily dose ranges from AUC 2 to AUC 7. In some implementations, the maximum daily dose of carboplatin is up to AUC 7, such as up to AUC 6, such as up to AUC 5, such as up to AUC 4, such as up to AUC 3, such as up to AUC 2. In some implementations, the total carboplatin dose is approximately AUC 5. olol Ln / Lznz / E / Yi Patients undergoing carboplatin chemotherapy generally do not receive carboplatin daily; instead, it is typically administered in treatment cycles. In some cases, the treatment cycle is up to 21 days, or up to 14 days, or up to 7 days. In some cases, carboplatin is administered on day 1 of each treatment cycle. In some cases, carboplatin is administered only on day 1 of a 21-day treatment cycle. PEMETREXED In one embodiment, the total daily dose of pemetrexed is up to approximately 500 mg / m2. In additional embodiments, pemetrexed is administered on day 1 of a treatment cycle lasting 21 days. In some cases, pemetrexed is administered with vitamin supplementation, such as vitamin B12 and folic acid. In one embodiment, there is a 21-day cycle in which pemetrexed (total daily dose of approximately 500 mg / m², optionally with vitamin supplementation) is administered plus either cisplatin (total daily dose of approximately 75 mg / m²) or carboplatin (total daily dose of approximately AUC 5 or approximately AUC 6) on a single day of the 21-day cycle. In further embodiments, there are four sequential 21-day cycles. In still further embodiments, the four sequential 21-day cycles are followed by pemetrexed maintenance therapy, wherein the pemetrexed maintenance therapy comprises administration of pemetrexed (total daily dose of approximately 500 mg / m², optionally with vitamin supplementation) once every 21 days until disease progression or unacceptable toxicity occurs. CLINICAL OUTCOME Patients with metastatic or locally advanced EGFR-mutant NSCLC who receive an EGFR TKI according to this description may benefit from an improved prognosis compared to the existing standard of care. In particular, such patients may benefit from one or more of the following: improved progression-free survival (PFS); increased objective response rate; improved duration of response (DoR); or improved overall survival (OS). In these embodiments, the patient benefits from progression-free survival of at least 12 months, such as at least 14 months, such as at least 16 months, such as at least 18 months, such as at least 20 months, such as at least 22 months, such as at least 24 months, such as at least 26 months, such as at least 28 months, such as at least 30 months, such as at least 32 months, such as at least 34 months, such as at least 36 months. In further embodiments, the patient benefits from a response duration of at least 14 months, such as at least 16 months, such as at least 18 months, such as at least 20 months, such as at least 25 months, such as at least 30 months, such as ÍUOL Ln / Lznz / E / Yli as at least 35 months. In additional realizations, the patient benefits from an overall survival of at least 30 months, such as at least 35 months, such as at least 40 months, such as at least 45 months, such as at least 50 months, such as at least 55 months, such as at least 60 months, such as at least 65 months, such as at least 70 months. Patients with metastatic or advanced EGFR-mutant NSCLC with CNS metastases on a baseline brain scan who received an EGFR TKI in accordance with this descriptive memorandum may particularly benefit from an improved prognosis compared to the existing standard of care. In realizations, therefore, the patient with CNS metastases on a baseline brain scan benefits from progression-free survival of at least 12 months, such as at least 14 months, such as at least 16 months, such as at least 18 months, such as at least 20 months, such as at least 22 months, such as at least 24 months, such as at least 26 months, such as at least 28 months, such as at least 30 months, such as at least 32 months, such as at least 34 months, such as at least 36 months. Within this disclosure, central nervous system progression-free survival (CNS PFS) means the time from the start of study treatment until progression of an existing CNS injury and / or a new CNS injury or death in the absence of CNS progression. Patients with metastatic or advanced EGFR-mutant NSCLC with CNS metastases on baseline brain scan who received an EGFR TKI in accordance with this descriptive memorandum may particularly benefit from an improved prognosis compared to the existing standard of care following an improvement in CNS progression-free survival by means of (i) preventing / delaying the development of new central nervous system metastases, particularly brain metastases and / or (ii) preventing / delaying the progression of pre-existing CNS metastases, particularly brain metastases and / or (iii) preventing / delaying death in the absence of CNS progression. In realizations, therefore, the patient with CNS metastasis on a baseline brain scan benefits from CNS progression of at least 12 months, such as at least 14 months, such as at least 16 months, such as at least 18 months, such as at least 20 months, such as at least 22 months, such as at least 24 months, such as at least 26 months, such as at least 28 months, such as at least 30 months, such as at least 32 months, such as at least 34 months, such as at least 36 months. In realizations, therefore, the EGFR TKI provided in accordance with this descriptive memorandum is for use to improve in a patient with CNS metastases on a baseline brain scan one or both of duration of response (DoR) and overall survival (OS). ÍUOL Ln / Lznz / E / Yli EXAMPLES A multinational, multicenter, placebo-controlled, double-blind, randomized phase III study of osimertinib in combination with chemotherapy as first-line treatment for patients with metastatic or locally advanced EGFR mutation-positive NSCLC. The title of the study is, “A randomized, open-label, phase III study of osimertinib with or without platinum-based chemotherapy plus pemetrexed, as first-line treatment in patients with metastatic or locally advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. The following study is being conducted to confirm the benefit of combining osimertinib, pemetrexed, and platinum-based chemotherapy in the treatment of patients with metastatic or locally advanced EGFR-mutant positive NSCLC. STUDY DESIGN SUMMARY This will be a randomized, open-label, global phase III study in patients with metastatic or locally advanced 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) functional status (FS) of 0 or 1. Approximately 556 patients will be enrolled in approximately 24 countries. The study will enroll approximately 60% Asian patients and 40% non-Asian patients. Prior to the start of the randomized phase III portion of the study, a non-randomized safety pre-enrollment phase will enroll up to 30 patients to assess the safety and tolerability of the combination of osimertinib with platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed. The proposed study will only allow enrollment of EGFR mutation-positive NSCLC patients who have either: (1) a pre-existing positive tissue assay (Ex19del or L858R) obtained from a Clinical Laboratory Improvement Amendments (CLIA) certified local laboratory (for US sites) or an accredited local laboratory (for non-US sites); or (2) have an EGFR Ex19del or L858R positive tissue EGFR mutation assay based on the COBAS™ v2 EGFR mutation assay performed prospectively in a central laboratory. During the safety pre-enrollment portion of the study, two patient cohorts (osimertinib plus cisplatin / pemetrexed and osimertinib plus carboplatin / pemetrexed) will be studied in a non-randomized manner. Up to 15 patients per cohort will receive osimertinib 80 mg once daily in combination with either cisplatin (75 mg / m2) or carboplatin (AUC 5) and pemetrexed (500 mg / m2), both administered once every 3 weeks for 4 cycles, followed by osimertinib 80 mg once daily plus maintenance with pemetrexed (500 mg / m2) once every 3 weeks until progression as defined by RECIST v1.1 or until another discontinuation criterion is met. For each safety pre-enrollment cohort, safety data from at least 12 evaluable patients who have completed at least 3 cycles of platinum / pemetrexed doublet therapy in combination with osimertinib will be reviewed by a Safety Review Committee (SRC). The SRC will recommend whether the data support initiation of the randomized portion of the study. Patients enrolled in the safety pre-enrollment will continue their protocol-assigned treatment. Safety and tolerability data from the safety pre-enrollment portion of the study will be reviewed for all patients who received at least one dose of osimertinib and initiated a course of chemotherapy. These data will be assessed by the Clinical Research Committee (CRC). Patients included in the safety pre-enrollment component of the study will be excluded from the analysis of the randomized phase III component. Following completion of safety pre-enrollment, subject to discussion with the SRC, new patients will be randomized in a 1:1 ratio to receive osimertinib alone or in combination with either pemetrexed or either cisplatin or carboplatin. Patients will be stratified prior to randomization by race (Chinese / Asian vs. non-Chinese / Asian vs. non-Asian, with a total of approximately 60% Asian and 40% non-Asian), functional status (FS) according to the World Health Organization (WHO) (0 or 1), and method of tissue sampling (central vs. local). The investigator will decide prior to randomization which chemotherapy regimen (carboplatin / pemetrexed or cisplatin / pemetrexed) a patient would receive if assigned to the osimertinib plus chemotherapy arm. The two treatment regimens will be as follows; a) Osimertinib 80 mg once a day; or b) Osimertinib 80 mg once daily in combination with pemetrexed (500 mg / m2) (with vitamin supplement) plus either cisplatin (75 mg / m2) or carboplatin (AUC5), all administered on day 1 of 21-day cycles for 4 cycles, followed by maintenance with pemetrexed (500 mg / m2) once every 3 weeks. Randomized treatment will continue until progression as defined by RECIST v1.1 or until another discontinuation criterion is met. Following discontinuation of treatment, subsequent therapy will be at the investigator's discretion. Patients will be followed to determine any second progression on subsequent treatment, defined according to local practice, and to determine survival. Safety and tolerability monitoring of the randomized phase of the study will be provided solely by an Independent Data Monitoring Committee (IDMC), with completely independent members. ÍUOL Ln / Lznz / E / Yli The primary endpoint will be progression-free survival (PFS) based on investigator assessment using RECIST v1.1. A blinded, independent central review (BICR) sensitivity analysis of efficacy data from all randomized patients will also be performed. Secondary endpoints will include overall survival (OS), baseline OS, progression-free survival (PFS2), end-response rate (ORR), duration of response (DoR), duration of response (DCR), safety and tolerability (based on adverse events, laboratory assays [clinical biochemistry, hematology, urinalysis], vital signs [pulse and blood pressure], physical examination, weight, electrocardiogram [ECG] parameters, left ventricular ejection fraction), pharmacokinetics, and patient-reported outcomes. KEY INCLUSION CRITERIA a) Pathologically confirmed non-squamous NSCLC b) Locally advanced (clinical stage IIIB, IIIC) or metastatic (clinical stage IVA or IVB) NSCLC newly diagnosed or recurrent NSCLC (per version 8 of the International Association for the Study of Lung Cancer [IASLC] staging manual in thoracic oncology), not amenable to curative surgery or radiotherapy. c) The tumor harbors 1 of the 2 common activating EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations, as assessed by a CLIA-certified laboratory (US sites) or a local accredited laboratory (sites outside the US) or by central prospective assay. d) Mandatory submission of a baseline plasma sample and an unstained, archival tumor tissue sample in sufficient quantity to allow central confirmation of EGFR mutation status. Please refer to the Laboratory Manual for details. e) Patients must have untreated advanced NSCLC that is not amenable to curative surgery or radiotherapy. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biological therapy, experimental agents) or definitive radiation / chemoradiation with or without regimens including immunotherapy, biological therapy, and experimental agents are permitted, provided that treatment was completed at least 12 months before the development of recurrent disease. f) EF according to the CMS from 0 to 1 in the section with clinically non-significant deterioration in the previous 2 weeks. (g) At least one previously non-irradiated lesion that can be accurately measured at baseline as >10 mm in the largest diameter (except for lymph nodes, which must have a short axis of >15 mm) by CT or MRI and is suitable for accurate repeated measurements. If only one measurable lesion exists, it may be acceptable for use (as a target lesion) provided it has not been previously irradiated and baseline tumor assessment scans are not performed within 14 days of a lesion biopsy. olol Ln / Lznz / E / Yi KEY EXCLUSION CRITERIA a) Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids, and have a stable neurological status for at least 2 weeks after completing definitive therapy and steroids. Patients with asymptomatic brain metastases may be enrolled if, in the investigator's opinion, immediate definitive treatment is not indicated. b) Past medical history of ILD, drug-induced ILD, radiation pneumonitis, requiring steroid treatment or any evidence of clinically active ILD. c) Any evidence of serious or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diathesis, which in the investigator's opinion may make participation in the trial undesirable for the patient or would impair adherence to the protocol, or active infection, including hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. d) Any of the following cardiac criteria: • Mean corrected resting QT interval (QTc) >470 ms, obtained from 3 electrocardiograms (ECGs), using the selection of the QTcF value derived from the clinical ECG machine; • Any clinically significant abnormality in rhythm, conduction, or morphology of the resting ECG; for example, complete left bundle branch block, third-degree heart block, second-degree heart block; • Any factor that increases the risk of QTc prolongation or risk of arrhythmic events 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 unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause polymorphic ventricular tachycardia in twisting, Torsades de Pointes. * Correction of electrolyte abnormalities within normal ranges can be performed during selection. e) Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: • Absolute neutrophil count below the lower limit of normal ( <LLN) * olol Ln / Lznz / B / Yi • Recuento de plaquetas por debajo del LLN* • Hemoglobina <90 g / F * EI uso de soporte de factor estimulante de colonias de granulocitos, transfusión de plaquetas y transfusiones de sangre para cumplir estos criterios no está permitido. • ALT > 2.5 x the upper limit of normal (ULN) if liver metastasis cannot be demonstrated or >5 x ULN in the presence of liver metastasis. • AST >2.5 x ULN if liver metastasis cannot be demonstrated or >5 x ULN in the presence of liver metastasis. • Total bilirubin >1.5 x ULN if there is no liver metastasis or >3 x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastasis. • Creatinine clearance <60 ml / min calculated by the Cockcroft and Gault equation. f) Prior treatment with any systemic anti-cancer therapy for advanced NSCLC not amenable to curative surgery or radiation, including chemotherapy, biological therapy, immunotherapy, or any experimental drug. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biological therapy, experimental agents) or definitive radiation / chemoradiation with or without regimens including immunotherapy, biological therapies, and experimental agents are permitted, provided that treatment was completed at least 12 months before the development of recurrent disease. g) Prior treatment with an EGFR-TKL ANALYSIS The phase III component of the study will begin only after a review of data from up to 30 patients included in the pre-enrollment safety component of the study. Up to 15 patients (with a minimum of 12 patients) will be treated with osimertinib in combination with each of the two chemotherapy regimens for at least three cycles. The safety and tolerability data from the pre-enrollment safety portion of the study will be reviewed for all patients who received at least one dose of osimertinib and initiated a course of chemotherapy. These data will be assessed by the Safety Review Committee (SRC) and will be valid only during the pre-enrollment safety portion. Patients included in the pre-inclusion safety component of the study will be excluded from the analysis of the phase III randomized component. 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 progression-free survival (PFS) based on investigator assessment (according to RECIST v1.1). nLOLLn / Lznz / E / Yi Progression-free survival will be defined as the time from randomization to the date of target disease progression or death (from any cause in the absence of progression), regardless of whether the patient withdraws from randomized therapy or receives other antineoplastic therapy before progression. Patients who have not progressed or died at the time of the analysis will be censored at the time of their last evaluable RECIST assessment date. The primary progression-free survival (PFS) analysis based on investigator assessment (according to RECIST 1.1) will occur when approximately 278 PFS events have been observed in the 556 randomized patients (approximately 50% maturity). This is expected to occur approximately 33 months after the first patient is randomized (assuming a 15-month exponential recruitment period). If the true progression-free survival (PFS) risk ratio (RR) for comparing osimertinib with chemotherapy versus osimertinib monotherapy is 0.68, 280 progression events will provide the 90% threshold needed to demonstrate a statistically significant difference in PFS at a 5% two-sided significance level. This translates to an approximate improvement in median PFS from 19 months to 28 months, assuming an exponential distribution and proportional hazards. The minimum critical RR is 0.79, which translates to an approximate improvement in median PFS from 19 months to 24 months. Progression-free survival will be analyzed using a log-rank assay stratified by race (Chinese / Asian vs. non-Chinese / Asian vs. non-Asian), WHO EF (0 vs. 1), and tissue assay method (central vs. local) for p-value generation, using the Breslow approach for treatment linkages. The proportionality assumption will be tested. A PFS sensitivity analysis will be performed based on data submitted via blinded independent central review (BICR) for all patients. A pre-specified subgroup analysis will be performed in patients with centrally confirmed EGFR mutation status by COBAS™ tissue or COBAS™ plasma assays, or used for study eligibility, or retrospectively if eligibility was based on a locally accredited assay. The key secondary OS endpoint will be tested in a hierarchical procedure, at the time of the PFS analysis and after the primary PFS analysis when the OS data are approximately 60% mature (approximately 334 death events across both arms). Alpha will be controlled by the two OS analyses; that is, at the time of the primary PFS analysis and at the end of the OS analysis, with the overall type I error tightly controlled at 5% (two-sided) to test the OS under the O'Brien and Fleming rule. Assuming medians of 40 months and 52 months (RR = 0.77) for osimertinib monotherapy and osimertinib with chemotherapy, respectively, 170 observed events (information fraction of 0.51) are expected at the time of the primary PFS analysis with a two-sided alpha of 0.0034, with the remaining alpha allocated to the final OS analysis (0.0490). Additional efficacy endpoints will be included such as ORR and time to second progression or death (SLP2). The investigator will identify the chemotherapy regimen to be used (cisplatin / pemetrexed or carboplatin / pemetrexed) if the patient is randomized to the combination arm before randomization. The choice of chemotherapy regimen will be made at the patient level. After disease progression, the choice of subsequent therapy will be at the investigator's discretion. An IDMC composed of completely independent members will be convened and will meet periodically to review the safety data and will make recommendations to continue, modify, or discontinue the study based on the findings. Serious AA, AA and other safety data will be reviewed and individual and aggregated safety data will be assessed by the IDMC.

Claims

NOVELTY OF THE INVENTION Having described the present invention as above, the following claims are considered novel and are therefore claimed as property: CLAIMS 1. An EGFR TKI for use in the treatment of an EGFR TKI-naïve patient with metastatic or locally advanced EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed and wherein the EGFR TKI is either a second-generation or third-generation EGFR TKI.

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

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

4. An EGFR TKI for use according to either claim 1 or claim 2, wherein platinum chemotherapy and pemetrexed are administered on day 1 only of a 21-day treatment cycle for four sequential cycles, followed by administration of pemetrexed once every 21 days until disease progression or unacceptable toxicity.

5. An EGFR TKI for use according to any one of the preceding claims, wherein the EGFR-positive mutation NSCLC comprises activating mutations in EGFR selected from exon 19 deletions or L858R substitution mutations.

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

7. An EGFR TKI for use according to any one of the preceding claims, wherein the EGFR TKI is a second-generation EGFR TKI.

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

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

10. An EGFR TKI for use according to claim 9, wherein 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.

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

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

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

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

15. A method for treating metastatic or locally advanced EGFR mutation-positive NSCLC in a previously EGFR TKI-naïve human patient comprising administering an EGFR TKI to the patient, wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed, and wherein the EGFR TKI is either a second-generation or third-generation EGFR TKI.

16. The use of an EGFR TKI in the manufacture of a medicinal product for the treatment of an EGFR TKI-naïve patient with metastatic or locally advanced EGFR mutation-positive NSCLC, wherein the EGFR TKI is administered in combination with platinum-based chemotherapy and pemetrexed and wherein the EGFR TKI is either a second-generation or third-generation EGFR TKI.