EGFR TKI for the treatment of non-small cell lung cancer

Abstract

The present specification relates to EGFR TKIs for the treatment of non-small cell lung cancer, in particular to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for use in adjuvant therapy in patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) following tumor resection.

Description

[0001] This application is a divisional application of the invention patent application filed on May 26, 2021, with application number 202180037402.7 and entitled "EGFR TKI for the Treatment of Non-Small Cell Lung Cancer". Technical Field

[0002] This product information specification describes the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as adjuvant therapy in patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) following tumor resection. Specifically, this product information specification describes the use of second- or third-generation EGFR TKIs as adjuvant therapy in this context. Background Technology

[0003] Primary lung cancer is the most common form of cancer worldwide (accounting for approximately 13.5% of all new cancer cases in 2018) and remains the leading cause of cancer-related deaths globally (accounting for 25.3% of all cancer deaths). Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 90% of all lung cancers (National Comprehensive Cancer Network (NCCN) Guidelines for NSCLC 2019). Approximately 30% of all NSCLC patients present with early-stage (I–IIIA) disease and surgery is the primary treatment. Although patients treated with surgery have a better prognosis, the 5-year survival rate for patients treated with surgery alone is low, ranging from 57% (stage IB) to 23% (stage IIIA). To improve survival, postoperative platinum-based adjuvant chemotherapy has become the standard of care for patients who have undergone resection of stage II and III NSCLC, as well as selected patients who have undergone resection of stage IB disease. Pignon et al. (J Clin Oncol 2008;26:3552-9) found a 5.4% absolute 5-year benefit from surgery and adjuvant chemotherapy, but the recurrence or mortality rates in these patients remained high, with 5-year overall survival (OS) rates ranging from 60%-74% (stage I) to 38% (stage IIIA). Therefore, more effective treatments are needed.

[0004] In 2004, it was reported that activating mutations in exons 18-21 of EGFR were associated with response to EGFR-TKI therapy in NSCLC. Science [Science]

[2004] , Vol. 304, pp. 1497-1500; New England Journal of Medicine[New England Journal of Medicine]

[2004] , Vol. 350, 2129-2139). These mutations are estimated to be prevalent in approximately 10%-16% of human patients with NSCLC in the United States and Europe, and approximately 30%-50% of human patients with NSCLC in Asia. Two of the most prominent EGFR activating mutations are exon 19 deletions and missense mutations in exon 21. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven distinct mutations resulting in the deletion of three to seven amino acids have been detected in exon 19, all centered around a codon with a consistent deletion of amino acids 747-749. The most prominent exon 19 deletion is E746-A750. Missense mutations in exon 21 account for approximately 39%-45% of known EGFR mutations, with the substitution mutation L858R accounting for approximately 39% of all mutations in exon 21. J. Thorac. Oncol. [Journal of Thoracic Oncology]

[2010] , 1551-1558.

[0005] Currently, two first-generation (erlotinib and gefitinib), two second-generation (afatinib and dacomitinib), and one third-generation (osimertinib) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are available for the treatment of advanced (metastatic) EGFR mutation-positive NSCLC. All of these TKIs are effective in NSCLC patients whose tumors carry an in-frame deletion in exon 19 and an L858R point mutation in exon 21. These two mutations account for approximately 90% of all EGFR mutations. In approximately 50% of patients, resistance to first- and second-generation EGFR TKIs is mediated by the acquisition of the "gatekeeper" mutation T790M. Currently, osimertinib is the only registered EGFR TKI that is active against exon 19 deletions and L858R mutations (regardless of the presence of the T790M mutation).

[0006] Although studies have been conducted on first-generation EGFR TKIs in adjuvant therapy (Cheng et al., Lung Cancer 2019;137:7-13; Zhong et al., Lancet Oncol 2018), the role of EGFR TKIs in adjuvant therapy after complete surgical resection of the tumor remains under investigation. In this context, the efficacy of second- and third-generation EGFR TKIs remains to be explored.

[0007] Osimertinib is a third-generation EGFR TKI, and its efficacy in EGFRm advanced NSCLC is superior to that of first-generation EGFR TKIs. The Phase III FLAURA study compared the efficacy and safety of osimertinib as first-line therapy with gefitinib or erlotinib in patients with advanced mutation-positive EGFR (Ex19del or L858R) NSCLC. N. Engl. J Med. [New England Journal of Medicine] 2018, 378, 113-25; N Engl J Med A study published in the New England Journal of Medicine (2020, 382(1):41-50) showed that compared with erlotinib or gefitinib (10.2 months [95% confidence interval [CI]: 9.6, 11.1]), the median progression-free survival (PFS) in the osimertinib group was significantly improved (18.9 months [95% CI: 15.2, 21.4]), with a hazard ratio (HR) of 0.46 (95% CI: 0.37, 0.57; p < 0.0001). The median overall survival in the osimertinib group was 38.6 months (95% confidence interval [CI], 34.5 to 41.8), compared with 31.8 months (95% CI, 26.6 to 36.0) in the comparison group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). Based on the results of the FLAURA study, the NCCN expert panel recommended osimertinib as the preferred first-line therapy for these patients. Notably, in the FLAURA study, CNS progression events were observed in 6% of patients in the osimertinib group and 15% of patients in the standard EGFR TKI group, regardless of the status of known or treated central nervous system (CNS) metastases at trial initiation. Furthermore, in patients with CNS metastases based on baseline brain scans, osimertinib demonstrated a nominally statistically and clinically significant improvement in CNS progression-free survival (PFS) compared to standard EGFR-TKIs, with a 52% reduction in the risk of CNS progression (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)) compared to 13.9 months (95% CI 8.3 to NC). J Clin Oncol [Journal of Clinical Oncology]

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

[0008] ADAURA (NCT02511106); Clinical Lung Cancer[Clinical Lung Cancer]

[2018] , Vol. 19, No. 4, e533-36) was a phase 3, double-blind, randomized study evaluating the efficacy and safety of osimertinib compared to placebo in patients classified as having stage IB-IIIA EGFRm NSCLC after complete surgical resection and adjuvant chemotherapy (when indicated). Unexpectedly, ADAURA was unblinded early on the recommendation of the independent data monitoring committee due to overwhelming efficacy. We have found that, in the adjuvant setting, osimertinib demonstrated a statistically and clinically significant improvement in disease-free survival (DFS) in patients classified as having stage IB / II / IIIA EGFRm NSCLC. Summary of the Invention

[0009] In a first aspect, this specification describes an EGFR TKI for adjuvant therapy in patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) after tumor resection, wherein the EGFR TKI is a second- or third-generation EGFR TKI.

[0010] On the other hand, this specification describes an EGFR TKI for adjuvant therapy in patients classified as having stage IB, II, or IIIA epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection, wherein the EGFR TKI is a second- or third-generation EGFR TKI.

[0011] On the other hand, a method is provided for treating a patient with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), the method comprising adjuvant therapy with a second- or third-generation EGFRTKI after tumor resection.

[0012] On the other hand, a method is provided for treating a patient with stage IB, II, or IIIA epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection, the method comprising adjuvant therapy to the patient with a second- or third-generation EGFR TKI.

[0013] On the other hand, the use of an EGFR TKI in the manufacture of a medicine for adjuvant therapy in patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) after tumor resection is provided, wherein the EGFR TKI is a second- or third-generation EGFR TKI.

[0014] On the other hand, the use of an EGFR TKI in the manufacture of a medicine for adjuvant therapy in patients classified as having stage IB, II, or IIIA epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection is provided, wherein the EGFR TKI is a second- or third-generation EGFR TKI.

[0015] On the other hand, a method is provided to improve disease-free survival (DFS) in patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), which involves adjuvant therapy with a second- or third-generation EGFR TKI after tumor resection.

[0016] On the other hand, a method is provided to improve disease-free survival (DFS) in patients classified as having stage IB, II, or IIIA epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection, the method comprising adjuvant therapy to the patient with a second- or third-generation EGFR TKI.

[0017] This instruction manual further describes this treatment, wherein the adjuvant EGFR TKI treatment results in one or more of the following: improved disease-free survival (DFS), delayed time to first follow-up treatment (TFST), or improved overall survival (OS). Attached Figure Description

[0018] Figure 1 Kaplan-Meier (KM) plot of DFS for the entire ADAURA patient population (Stages IB / II / IIIA); Figure 2 KM plot of DFS in ADAURA patients with stage II-IIIA disease; Figure 3 KM plot of DFS in ADAURA patients with stage IB disease; Figure 4 KM plot of DFS in ADAURA patients with stage II disease; Figure 5 KM plot of DFS in ADAURA patients with stage IIIA disease; Figure 6 DFS across subgroups throughout the entire ADAURA population; Figure 7 KM plot of DFS in ADAURA patients who had previously received adjuvant chemotherapy; Figure 8 KM plot of DFS in ADAURA patients who have not received prior adjuvant chemotherapy. Detailed Implementation

[0019] As used herein, when referring to any given numerical value, the term “about” means within ±10%, ±5%, or ±2% of that value.

[0020] EGFR mutation-positive NSCLC and diagnostic methods Technicians should be aware of EGFR mutations associated with improved response to EGFR-TKI therapy. In various aspects of this specification, EGFR mutation-positive NSCLC includes activating mutations in EGFR, alone or in combination with other EGFR mutations, including T790M. In other aspects, activating mutations in EGFR include activating mutations in exons 18-21, alone or in combination with other EGFR mutations, including T790M. In other aspects, activating mutations in EGFR include exon 19 deletions or missense mutations in exon 21, alone or in combination with other EGFR mutations, including T790M. In other aspects, activating mutations in EGFR include exon 19 deletions or exon 21 L858R substitution mutations, alone or in combination with other EGFR mutations, including T790M. In other aspects, activating mutations in EGFR include exon 19 deletions or L858R substitution mutations. In other aspects, activating mutations in EGFR include exon 19 deletions or exon 21 L858R substitution mutations.

[0021] Technicians should be familiar with the many methods for detecting EGFR activating mutations. Tests suitable for these methods have been approved by the U.S. Food and Drug Administration (FDA). These include tumor tissue-based and plasma-based diagnostic methods. Typically, tumor tissue samples derived from a patient are used to assess EGFR mutation status. A specific example of a suitable diagnostic test for detecting EGFR activating mutations, particularly for detecting exon 19 deletions or exon 21 L858R substitution mutations, is the Cobas... TM EGFR mutation test v2 (Roche Molecular Diagnostics).

[0022] Therefore, in all respects, EGFR mutation-positive NSCLC includes activating mutations in EGFR (such as activating mutations in exons 18-21, e.g., exon 19 deletion or missense mutations in exon 21, e.g., exon 19 deletion or exon 21 L858R substitution mutation), in which the patient's EGFR mutation status has been determined using appropriate diagnostic tests. In other respects, EGFR mutation status has been determined using tumor tissue samples. In other respects, EGFR mutation status has been determined using plasma samples. In other respects, diagnostic methods use FDA-approved tests. In other respects, diagnostic methods use Cobas... TM EGFR mutation test (v1 or v2).

[0023] EGFR TKI EGFR TKIs can be characterized as first-generation, second-generation, or third-generation EGFR TKIs, as described below.

[0024] First-generation EGFR TKIs are reversible inhibitors of EGFR with activating mutations, and they do not significantly inhibit EGFR with the T790M mutation. Examples of first-generation TKIs include gefitinib and erlotinib.

[0025] Second-generation EGFR TKIs are irreversible inhibitors of EGFR with activating mutations, and they do not significantly inhibit EGFR with the T790M mutation. Examples of second-generation TKIs include afatinib and dacomitinib.

[0026] Third-generation EGFR TKIs are inhibitors of EGFR with activating mutations, which also significantly inhibit EGFR with the T790M mutation, but do not significantly inhibit wild-type EGFR. Examples of third-generation TKIs include compounds with formula (I), osimertinib, AZD3759, lazertinib, nazartinib, CO1686 (rociletinib), HM61713, ASP8273, EGF816, PF-06747775 (mavelertinib), avitinib / abivertinib, alflutinib (AST2818), CK-101 (RX-518), HS-10296, and BPI-7711. Other examples include oritinib (SH-1028), befortinib (D-0316), ASK-120067, ZN-e4, YZJ-0318, TL007, XZP (kenaitinib), YK-029A, SLC005-I, TY-9591, XZP-5809-TT1, ZSP0391, and TQB3456.

[0027] On the one hand, EGFR TKIs are second-generation EGFR TKIs. On the other hand, second-generation EGFR TKIs are selected from dacomitinib or its pharmaceutically acceptable salts and afatinib or its pharmaceutically acceptable salts.

[0028] On one hand, an EGFR TKI is a third-generation EGFR TKI. On the other hand, a third-generation EGFR TKI is a compound having formula (I) as defined below. On the other hand, a 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, lazatinib or a pharmaceutically acceptable salt thereof, avitinib or a pharmaceutically acceptable salt thereof, aflutinib or a pharmaceutically acceptable salt thereof, CK-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof, and BPI-7711 or a pharmaceutically acceptable salt thereof. On the other hand, a third-generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

[0029] Compounds having formula (I) On one hand, EGFR TKI is a compound having formula (I): in: G is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a Pyridin-3-yl, indole-3-yl, indazole-1-yl, 3,4-dihydro-1H-[1,4]oxazinro[4,3-a]indole-10-yl, 6,7,8,9-tetrahydropyrido[1,2-a]indole-10-yl, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-yl, pyrrolo[3,2-b]pyridin-3-yl, and pyrazolo[1,5- a ]pyridin-3-yl; R 1 Selected from hydrogen, fluorine, chlorine, methyl, and cyano groups; R 2 Selected from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, and methyl; R 3 Selected from (3) R )-3-(dimethylamino)pyrrolidine-1-yl, (3 S )-3-(dimethyl-amino)pyrrolidone-1-yl, 3-(dimethylamino)azacyclobutane-1-yl, [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy, 2-(methylamino)ethoxy, 5-methyl-2,5-diazaspiro[3,4]oct-2-yl, (3a R ,6a R )-5-methylhexahydro-pyrrolo[3,4- b ]Pyrrole-1(2 H )-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2 S [-2-aminopropionyl]piperazin-1-yl; R 4 Selected from hydrogen, 1-piperidinylmethyl and N,N-dimethylaminomethyl; R 5 Independently selected from methyl, ethyl, propyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, fluorine, chlorine and cyclopropyl; X is CH or N; and n is 0, 1, or 2; Or its pharmaceutically acceptable salt.

[0030] On the other hand, compounds having formula (I) as defined above are provided, wherein G is selected from indole-3-yl and indazole-1-yl; R 1Selected from hydrogen, fluorine, chlorine, methyl, and cyano groups; R 2 Selected from methoxy and 2,2,2-trifluoroethoxy; R 3 Selected from [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy, and 2-(methylamino)ethoxy; R 4 It is hydrogen; R 5 It is selected from methyl, 2,2,2-trifluoroethyl and cyclopropyl; X is CH or N; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0031] Examples of compounds having formula (I) include those described in WO 2013 / 014448, WO 2015 / 175632, WO2016 / 054987, WO 2016 / 015453, WO 2016 / 094821, WO 2016 / 070816 and WO 2016 / 173438.

[0032] Osimertinib and its pharmaceutical compositions Osimertinib has the following chemical structure: The chemical name of the free base of osimertinib is known to be: 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 WO2013 / 014448. Osimertinib is also known as AZD9291.

[0033] Osimertinib can exist in the following mesylate forms: N Osimertinib mesylate is a 2-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate. Osimertinib mesylate is also known as TAGRISSO. TM .

[0034] Osimertinib mesylate is currently approved as a once-daily oral tablet formulation in a dose of 80 mg (expressed as free base, equivalent to 95.4 mg osimertinib mesylate) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC. If a dose modification is required, a 40 mg once-daily oral tablet formulation (expressed as free base, equivalent to 47.7 mg osimertinib mesylate) is available. The tablet core contains drug diluents (such as mannitol and microcrystalline cellulose), disintegrants (such as low-substituted hydroxypropyl cellulose), and lubricants (such as sodium stearoyl fumarate). The tablet formulation is described in WO 2015 / 101791.

[0035] Therefore, on the one hand, osimertinib or its pharmaceutically acceptable salts are in the form of mesylate, i.e. N -(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate.

[0036] On the one hand, osimertinib or a pharmaceutically acceptable salt thereof is administered once daily. On the other hand, osimertinib mesylate is administered once daily.

[0037] On one hand, the total daily dose of osimertinib is approximately 80 mg. On the other hand, the total daily dose of osimertinib mesylate is approximately 95.4 mg.

[0038] On one hand, the total daily dose of osimertinib is approximately 40 mg. On the other hand, the total daily dose of osimertinib mesylate is approximately 47.7 mg.

[0039] On the one hand, osimertinib or its pharmaceutically acceptable salts are available in tablet form.

[0040] On one hand, osimertinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. On the other hand, 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 stearoyl fumarate).

[0041] In one aspect, 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 drug diluents; (c) from 2 to 15 parts of one or more drug disintegrants; and (d) from 0.5 to 3 parts of one or more drug lubricants; and wherein all parts are by weight, and the sum of the parts (a) + (b) + (c) + (d) = 100.

[0042] In one aspect, 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 include microcrystalline cellulose and mannitol; (c) from 2 to 8 parts of a pharmaceutical disintegrant, wherein the pharmaceutical disintegrant includes low-substituted hydroxypropyl cellulose; (d) from 1.5 to 2.5 parts of a pharmaceutical lubricant, wherein the pharmaceutical lubricant includes sodium stearoyl fumarate; and wherein all parts are by weight, and the sum of the parts (a) + (b) + (c) + (d) = 100.

[0043] In one aspect, the composition is in the form of a tablet, wherein the tablet core comprises: (a) about 19 parts of osimertinib mesylate; (b) about 59 parts of mannitol; (c) about 15 parts of microcrystalline cellulose; (d) about 5 parts of low-substituted hydroxypropyl cellulose; and (e) about 2 parts of sodium stearoyl fumarate; and wherein all parts are by weight, and the sum of the parts (a) + (b) + (c) + (d) + (e) = 100.

[0044] AZD3759 AZD3759 has the following chemical structure: The chemical name of the free base of AZD3759 is known to be: 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl (2 R 2,4-Dimethyl-1-piperazine carbamate. AZD3759 is described in WO 2014 / 135876.

[0045] On the one hand, AZD3759 or a pharmaceutically acceptable salt thereof is administered twice daily. On the other hand, AZD3759 is administered twice daily.

[0046] On one hand, the total daily dose of AZD3759 is approximately 400 mg. On the other hand, approximately 200 mg of AZD3759 is administered twice daily.

[0047] Lazazantinib Lazatinib has the following chemical structure: The chemical name of the free base of lazatinib is known to be... NLazatinib is described in WO 2016 / 060443. It is also known as YH25448 and GNS-1480.

[0048] On the one hand, lazatinib or its pharmaceutically acceptable salts are administered once daily. On the other hand, lazatinib is administered once daily.

[0049] On the one hand, the total daily dose of lazatinib is approximately 20 to 320 mg.

[0050] On the one hand, the total daily dose of lazatinib is approximately 240 mg.

[0051] avitinib / abivertinib Avitinib has the following chemical structure: The known chemical name of the free base of avitinib is: N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)phenyl)prop-2-enamide. Avitinib is disclosed in US2014038940. Avitinib is also known as abivertinib.

[0052] On the one hand, avitinib or a pharmaceutically acceptable salt thereof is administered twice daily. On the other hand, avitinib maleate is administered twice daily.

[0053] On the one hand, the total daily dose of avitinib maleate is approximately 600 mg.

[0054] Aflutinib (furmonertinib) Aflutinib has the following chemical structure: The known chemical name of the free base of aniflutinib is: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide. Aiflutinib is disclosed in WO 2016 / 15453. Aiflutinib is also known as AST2818.

[0055] On the one hand, aniflutinib or a pharmaceutically acceptable salt thereof is administered once daily. On the other hand, aniflutinib mesylate is administered once daily.

[0056] On the one hand, the total daily dose of aniflutinib mesylate is approximately 80 mg.

[0057] On the one hand, the total daily dose of aniflutinib mesylate is approximately 40 mg.

[0058] Afatinib Afatinib has the following chemical structure: The chemical name of the free base of afatinib is known to be: N -[4-(3-chloro-4-fluoroaniline)-7-[(3 S Afatinib is a compound containing 3-oxapentane-3-yl]oxyquinazoline-6-yl]-4-(dimethylamino)but-2-enamide. It is disclosed in WO 02 / 50043. Afatinib is also known as Gilotrif.

[0059] On the one hand, afatinib or a pharmaceutically acceptable salt thereof is administered once daily. On the other hand, afatinib maleate is administered once daily.

[0060] On the one hand, the total daily dose of afatinib maleate is approximately 40 mg.

[0061] On the one hand, the total daily dose of afatinib maleate is approximately 30 mg.

[0062] CK-101 CK-101 has the following chemical structure: The chemical name of the free base of CK-101 is known to be: N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide. CK-101 is disclosed in WO 2015 / 027222. CK-101 is also known as RX-518.

[0063] HS-10296 (almonertinib) HS-10296 (Ametinib) has the following chemical structure: The chemical name of the free base of HS-10296 is known to be: N-[5-[[4-(1-cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-phenyl]prop-2-enamide. HS-10296 is disclosed in WO 2016 / 054987.

[0064] On the one hand, the total daily dose of HS-10296 is approximately 110 mg.

[0065] BPI-7711 BPI-7711 has the following chemical structure: The chemical name of the free base of BPI-7711 is known to be: N-[2-[2-(dimethylamino)ethoxy]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide. BPI-7711 is disclosed in WO 2016 / 94821.

[0066] On the one hand, the total daily dose of BPI-7711 is approximately 180 mg.

[0067] Dacomitinib Dacomitinib has the following chemical structure: The chemical name of the free form of dacomitinib is known to be: (2) E )- N -{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazoline-6-yl}-4-(piperidin-1-yl)but-2-enamide. Dacomitinib is described in WO 2005 / 107758. Dacomitinib is also known as PF-00299804.

[0068] Dacomitinib can exist in the form of dacomitinib monohydrate as follows: (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazoline-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate.

[0069] On the one hand, dacomitinib or a pharmaceutically acceptable salt thereof is administered once daily. On the other hand, dacomitinib monohydrate is administered once daily.

[0070] On the one hand, the total daily dose of dacomitinib monohydrate is approximately 45 mg.

[0071] On the one hand, dacomitinib or its pharmaceutically acceptable salts are available in tablet form.

[0072] On one hand, dacomitinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. On the other hand, the one or more pharmaceutically acceptable excipients include lactose monohydrate, microcrystalline cellulose, sodium glycolate starch, and magnesium stearate.

[0073] Nazartinib Nazatinib has the following chemical structure: The known chemical name of the free base of nazatinib is: N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azacycloheptane-3-yl)-1H-benzo[r]imidazol-2-yl)-2-methylisonicotinamide. Nazatinib is disclosed in WO2013 / 184757.

[0074] On the one hand, the total daily dose of nazatinib is approximately 150 mg, approximately 225 mg, or approximately 350 mg.

[0075] Patients and clinical outcomes Patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) who may be optionally classified as having stage IB, II, or IIIA disease and who receive an EGFR TKI for use as described in this instruction manual after tumor resection can benefit from improved prognosis compared to existing standard of care, placebo, or no treatment. Specifically, adjuvant EGFR TKI therapy after tumor resection can provide one or more of the following: improved disease-free survival (DFS); delayed time to first subsequent treatment (TFST); or improved overall survival (OS).

[0076] Disease-free survival (DFS) is defined as the time from randomization (or initiation of treatment) until the date of disease relapse or death. Improvements in DFS can be measured relative to existing standard of care, placebo, or no treatment. In one respect, DFS can be measured relative to placebo or no treatment.

[0077] On the one hand, adjuvant EGFR TKI therapy provides a reduction of at least approximately 50% (such as at least approximately 60%, at least approximately 70%, or at least approximately 80%) in the risk of disease recurrence or death. On the other hand, the patient may optionally be classified as having stage IB, II, or IIIA EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 75% to approximately 90% (such as 77% to approximately 88%; or such as 77% to approximately 82%; or such as approximately 78% to approximately 80%) in the risk of disease recurrence or death. On the other hand, the patient may optionally be classified as having stage II or IIIA EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 80% (such as 81%, 82%, 83%, 84%, or 85%) in the risk of disease recurrence or death. Alternatively, the patient may optionally be classified as having stage II or IIIA EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 80% to approximately 90% (such as approximately 80% to approximately 85%; or such as approximately 82% to approximately 84%) in the risk of disease recurrence or death. Alternatively, the patient may optionally be classified as having stage IB EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 50% (such as 48%, 49%, 50%, 51%, or 52%) in the risk of disease recurrence or death. On the other hand, the patient may optionally be classified as having stage IB EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 45% to approximately 55% (e.g., approximately 48% to approximately 52%; or such as approximately 49% to approximately 51%) in the risk of disease recurrence or death. On the other hand, the patient may optionally be classified as having stage II EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 80% (e.g., 81%, 82%, 83%, 84%, or 85%) in the risk of disease recurrence or death. On the other hand, the patient may optionally be classified as having stage II EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 80% to approximately 90% (e.g., approximately 80% to approximately 85%; or such as approximately 82% to approximately 84%) in the risk of disease recurrence or death.On the other hand, the patient may have been optionally classified as having stage IIIA EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 85% (such as 86%, 87%, 88%, 89%, or 90%) in the risk of disease recurrence or death. Alternatively, the patient may have been optionally classified as having stage IIIA EGFRm NSCLC after complete tumor resection, and adjuvant EGFR TKI therapy provides a reduction of approximately 85% to approximately 95% (such as approximately 85% to approximately 90%; or such as approximately 87% to approximately 89%) in the risk of disease recurrence or death.

[0078] On the one hand, adjuvant EGFR TKI therapy provides at least about 12 months of DFS (such as at least about 24 months, such as at least about 36 months, such as at least about 48 months, or such as at least about 60 months).

[0079] On the one hand, adjuvant EGFR TKI therapy provides a disease-free survival (DFS) probability of approximately 97% (e.g., 95%, 96%, 97%, 98%, or 99%) at approximately 12 months. On the other hand, adjuvant EGFR TKI therapy provides a DFS probability of approximately 95% to approximately 99% (e.g., approximately 95% to approximately 98%; or such as approximately 96% to 98%) at approximately 12 months. On the other hand, adjuvant EGFR TKI therapy provides a DFS probability of approximately 90% (e.g., 87%, 88%, 89%, 90%, 91%, or 92%) at approximately 24 months. On the other hand, adjuvant EGFR TKI therapy provides a DFS probability of approximately 85% to approximately 95% (e.g., approximately 86% to approximately 92%; or such as approximately 87% to approximately 91%) at approximately 24 months. On the other hand, adjuvant EGFR TKI therapy provides a DFS probability of approximately 80% (e.g., 77%, 78%, 79%, 80%, 81%, or 82%) at approximately 36 months. On the other hand, adjuvant EGFR TKI therapy provides a probability of DFS of about 75% to about 85% (such as about 77% to about 82%; or such as about 78% to about 80%) at about 36 months.

[0080] On the one hand, adjuvant EGFR TKI therapy increases the probability of providing at least approximately 30% (such as at least approximately 28%, 29%, 30%, 31%, or 32%) DFS at approximately 24 months. On the other hand, adjuvant EGFR TKI therapy increases the probability of providing at least approximately 28% to approximately 32% (such as at least approximately 29% to approximately 31%) DFS at approximately 24 months. On the other hand, adjuvant EGFR TKI therapy increases the probability of providing at least approximately 30% (such as at least approximately 28%, 29%, 30%, 31%, or 32%) DFS at approximately 36 months. On the other hand, adjuvant EGFR TKI therapy increases the probability of providing at least approximately 28% to approximately 32% (such as at least approximately 29% to approximately 31%) DFS at approximately 36 months.

[0081] On the one hand, adjuvant EGFR TKI therapy provides a median DFS of at least approximately 48 months. On the other hand, adjuvant EGFR TKI therapy provides a median DFS of at least approximately 54 months. On the other hand, adjuvant EGFR TKI therapy provides a median DFS of at least approximately 60 months. On the other hand, adjuvant EGFR TKI therapy provides a median DFS of at least approximately 66 months. On the other hand, adjuvant EGFR TKI therapy provides a median DFS of at least approximately 72 months.

[0082] TFST is defined as the earlier of the date of randomization (or treatment initiation) to the date of initiation of anticancer therapy after discontinuation of adjuvant EGFR TKI therapy or the date of death.

[0083] On the one hand, adjuvant EGFR TKI therapy provides at least approximately 12 months (such as at least approximately 24 months, such as at least approximately 36 months, such as at least approximately 48 months, or such as at least approximately 60 months) of TFST.

[0084] OS is the time from randomization (or start of treatment) to the day of death (for any reason).

[0085] On the one hand, adjuvant EGFR TKI therapy provides a median overall survival (OS) of at least approximately 60 months. On the other hand, adjuvant EGFR TKI therapy provides a median OS of at least approximately 72 months. On the other hand, adjuvant EGFR TKI therapy provides a median OS of approximately at least approximately 84 months. On the other hand, adjuvant EGFR TKI therapy provides a median OS of approximately at least approximately 96 months.

[0086] Patients with locally advanced or metastatic EGFR mutation-positive NSCLC, based on pathological criteria, may have been classified postoperatively as having stage IB, II, or IIIA disease and receive an EGFR TKI for use as described in this instruction manual. Staging can be determined according to the TNM (tumor, lymph node, metastasis) staging system for lung cancer (AJCC Cancer Staging Manual, 7th edition, Springer, New York).

[0087] In one instance, the patient was classified as having stage IB, II, or IIIA epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection. (This sentence is repeated four times in the original text.)

[0088] On the one hand, the patient received adjuvant chemotherapy. On the other hand, the patient did not receive adjuvant chemotherapy.

[0089] Example Used to evaluate the efficacy of AZD9291 compared to placebo after complete tumor resection with or without adjuvant chemotherapy. Efficacy and safety in patients with epidermal growth factor receptor mutation-positive stage IB-IIIA non-small cell lung cancer. The Phase III, double-blind, randomized, placebo-controlled, multicenter study (ADAURA) ADAURA (NCT02511106); Clinical Lung Cancer [Clinical Lung Cancer]

[2018] , Vol. 19, No. 4, e533-36) is a phase 3, double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of AZD9291 compared to placebo in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) having centrally confirmed most common sensitive EGFR mutations (Ex19Del and L858R) (alone or in combination with other EGFR mutations) (as confirmed by central testing), who have had complete tumor resection and have received or have not received postoperative adjuvant chemotherapy. Adjuvant chemotherapy should consist of up to 4 cycles of platinum-based doublet chemotherapy.

[0090] Research Design Overview Patients were randomized 1:1 to receive either AZD9291 or placebo. Patients had fully recovered from surgery and completed any standard-of-care adjuvant chemotherapy prior to randomization. Without adjuvant chemotherapy, patients were randomized within 10 weeks of complete surgical resection; with adjuvant chemotherapy, patients were randomized within 26 weeks of surgery.

[0091] Considering the presence of wild-type EGFR, sample depletion, and a 10% screening failure rate due to other reasons, it is estimated that approximately 3200 patients will be screened, with approximately 700 randomly assigned to each group. Approximately 60% of patients will be recruited from Asia, and approximately 40% from non-Asian countries. The proportion of randomly assigned patients with stage 1B cancer is approximately 30%, and the proportion with stage II-IIIA cancer is approximately 70%. At randomization, patients will be stratified by stage (IB vs. II vs. IIIA), mutation type (Ex19Del / L858R, alone or in combination with other EGFR mutations) (as confirmed by a central laboratory using tissue-based testing), and ethnicity (Asian / non-Asian).

[0092] After complete resection, all patients are required to undergo a baseline CT scan (chest and abdomen, including liver and adrenal glands) within 28 days prior to the start of treatment to confirm the absence of disease.

[0093] Patients underwent safety assessments at baseline, 2 weeks, 4 weeks, 12 weeks, and every 12 weeks until treatment was completed or discontinued. All study patients were required to be followed up for 28 days after treatment discontinuation. Patients were treated for a maximum of 3 years, or until disease relapse or other discontinuation criteria were met.

[0094] Patients underwent routine CT scans (chest and abdomen, including the liver and adrenal glands) in response to disease recurrence, along with additional anatomical imaging as indicated by the patient's physical signs and symptoms. Disease-free survival (DFS) should be measured from the date of randomization until the date of assessment of disease recurrence at the study site or death without recurrence (for any cause).

[0095] Patients will be followed up for disease recurrence at 12 and 24 weeks, then every 24 weeks until 5 years (considered 264 weeks), and annually thereafter. After disease recurrence, patients will be followed up for overall survival (OS) every 24 weeks until 5 years (considered 264 weeks), and annually thereafter.

[0096] Upon disease recurrence, the patient will be re-staging, and all sites of NSCLC recurrence will be recorded. The treatment received after recurrence will be determined by the physician. Cancer treatment and procedures following recurrence will be documented.

[0097] The Independent Data Monitoring Committee (IDMC) will convene and meet approximately every six months for the first two years after the first patient is randomized, and approximately annually thereafter. The IDMC will review the safety assessment and make recommendations to continue, modify, or discontinue the study based on safety findings. Serious adverse events, adverse events, and other safety data will be reviewed, and the IDMC will evaluate individual and aggregate safety data.

[0098] Patients will initially be followed according to the study protocol until the data cutoff for the preliminary analysis (estimated to be 68-70 months after the first subject is randomized, based on a 28-month recruitment period). If there are significantly fewer than 70 DFS events in the IB cohort at the time of the preliminary analysis, all patients will be followed up further according to the same study protocol until the “IB analysis”.

[0099] Following the preliminary analysis (or "IB analysis," if necessary), patients will be followed up for survival (OS extension) according to the simplified study protocol until the data cutoff for the extended OS analysis, which will occur approximately one year after the data cutoff date of the preliminary analysis. Alternatively (or additionally), patients will be followed up for survival for 5 years after the last subject enrollment (LSI), which will occur approximately two years after the data cutoff date of the preliminary analysis. This extended OS analysis will not be driven by the number of events, and therefore the results will be considered exploratory only. If any patients remain on the investigational drug at the data cutoff date of the extended OS analysis, they will be able to continue study treatment until completion or the treatment discontinuation criteria are met.

[0100] Following the extended OS analysis, the ADAURA study will be closed, and the collection of survival, cancer treatment, and safety data from globally recruited patients who are no longer receiving the study treatment will cease entirely. Any patients still receiving the study drug will be managed outside of the study.

[0101] Target patient group Male and female patients who met the criteria for this study were 18 years of age or older (at least 20 years of age for patients from Japan / Taiwan), histologically confirmed primary non-squamous non-small cell lung cancer, with complete surgical resection of the primary tumor, and classified postoperatively as stage IB, II, or IIIA according to pathological criteria (stage IB patients were excluded in Japan). Recruitment of patients with stage IB disease was closed when approximately 210 (30%) patients had been randomized; and recruitment of patients with stage II-IIIA disease was closed when approximately 470 (70%) patients had been randomized. Patients were confirmed to have tumors carrying one of the most common EGFR mutations (Ex19Del; L858R) known to be associated with EGFR-TKI sensitivity, alone or in combination with other EGFR mutations, as confirmed by central testing.

[0102] The patient may have received up to four cycles of prior platinum-based adjuvant chemotherapy under standard care, but must not have received prior radiotherapy. Preoperative (neoadjuvant) platinum-based or other chemotherapy is not permitted.

[0103] Treatment duration After randomization, patients will begin treatment with either AZD9291 (80 mg once daily) or placebo. Patients will continue randomized treatment until disease relapse, treatment discontinuation criteria are met, or treatment is completed. The maximum duration of treatment is 3 years (156 weeks).

[0104] Research products, dosages, and administration methods. AZD9291 is an orally administered, potent, selective, central nervous system (CNS) active, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that effectively combats both EGFR-TKI sensitivity and resistance mutations in NSCLC with a significant selectivity margin relative to wild-type EGFR. Patients are randomly assigned to receive either AZD9291 (80 mg orally once daily) or a matching placebo.

[0105] Key inclusion criteria a) Histologically confirmed as primary non-small cell lung cancer (NSCLC), primarily non-squamous histology.

[0106] b) Based on pathological criteria, the patient must be classified as stage IB, II, or IIIA postoperatively. Staging will be based on the TNM (tumor, lymph node, metastasis) staging system for lung cancer (7th edition).

[0107] c) The central laboratory confirmed that the tumor carries one of the two common EGFR mutations (Ex19del, L858R) known to be associated with EGFR-TKI sensitivity, either alone or in combination with other EGFR mutations, including T790M.

[0108] d) Complete surgical resection of primary NSCLC is mandatory. All gross lesions must be removed at the end of the surgery. All surgical margins to be resected must be tumor-negative. Resection can be performed using open or video-assisted thoracic surgery (VATS) techniques.

[0109] e) Complete recovery from surgery and standard postoperative treatment (if applicable) at randomization. Treatment cannot be initiated within 4 weeks postoperatively. For patients who have not received adjuvant chemotherapy, the interval between surgery and randomization may not exceed 10 weeks; for patients who have received adjuvant chemotherapy, the interval may not exceed 26 weeks. Postoperative wounds must be completely healed after any surgery. For patients who have received postoperative platinum-based adjuvant chemotherapy, at least 2 weeks (but no more than 10 weeks) must have elapsed from the last dose of chemotherapy to the date of randomization. At the start of study treatment, patients must have recovered from all prior therapy toxicities greater than CTCAE grade 1, except for alopecia and grade 2 neuropathy associated with prior platinum therapy.

[0110] f) The World Health Organization's physical condition score ranges from 0 to 1.

[0111] Key Exclusion Criteria a) Treatment with any of the following: preoperative or postoperative or planned radiation therapy for current lung cancer; preoperative (neoadjuvant) platinum-based or other chemotherapy; any prior anticancer therapy for NSCLC other than standard platinum-based doublet postoperative adjuvant chemotherapy, including investigational therapy; prior treatment with neoadjuvant or adjuvant EGFR-TKIs; major surgery (including primary tumor surgery, excluding vascular access placement) within 4 weeks of the first dose of investigational drug; the patient is currently receiving (or cannot discontinue before receiving the first dose of investigational therapy) a drug or herbal supplement known to be an effective inducer of CYP3A4 (at least 3 weeks prior); treatment with investigational drug within five half-lives of the compound or any related material thereof (if known).

[0112] b) Patients who have only undergone segmental resection or wedge resection.

[0113] c) History of other malignancies, except for: well-treated non-melanoma skin cancer, effectively treated carcinoma in situ, or other effectively treated solid tumors, which have no evidence of disease for more than 5 years after the end of treatment and, in the opinion of the treating physician, have no significant risk of recurrence of the prior malignancy.

[0114] d) All unresolved prior therapy toxicities greater than CTCAE grade 1 at the start of the study, except for alopecia and grade 2 neuropathy associated with prior platinum therapy.

[0115] e) Any evidence of severe or uncontrolled systemic disease, including uncontrolled hypertension and active bleeding disorder, which, in the investigator's view, would make the patient unwilling to participate in the trial or would compromise protocol adherence; or any evidence of active infection, including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV). Active infection will include any patient receiving intravenous treatment for infection; active hepatitis B infection will include at least all patients who are serologically positive for hepatitis B surface antigen (HBsAg).

[0116] f) Intractable nausea and vomiting, chronic gastrointestinal disease, inability to swallow the prepared product, or previous colectomy that precludes adequate absorption of AZD9291.

[0117] g) Any of the following cardiac criteria: a mean resting corrected QT interval (QTc) >470 msec obtained from 3 ECGs using QTcF values ​​derived from a screening clinic ECG machine; any clinically significant abnormalities in the rhythm, conduction, or morphology of the resting ECG, such as complete left bundle branch block, third-degree heart block, or second-degree heart block; any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, a family history of long QT syndrome or unexplained sudden death of a first-degree relative under the age of 40, or any concomitant medications known to prolong the QT interval.

[0118] h) ILD, drug-induced ILD, a history of radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD.

[0119] i) Insufficient bone marrow reserve or organ dysfunction, as indicated by any of the following laboratory values: absolute neutrophil count <1.5 x 10⁹ / L; platelet count <100 x 10⁹ / L; hemoglobin <90 g / L; p-alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) >2.5 x ULN; total bilirubin >1.5 x ULN or >3 x ULN in the presence of documented Gilbert syndrome (unconjugated hyperbilirubinemia); creatinine >1.5 x ULN with creatinine clearance <50 mL / min (measured or calculated using the Cockcroft and Gault formula); creatinine clearance should only be confirmed when creatinine >1.5 x ULN.

[0120] Efficacy evaluation Disease-free survival (DFS) Disease-free survival was the primary endpoint of this study and was defined as the time from the date of randomization until the date of disease recurrence or death from any cause in the absence of disease recurrence. Disease recurrence was defined as evidence of disease recurrence assessed on-site based on CT or MRI scans and / or based on pathological disease from biopsy. The primary population consisted of stage II / IIIA patients.

[0121] The 2-, 3-, 4-, and 5-year DFS rates were defined as the proportion of patients who were alive and disease-free at 2, 3, 4, and 5 years, respectively, and were estimated based on the Kaplan-Meier plot of the primary endpoint of DFS at the time of the initial analysis.

[0122] The DFS of a subset of patients with stage II-IIIA cancer will be analyzed using log-rank tests stratified by stage (II, IIIA), mutation type (Ex19Del, L858R, alone or in combination with other EGFR mutations), and ethnicity (Asian, non-Asian) to generate p-values, and the Breslow method will be used to handle relationships. The DFS of the entire population will be analyzed using log-rank tests stratified by stage (IB, II, IIIA), mutation status (Ex19Del, L858R, alone or in combination with other EGFR mutations, as confirmed by central testing), and ethnicity (Asian, non-Asian) to generate p-values, and the Breslow method will be used to handle relationships. The hazard ratio and confidence interval can be obtained directly from the U and V statistics as follows (Berry et al. 1991, Statistics in Medicine, Vol. 10, pp. 749-55; Selke and Siegmund 1983, Biometrika, Vol. 70, pp. 315-26): HR = exp(U / V) 95% CI of HR = (exp{U / V - 1.96 / √V}, exp{U / V + 1.96√V}) Where U = ∑ i (d 1i -e 1i ) is the log-rank test statistic (where d) 1i and e 1i √V represents the observed and expected events in group 1, and √V is the standard deviation of the log-rank test statistic obtained from the LIFETEST procedure with the stratification term (STRATA) as the stratification variable. HR is the hazard ratio, and CI is the confidence interval.

[0123] Kaplan-Meier (KM) plots of DFS will be provided for each treatment group.

[0124] Overall lifespan (OS) Overall survival is defined as the time from randomization to death (for any reason).

[0125] After randomization, patients will be followed up on survival every 24 weeks for 5 years (264 weeks), and then annually thereafter until the study is closed.

[0126] The 2-, 3-, 4-, and 5-year OS rates were defined as the proportion of patients who survived at 2, 3, 4, and 5 years, respectively, and were estimated based on the Kaplan-Meier plot of OS at the time of the initial analysis.

[0127] In the initial analysis, log-rank tests stratified by stage (IB, II, IIIA), mutation type (Ex19Del, L858R, alone or in combination with other EGFR mutations), and ethnicity (Asian, non-Asian) will be used to generate p-values, and the Breslow method will be used to analyze OS data. Hazard ratios and confidence intervals will be obtained directly from the U and V statistics as described above (provided there are enough events available for meaningful analysis (>20 deaths); otherwise, a descriptive summary will be provided).

[0128] Time until first follow-up treatment or time until death Time to first subsequent treatment (TFST) or time to death is defined as the earlier of the date of randomization to the date of initiation of anticancer therapy after discontinuation of study drug or the date of death. Any patient whose status of subsequent treatment was unknown at the time of analysis or whose death was unknown was truncated at the last known time of non-recurrence of subsequent treatment; that is, the last follow-up confirming this.

[0129] result Following the recommendation of the Independent Data Monitoring Committee (IDMC), ADAURA was unblinded early on based on its overwhelming efficacy. The results presented in this paper are from analyses conducted after the January 2020 data cutoff. The DCO was initially projected for February 2022.

[0130] The KM plots of DFS for the entire patient group, patients with stage II-IIIA disease, patients with stage IB disease, patients with stage II disease, patients with stage IIIA disease, and patients who received and did not receive adjuvant chemotherapy are shown in the figures below. Figures 1-5 , Figure 7 and Figure 8 The data is summarized in Tables 1 and 2 below.

[0131] The key findings are: • In the primary cohort of stage II / IIIA patients, the risk of disease relapse or death was reduced by 83% with osimertinib compared to placebo (DFS HR = 0.17 (0.12, 0.23); p < 0.0001). • In the entire population, compared with placebo, the risk of disease relapse or death was reduced by 79% with osimertinib (DFS HR 0.21 [95% CI 0.16, 0.28]: p<0.0001). • In the entire population, the 2-year DFS rate of osimertinib was 89% compared to 53% for placebo. • Regardless of whether the patient had received prior adjuvant chemotherapy, DFS consistently improved. • Immature OS (5% maturity) showed a favorable survival trend for osimertinib: o Stage II / IIIA patients: osimertinib: 8 deaths (3%), placebo: 17 deaths (7%).

[0132] Table 1 DFS, disease-free survival; n, number of patients receiving osimertinib (o) or placebo (p); HR, hazard ratio; CI, confidence interval; NR, not reached; NC, not calculated; p, probability value.

[0133] Table 2 DFS, disease-free survival; n, number of patients receiving osimertinib (o) or placebo (p); HR, hazard ratio; CI, confidence interval; NR, not reached; NC, not calculated; p, probability value.

Claims

1. Use in the preparation of a medicament for adjuvant therapy in patients with stage IB-IIIA epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) after tumor resection, wherein the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof, wherein the EGFRm NSCLC contains activating mutations in EGFR selected from exon 19 deletions or exon 21L858R substitution mutations; The patient had received adjuvant chemotherapy. This adjuvant EGFR TKI therapy provides improved disease-free survival (DFS).

2. The use according to claim 1, wherein the adjuvant EGFR TKI treatment provides a probability of about 85% to about 95% DFS at about 24 months.

3. The use according to claim 1, wherein the osimertinib or a pharmaceutically acceptable salt thereof is administered once daily.

4. The use according to claim 1, wherein the osimertinib or a pharmaceutically acceptable salt thereof is administered in tablet form.

5. The use according to claim 1, wherein the osimertinib or a pharmaceutically acceptable salt thereof is osimertinib mesylate.

Images