TREATMENT-RESISTANT EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITOR MUTANT L718 AND / OR L792.

Abstract

The present invention provides an antitumor agent for treating a patient with a malignant tumor expressing EGFR who has at least one mutation selected from the group consisting of the L718X mutation in exon 18 and the L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue, the antitumor agent comprising (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (A)) or a salt thereof.

Description

EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITOR RESISTANT TO MOTANTING TREATMENT L718 AND / OR L792 The present invention relates to an antitumor agent against cancer, comprising a treatment-resistant mutating epidermal growth factor receptor (hereinafter referred to as EGFR) in exon 18 and / or exon 20. BACKGROUND OF THE INVENTION EGFR is a receptor-type tyrosine kinase that exerts its physiological function in normal tissue by binding to epidermal growth factor (hereafter also referred to as EGF), which is a ligand, and contributes to growth and inhibition of apoptosis in epithelial tissues (NPL 1). Furthermore, somatic mutations of the EGFR gene have been identified as cancer-causing genes; for example, EGFR with codons 746 to 750 in exon 19 deleted (hereafter also referred to as the exon 19 deletion mutation) and EGFR with the leucine encoded by codon 858 in exon 21 mutated to arginine (hereafter also referred to as the L858R mutation) consistently induce EGF-independent kinase activity and contribute to the growth and survival of cancer cells (NPL 2). These mutations are observed, for example, in 30 to 50% of the non-small cell lung cancer in East Asia.Mutations are also observed in approximately 10% of non-small cell lung cancer in Europe and the United States, and are considered to be one of the causes of cancer (NPL 3). Therefore, research and development of EGFR inhibitors as antitumor agents has been actively pursued, and they have been introduced into the treatment of several types of EGFR-positive lung cancer (NPL2 and NPL4). Gefitinib, erlotinib, and afatinib have been used as therapeutic agents against EGFR-positive lung cancers mutating due to exon 19 deletion and L858R mutations. The exon 19 deletion and L858R mutations account for 90% of EGFR mutations. Furthermore, acquired resistance is known to occur during treatment with these agents, and 50% of this resistance is caused by EGFR with a resistance mutation in which codon 790 of exon 20 changes from threonine to methionine (hereafter also referred to as the T790M mutation). Osimertinib has been used as a therapeutic agent to treat lung cancer types with this mutation.Therefore, treatments using EGFR inhibitors are in the process of being established for lung cancer patients who have major EGFR mutations. zco? nn / Lznz / E / YiAi List of appointments Patent Literature [PTL1] WO2015 / 175632A1 [PTL 2] WO2015 / 025936A1 Non-Patent Literature [NPL 1] Nat. Rev. Cancer, vol. 6, pp. 803-812 (2006) [NPL 2] Nature Medicine, vol. 19, pp. 1389-1400 (2013) [NPL 3] Nat. Rev. Cancer, vol. 7, pp. 169-181 (2007) [NPL 4] Clin. Cancer Res., vol. 24, pp. 3097-3107 (2018) BRIEF DESCRIPTION OF THE INVENTION Technical Problem Treatments using EGFR inhibitors are being established for lung cancer patients with significant EGFR mutations. In contrast, patients resistant to osimertinib treatment are also known. Some of the reported causes of this resistance are mutations in the EGFR gene (NPL4).It has been confirmed that, for example, the lung cancer he has, in addition to the exon 19 deletion mutation or L858R mutation, both of which are de novo mutations, and the T790M mutation, which is an acquired resistance mutation, a point mutation in which the leucine encoded by codon 718 in exon 18 is replaced with an arbitrary amino acid (hereafter also referred to as the L718X mutation) or a point mutation in which the leucine encoded by codon 792 in exon 20 is replaced with an arbitrary amino acid (hereafter also referred to as the L792X mutation), is resistant to treatment with osimertinib. It is proposed that amino acid substitution caused by the L718X or L792X mutation induces steric hindrance and decreased hydrophobic binding, thereby preventing EGFR from binding to osimertinib (NPL 4).Therefore, there is a demand for the development of inhibitors with high inhibitory activity against EGFR with a composite mutation of active de novo mutation, zco? nn / Lznz / E / YiAi mutation acquired resistance of T790M and L718X mutation or L792X mutation. Therefore, it is assumed that the development of drugs with high inhibitory activity against EGFR with a compound mutation containing L718X or L792X makes it possible to exhibit antitumor effects against lung cancer that is resistant to osimertinib treatment, and is expected to contribute to prolonging the life and improving the quality of life of patients with EGFR-positive mutant cancer for whom no therapy has been established. Furthermore, it is expected that a drug with high inhibitory activity against T790M, which is an acquired resistance mutation against treatments using EGFR inhibitors, will reduce the frequency of acquired resistance expression during treatments using EGFR inhibitors against EGFR mutants in exon 19 or exon 21, which is a nova mutation, and is therefore expected to contribute to prolonging the life of cancer patients. Under these circumstances, an objective of the present invention is to provide an inhibitor having high inhibitory activity against the L718 and L792 mutant EGFR, which is a mutation resistant to osimertinib treatment, and for which the therapeutic effects of previously known EGFR inhibitors are insufficient. Solution to the problem The inventors of the present invention conducted extensive research and found that conventionally introduced EGFR inhibitors have poor inhibitory activity against the mutant EGFR compound containing L718 and L792 mutations, as well as the active mutation and the acquired resistance mutation of T790M. Furthermore, the inventors conducted extensive research based on the comparison of cocrystal structures of compounds and also found that the compound of the present invention exhibits excellent inhibitory activity against EGFR containing L718 and L792 mutations, and also exhibits excellent inhibitory activity against the aforementioned mutant EGFR compound. With this finding, the inventors have completed the present invention. The present invention encompasses the following modalities. Point 1. An antitumor agent for treating a patient with a malignant tumor expressing EGFR having at least one mutation selected from the group consisting of the L718X mutation in exon 18 and the L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue, the antitumor agent comprising (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9dihydropyramide[5,4-b]indolizin-8-1)acrylamide (Compound (A)) or a salt thereof. zco? nn / Lznz / E / YiAi Point 2. The antitumor agent according to Point 1, wherein EGFR also has at least one mutation selected from the group consisting of exon 19 deletion mutation, L858R, L861Q, G719X, E709X, and exon 20 insertion mutation. Point 3. The antitumor agent according to Point 2, where EGFR also has a T790M mutation. point 4. The antitumor agent according to any of Points 1 to 3, wherein the L718X mutation is the L718Q mutation. Point 5. The antitumor agent according to any of Points 1 to 4, wherein the L792X mutation is L792H, L792F, or L792Y. Point 6. A method for treating a malignant tumor patient, comprising the step of administering (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof to an EGFR-expressing malignant tumor patient having at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20. Point 7. (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyrimido[5,4-b]indolizin-8yl)acrylamide or a salt thereof for treating a patient with an EGFR-expressing malignant tumor having at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20. Point 8. Use of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof to treat a patient with an EGFR-expressing malignant tumor having at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20. zco? nn / Lznz / E / YiAi Point 9. Use of (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyrimido[5,4-b]indolizin-8-1)acrylamide or a salt thereof for the production of a pharmaceutical agent to treat a patient with an EGFR-expressing malignant tumor having at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20. Point 10. A pharmaceutical composition comprising (S)-N-(4-amino-6-methyl-5-(quinolin-31)-8,9-dihydropyrimido[5,4-b]indolizin-8-1)acrylamide or a salt thereof and a pharmaceutically acceptable carrier, for treating a patient with an EGFR-expressing malignant tumor having at least one mutation selected from the group consisting of an L718X mutation in exon 18 and an L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue. Item 11. A method for predicting the therapeutic effects of chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof in a patient with a malignant tumor, the method comprising steps (1) and (2) as set forth below: (1) a step for detecting the presence or absence of the EGFR gel mutation contained in a biological sample obtained from the patient; and (2) a step for predicting that chemotherapy is highly likely to show sufficient therapeutic effects with respect to the patient when the screening results in step (1) find that the EGFR gene has at least one mutation selected from the group consisting of the L718X mutation in exon 18 and the L792X mutation in exon 20, where X represents an arbitrary amino acid residue. Item 12. A method for treating a patient with a malignant tumor, comprising the steps (1) to (3) set out below: (1) a step to detect the presence or absence of the EGFR gel mutation contained in a biological sample obtained from the patient; (2) a step in predicting that chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyramide[5,4b]indolizin-8-1)acrylamide or a salt thereof is highly likely to show sufficient therapeutic effects with respect to the patient when the screening results in step (1) find that the EGFR gene has at least one mutation selected from the group consisting of the L718X mutation in exon 18 and the L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue;and (3) a step for administering (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof to a patient with a malignant tumor who has been predicted to have a high probability of responding sufficiently to chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof, in step (2).; Advantageous Effects of the Invention The antitumor agent of the present invention exerts high inhibitory activity against EGFR with L718 and L792 mutations. Therefore, the antitumor agent of the present invention is useful for providing an antitumor agent that exerts superior therapeutic effects for a patient with a malignant tumor expressing EGFR that has L718 and L792 mutations. The present invention is also useful in terms of providing a method for treating a patient with a malignant tumor expressing EGFR who has L718 and L792 mutations. The EGFR inhibitory activity of conventional EGFR inhibitors was significantly reduced in the presence of the T790M mutation, an acquired resistance mutation in the exon 20 region, or in the presence of the L718 and L792 mutations. Thus, it was difficult to achieve sufficient therapeutic effects. In contrast, the antitumor agent of the present invention has high inhibitory activity against EGFR with the L718 and / or L792 mutations, in addition to having an active mutation, such as the Exl9del or L858R mutation. Therefore, the antitumor agent of the present invention can exert superior therapeutic effects for a patient with a malignant tumor expressing EGFR with these complex mutations.The antitumor agent of the present invention has high inhibitory activity against EGFR having the L718 and / or L792 mutation, even though it has the T790M mutation in addition to the above mutations; thus, the antitumor agent of the present invention can exert superior therapeutic effects for a patient with a malignant tumor that expresses EGFR in a complex manner and that has these mutations. Furthermore, the antitumor agent of the present invention is also useful in terms of reducing the frequency of expression of acquired resistance during treatments using EGFR inhibitors against mutant EGFR in exon 19 or exon 21, which is a de novo mutation, due to its high inhibitory activity against treatment-resistant mutant EGFR in exon 18 and exon 20 even under the presence of the T790M mutation, which is an acquired resistance mutation in the exon 20 region. zco? nn / Lznz / E / YiAi BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the results of the phosphorylation (inhibitory activity) assessment in a forced expression system of mutant EGFR using HEK293 cells. DETAILED DESCRIPTION OF THE MODALITIES The preferred examples of the various definitions within the scope of the present invention used in this specification are explained in detail below. In this specification, EGFR refers to a human epidermal growth factor receptor protein and also refers to ErbB-1 or HERI. In this specification, wild-type EGFR refers to a somatic mutation-free EGFR, which is a protein comprising the amino acid sequence represented by SEQ ID NO: 1 (Genbank accession number: NP_005219.2). In this specification, exon 18 refers to region 688-728 in the amino acid sequence of wild-type EGFR (SEQ ID NO: 1).In this specification, treatment-resistant mutation in exon 18 refers to a point mutation or deletion mutation in the amino acid in the exon 18 region of wild-type EGFR (SEQ ID NO: 1). The preferred treatment-resistant mutation in exon 18 is a point mutation with a 1-amino-acid substitution in the exon 18 region. More preferably, the treatment-resistant mutation in exon 18 is L718X (X representing, among the amino acids that constitute a genetically encoded protein, an arbitrary amino acid residue other than leucine), which is a point mutation in which the leucine encoded by codon 718 of exon 18 is substituted with an arbitrary amino acid.More specifically, preferred examples of L718X include L718Q, which is a point mutation where the leucine encoded by codon 718 in the exon 18 region is substituted with glutamine; and L718V, which is a point mutation where the leucine encoded by codon 718 is substituted with valine. In this specification, active mutation in exon 18 refers to a point mutation or deletion mutation in the amino acid in the exon 18 region of wild-type EGFR (SEQ ID NO: 1). The preferred active mutation in exon 18 is a point mutation with a 1-amino-acid substitution in the exon 18 region. More preferably, the active mutation in exon 18 is either E709X, which is a point mutation in which the glutamic acid encoded by codon 709 of exon 18 is substituted with an arbitrary amino acid; or G719X, which is a point mutation in which the glycine encoded by codon 719 of exon 18 is substituted with an arbitrary amino acid.More specifically, preferred examples of E709X include E709K, which is a point mutation where the glutamic acid encoded by codon 709 in the exon 18 region is replaced with lysine; and E709A, which is a point mutation where the glutamic acid encoded by codon 709 in the exon 18 region is replaced with alanine. Preferred examples of G719X include G719A, which is a point mutation where the glycine encoded by codon 719 in the exon 18 region is replaced with alanine; and G719S, which is a point mutation where the glycine encoded by codon 719 in the exon 18 region is replaced with serine. and G719C, which is a point mutation where the glycine encoded by codon 719 in the exon 18 region is replaced with cysteine. In the present invention, exon 20 refers to region 824-875 in the amino acid sequence of wild-type EGFR (SEQ ID NO: 1). In this specification, treatment-resistant mutation in exon 20 refers to a point mutation in the amino acid in the exon 20 region of wild-type EGFR (SEQ ID NO: 1). The preferred treatment-resistant mutation in exon 20 is a point mutation with a substitution of one amino acid in the exon 20 region. More preferably, the treatment-resistant mutation in exon 20 is L792X (X represents, among the amino acids that constitute a protein encoded by genetic information, an arbitrary amino acid residue other than leucine), which is a point mutation in which the leucine encoded by codon 792 in the exon 20 region is substituted with an arbitrary amino acid.Specific examples include L792H, a point mutation in which the leucine encoded by codon 792 in exon 20 is replaced with histidine; L792F, a point mutation in which the leucine encoded by codon 792 is replaced with phenylalanine; L792Y, a point mutation in which the leucine encoded by codon 792 is replaced with tyrosine; L792R, a point mutation in which the leucine encoded by codon 792 is replaced with arginine; L792V, a point mutation in which the leucine encoded by codon 792 is replaced with valine; and L792P, a point mutation in which the leucine encoded by codon 792 is replaced with proline. Among these, L792F, L792H, and L792Y are preferred. In this specification, exon 20 insertion mutation refers to mutation with insertion of one or more (preferably 1 to 7, more preferably 1 to 4) amino acids in the exon 20 region of EGFR (sequence of 761 to 823 amino acids in SEQ ID NO: 1). Preferred examples include mutation with insertion of the amino acid sequence FQEA (phenylalanine, glutamine, glutamic acid and alanine sequentially from the N-terminal side) between 763 alanine and 764 tyrosine in the exon 20 region (A763_Y764insFQEA), mutation with insertion of the amino acid sequence ASV (alanine, serine and valine sequentially from the N-terminal side) between 769 valine and 770 asparagic acid in the exon 20 region (V769_D770insASV), mutation with insertion of the amino acid sequence SVD (serine, valine and asparagic acid sequentially from the N-terminal side) between 770 asparagic acid and 771 asparagine in the exon 20 region (D770_N771insSVD),mutation with insertion of the amino acid sequence NPG (asparagine, proline and glycine sequentially from the N-terminal side) between 770 asparagic acid and 771 asparagine in the exon 20 region (D770_N771insNPG), mutation with insertion of the amino acid G (glycine) between 770 asparagic acid and 771 asparagine in the exon 20 region (D770_N771insG), mutation with insertion of the amino acid sequence GY (glycine and tyrosine sequentially from the N-terminal side) after deletion of 770 asparagic acid in the exon 20 region (D770>GY), mutation with insertion of the amino acid N (asparagine) between 771 asparagine and 772 proline in the exon 20 region (N771_P772insN), mutation with insertion of the amino acid sequence PR (proline and arginine sequentially from the N-terminal side) between 772 proline and 773 histidine in the region of exon 20 (P772_R773insPR), mutation with insertion of the amino acid sequence NPH (asparagine,proline and histidine sequentially from the N-terminal side) between 773 histidine and 774 valine in the exon 20 region (H773_V774insNPH), mutation with insertion of the amino acid sequence PH (proline and histidine sequentially from the N-terminal side) between 773 histidine and 774 valine in the exon 20 region (H773_V774insPH), mutation with insertion of the amino acid sequence AH (alanine and histidine sequentially from the N-terminal side) between 773 histidine and 774 valine in the exon 20 region (H773_V774insAH), mutation with insertion of the amino acid H (histidine) between 773 histidine and 774 valine in the exon 20 region (H773_V774insH), mutation with insertion of the amino acid sequence HV (histidine and valine sequentially from the N-terminal side) between 774 valine and 775 cysteine ​​in the region of exon 20 (V774_C774insHV), mutation with insertion of the amino acid sequence EAFQ (glutamic acid, alanine,phenylalanine and glutamine sequentially from the N-terminal side) between 761 alanine and 762 glutamic acid in the exon 20 region (A761_E762insEAFQ), and similar. Preferred examples include the mutation with the insertion of the amino acid sequence ASV (alanine, serine, and valine sequentially from the N-terminal side) between 769 valine and 770 asparagic acid in the exon 20 region (V769_D770insASV), the mutation with the insertion of the amino acid sequence SVD (serine, valine, and asparagic acid sequentially from the N-terminal side) between 770 asparagic acid and 771 asparagine in the exon 20 region (D770_N771insSVD), the mutation with the insertion of the amino acid G (glycine) between 770 asparagic acid and 771 asparagine in the exon 20 region (D770_N771insG), and the mutation with the insertion of the amino acid sequence NPH (asparagine, proline, and histidine sequentially from the N-terminal side) between 773 histidine. and 774 valine in the exon 20 region (H773_V774insNPH),and a mutation with the insertion of the amino acid sequence PH (proline and histidine sequentially from the N-terminal side) between 773 histidine and 774 valine in the exon 20 region (H773_V774insPH). Particularly preferable examples include a mutation with the insertion of the amino acid sequence FQEA (phenylalanine, glutamine, glutamic acid, and alanine sequentially from the N-terminal side) between 763 alanine and 764 tyrosine in the exon 20 region (A763_Y764insFQEA), and a mutation with the insertion of the amino acid sequence ASV (alanine, serine, and valine sequentially from the N-terminal side) between 769 valine and 770 asparagic acid in the zco region. nn / Lznz / E / YiAi of exon 20 (V769_D770insASV), mutation with insertion of the SVD amino acid sequence (serine, valine and asparagic acid sequentially from the N-terminal side) between 770 asparagic acid and 771 asparagine in the region of exon 20 (D770_N771insSVD),mutation with insertion of the amino acid G (glycine) between 770 asparagic acid and 771 asparagine in the region of exon 20 (D770_N771insG), mutation with insertion of the amino acid sequence NPH (asparagine, proline and histidine sequentially from the N-terminal side) between 773 histidine and 774 valine in the region of exon 20 (H773_V774inchsNPH), mutation with insertion of the amino acid sequence PH (proline and histidine sequentially from the N-terminal side) between 773 histidine and 774 valine in the region of exon 20 (H773_V774insPH), and similar mutations. In the present invention, exon 21 refers to region 824-875 in the amino acid sequence of wild-type EGFR (SEQ ID NO: 1). In this specification, active mutation in exon 21 refers to a point mutation in the amino acid in the exon 21 region of wild-type EGFR (SEQ ID NO: 1). The preferred active mutation in exon 21 is a point mutation with a 1-amino-acid substitution in the exon 21 region. More preferably, the active mutation in exon 21 is either L858X, which is a point mutation in which the leucine encoded by codon 858 in the exon 21 region is substituted with an arbitrary amino acid; or L861X, which is a point mutation in which the leucine encoded by codon 861 in the exon 21 region is substituted with an arbitrary amino acid (X represents, from among the amino acids that constitute a genetically encoded protein, an arbitrary amino acid residue other than leucine).More specifically, preferred examples include L858R, which is a point mutation where the leucine encoded by codon 858 in the exon 21 region is mutated with arginine; and L861Q, which is a point mutation where the leucine encoded by codon 861 in the exon 21 region is substituted with glutamine. In the present invention, treatment-resistant mutation in exon 18 and / or exon 20 encompasses treatment-resistant mutation in exon 18, treatment-resistant mutation in exon 20, and treatment-resistant mutation in exon 18 and exon 20. In the present invention, a point mutation refers to a mutation that results in the substitution, insertion, or deletion of one or more (for example, approximately 1 to 10, preferably approximately 1 to 5, more preferably approximately 1, 2, or 3) amino acid residues; and may include insertion and / or deletion mutations in nucleic acid frames. EGFR with a treatment-resistant mutation in exon 18 and / or exon 20 encompasses EGFR with a treatment-resistant mutation in exon 18, EGFR with a treatment-resistant mutation in exon 20, and EGFR with a treatment-resistant mutation in exon 18 and exon 20. 21. In this specification, EGFR with a treatment-resistant mutation in exon 18 refers to EGFR that has at least the above L718X mutation in exon 18 as the treatment-resistant mutation in exon 18. EGFR may also have a mutation in exon 18 other than L718X, but preferably has only one L718X mutation as the treatment-resistant mutation in exon 18. In addition, EGFR may have a mutation other than the treatment-resistant mutation in exon 18 (e.g., deletion mutation in exon 19, L858R mutation, and L790M mutation). In this specification, EGFR with a treatment-resistant mutation in exon 20 refers to EGFR that has at least the above L792X mutation in exon 20 as the treatment-resistant mutation in exon 20. EGFR may have a mutation other than the L792X mutation, but preferably has a single L718X mutation as the treatment-resistant mutation in exon 20. In addition, EGFR may have a mutation other than the treatment-resistant mutation in exon 20 (e.g., deletion mutation in exon 19, L858R mutation, and L790M mutation). In this specification, exon 19 refers to region 729-823 in the amino acid sequence of wild-type EGFR (SEQ ID NO: 1). In this specification, exon 19 deletion mutation refers to a mutation involving the deletion of one or more amino acids in the exon 19 region of wild-type EGFR (SEQ ID NO: 1). In addition to deletion in this region, mutation involving the insertion of one or more arbitrary amino acids is also included. Examples of deletion mutation in exon 19 include mutation with deletion of 5 amino acids from 746 glutamic acid to 750 alanine in the exon 19 region (Del E746-A750), mutation with serine insertion after deletion of 7 amino acids from 747 leucine to 753 proline in the exon 19 region (Del 747-P753insS), mutation with deletion of 5 amino acids from 747 leucine to 751 threonine in the exon 19 region (Del L747-T751), mutation with proline insertion after deletion of 4 amino acids from 747 leucine to 750 alanine in the exon 19 region (Del 747-A750insP), and the like.Preferred examples include mutation with deletion of 5 amino acids from 746 glutamic acid to 750 alanine in the exon 19 region (Del E746-A750). Furthermore, EGFR with a treatment-resistant mutation in exon 18 and / or exon 20 may also have at least one mutation selected from the group consisting of the exon 19 deletion mutation, L858R, L861Q, G719X, E709X, and exon 20 insertion mutation. Specific examples include EGFR with the L718X mutation in the exon 18 region that also has a deletion mutation in exon 19, EGFR with the L792X mutation in the exon 20 region that also has a deletion mutation in exon 19, EGFR with the L718X mutation in the exon 18 region that also has L858R, EGFR with the L792X mutation in the exon 20 region that also has L858R, and EGFR with the L718X mutation. in the region of exon zco? nn / Lznz / E / YiAi which also has L861Q, EGFR which has the L792X mutation in the region of exon 20 which also has L861Q, EGFR which has the L718X mutation in the region of exon 18 which also has G719X,EGFR with the L792X mutation in the exon 20 region that also has G719X, EGFR with the L718X mutation in the exon 18 region that also has E709X, EGFR with the L792X mutation in the exon 20 region that also has E709X, EGFR with the L718X mutation in the exon 18 region that also has an insertion mutation in exon 20, and EGFR with the L792X mutation in the exon 20 region that also has an insertion mutation in exon 20. Among these, the preferred ones are EGFR with the L718X mutation in the exon 18 region that also has a deletion mutation in exon 19, and EGFR with the L792X mutation in the exon 20 region that also has a deletion mutation in exon 19. 19, EGFR having the L718X mutation in the exon 18 region that also has L858R, and EGFR having the L792X mutation in the exon 20 region that also has L858R., Furthermore, EGFR receptors with the treatment-resistant mutation in exon 18 and / or exon 20 may also carry the T790M mutation, in addition to the deletion mutation in exon 19, L858R, L861Q, G719X, E709X, and the insertion mutation in exon 20. T790M is an acquired resistance mutation in the exon 20 region. It is known that T790M is induced by the use of existing EGFR inhibitors. Acquisition of T790M frequently reduces the effectiveness of existing drugs in patients with malignant tumors. In the present invention, examples include EGFR having the L718X mutation in the exon 18 region having a deletion mutation in exon 19 and further having the T790M mutation, EGFR having the L792X mutation in the exon 20 region having a deletion mutation in exon 19 and further having the T790M mutation, EGFR having the L718X mutation in the exon 18 region having L858R and further having the T790M mutation, EGFR having the L792X mutation in the exon 20 region having L858R and further having the T790M mutation, EGFR having the L718X mutation in the exon 18 region having L861Q and further having the T790M mutation, EGFR having the L792X mutation in the exon region 20 which has L861Q which also has the T790M mutation, EGFR which has the L718X mutation in the region of exon 18 which has G719X which also has the T790M mutation, EGFR which has the L792X mutation in the region of exon 20 which has G719X which also has the T790M mutation,EGFR with an L718X mutation in the exon 18 region containing E709X and also a T790M mutation; EGFR with an L792X mutation in the exon 20 region containing E709X and also a T790M mutation; EGFR with an L718X mutation in the exon 18 region containing an insertion mutation in exon 20 and also a T790M mutation; and EGFR with an L792X mutation in the exon 20 region containing an insertion mutation in exon 20 and also a T790M mutation. Which of these is preferable: EGFR with an L718X mutation in the exon 18 region containing a deletion mutation in exon 19? nn / Lznz / E / YiAi which also has a T790M mutation, EGFR which has an L792X mutation in the exon 20 region which has a deletion mutation in exon 19 which also has a T790M mutation, EGFR which has an L718X mutation in the exon 18 region which has L858R which also has a T790M mutation,and EGFR which has an L792X mutation in the exon 20 region which has L858R which also has a T790M mutation. Among the EGFRs that have the above composite mutations, EGFRs that have the L718Q mutation in the exon 18 region, EGFRs that have the L792F mutation in the exon 20 region, EGFRs that have the L792H mutation, and EGFRs that have the L792Y mutation are particularly preferable. In the present invention, the method for detecting mutations in the EGFR expressed by a patient with a malignant tumor is not particularly limited in the extent to which the method is capable of detecting the mutations, and any known detection method may be used. The sample used for EGFR mutation detection is not specifically limited, provided it is a biological sample isolated from a patient with a malignant tumor, specifically a sample obtained from a patient with a malignant tumor and containing malignant tumor cells. Examples of biological samples include body fluids (e.g., blood, urine, etc.), tissues, their extracts, and tissue cultures. The method for obtaining a biological sample can be appropriately selected depending on the type of biological sample. The biological sample is prepared by appropriate treatment according to the measurement method. Furthermore, the reagent, comprising an initiator or probe used for detection, can be prepared using a conventional method in accordance with the measurement method. In one embodiment of the present invention, a step for detecting the presence of the mutation of the present invention in the EGFR expressed by a malignant tumor patient can be performed before the administration of an antitumor agent to the malignant tumor patient. A malignant tumor can include two or more different types of malignant tumor cells. Furthermore, two or more malignant tumors can arise in a single patient. Therefore, a single patient can have different EGFR mutations (for example, the mutation in exon 18 is L718Q and L718V; and the mutation in exon 20 is L792F, L792H, L792Y, L792R, L792V, and the mutation in exon 20 is L792P; however, there is no limit to this) at the same time. The antitumor agent of the present invention comprises, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyrimido[5,4-b]indolizin-8-1)acrylamide (Compound (A)) or a salt thereof. Compound (A) is represented by the following chemical formula. [Chem. 1] nh2 A / f W / HN-^^ EITHER The method for producing the compound of the present invention is explained below. Compound A of the present invention can be produced, for example, by the production method described in WO2015 / 025936A1, the methods described in the Examples, and similar methods. However, the production method of the compound of the present invention is not limited to these reaction examples. When compound A of the present invention has isomers such as optical isomers, stereoisomers, and tautomers, any of the isomers and mixtures thereof are included within the scope of the compound of the present invention, unless otherwise specified. For example, when the compound of the present invention has optical isomers, racemic mixtures and optical isomers separated from a racemic mixture are also included within the scope of the compound of the present invention, unless otherwise specified. Salts of compound A refer to any of the pharmaceutically acceptable salts; examples include base addition salts and acid addition salts. Examples of base addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N'-dibenzylethylenediamine salts. Examples of acid addition salts include salts of inorganic acids such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates; salts of organic acids such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates, and trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluenesulfonates. The compound of the present invention or salts thereof also encompass prodrugs thereof. A prodrug refers to a compound that can be converted into the compound of the present invention or a salt thereof through a reaction with an enzyme, gastric acid, or the like, under physiological conditions in vivo; that is, a compound that can be converted into the compound of the present invention or a salt thereof by oxidation, reduction, enzymatic hydrolysis, or the like; or a compound that can be converted into the compound of the present invention or a salt thereof by hydrolysis or the like with gastric acid or the like. Furthermore, the prodrug may be a compound that can be converted into the compound of the present invention or a salt thereof under physiological conditions, such as those described in [Development of Pharmaceuticals], Vol. 7, Molecular Design, published in 1990 by Hirokawa Shoten Co., pp.163-198. Description of the diseases Specific examples of tumors targeted by the present invention include, but are not particularly limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer and rectal cancer), etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, malignant lymphoma, and multiple myeloma), osteosarcoma, soft tissue sarcoma, skin cancer, brain tumor, and the like.Preferred examples include lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, gastrointestinal cancer, hematopoietic tumor, and skin cancer. Lung cancer is particularly preferred. When the compound of the present invention, or a salt thereof, is used as a pharmaceutical agent, a pharmaceutical carrier may be added, if necessary, thereby forming a suitable dosage form for the purposes of prevention and treatment. Examples of dosage forms include oral preparations, injections, suppositories, ointments, patches, and the like. Oral preparations are preferred. Such dosage forms may be formed by methods conventionally known to persons skilled in the art. As a pharmaceutically acceptable carrier, various conventional organic or inorganic carrier materials used as preparation materials can be blended as an excipient, binder, disintegrant, lubricant, or colorant in solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonic agent, pH regulator, or soothing agent in liquid preparations. Furthermore, pharmaceutical preparation additives, such as antiseptics, antioxidants, colorants, sweeteners, and stabilizers, may also be used, if required. Solid oral preparations are prepared as follows. After an excipient, such as a binder, disintegrant, lubricant, colorant, flavor masking agent, or flavoring, is optionally added to the compound of the present invention, the resulting mixture is formulated into tablets, coated tablets, granules, powders, capsules, or the like by ordinary methods. Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicon dioxide. Examples of binders include water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid α-starch, liquid gelatin, D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, and the like. Examples of disintegrants include dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and the like. Examples of lubricants include purified talc, sodium stearate, magnesium stearate, borax, polyethylene glycol, and the like. Examples of colorants include titanium oxide, iron oxide, and the like.Examples of flavor masking agents and flavoring agents include sucrose, bitter orange peel, citric acid, tartaric acid, and the like. When preparing a liquid preparation for oral administration, a flavor masking agent, a pH regulator, a stabilizer, a flavoring agent, and the like may be added to the compound of the present invention; and the resulting mixture may be formulated into an oral liquid preparation, syrup, elixir, etc., according to an ordinary method. When preparing an injection agent, a pH regulator, a stabilizer, an isotonic agent, a local anesthetic, and the like may be added to the compound of the present invention; and the mixture may be formulated for subcutaneous, intramuscular, or intravenous injections according to an ordinary method. Examples of pH adjusters and pH regulators used herein include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium pyrosulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride, glucose, D-mannitol, and glycerol. When preparing a suppository, pharmaceutically acceptable carriers known in the related field, such as polyethylene glycol, lanolin, cocoa butter, and fatty acid triglycerides; and, as required, surfactants such as Tween 80 (registered trademark) may be added to Compound A, and the resulting mixture may be formulated into a suppository according to an ordinary method. When preparing an ointment, a commonly used base, stabilizer, wetting agent, preservative, and the like may be mixed into compound A, as required; and the resulting mixture is blended and formulated into an ointment according to an ordinary method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyl dodecyl alcohol, and paraffin. Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate. When preparing a patch, the aforementioned ointment, cream, gel, paste, or similar, can be applied to an ordinary substrate according to an ordinary method. Examples of substrates include woven or non-woven fabrics comprising cotton, staple fibers, or chemical fibers; and films or sheets of soft vinyl chloride foam, polyethylene, polyurethane, etc., can also be used. The amount of compound A to be incorporated into each of these unit-dose forms depends on the patient's condition, the dosage form, and other factors. Generally, for an oral agent, the amount of compound is preferably 0.05 to 1000 mg per unit-dose form. For an injection, the amount of compound is preferably 0.01 to 500 mg per unit-dose form; and for a suppository, the amount of compound is preferably 1 to 1000 mg per unit-dose form. Furthermore, the daily dose of the medicine in this dosage form depends on the patient's condition, body weight, age, sex, etc., and cannot be generalized. Generally, the daily dose for an adult (body weight: 50 kg) of the compound of the present invention can be 0.05 to 5000 mg, and preferably 0.1 to 1000 mg; and is preferably administered in one dose, or in two or three divided doses, per day. The present invention also provides a method for treating a malignant tumor patient, comprising the step of administering compound A or a salt thereof to a malignant tumor patient expressing EGFR that has a treatment-resistant mutation in exon 18 and / or exon 20. The present invention also provides compound A or a salt thereof for treating a patient with a malignant tumor expressing EGFR who has a treatment-resistant mutation in exon 18 and / or exon 20. The present invention also provides for the use of compound A or a salt thereof to treat a patient with a malignant tumor expressing EGFR that has a treatment-resistant mutation in exon 18 and / or exon 20. The present invention also provides for the use of compound A or a salt thereof for the production of a pharmaceutical agent to treat a patient with a malignant tumor expressing EGFR that has a treatment-resistant mutation in exon 18 and / or exon 20. The present invention also provides a method for predicting the therapeutic effects of chemotherapy using an antitumor agent comprising, as an active ingredient, compound A or a salt thereof in a patient with a malignant tumor, the method comprising steps (1) and (2) as set forth below: (1) a step to detect the presence or absence of the EGFR gel mutation contained in a biological sample obtained from the patient; and (2) a step to predict that chemotherapy is highly likely to show sufficient therapeutic effects for the patient when the screening results in step (1) find that the EGFR gene has a treatment-resistant mutation in exon 18 and / or exon 20. The present invention also provides a method for treating a patient with a malignant tumor, comprising steps (1) to (3) as set forth below: (1) a step for detecting the presence or absence of the EGFR gel mutation contained in a biological sample obtained from the patient; and (2) a step for predicting that chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4b]indolizin-8-yl)acrylamide or a salt thereof is highly likely to show sufficient therapeutic effects with respect to the patient when the screening results in step (1) find that the EGFR gene has a treatment-resistant mutation in exon 18 and / or exon 20;and (3) a step for administering (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof to a patient with a malignant tumor who has been predicted to have a high probability of responding sufficiently to chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof, in step (2).; The base sequence of the EGFR gene is publicly known. The GenBank accession number for the base sequence of a cDNA is NM_005228.4. Therapeutic effects can be assessed by tumor shrinkage, relapse suppression, life prolongation, and similar measures. Relapse suppression can be shown as the degree of extension of the relapse-free period or the degree of improvement in the relapse rate; and life prolongation can be shown as the degree of overall survival or the degree of extension of median progress-free survival, or similar measures.Sufficient therapeutic effects of chemotherapy using an antitumor agent comprising, as an active ingredient, compound A or a salt thereof means, for example, that superior therapeutic effects are obtained by administering the antitumor agent comprising, as an active ingredient, compound A or a salt thereof, such as extension of survival time, suppression of relapses, and the like, compared to non-administration. EXAMPLES The present invention is described in more detail below with reference to the following Test Example. However, the present invention is not limited to this Example (Test Example). TEST EXAMPLE 1 In vitro drug efficacy test Results of evaluation of intracellular phosphorylation in the forced expression system of the mutant EGFR using HEK293 cells (inhibitory activity) The inhibitory activity of the compounds against the intracellular target was assessed based on the following as an index: intracellular phosphorylation of EGFR in a forced expression system of mutant EGFR using HEK293 Jump-In Grip cells (Thermo Fisher Scientific Inc.) (hereafter also referred to as HEK293 cells). The HEK293 cells were maintained in D-MEM with GlutaMAX (high glucose) (Thermo Fisher Scientific Inc.) containing 10% dialyzed FBS. The HEK293 cells were seeded in each well of a 96-well flat-bottom microplate so that the cell count per well was 10,000, and incubated in an incubator containing 5% CO2 gas at 37°C overnight. Then, a pcDNA™ 6 vector was used.2 / V5-DEST encoding a human EGFR gene (Del E746-A750 (hereafter also referred to as Exl9del), Exl9del+T790M (the symbol + indicates that both mutations are contained), Exl9del+T790M+L718Q, Exl9del+T790M+L792H, Exl9del+T790M+L792F, Exl9del+T790M+L792Y, L858R, L858R+T790M, L858R+T790M+L718Q, L858R+T790M+L792H, L858R+T790M+L792F, or L858R+T790M+L792Y) was introduced, along with Opti-MEM (trademark) I (Thermo Fisher Scientific Inc.), using a ViaFect transfection reagent (trademark) (Promega Corporation). The cells were re-incubated in an incubator containing 5% CO2 gas at 37°C overnight. The following day, compound A, erlotinib, afatinib, and osimertinib (erlotinib, afatinib, and osimertinib may each be referred to hereafter as a comparative compound) were individually dissolved in DMSO, and diluted with DMSO or a medium.The solutions were then added individually to each well of the cell culture plate, and the cells were incubated in an incubator containing 5% CO2 gas at 37°C for 6 hours. After incubation, the cells were immobilized using 20% ​​pH-neutral formalin (Wako Puré Chemical Industries, Ltd.) and blocked with Odyssey Blocking pH Regulator (PBS) (M&S TechnoSystems Inc.). The cells were then reacted with a primary antibody (EGFR Antibody Cocktail #AHR5062 (Thermo Fisher Scientific Inc.) and PhosphoEGFR Receptor Antibody (Tyrl068) #2234L (CST)) diluted with Odyssey Blocking pH Regulator (PBS) at 1 / 200, and the cells were allowed to stand overnight at 4°C. The next day, the cells were reacted with a secondary antibody (IRDye 800CW Goat aRabbit #926-32211 and IRDye 680RD Goat aMouse #926-68070 (M&S TechnoSystems Inc.The solution was diluted with Odyssey blocking pH regulator (PBS) at 1 / 800, and the cells were allowed to stand at room temperature for 1 hour. Fluorescence intensity (hereafter also referred to as FI) was detected using an Odyssey CLx infrared imaging system (LI-COR Bioscience) at fluorescence wavelengths of 800 nm and 700 nm. The value obtained by subtracting the IF of a well without the primary antibody from the IF detected at a fluorescence wavelength of 800 nm or 700 nm is referred to as IF(800, EGFR)-Blank (for 800 nm) and IF(700, p-EGFR)-Blank (for 700 nm). The value obtained by dividing the IF(700, p-EGFR)-Blank of each well by the IF(800, EGFR)-Blank was determined to be IF(pEGFR / EGFR). The rate of EGFR phosphorylation was calculated using the following formula to determine the concentration of the test compounds where EGFR was 50% phosphorylated (IC50 (μM)). Table 1 illustrates the results. Phosphorylated EGFR Rate (%) = T / C x 100 T: FI (p-EGFR / EGFR) of a well to which a test compound was added. C: FI (p-EGFR / EGFR) from a well to which no test compound was added. As is clear from Table 1, compound A exhibited high inhibitory activity against intracellular phosphorylation of the mutant EGFR compound containing L718Q and L792X; and the activity was higher than that of erlotinib, afatinib, and osimertinib. zco? nn / Lznz / E / YiAi zco? nn / Lznz / Ε / γΐΛΐ TABLE 1 Compound A of the present invention Osimertinib Afatinib Erlotinib Exl 9del 11.2±6.4 52 .1±23. 6 18.5±10.2 201±6 Exl9del+T790M 16.9±5.9 69.7±15.6 250±64 >1000 Exl9del+T790M+L71 82.5±9.0 5800±2940 >10000 >10000 Exl9del+T790M+L79 11.1±5.6 513±280 8190±560 >10000 Exl9del+T790M+L79 6. 25±1. 83 65.7±15.5 692±325 >10000 Exl9del+T790M+L79 6. 54±1.49 111±38 508±218 >10000 L858R 13.8±3.8 53.3±11.0 17.9±3.0 167±22 L858R+T790M 16.0±2.6 59.0±10.9 162±38 >1000 L858R+T790M+L718Q 104±40 7880±950 3670±1690 >10000 LB 58R+T7 9 OM+L7 92 H 15.3±5.0 441±161 2190±1310 >10000 L858R+T790M+L792F 9.07±4.74 124±40 538±274 >10000 L858R+T7 90M+L7 92Y 11.3±5.8 273±72 512±269 >10000 NOVELTY OF THE INVENTION

Claims

1. An antitumor agent for treating a patient with a malignant tumor expressing EGFR having at least one mutation selected from the group consisting of the L718X mutation in exon 18 and the L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue, the antitumor agent comprising (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (A)) or a salt thereof.

2. The antitumor agent according to claim 1, further characterized in that the EGFR further has at least one mutation selected from the group consisting of exon 19 deletion mutation, L858R, L861Q, G719X, E709X, and exon 20 insertion mutation.

3. The antitumor agent according to claim 2, further characterized in that the EGFR also has a T790M mutation.

4. The antitumor agent according to any of claims 1 to 3, further characterized in that the L718X mutation is an L718Q mutation.

5. The antitumor agent according to any of claims 1 to 4, further characterized in that the L792X mutation is L792H, L792F, or L792Y.

6. A method for treating a malignant tumor patient, comprising the step of administering (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof to an EGFR-expressing malignant tumor patient having at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20. 7.- (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyrimide[5,4-b]indolizin-8-1)acrylamide or a salt thereof for treating a patient with a malignant tumor expressing EGFR who has at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20. 8.- The use of (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyrimido[5,4b]indolizin-8-1)acrylamide or a salt thereof to treat a patient with a malignant tumor expressing EGFR who has at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20.

9. The use of (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyramide[5,4b]indolizin-8-1)acrylamide or a salt thereof for the production of a pharmaceutical agent to treat a patient with a malignant tumor expressing EGFR who has at least one zco?nn / Lznz / E / YiAi mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20.

10. A pharmaceutical composition comprising (S)-N-(4-amino-6-methyl-5(quinolin-3-yl)-8,9-dihydropneumo[5,4-b]indolizin-8-yl)acrylamide or a salt thereof and a pharmaceutically acceptable carrier, for treating a patient with a malignant tumor expressing EGFR having at least one mutation selected from the group consisting of L718X mutation in exon 18 and L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue.

11. A method for predicting the therapeutic effects of chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)8,9-dihydropyramide[5,4-b]indolizin-8-l)acrylamide or a salt thereof in a patient with a malignant tumor, the method comprising steps (1) and (2) as follows: (1) a step for detecting the presence or absence of the EGFR gel mutation contained in a biological sample obtained from the patient; and (2) a step to predict that chemotherapy is highly likely to show sufficient therapeutic effects with respect to the patient when the screening results in step (1) find that the EGFR gene has at least one mutation selected from the group consisting of the L718X mutation in exon 18 and the L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue.

12. A method for treating a patient with a malignant tumor, comprising the following steps (1) to (3): (1) a step for detecting the presence or absence of the EGFR gel mutation contained in a biological sample obtained from the patient; (2) a step for predicting that chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolyzin-8-yl)acrylamide or a salt thereof is highly likely to show sufficient therapeutic effects with respect to the patient when the screening results in step (1) find that the EGFR gene has at least one mutation selected from the group consisting of the L718X mutation in exon 18 and the L792X mutation in exon 20, wherein X represents an arbitrary amino acid residue;and (3) a step for administering (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a salt thereof to a patient with a malignant tumor who has been predicted to have a high probability of responding sufficiently to chemotherapy using an antitumor agent comprising, as an active ingredient, (S)-N-(4-amino-6-methyl-5-(quinolin-3-1)-8,9-dihydropyrimido[5,4b]indolizin-8-1)acrylamide or a salt thereof, in step (2).;