中部乳癌最終版

Transcription

1 第 14 回 本乳癌学会中部地 会教育講演 1 固形癌薬物療法の潮流と乳癌の課題 昭和 学医学部内科学講座腫瘍内科学部 昭和 学腫瘍分 物学研究所 飯 市 病院腫瘍内科 佐々 康綱 2017 年 9 9 飯 市

2 Chronological Order of 41 NMEs Approved by the FDA to Treat Cancer Indications ( ) Cancer Chemother Pharmacol (2016) 77:

3 Development of Oncology Drugs Category Breast Gastric CRC NSCLC Ovary Melanoma Chemotherapy Hormonetherapy Enhancer Targeted: Antibody Anthracyclines Taxanes Fluorpyrimidines Cyclophosphamide Eribulin Gemcitabin Vinorelbine Everolimus Palbociclib Trastuzumab Pertuzumab Bevacizumab T-DM1 Fluoropyrimidines Platinum Taxanes Anthracyclines Trastuzumab Ramucirumab Fluorpyrimidines Oxaliplatin Irinotecan Trifluridine/ tipiracil Bevacizumab Cetuximab/ Panitumumab Ramucirumab Platinum Taxanes Fluoropyrimidines Irinotecan Pemetrexed Gemcitabine Vinorelbine Bevacizumab Ramucirumab Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib Afatinib Osimeritinib Crizotinib/Alectinib Targeted: PARP-I Immunooncology Olaparib Nivolumab/ Pembrolizumab Nivolumab/ Pembrolizumab Platinum Taxanes Camptothecins Liposomal-Dox Gemcitabine Bevacizumab Olaparib Rucaparib Niraparib Dacarbazine Vemurafenib Ipirimumab Nivolumab/ Pembrolizumab

4 抗悪性腫瘍薬の開発 : この 10 年間の動き 薬剤開発の潮流 n 従来からの化学療法薬の開発が鈍化 n 分 標的薬の台頭 分 製剤 抗体薬 n 免疫チエックポイント阻害薬の登場 開発の戦略と実地医療の課題 n ICH の原則に基づいた世界共同開発 n 第 3 相試験による全 存期間の延 n バイオマーカーの同定に基づいた対象患者の絞り込み n バイオマーカーを利 した薬剤耐性の克服 n 多彩な有害事象に対する対策 n 費 対効果に対する問題意識

5 Clinical Endpoints Used in Cancer Trials Michelle K Wilson, Lancet Oncology 2015

6 Development of Oncology Drugs Category Breast Gastric CRC NSCLC Ovary Melanoma Chemotherapy Hormonetherapy enhancer Targeted: Antibody Anthracyclines Taxanes Fluorpyrimidines Cyclophosphamide Eribulin Gemcitabin Vinorelbine Everolimus Palbociclib Trastuzumab Pertuzumab Bevacizumab T-DM1 Fluoropyrimidines Platinum Taxanes Anthracyclines Trastuzumab Ramucirumab Fluorpyrimidines Oxaliplatin Irinotecan Trifluridine/ tipiracil Bevacizumab Cetuximab/ Panitumumab Ramucirumab Platinum Taxanes Fluoropyrimidines Irinotecan Pemetrexed Gemcitabine Vinorelbine Bevacizumab Ramucirumab Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib Afatinib Osimeritinib Crizotinib/Alectinib Targeted: PARP-I Immunooncology Olaparib Nivolumab/ Pembrolizumab Nivolumab/ Pembrolizumab Platinum Taxanes Camptothecins Liposomal-Dox Gemcitabine Bevacizumab Olaparib Rucaparib Niraparib Dacarbazine Ipirimumab Nivolumab/ Pembrolizumab

7 Eribulin vs. TPC in Patients with m-bc Lancet 2011; 377:

8 Eribulin vs. DTIC in Patients with Advanced Liposarcoma or Leiomyosarcoma Lancet 2016; 387:

9 Development of Oncology Drugs Category Breast Gastric CRC NSCLC Ovary Melanoma Chemotherapy Hormonetherapy Enhancer Targeted: Antibody Anthracyclines Taxanes Fluorpyrimidines Cyclophosphamide Eribulin Gemcitabin Vinorelbine Everolimus Palbociclib Trastuzumab Pertuzumab Bevacizumab T-DM1 Fluoropyrimidines Platinum Taxanes Anthracyclines Trastuzumab Ramucirumab Fluorpyrimidines Oxaliplatin Irinotecan Trifluridine/ tipiracil Bevacizumab Cetuximab/ Panitumumab Ramucirumab Platinum Taxanes Fluoropyrimidines Irinotecan Pemetrexed Gemcitabine Vinorelbine Bevacizumab Ramucirumab Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib Afatinib Osimeritinib Crizotinib/Alectinib Targeted: PARP-I Immunooncology Olaparib Nivolumab/ Pembrolizumab Nivolumab/ Pembrolizumab Platinum Taxanes Camptothecins Liposomal-Dox Gemcitabine Bevacizumab Olaparib Rucaparib Niraparib Dacarbazine Ipirimumab Nivolumab/ Pembrolizumab

10 Potential Combination Strategies for mtor and CDK4/6 Inhibitors with Hormone Therapy. Cancer Discov; 6(7);

11 BOLERO-2 : Phase III of Everolimus for Hormone Sensitive BC N Engl J Med 366;6 February 9, 2012

12 mtor Inhibitor-Associated Stomatitis (mias) Grade 3 への対応 腔内の清潔保持の継続 医療者による 腔ケアの介 含嗽の励 疼痛緩和の徹底 鎮痛薬 ( アセトアミノフェン NSAIDs 時間作 型オピオイド レスキュードーズの併 局所 酔薬の使 栄養管理 PEG( 胃瘻 ) や経 胃管の使 Grade 4 への対応 抗がん治療の中 有害事象への積極的な治療 腔内の清潔保持の継続 医療者による 腔ケアの介 敗 症 ( 全 感染症 ) の予防 疼痛緩和 オピオイド持続静注の使 栄養管理 PEG( 胃瘻 ) や経 胃管の使 中 静脈栄養の使

13

14 Phase III of Palbociclib in HR Positive Advanced BC: 1 st Line N Engl J Med 2016;375: DOI: /NEJMoa

15 Phase III of Palbociclib in HR Positive Advanced BC: 1 st Line N Engl J Med 2016;375: DOI: /NEJMoa

16 Phase III of Palbociclib in HR Positive Advanced BC: 2 nd Line n The primary end point was investigator-assessed progression-free survival. n Secondary end points included overall survival, objective response, rate of clinical benefit, patient- reported outcomes, and safety. N Engl J Med 2015;373: DOI: /NEJMoa

17 Cost-effectiveness of Palbociclib in HR Positive Advanced Breast Cancer n Conclusion: From a societal perspective, PAL treatment of both patient groups (with and without prior endocrine therapy) is highly unlikely to be cost-effective compared with the usual care in the USA. Ann Oncol 2017; 28:

18 Development of Oncology Drugs Category Breast Gastric CRC NSCLC Ovary Melanoma Chemotherapy Hormonetherapy Enhancer Targeted: Antibody Anthracyclines Taxanes Fluorpyrimidines Cyclophosphamide Eribulin Gemcitabin Vinorelbine Everolimus Palbociclib Trastuzumab Pertuzumab Bevacizumab T-DM1 Fluoropyrimidines Platinum Taxanes Anthracyclines Trastuzumab Ramucirumab Fluorpyrimidines Oxaliplatin Irinotecan Trifluridine/ tipiracil Bevacizumab Cetuximab/ Panitumumab Ramucirumab Platinum Taxanes Fluoropyrimidines Irinotecan Pemetrexed Gemcitabine Vinorelbine Bevacizumab Ramucirumab Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib Afatinib Osimeritinib Crizotinib/Alectinib Targeted: PARP-I Immunooncology Olaparib Nivolumab/ Pembrolizumab Nivolumab/ Pembrolizumab Platinum Taxanes Camptothecins Liposomal-Dox Gemcitabine Bevacizumab Olaparib Rucaparib Niraparib Dacarbazine Ipirimumab Nivolumab/ Pembrolizumab

19 HER2 Overexpressing Cancers Breast Cancer Gastric Cancer Slamon J NEngl J Med, Vol. 344, No. 11 Bang YJ, Lancet 376

20 Basket Trial Histology-Independent, Aberration-Specific Clinical Trial Design Sleijfer S et al. JCO 2013;31:

21 Umbrella Trial Histology-Based Clinical Trial Design to Evaluate Multiple Molecular Aberrations Sleijfer S et al. JCO 2013;31:

22 Basket Trial Vemurafenib in Multiple Non-melanoma Cancers with BRAFV600 Mutations N Engl J Med 2015; 373: DOI: /NEJMoa

23 Basket Trial Vemurafenib in Multiple Non-melanoma Cancers with BRAFV600 Mutations N Engl J Med 2015; 373: DOI: /NEJMoa

24 T-DM1 for Trastuzumab Resistant HER2 Overexpressing Cancers Breast Cancer Gastric Cancer Sunil Verma, N Engl J Med 2012;367: Peter C Thuss-Patience, Lancet Oncol 2017

25 Continuing Trastuzumab Beyond Progression in HER2 Positive BC Trastzumab PD Trastzumab PD Trastzumab PD Trastzumab Taxane Capecitabine Vinorelbine Gemcitabin

26 Trastuzumab Beyond Progression in HER2 Positive Advanced BC J Clin Oncol 27:

27 Bevacizumab beyond Progression for CRC BRiTE ML18147 J Clin Oncol 26: Lancet Oncol 2013; 14: 29 37

28 CLEOPATRA OS and PFS N Engl J Med 2015;372: DOI: /NEJMoa

29 Continuing Trastuzumab/Pertuzumab Beyond Progression in HER2 Positive BC Trastzumab Trastzumab Trastzumab Trastzumab Pertuzumab PD Pertuzumab PD Pertuzumab PD Pertuzumab Docetaxel Capecitabine Vinorelbine Gemcitabin

30 Continuing Trastuzumab Beyond Progression n During the last decade, most oncologists empirically adopted the practice of continuing trastuzumab beyond progression of disease in patients with human epidermal growth factor 2 (HER-2) positive metastatic breast cancer, deviating from the established paradigm of stopping and switching drugs or interventions when patients develop disease progression. n With trastuzumab, they simply switched the cytotoxic agent paired with this monoclonal anti HER-2 antibody. nthis practice was not based on any prospective randomized data establishing benefit. Mohammad Jahanzeb JCO 20, 2009 vol. 27 no

31 Hormone Receptor-Negative and HER2- Positive Disease n Disease progression while receiving trastuzumab For patients who are receiving treatment with trastuzumab for advanced breast cancer, discontinue treatment with trastuzumab at the time of disease progression outside the central nervous system. Do not discontinue trastuzumab if disease progression is within the central nervous system alone. NICE Guidance Advanced Breast Cancer: Diagnosis and Treatment

32 Trastuzumab Beyond Progression in HER2 Positive Advanced Gastric Cancer Nobody prescribe Trastuzumab for gastric cancer in this setting

33 Phase II Study of Eribulin Mesylate with Trastuzumab as First-Line Therapy for HER2- Positive BC Clinical Breast Cancer, Vol. 14, No. 6, ª 2014

34 Patritumab plus Trastuzumab and Paclitaxel in HER2 Overexpressing m-bc Cancer Sci 107 (2016)

35 Clinical Endpoints Used in Cancer Trials Endpoints Regulatory approval Study design Overall survival Regular approval (clinical benefit) Randomized studies; masking not essential Symptom endpoints (patient-reported outcomes) Progression-free survival (includes all deaths) Objective response rate Regular approval (clinical benefit) Accelerated approval or regular approval (surrogate endpoint) Accelerated approval or regular approval (surrogate endpoint) Randomized, masked studies Randomized studies; masking preferred in comparative studies; masked review recommended; Single-arm or randomized studies; masking preferred in comparative studies; masked review recommended Michelle K Wilson, Lancet Oncology 2015

36 Paclitaxel Carboplatin ±Bevacizumab for NSCLC N Engl J Med 2006; 355:

37 Paclitaxel ± Bevacizumab for m-bc N Engl J Med 2007;357:

38 Avastin No Longer Approved for Breast Cancer, FDA Says n November 18, 2011 The US Food and Drug Administration (FDA) announced today that it is rescinding its approval of bevacizumab (Avastin, Genentech) for treating metastatic breast cancer because the drug has not proven itself to be safe and effective for that indication.

39 Bevacizumab for Gastric Cancer AVAGAST Trial Overall Survival Progression Free Survival J Clin Oncol 2012; 30:

40 Cost-Effectiveness

41 Linear Regression Analysis of Drug Price vs. % Improvement in PFS and OS Drug cost (x10 5 ) y=3366x+6.167x10 6 R 2 =1.18x y=-5781x+6.778x10 6 R 2 =1.23x Improvement of PFS (%) Improvement of OS (%) Satoh E and Sasaki Y JSMO 2017

42 New Model for Assessing Cost-Effectiveness of Oncology Drugs Progression-free survival (control) Progression-free survival (experimental) ΔPFS Cost Index PFS ( ) = PDP/ΔPFS Cost Index OS ( ) = PDP/ΔOS ΔOS Overall survival (control) Overall survival (experimental) Total prices of cancer drugs until disease progression (prescribed drug price: PDP) Satoh E and Sasaki Y JSMO 2017

43 The Cost Required to Prolong PFS or OS by 1 Day p = Cost for 1 day prolongation of PFS or OS (x10 3 ) PFS OS Satoh E and Sasaki Y JSMO 2017

44 Development of Oncology Drugs Category Breast Gastric CRC NSCLC Ovary Melanoma Chemotherapy Hormonetherapy enhancer Targeted: Antibody Anthracyclines Taxanes Fluorpyrimidines Cyclophosphamide Eribulin Gemcitabin Vinorelbine Everolimus Palbociclib Trastuzumab Pertuzumab Bevacizumab T-DM1 Fluoropyrimidines Platinum Taxanes Anthracyclines Trastuzumab Ramucirumab Fluorpyrimidines Oxaliplatin Irinotecan Trifluridine/ tipiracil Bevacizumab Cetuximab/ Panitumumab Ramucirumab Platinum Taxanes Fluoropyrimidines Irinotecan Pemetrexed Gemcitabine Vinorelbine Bevacizumab Ramucirumab Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib Afatinib Osimeritinib Crizotinib/Alectinib Targeted: PARP-I Immunooncology Olaparib Nivolumab/ Pembrolizumab Nivolumab/ Pembrolizumab Platinum Taxanes Camptothecins Liposomal-Dox Gemcitabine Bevacizumab Olaparib Rucaparib Niraparib Dacarbazine Ipirimumab Nivolumab/ Pembrolizumab

45 Small-Molecule TKIs Approved by the FDA and the EMA according to Their Indications Trends in Pharmacological Sciences 2016; 37:

46 Druggable Somatic Mutation in NSCLC nature medicine volume 18 number 3 MARCH 2012

47 EGFR-TKI Sensitive Mutations in NSCLC Ohashi K et al. JCO 2013;31:

48 NEJ002 Chemo vs. Gefitinib in EGFR mt NSCLC Progression-Free Survival Overall Survival Maemondo M et al. N Engl J Med 2010;362:

49 EGFR-Tyrosine Kinase Inhibitors Lapatinib

50 Lapatinib Plus Capecitabine in Women with HER-2 Positive Advanced Breast Cancer ITT Population Adjusted for ECOG PS n Conclusions. Although premature enrollment termination and subsequent crossover resulted in insufficient power to detect differences in overall survival, exploratory analyses demonstrate a trend toward a survival advantage with lapatinib plus capecitabine. These data continue to support the efficacy of lapatinib in patients with HER-2 MBC. The Oncologist 2010;15:

51 Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI Resistant Lung Adenocarcinoma Yamaoka T Mol Cancer Ther; 15(12) December 2016

52 EGFR-TKI Resistant Mutation in NSCLC Ohashi K et al. JCO 2013;31:

53 Liquid Biopsy Plasma vs. Tumor Genotyping Assays Plasma T790M+ (n=158) Cancer tissue T790M+ (n=129) 111 (70.3 sensitivity) 18 T790M- (n=58) T790M- (n=87) (69.0% specificity) Osimeritinib Geoffrey R. Oxnard et al. JCO doi: /jco

54 Targeting Agents in Cancer Therapeutics New Paradigm for Treatment Selection Target Tumor BM Testing Drug Selection

55 Phase I of Farletuzumab PFS and Expression of FRA Sasaki Y., Invest New Drugs 2014

56 Biomarker Screening in NSCLC Mutation Incidence Effective Drugs EGFR sensitive mutation 40 % in Asian Gefitinib/Erlotinib/Afatinib EGFR resistant mutation Osimeritinib EML4-ALK 4-5% Crizotinib/Alectinib ROS1 0.5% Crizotinib PD-L % Pembrolizumab Companion Diagnostics

57 Development of Oncology Drugs Category Breast Gastric CRC NSCLC Ovary Melanoma Chemotherapy Hormonetherapy enhancer Targeted: Antibody Anthracyclines Taxanes Fluorpyrimidines Cyclophosphamide Eribulin Gemcitabin Vinorelbine Everolimus Palbociclib Trastuzumab Pertuzumab Bevacizumab T-DM1 Fluoropyrimidines Platinum Taxanes Anthracyclines Trastuzumab Ramucirumab Fluorpyrimidines Oxaliplatin Irinotecan Trifluridine/ tipiracil Bevacizumab Cetuximab/ Panitumumab Ramucirumab Platinum Taxanes Fluoropyrimidines Irinotecan Pemetrexed Gemcitabine Vinorelbine Bevacizumab Ramucirumab Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib Afatinib Osimeritinib Crizotinib/Alectinib Targeted: PARP-I Immunooncology Olaparib Nivolumab/ Pembrolizumab Nivolumab/ Pembrolizumab Platinum Taxanes Camptothecins Liposomal-Dox Gemcitabine Bevacizumab Olaparib Rucaparib Niraparib Dacarbazine Ipirimumab Nivolumab/ Pembrolizumab

58 Poly (ADP-ribose) Polymerase (PARP) Inhibition as a Therapeutic Strategy n PARP1 and 2 are involved in single-strand breaks. n Inhibition of PARP results in trapping of protein on DNA, inhibition of replication fork progression and increased as DNA brakes. n Resolution of lesions caused by PARP inhibition dependent on functioning homologous recombination n BRCA1 and BRCA2 are important components of homologous recombination pathway n Cells lacking BRCA1/2 are sensitive to PARP inhibition ( synthetic lethality ) in vitro. Lord CJ Science 2017; 355:

59 Homologous Recombination: 相同組換え n 物が ら制御して遺伝情報を再編成することを遺伝的組換え (Genetic recombination) といいます 遺伝的組換えは, さらに以下の 4 種類に分けられます 1. 相同組換え (Homologous recombination)(= 普遍的組換え (general recombination)) 異なる DNA 分 間で 相互の分 に含まれる同じ DNA 配列を持つ領域間で 本鎖が形成されることがきっかけとなって分 間の再結合が起こることにより もとの DNA 分 の鎖が相互に置き換わった分 が形成されること 2. 部位特異的組換え (Site-specific recombination) [ 特定の部位で起こる組換え : 酵 の性転換や抗体形成過程で われる ] 3. トランスポゾン (Transposon)[DNA 断 が染 体上を動き回るような組換え ] 4. 正統的組換え (Illegitimate recombination)[ 上記以外の組換え ] 相同組換え ( 相同的組換え ) は,DNA の塩基配列がよく似た部位 ( 相同部位 ) で起こる組換えです 様々な化学物質や放射線により切断された DNA は主に相同組換えによって修復されます また, 減数分裂に伴い 頻度で起こり 相同組換えがうまくいかないと配偶 が形成されません 本 学 物資源科学部応 物科学科核酸 蛋 質科学研究室

60 Synthetic Lethality : 合成致死性 n Synthetic lethality( 合成致死性 ): 単独遺伝 損では細胞や個体に対する致死性を さないのに, 複数の遺伝 の 損が共存すると致死性を発揮する現象 n 創薬標的の場合は 2 つの遺伝 変異で疾患との相関が強くなる創薬ターゲットを指す の遺伝 変異をコンパニオン診断薬の標的とし, 他 の活性を阻害することで治療薬の開発をめざす創薬の新しいコンセプトとして注 されている.

61 Strategy for Synthetic Lethality based Cancer Therapy Nucleic Acids Research, doi: /nar/gku284

62 BRCA1/2 Mutations Can Be Present Both in Tumor and Germline Bradley J. Monk, MD, FACS, FACOG

63 Genetic Testing in Ovarian Cancer The Dream Test GERMLINE n BRCA1/2 n All other HRD genes n LYNCH, other syndromic genes (PTEN, STK11, CDH1, p53) DICER TUMOR n BRCA1/2 n All other HRD genes n LOH/HRD-type metric/biomarker n Meth BRCA1, RAD51C, etc? n LYNCH genes, MSI, meth MLH1, POLE n MTB (mutation/mb) Bradley J. Monk, MD, FACS, FACOG

64 Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer n The patients had recurrent ovarian or fallopiantube cancer or primary peritoneal cancer with high grade serous features or a serous component, which was platinum-sensitive. n BRCA1/2 mutation status was not required. N Engl J Med 2012;366:

65 Olaparib Maintenance Therapy in Platinum- Sensitive Relapsed Ovarian Cancer 1.0 N Engl J Med 2012;366:

66 Maintenance Olaparib in Platinum-Sensitive Recurrent Ovarian Cancer: Phase II BRCAm BRCAwt n Known BRCA m status was not required for eligibility, but was established via case report forms documenting previous local germline BRCA testing, or via retrospective germline BRCA testing Lancet Oncol 2016; 17:

67 Niraparib Maintenance Therapy in Platinum- Sensitive, Recurrent Ovarian Cancer n We enrolled two independent cohorts on the basis of the presence or absence of a germline BRCA mutation (gbrca cohort and non-gbrca cohort), as determined on BRACAnalysis testing (Myriad Genetics). N Engl J Med 2016;375: DOI: /NEJMoa

68 Niraparib Maintenance Therapy in Platinum- Sensitive, Recurrent Ovarian Cancer N Engl J N Med Engl 2016;375: DOI: J Med 2016;375: DOI: /NEJMoa /NEJMoa

69 FDA-Approved PARP Inhibitors in Ovarian Cancer n Olaparib (Dec 19, 2014) >3rd line, germline BRCA, treatment n Rucaparib (Dec 19, 2016) >2nd line, germline and somatic BRCA, treatment n Niraparib (March 27, 2017) >2nd line, no biomarker, maintenance

70 Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation n The patients had HER2-negative metastatic breast cancer that was hormone-receptor positive or was triple negative. n Patients had a confirmed deleterious or suspected deleterious germline BRCA mutation; the mutation was detected by central testing with BRACAnalysis (Myriad Genetics) in 297 patients and by local testing in 167 patients. n Patients had received no more than two previous chemotherapy regimens for metastatic disease, N Engl J Med 2017;377: DOI: /NEJMoa

71 Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation N Engl J Med 2017;377: DOI: /NEJMoa

72 Genetic Testing in Ovarian Cancer n NCCN Guidelines Version [Any] patients with a personal history of invasive [nonmucinous] epitherail cancer [including fallopian, peritoneal] diagnosed at any age n ASCO Expert Statement Epithelial ovarian, fallopian, or peritoneal cancer. Even in the absence of family history n SGO Clinical Practice Statement October All women with ovarian, fallopian, and peritoneal carcinoma ~1 in 4 ovarian cancer patients harbor a hereditary mutation National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Ovarian Cancer. Version Lu KH et al. J Clin Oncol. 2014;32: Accessed May 24, 2017.

73 乳癌に対する PARP 阻害薬の対象患者の選択? BRCA1/2 変異を伴う正常細胞 n Germ line mutation BRCA1/2 変異を伴う癌細胞 n Somatic mutation

74 Development of Oncology Drugs Category Breast Gastric CRC NSCLC Ovary Melanoma Chemotherapy Hormonetherapy enhancer Targeted: Antibody Anthracyclines Taxanes Fluorpyrimidines Cyclophosphamide Eribulin Gemcitabin Vinorelbine Everolimus Palbociclib Trastuzumab Pertuzumab Bevacizumab T-DM1 Fluoropyrimidines Platinum Taxanes Anthracyclines Trastuzumab Ramucirumab Fluorpyrimidines Oxaliplatin Irinotecan Trifluridine/ tipiracil Bevacizumab Cetuximab/ Panitumumab Ramucirumab Platinum Taxanes Fluoropyrimidines Irinotecan Pemetrexed Gemcitabine Vinorelbine Bevacizumab Ramucirumab Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib Afatinib Osimeritinib Crizotinib/Alectinib Targeted: PARP-I Immunooncology Olaparib Nivolumab/ Pembrolizumab Nivolumab/ Pembrolizumab Platinum Taxanes Camptothecins Liposomal-Dox Gemcitabine Bevacizumab Olaparib Rucaparib Niraparib Dacarbazine Ipirimumab Nivolumab/ Pembrolizumab

75 がん免疫のメカニズム n 腫瘍に対する免疫反応はリンハ 節において T 細胞か 腫瘍抗原を認識し活性化され その後 活性化された T 細胞が 腫瘍部位に到達して腫瘍細胞の排除に働く事て 成 する n ヒトには免疫反応の調節メカニス ムとして もともと に対する過剰な免疫反応や正常組織への障害を抑えるための免疫チェックホ イント機構か 備わっており T 細胞か 活性化すると細胞膜上に発現される CTLA-4 や PD-1 か 抗原提 細胞上の CD28 リカ ントブァミリーと結合する事て 免疫反応か 鎮静化される n 腫瘍環境てばこの免疫チェックホ イント機構か 増強しており 腫瘍細胞上の CD28 リカ ントブァミリーと活性化リンハ 球の CTLA-4 や PD-1 か 結合する事て 腫瘍免疫の抑制反応か 起こり 免疫反応による抗腫瘍効果からの回避か 可能となっている 東みゆき医学の歩み 2013 年 3 2 p 京都 学医学研究科呼吸器内科 / 腫瘍薬物治療学講座永井宏樹先 の総説を改変

76 Immune Checkpoints and Inhibitors 京都 学 本庶佑教授 NATURE 497, 7 Nov.

77 Phase I Study of Nivolumab N Engl J Med 2012;366:

78 Clinical Response of Nivolumab in Melanoma Patients : Spider Plot Disease progression Pseudo progression Complete response Long term disease stabilization N Engl J Med N Engl 2012;366: J Med

79 The Prevalence of Somatic Mutations across Human Cancer Types. LB Alexandrov et al. Nature 500, 1-7 (2013) doi: /nature12477

80 PD-L1 Expression in NSCLC KEYNOTE-001 Proportion score of less than 1% (Panel A), a score of 1 to 49% (Panel B), and a score of at least 50% (Panel C) N Engl J Med 2015;372: DOI: /NEJMoa

81 PD-L1 Expression in NSCLC as a Predictive Factor of Pembrolizumab?: KEYNOTE-001 N Engl J Med 2015;372: DOI: /NEJMoa

82 Pembrolizumab vs. Chemotherapy for PD-L1 Positive NSCLC N Engl J Med 2016;375: DOI: /NEJMoa

83 PD-L1 Expression in TNBC Cancer Immunol Res 2014; 2(4);

84 Pembrolizumab in Patients with Advanced TNBC: Phase Ib : KEYNOTE-012 Study Among the 27 patients who were evaluable for antitumor activity, the overall response rate was 18.5%, There was evidence of an increasing probability of response (one-sided P =.028 for ORR) and a reduction in the hazard (one-sided P =.012 for PFS) with increasing expression of PD-L1. J Clin Oncol 2016; 34:

85 Tumor Response in Patients with dmmr/ MSI-H m-crc Lancet Oncol 2017 Published Online July 19,

86 PD-1 Blockade by Nivolumab in Tumors with Mismatch-Repair Deficiency: CM 142 N Engl J Med 2015;372: DOI: /NEJMoa

87 FDA Approvals Timeline for Solid Tumor Dung Le ASCO 2017

88 MSI-H Frequency by Site TheOncologist 2016;21:

89 The Clinical Spectrum of Immune Related Adverse Events European Journal of Cancer 54 (2016) 139e148

90 Take Home Message n 抗癌薬物療法を理解するためには 乳癌以外薬物療法の最低限の知識が必要 n 乳癌の薬物療法の常識は必ずしも他癌腫では常識ではない n それぞれの薬剤承認の基となった臨床試験の知識は必須であり 患者に対する具体的な貢献度合いを吟味する n わが国でも抗癌薬物療法に対する 費 対効果 を論じるべき時代が到来した n 今後乳癌薬物療法が発展するにつれて多彩な副作 の管理をはじめとする内科的なアプローチが求められる