教育シンポジウム「がん免疫療法：特に免疫チェックポイント阻害剤」 消化管癌（食道・胃・大腸癌）における 免疫チェックポイント阻害薬の可能性 ESY-7 室 圭 （愛知県がんセンター中央病院 薬物療法部） 2016/10/21 横浜 第54回日本癌治療学会学術集会 各癌種における体細胞変異の頻度 教育シンポジウム 「がん免疫療法：特に免疫チェックポイント阻害剤」 消化管癌（食道・胃・大腸癌）における 免疫チェックポイント阻害薬の可能性 愛知県がんセンタｰ中央病院 薬物療法部長／外来化学療法センター長 室 圭 kmuro@aichi-cc.jp Lawrence MS, Stojanov P, Polak P, et al. Nature 499:214–218, 2013 1 2 PD-1/PD-L1 Antibodies Are Being Investigated in A Wide Range of Tumor Types ESOPHAGEAL BRAIN GLIOBLASTOMA LUNG HEAD & NECK HEPATOCELLULAR LYMPHOMA PANCREATIC BREAST GASTRIC MERKEL CELL CARCINOMA OVARIAN MELANOMA HEMATOLOGICAL COLORECTAL COLORECTAL Available from ClinicalTrials.gov. Accessed September 2015. RENAL/BLADDER/GU Mechanism of Immune Checkpoint Inhibitors SARCOMA Nivolumab, Pembrolizumab, et al. Ipilimumab, Tremelimumab, et al. Avelumab, Durmalumab Atezolizumab, et al. 3 4 食道癌に対する抗PD-1抗体薬の臨床試験 各臨床試験の体制・特徴 KEYNOTE-028 (Pembrolizumab) Esophageal Cancer ONO-4538-07 (Nivolumab) 薬剤 Pembrolizumab 10 mg/kg, q2w Nivolumab 3 mg/kg, q2w 相 治療Line 第Ib相 第II相 標準治療不応・不耐 標準治療不応・不耐 症例数 23 65 PD-L1 status 陽性 （腫瘍/炎症性細胞が1%以上） 陽性+陰性 (all comer) 組織型 扁平上皮癌 74% 22% 腺癌 4% 粘表皮癌 扁平上皮癌 100% 実施国 日、米、仏、英、台、韓 日本 臨床試験登録 NCT02054806 JapicCTI-142422 Kojia T, Muro K, et al. ASCO-GI 2016, Doi T, et al. ASCO-GI 2016 5 JSCO 第51巻第２号 6 345 食道癌に対する抗PD-1抗体薬の有効性 食道癌に対する抗PD-1抗体薬の奏効割合 KEYNOTE-028 Spider Plots & Waterfall Plots (Pembrolizumab) Overall Response KEYNOTE-028 (Pembrolizumab) -investigator review- ONO-4538-07 (Nivolumab) -central review- Response CR PR SD PD n 0 7 2 13 % 0 30% 9% 56% n 1 10 16 29 % 2% 16% 25% 45% NE ORR Total 1 7 23 4% 30% 8 11 65 13% 17% 100 80 60 40 20 0 -20 -40 -60 -80 -100 ORR by histology 29.4% for squamous cell carcinoma (5 of 17) 40.0% for adenocarcinoma (2 of 5) Kojia T, Muro K, et al. ASCO-GI 2016, Doi T, et al. ASCO-GI 2016 ONO-4538-07 (Nivolumab) Squamous cell Adenocarcinoma Mucoepidermoid Kojia T, Muro K, et al. ASCO-GI 2016, Doi T, et al. ASCO-GI 2016 8 7 食道癌に対する抗PD-1抗体薬の有害事象 現在進行中の食道癌に対する 抗PD-1抗体薬の第3相試験 Treatment-Related Adverse Events KEYNOTE-028 (Pembrolizumab) ONO-4538-07 (Nivolumab) Ongoing Trials Any grade G3以上 Any grade G3以上 Any 9 (39%) 4 (17%) 55(85%) 19 (29%) 肝機能異常 1 (4%) 1 (4%) 4 (6%) 2 (3%) Rash 2 (9%) 0 7 (11%) 0 甲状腺機能異常 食欲不振 下痢 間質性肺炎 副腎不全 掻痒症 2 (9%) 0 3 (5%) 0 - - 13 (20%) 2 (3%) - - 13 (20%) 1 (2%) - - 5 (8%) 0 2 (9%) 0 - - 1 (4%) 1 (4%) 5 (8%) 0 Pembrolizumab (KEYNOTE-181) Nivolumab (OPERA) NCT02564263 NCT02569242 Kojia T, Muro K, et al. ASCO-GI 2016, Doi T, et al. ASCO-GI 2016 9 10 RCTs with Targeting Agents for Metastatic GC Gastric Cancer Line Study Agent Tested Molecular Target Control Arm 1st ToGA (HER2) trastuzumab HER2 XP/FP OS LOGiC(HER2) lapatinib HER2 XELOX OS JACOB (HER2) pertuzumab HER2 XP + trastuzumab 2nd OS AVAGAST bevacizumab VEGF XP OS EXPAND cetuximab EGFR XP PFS REAL-3 panitumumab EGFR EOX RILOMET-1, 2 rilotumumab cMET ECX, XP OS RAINFALL ramucirumab VEGFR2 XP PFS TyTAN (HER2) lapatinib OS HER2 weekly paclitaxel OS GATSBY (HER2) TDM-1 HER2 weekly paclitaxel OS RAINBOW ramucirumab VEGFR2 weekly paclitaxel OS GRANITE2 everolimus mTOR weekly paclitaxel PFS ENRICH nimotuzumab EGFR irinotecan OS REGARD ramucirumab VEGFR2 BSC (placebo) OS GOLD olaparib PARP weekly paclitaxel OS BRIGHTER 11 Pri. End. BBI-608 STAT3 weekly paclitaxel OS KEYNOTE 061 pembrolizumab PD-1 weekly paclitaxel OS 2nd / 3rd GRANITE1 everolimus mTOR BSC (placebo) OS 3rd～ ONO-4538-12 nivolumab PD-1 BSC (placebo) OS 12 346 JSCO 第51巻第２号 第54回 日本癌治療学会学術集会Educational Book RCTs with Targeting Agents for Metastatic GC Line Study Agent Tested Molecular Target Control Arm 1st ToGA (HER2) trastuzumab HER2 XP/FP OS LOGiC(HER2) lapatinib HER2 XELOX OS JACOB (HER2) pertuzumab HER2 XP + trastuzumab OS AVAGAST bevacizumab VEGF XP OS EXPAND cetuximab EGFR XP PFS 2nd 胃癌に対する抗PD-1抗体薬の臨床試験 Pri. End. 各臨床試験の体制・特徴 KEYNOTE-012 (Pembrolizumab) 薬剤 OS CheckMate-032 (Nivolumab) Pembrolizumab 10 mg/kg, q2w Nivolumab 3 mg/kg, q2w 第I / II相 REAL-3 panitumumab EGFR EOX RILOMET-1, 2 rilotumumab cMET ECX, XP OS 相 第Ib相 RAINFALL ramucirumab VEGFR2 XP PFS TyTAN (HER2) lapatinib HER2 weekly paclitaxel OS 治療Line 標準治療不応・不耐 標準治療不応・不耐 GATSBY (HER2) TDM-1 HER2 weekly paclitaxel OS 症例数 39 59 RAINBOW ramucirumab VEGFR2 weekly paclitaxel OS GRANITE2 everolimus mTOR weekly paclitaxel PFS ENRICH nimotuzumab EGFR irinotecan OS REGARD ramucirumab VEGFR2 BSC (placebo) OS GOLD olaparib PARP weekly paclitaxel OS BRIGHTER BBI-608 STAT3 weekly paclitaxel OS KEYNOTE 061 pembrolizumab PD-1 weekly paclitaxel OS 2nd / 3rd GRANITE1 everolimus mTOR BSC (placebo) OS 3rd～ ONO-4538-12 nivolumab PD-1 BSC (placebo) OS PD-L1 status 陽性（腫瘍1%以上、間質） 陽性+陰性 (all comer) 原発部位 － 食道 接合部 胃 実施国 臨床試験登録 日米台韓以 米加丁芬 独伊西英 NCT01848834 NCT01928394 15% 53% 31% 丁：デンマーク、芬：フィンランド、西：スペイン、以：イスラエル Muro K, et al. Lancet Oncol 2016, Le DT, et al. ASCO-GI 2016 13 14 胃癌に対する抗PD-1抗体薬の有効性 胃癌に対する抗PD-1抗体薬の奏効割合 Overall Response KEYNOTE-012 Pembrolizumab -central review- CheckMate-032 Nivolumab n % n CR 0 0 - - PR 8 22% - - SD 5 14% - - PD 19 53% - - NE 1 3% - - ORR 8 22% 8 14% Total 36 Response KEYNOTE-012 (Pembrolizumab) Spider Plots & Waterfall Plots CheckMate-032 (Nivolumab) % 59 Muro K, et al. Lancet Oncol 2016 Le DT, et al. ASCO-GI 2016 Muro K, et al. Lancet Oncol 2016, Le DT, et al. ASCO-GI 2016 15 16 胃癌に対する抗PD-1抗体薬の有害事象 胃癌に対する抗PD-1抗体薬の有効性 KEYNOTE-012 (Pembrolizumab) Overall Survival Treatment-Related Adverse Events KEYNOTE-012 (Pembrolizumab) CheckMate-032 (Nivolumab) 6mOS rate: 66% mOS: 11.4ms Any grade G3以上 2 (5%) 19 (32%) 1 (2%) 0 9 (15%) 0 5 (13%) 1 (3%) - - 5 (13%) 0 10 (17%) 0 Any grade G3以上 Any 26 (67%) 5 (13%) 疲労 食欲不振 甲状腺機能低下 掻痒症 関節痛 間質性肺炎 下痢 悪心 7 (18%) 5 (13%) 4 (10%) 0 - - - 1 (3%) - - - - 9 (15%) 1 (2%) - - 9 (15%) 0 Muro K, et al. Lancet Oncol 2016, Le DT, et al. ASCO-GI 2016 Muro K, et al. Lancet Oncol 2016, Le DT, et al. ASCO-GI 2016 17 JSCO 第51巻第２号 CheckMate-032 (Nivolumab) 18 347 Phase I/II Open-Label Study of Nivolumab Alone or With Ipilimumab in Advanced Metastatic GC CheckMate 032 胃癌に対する 複合がん免疫療法 Janjigian YY, et al. ASCO 2016 19 20 Phase I/II Open-Label Study of Nivolumab Alone or With Ipilimumab in Advanced Metastatic GC CheckMate 032: Summary of Efficacy CheckMate 032 Nivolumab N PD-L1+ PFS OS RR/DCR (%) Nivo1mg/kg + Ipi 3mg/kg Nivo 3mg/kg + Ipi 1mg/kg 59 49 52 25% 11% 18% 1.4 M 1.6M 1.5M 5.0 M 6.9 M 4.8 M 14/32 ％ 26/41 % 10/43 % Janjigian YY, et al. ASCO 2016 Janjigian YY, et al. ASCO 2016 21 22 Maintenance Therapy of Ipilimumab for AGC Primary Endpoints ir-PFS Secondary Endpoints mWHO-PFS, OS , ir-BORR Ipilimumab rPhase II Trial N=114 胃癌に対する メンテナンス免疫療法 Study Specific Eligibility Criteria R •Advanced gastric and gastro-esophageal junction 1:1 •Measurable disease by mWHO criteria SD or better •First-line pretreatment with chemotherapy using fluoropyrimidine and platinum combination without disease progression (12-18wks) •No HER2 positive status •No brain metastases NCT01585987 10 mg/kg IV q3w x 4 then q12w until PD treat up to 3 years Best supportive care Can include continuation of first-line fluoropyrimidine, but no other systemic anti-cancer therapy Moehler M, et al. ASCO 2016 23 24 348 JSCO 第51巻第２号 第54回 日本癌治療学会学術集会Educational Book Maintenance Therapy of Ipilimumab for AGC 胃癌に対する抗PD-1抗体薬Avelumabの有効性 JAVELIN Phase Ib PD-L1+ : 49% (74/151) BSC: median irPFS 4.9m Ipi: median irPFS 2.9m HR 1.44 P=0.097 Platinum-containing doublet/triplet Ipi: median OS 16.8m BSC: median OS 12.1m Maintenance (Mn) HR 0.87 P=0.643 2nd line (2L) mPFS: 1.5M RR: 10％, DCR: 29％ mPFS 3.0M RR: 9％, DCR: 58％ Chung HC, et al. ASCO 2016 Moehler M, et al. ASCO 2016 25 26 胃癌に対する 各種免疫チェックポイント阻害薬の効果 KEYNOTE-012 JAVELIN PI Pembrolizumab Avelumab Nivolumab 3mg/kg CHECKMATE-032 Anti-PD-1 Anti-PD-L1 Anti- PD-1 Refractory, PD-L1+ 1st Maintenance /2nd 36 89/62 59 49 52 100% 49% 25% 11% 18% PFS 1.9 M 3.0/1.5 M 1.4 M 1.6M 1.5M OS 11.4 M NA 5.0 M 6.9 M 4.8 M Agent 胃癌における 現在進行中の臨床試験 Patients N PD-L1+ Nivo 1mg/kg+ Ipi 3mg/kg Nivo 3mg/kg+ Ipi 1mg/kg Anti-PD-1 + Anti-CTLA-4 Refractory (PD on at least 1 prior regimen) 6M-OS rate 66 % NA 36 % 34% NA RR (%) 22 % 9.0/9.7 % 14 ％ 26 % 10 % MSI-H 17% (4/24) NA 27 28 現在進行中の臨床試験 (Pembrolizumab) KEYNOTE-059, 061, 062 現在進行中の臨床試験 (Nivolumab) ONO-4538-12 Phase II: KEYNOTE-059 NCT02335411 Cohort 1 PD-L1 +/≥2 prior CTx N=180 Cohort 2 PD-L1 +/1st-line N=40 Pembro Pembro +FP/XP Cohort 3 PD-L1+ 1st-line N=50 Pembro Adaptive Design Primary Endpoint: AE, ORR Phase III: KEYNOTE-062 NCT02494583 Phase III: KEYNOTE-061 NCT02370498 PD-L1 +/≥1 prior CTx N=720 R Pembro wPTX Primary Endpoint: PFS, OS PD-L1 + 1st-line N=750 R Primary Endpoint: PFS, OS GC or GEJ Adenocarcinoma • Refractory to or Intorerant of standard Cx. • PS 0-1 • PD-L1 +/ • N=480 Pembro Pembro +FP/XP FP/XP Nivolumab 3mg/kgQ2W 2:1 R Primary Endpoint: OS N=195〜 Placebo N=95〜 NCT02267343 AE; adverse event, ORR; objective response rate, PFS; progression free survival, OS; overall survival 29 JSCO 第51巻第２号 2014.11～ 30 349 JAVELIN: Avelumab for Advanced Gastric or GEJ Adenocarcinoma Phase III, JAVELIN Gastric 100 1st line Maintenance Phase III, JAVELIN Gastric 300 Colorectal Cancer In salvage line Moehler M, et al. ASCO 2016 Bang YJ, et al. ASCO 2016 31 32 Microsatellite Instability (MSI) Immune Microenvironment of MSI Tumors MSI is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR) IHC for MMR protein status MLH1+ MSH2- MLH1- MSH2+ The high mutational load in MSI tumors creates many tumor-specific neoantigens PCR on tumor DNA for MSI (microsatellite instability) Some of these neoantigens will be processed, presented on MHC, and recognized as foreign by T cells High level of tumor-infiltrating lymphocytes (TIL) and lymphocytic reaction in MSI tumors Imai and Yamamoto. Carcinogenesis 2008 Umetani, Annals of Surgical Oncology 2000 Rosen et al. Modern Pathology (2006) 19, 1414-1420 Xiao Y, et al. Cancer Discovery 2015 Llosa N, et al. Cancer Discov 2015 Dung TL, et al. ASCO 2015 33 34 Phase II Study of Pembrolizumab in Tumors with Mismatch Repair Deficiency Baseline Characteristics Study Design Dung TL, et al. ASCO 2015 Le DT, et al. N Engl J Med 2015 Dung TL, et al. ASCO 2015 Le DT, et al. N Engl J Med 2015 35 36 350 JSCO 第51巻第２号 第54回 日本癌治療学会学術集会Educational Book Immune-Related Response Objective Responses Progression-Free Survival Water-Fall Plots NR v.s.2.3m p<0.0001 Duration of Disease Control Dung TL, et al. ASCO 2015 Le DT, et al. N Engl J Med 2015 Dung TL, et al. ASCO 2015 Le DT, et al. N Engl J Med 2015 37 38 Baseline PD-L1 Expression & CD8+ Cell Infiltration Mutation Burden Correlates with Response Somatic mutations, mean Mutation-associated neoantigens, mean MMR-D n=9 MMR-P n=6 p 1782 73 0.007 578 (32%) 21 (29%) - Dung TL, et al. ASCO 2015 Le DT, et al. N Engl J Med 2015 Dung TL, et al. ASCO 2015 Le DT, et al. N Engl J Med 2015 39 40 The Cancer-Immunity Cycle Anti-PD1 and Anti-PDL1 MAPK inhibitors T cell activation and tumor cell killing MAPK阻害薬と 免疫チェックポイント阻害薬 MAPK inhibitors T cell infiltration VEGF inhibitors T cell trafficking Tumor cell death MAPK inhibitors Antigen acquisition by dendritic cells T cell priming VEGF inhibitors Anti-CTLA4 Hughes PE, et al.Trends Immunol 2016 41 JSCO 第51巻第２号 42 351 PD-L1 and MEK Inhibition: A Rational Combination Cobimetinib: A Highly Selective MEK1/2 Inhibitor Atezolizumab: An Anti-PDL1 Antibody Cobimetinib MAP Kinase Pathway • MEK inhibition alone can result in intratumoral T-cell accumulation and MHC1 upregulation,and sygnergizes with anti-PDL1 agent to promote durable tumor regression1 Atezolizumab Growth factor receptor 0.04 CD8* T cell per tumor cell 15,000 Class I MHC 3,000 Tumor volume（mm3） Control p=0.0024 Anti-PDL1 MEKi（38963） 0.03 10,000 2,000 5,000 1,000 MEKi + anti-PDL1 0.02 Cobimetinib 0.01 Binding of PD-L1 to its receptors PD-L1 and B7.1 • 0.00 Single agent MEK inhibition has shown little activity in mCRC ND MEKi 0 ND 0 0 20 40 60 80 100 Day • To examine the possible benefits of MEK inhibition with an anti-PDL1 agent, we evaluated cobimetinib + atezolizumab in patients with advanced solid tumors 1. Ebert et al. Immunity 2016 MHC, major histocompatibility complex; Bendell J. et al. Cobimetinib and atezolizumab in CRC. ASCO 2016 ND, no drug（vehicle alone） This inhibition can enhance T-cell priming and restore anti-tumor T-cell activity MEKi CT26（KRASmt）CEC models. Bendell J, et al.: 2016 ASCO #3502 Bendell J, et al.: 2016 ASCO #3502 43 44 Phase 1b Dose Escalation and Cohort Expansion Study（NCT01988896） n=2 1 KRASmt; 1 wt Dose-escalation stage （3 + 3） 40mg cobi PO QDa 800mg atezo IV q2w QDa 20mg cobi PO 800mg atezo IV q2w Patients with CRC Key eligibility Criteria • ECOG PS of 0 or 1 • Measurable disease per RECIST v1.1 n=1 1 KRASmt QDa 60mg cobi PO 800mg atezo IV q2w DLT window of 28 days until MTD for combination is benefit Dose-expansion stage KRASmt mCRC Baseline Characteristics （大腸癌コホート） Median age, y Range （n=23） 57 31-69 Patients with CRC Sex Primary Objectives • Safety and clinical activity of cobimetinib + atezolizumab Male 48% Female 52% ECOG PS 0 61% 1 39% n=20 Metastatic Melanoma Solid tumors serial biopsy Asian 31% White 61% Median 3 Range 1-5 Prior oxaliplatin and irinotecan 23（100%） Prior adjuvant therapy 12（52%） Stage of initial diagnosis Ethnicity（Race） NSCLC （n=23） No. of prior systemic therapies Stage Ⅰ-Ⅱ 13% Stage Ⅲ 48% Stage Ⅳ 30% Region Cobimetinib was administered on 21 days on/7 days off dosing schedule. atezo, atezolizumab; cobi, cobimetinib; DLT, drug limited toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; KRASmt, KRAS mutant; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; RECIST, Response Evaluation Criteria In Solid Tumors. a Asia 35% North America, Australia 65% Bendell J, et al.: 2016 ASCO #3502 Bendell J, et al.: 2016 ASCO #3502 45 46 Baseline Characteristics (cont.) （大腸癌コホート） Patients with CRC （n=23） Cancer type at diagnosis Efficacy: Confirmed ORR, PFS, OS （n=23） KRAS mutant CRC cohort （n=20） All CRC patients （n=23） Wild typea 4% 20% （5.7, 43.7） 17% （5.0, 38.8） Mutant 96% PR 20% 17% SD 20% 22% PD 50% 52% NE 10% 9% Median PFS（95％CI） 2.3 mo（1.8, 9.5） 2.3mo（1.8, 9.5） 35%（0.14, 0.56） Patients with CRC KRAS Colon 83% Rectal 17% ORR confirmed（95% CI） PD-L1 expression Location of primary tumor Left （splenic flexure to rectum） 74% Right （cecum to hepatic flexure） 26% Transverse 0% Metastatic pattern at study entry Liver only 0% Liver metastases and other sites 48% Extra-hepatic 52% IC2/3 17% IC0/1 70% Unknown 13% MSI status, investigatorreported MSI-high 0% 6-mo PFS（95％CI） 39％ （0.16, 0.61） MSI-low or stable 30% Median OS（95％CI） NE（6.5, NE） NE（6.5, NE） Unknown 70% 6-mo OS（95％CI） 77％（0.57, 0.97） 72％（0.52, 0.93） a • Response did not correlate with PD-L1 status: IC0（n=2）, IC1（n=1）and IC3（n=1） No expanded RAS or BRAF mutations identified by next generation sequencing Data cutoff, February 12, 2016 Bendell J, et al.: 2016 ASCO #3502 47 Bendell J, et al.: 2016 ASCO #3502 48 352 JSCO 第51巻第２号 第54回 日本癌治療学会学術集会Educational Book （%） PD 50 40 PD PD PD PD PD PD 20 0 PD PD PD PD SD CD8 T-Cell Accumulation and MHC I Expression SD SD PD SD SD PR PR PR PR TC 0 TC NA TC 0 TC 3 -20 -40 PD-L1 IC status IC0 NA -60 -80 PR PR SD PD SD PR PR SD SD PD PD PD SD PD PD PD PD PD PD PD NA NA PD IC1 • Median time to first response:3.7 mo （1.8 - 4.1 mo） IC2 First PR/CR First PD Death Last altezolizumab dose as of cut-off date Still on study treatment（atezolizumab/cobimetinib） 1 Biomarkers: 3 of 4 responders were mismatch-repair proficient（not MSI-H） Change in sum of longest diameters from baseline Maximum SLD reduction from baseline Efficacy: Change in Tumor Burden over Time 3 6 9 12 Time on study 15 TC 0 IC3 （%） 100 PD 80 SD PR/CR3 60 Discontinued atezolizumab 40 New lesion 20 0 -20 -40 -60 -80 -100 0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223（mo） Time on study 18（mo） Bendell J, et al.: 2016 ASCO #3502 Bendell J, et al.: 2016 ASCO #3502 49 50 What Is True Biomarkers of Immune Checkpoint Inhibitors for GI Tract Cancer? 免疫チェックポイント阻害薬のこれからの課題 - （１）Atypical Response (Pseudo-progression)の存在 （２）Biomarker解析（効く集団、効かない集団の同定） （３）複合がん免疫療法の開発 （免疫療法、抗癌剤、分子標的治療薬、放射線照射） Neoantigen CD4/CD8 infiltration PD-L1 expression Mutation load (Mutation burden) Immune-related gene expression signatures - e.g. IFN-γ genes - MSI-H - Smoking - Metastatic sites （４）免疫関連有害事象の理解と対策 - Higher response in Lung mets compared to Liver 玉田耕治先生のスライドから引用、一部改変 51 JSCO 第51巻第２号 52 353
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