Microsoft PowerPoint - 朴成和先生111008浜松.pptx

Transcription

1 211/1/8 第 9 回浜松オンコロジーフォーラム 胃癌治療における分子標的薬剤の現状と展望 聖マリアンナ医科大学臨床腫瘍学講座朴成和 RCTs with targeting agents for metastatic gastric cancer Line Study Agent tested Control arm Primary endpoint First ToGA (HER2) trastuzumab cape/cis OS LOGiC(HER2) lapatinib cape/oxa OS AVAGAST bevacizumab cape/cis OS EXPAND cetuximab cape/cis PFS REAL-3 panitumumab epiru/cape/oxa OS Second TyTAN (HER2) lapatinib paclitaxel OS RAINBOW ramucirumab paclitaxel OS GRANITE2 everolimus paclitaxel PFS ramucirumab placebo OS Second/ third GRANITE1 everolimus placebo OS 1

2 Her-2 陽性胃癌について 2

3 HER2 病理診断基準 Rushoff et al. N Pathologe, 21 HER2 病理診断基準 : 胃癌と乳癌での違い Gastric cancer Breast cancer IHC scoring Extent (Area Cut-off) Circularity Biopsy specimens 5 Cells Resection specimens: 1% Mostly missing (often only lateral in IHC2+/3+) 1% ( 3%) a A must in IHC2+/3+ (F)ISH analysis Cell number 2 cohesive tumor cells showing highest gene count 2 cohesive tumor cells showing highest gene count Amplification Ratio 2. Ratio 2. ( 2.2) a HER2 positivity Patient selection Tumor type Tumor location FISH vs. IHC About 3% of intestinal-type about 15% of mixed-type about 5% of diffuse type About 3% at cardiac/gej about 15% of gastric cancer 15 25% of ductal type (G2/G3) No correlation IHC more predictive than FISH: FISH/IHC equally predictive: IHC primary FISH only if IHC2+ Rushoff et al.: Virchow Arch, 21 3

4 Waterfall plot ( ITT population) 1 Change from Screening(%) 5-5 T+XP/FP 群 XP/FP 群 (n=247) (n=22) % of patients -1 JSMO211 O2-265 presented by Y.Hamamoto 4

5 Primary end point: OS Event FC + T FC Events Median OS HR.74 95% CI.6, Time (months) p value.46 No. at risk T, trastuzumab 5

6 6

7 7

8 ガイドライン委員会のコメント ( 案 ) 1) 本試験の結果 HER2 陽性胃癌 ( 切除不能な進行再発の胃癌 食道胃接合部癌 ) に対してトラスツズマブを含む化学療法が新たな標準治療となることが示された また 本試験では 3,665 例が IHC または FISH による HER2 スクリーニングを受け 81 例 (22.1%) が HER2 陽性 (IHC3+ または FISH 陽性 ) と判定されている 今後は 化学療法選択前に HER2 検査を実施することが推奨される ( 註 :211 年 4 月時点では IHC と FISH 検査を同月に検査することは保険で認められていない ) 2) 本試験では HER2 陽性の定義を IHC3+ または FISH+ とした なお サブセット解析の結果 IHC3+ または IHC2+ かつ FISH+ の HER2 高発現群 (446 例 76.4%) で生存期間の延長がより明確に示された (16. ヶ月 /11.8 ヶ月 ハザード比.65 ( )) 3) 本試験では重篤な循環器疾患が除外されたこともありトラスツズマブ群で特に目立った有害事象の増加は認められなかった しかし 乳癌でのトラスツズマブ使用経験から治療前や治療中および治療後の心機能等への留意が必要である 4) 本試験の試験群のレジメンはカペシタビン (or 5-FU) + シスプラチンとトラスツズマブの併用であり HER2 陽性胃癌に対してはこのレジメンが推奨される 本邦の進行胃癌に対する標準治療である S-1+ シスプラチンとトラスツズマブの併用に関しては有効性ならびに毒性等のプロファイルは不明であり 今後の臨床研究の課題である Evaluation of the appropriate use of trastuzumab in treatment for advanced or metastatic HER2-positive gastric cancer Yasuo Hamamoto On behalf of the ToGA investigators 16 JSMO211 O2-265 presented by Y.Hamamoto 8

9 Background : ToGA trial 多国籍多施設共同ランダム化非盲検第 Ⅲ 相試験 スクリーニング :3,87 例 HER2 陽性 :81 例 (22.1%) HER2 陽性進行胃癌 584 例 層別因子 ECOG PS -1 vs 2 カペシタビン vs 5-FU 局所進行性 vs 転移性 原発部位胃 vs 胃食道接合部 測定可能 vs 測定不能 < 治療レジメン> カペシタビン (X)1,mg/m 2 経口 1 日 2 回 第 1-14 日 5-FU (F) 8mg/m 2 / 日 静注 第 1-5 日シスプラチン (P) 8mg/m 2 トラスツズマブ (T) 6mg/kg( 初回 8mg/kg)PDまで Bang YJ et al.: Lancet 376, , 21 R 化学療法群 XP/FP 29 例 トラスツズマブ併用群 T+XP/FP 294 例 XP/FP 投与終了 * XP/FP 投与終了 * *3 週毎 6 コース (27 年 7 月以降は 6 コースを超えた投与が可能となった ) Observation only T 単剤 JSMO211 O2-265 presented by Y.Hamamoto 試験治療中止( 病勢進行等) 方法 対象と方法 ToGA 試験において 各症例の薬剤治療歴を抽出し 薬剤の組み合わせとその投与期間を集計した Observation only 期間の定義 P X 臨床検査 Observation only 期間 ( サイクル ) Observation only 期間 ( 日 ) 臨床検査 試験終了 対象 T 単剤投与期間の定義 T T T P X T 単剤期間 ( サイクル ) T 単剤期間 ( 日 ) ToGA ITT population (n=584) 試験終了 JSMO211 O2-265 presented by Y.Hamamoto 9

10 T 単剤投与症例と Observation only 症例の治療選択状況とその理由 <T 単剤または Observation only となった理由 > 例数 (%) XP/FP 群 Observation only となった症例 (n=97) T+XP/FP 群 T 単剤投与が行われた症例 (n=159) 化学療法 6サイクルの投与完遂 78 (8%) 131 (82%) その他 19 (2%) 28 (18%) <T 単剤または Observation only が終了した理由 > 例数 (%) XP/FP 群 Observation only となった症例 (n=97) T+XP/FP 群 T 単剤投与が行われた症例 (n=159) 効果不十分 73 (75%) 115 (72%) 治療継続拒否 4(3%) 9 (6%) 有害事象 9(9%) 5 (3%) その他 3 (1%) 2 (1%) 治療継続中 * 8 (8%) 28 (18%) * データカットオフ時に試験治療を継続していた症例 JSMO211 O2-265 presented by Y.Hamamoto XP/FP 群における各症例の投与薬剤組み合わせ別サイクル数 (n=29) XP/FP X/F CDDP Patient ID Observation サイクル数 平均 (SD) 中央値 ( 最小 - 最大 ) Observation only が行われた症例 (n=97) 4.5 (5.49) 3. (1-38) Number of cycles JSMO211 O2-265 presented by Y.Hamamoto 1

11 T+XP/FP 群における各症例の投与薬剤組み合わせ別サイクル数 (n=294) Patient ID T+XP/FP T+CDDP T+X/F XP T サイクル数 T 単剤投与が行われた症例 (n=159) 平均 (SD) 6.9 (7.33) 中央値 ( 最小 - 最大 ) 4. (1-43) Number of cycles JSMO211 O2-265 presented by Y.Hamamoto T 単剤期間と Observation only 期間 XP/FP 群 Observation only が行われた症例 (n=97) T+XP/FP 群 T 単剤投与が行われた症例 (n=159) 平均 ( 日 ) (SD) 中央値 ( 日 ) ( 最小 - 最大 ) 78.8 (112.46) 39. (1-796) (16.68) 7. (1-882) JSMO211 O2-265 presented by Y.Hamamoto 11

12 On-going lapatinib trials for HER2 gastric cancer Lapatinib is the standard for patients with mbc who has a prior history of trastuzumab. 1 st line LOGiC Global Trial; CapeOX +/- Lapatinib PE: OS, n=533 2 nd line TyTAN Asian Trial; weekly PTX +/- Lapatinib PE: OS, n=26 Very important to establish disease entity of HER2 positive GC and to follow breast story AVAGAST: A Randomized Double-Blind Placebo- Controlled Phase III Study Locally advanced or metastatic gastric cancer R Capecitabine*/Cisplatin (XP) + Placebo q3w Capecitabine*/Cisplatin (XP) + Bevacizumab q3w Stratification factors: 1. Geographic region 2. Fluoropirimidine backbone 3. Disease status *5-FU also allowed if cape contraindicated Cape 1 mg/m 2 oral bid, d1 14, 1-week rest Cisplatin 8 mg/m 2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of 6 cycles of cisplatin Cape and bevacizumab/placebo until PD Starting dose of bev/placebo: 3 minutes, subsequent doses: 15 minutes 12

13 5 Lesson from AVAGAST trial Regional difference cannot be ignored. Median survival time in developed countries is around one year. Thus, it is very difficult to show survival benefit in the 1 st line setting for all gastric cancers; > 2M difference is necessary to get a hazard ratio of.8 (11 vs 14M). Bevacizumab has no killing activity by itself. Because gastric cancers are very heterogeneous; There may be specific types of gastric cancer to some molecular target agents. Enriched population selected by bio-marker, like Herceptin. Single target such as Bevacizumab may not be sufficient; Multiple target TKI? Or Combination of molecular target agents?? 13

14 Ceiling effect of Bevacizumab? MST of placebo arm in Asia is longer than those of bevacizumab arm in other regions HRs in each region seem to be correlated with the results of placebo arms XP+placebo XP+bevacizumab Survival Post-Progression Trial Region Regimen mpfs MST MST - PFS AVAGAST trial FLAGS trial SPIRITS Asia Europe Pan-America Non-Asia Japan XP XP+Bev XP XP+Bev XP XP+Bev 5-FU+CDDP S-1+CDDP S-1 S-1+CDDP JCOG9912 Japan CPT-11+CDDP START Japan/Korea S-1+TXT

15 5 Lesson from AVAGAST trial Regional difference cannot be ignored. Median survival time in developed countries is around one year. Thus, it is very difficult to show survival benefit in the 1 st line setting for all gastric cancers; > 2M difference is necessary to get a hazard ratio of.8 (11 vs 14M). Bevacizumab has no killing activity by itself. Because gastric cancers are very heterogeneous; There may be specific types of gastric cancer to some molecular target agents. Enriched population selected by bio-marker, like Herceptin. Single target such as Bevacizumab may not be sufficient; Multiple target TKI? Or Combination of molecular target agents?? Simulations of PFS and OS by survival post progression(spp) OS is too high a bar when median SPP is long The timing at data cut off in AVAGAST might be too early for Asian population (= immature for Asia/Japan) Broglio K R, Berry D A JNCI J Natl Cancer Inst 29;11:

16 Study Treatments Stratified for PS & #prior therapy SLC regimen determined by investigators SLC continued until progression, toxicities, or withdrawal R A N D O M I Z A T I O N 2 1 Docetaxel 6 mg/m 2 q3wks or Irinotecan 15 mg/m 2 q2wks BSC alone Strict QC measures for BSC Standard BSC regimen a priori defined BSC patients could exit BSC at any time All patients treated & followed up in same way 211 ASCO Annual Meeting #44 Overall Survival Survival Probability Median f/u (95% CI) : 17 mo (16 18 mo) Median 95% CI SLC + BSC5.1 mo BSC alone 3.8 mo Log-rank P = Months 211 ASCO Annual Meeting #44 16

17 mtor Pathway Activation in Gastric Cancer Growth Signaling Nutrients PTEN EGF TSC2 TSC1 Akt Protein Synthesis PIK3CA Cell Growth Bioenergetics & Proliferation Angiogenesis IGF Cancer Cell mtor is activated in 6-64% of gastric cancers mtor pathway proteins are frequently over-activated in gastric cancer: PIK3CA: 4-25% p-akt: 29-78% IGFR 25% EGFR 22-43% Loss-of-function mutations PTEN (LOH): 17-76% 17

18 mtor expression is a worse prognostic factor in gastric cancer patients after R resection Xu D et al. BMC Cancer, 21 Remarkable response in pt with mgc everolimus phase I (NCCHE) 9-Jun-26 Baseline 4-Aug-26 2 months after everolimus 18

19 Everolimus phase 2 for second or third line AGC Decrease in Tumor Size from Baseline (Central Review) Best percent change from baseline (Target lesions) 1% 75% 5% 25% % 25% 5% 75% 1% N=53 Decreased pts 45.3% Increased pts 32.% Max 34.2% decreased Lymph node-abdominal and supraclavicular cm Ovary 88.2% progression cm Liver 64.8% progression cm ** SD PD DCR= 54.7% ( ) (29/53) Doi T et al. J Clin Oncol 21 Phase II Everolimus AGC Study: Progression-Free Survival Probability (%) Censoring Times Everolimus 1 mg/day (N=53) Time (months) No. of patients still at risk: Doi T, et al. J Clin Oncol. 21;28(11): Median: 2.7 months (95%CI: months) 2.6 months (95% CI, months) for second-line subset 2.8 months (95% CI, months) for third-line subset

20 Everolimus in Advanced Gastric Cancer: Progression-Free Survival 1 8 Paclitaxel Docetaxel Everolimus Irinotecan DCF 2.1 mo mo 2* 2.7 mo 3 3. mo 4* 5.6 mo 5* Probability (%) Median PFS = 2.7 months 95% CI: n=53 Censored observation Time (Months) Time (months) No. pts still at risk Hironaka S, et al. Gastric Cancer. 26;9:14 18; 2. Jo JC, et al. Jpn J Clin Oncol. 27;37: ; 3. Yamada Y, et al. Poster presentation at ASCO GI 29, San Francisco, CA, USA. Abstract 77; 4. Köhne CH, et al. Br J Cancer. 23;59:997 11; 5. Van Cutsem E, et al. J Clin Oncol. 26;24: Everolimus randomized study in mgc: GRANITE-1 Second or third line metastatic GC Placebo + BSC Everolimus + BSC Primary endpoint; OS Required sample size = 633 (2:1 randomization) Participants: Asia, EU, US Accrual completed & interim analysis coming soon 2

21 On-going trials of mtor inhibitor for gastric cancer Phase Drugs Status Phase III Monotherapy vs. Best Supportive Care Active, not recruiting Phase III Paclitaxel with and without Everolimus Not yet recruiting Phase II Monotherapy Completed Phase II Monotherapy Active, not recruiting Phase II Monotherapy Recruiting Phase II Combination with Cisplatin, 5-FU/LV Recruiting Phase I/II Combination with Capecitabine Recruiting Phase I Combination with Mitomycin C Active, not recruiting Phase I Combination with XELOX Recruiting Phase I Combination with Docetaxel Recruiting Phase I Combination with mfolfox6 Not yet recruiting Phase I Combination with TS-1, Cisplatin Not yet recruiting PI3K-Akt-mTOR Pathway inhibitors 2 4% of CRCs and GCs bear alterations in one of PI3K pathway genes (i.e., PIK3CA, PTEN, PDK1, Akt2). High incidence of PIK3CA Compounds in clinical development: PI3K inhibitors GDC-941 BEZ235, BGT226, BKM12 XL147, XL765 mtor inhibitors: Rapamycin (sirolimus) Temsirolimus (CCI779) Everolimus (RAD1) Deforolimus (AP23573) Dual mtorc1 and mtorc2 inhibitors Akt inhibitors: PBI-524 (oleandrin) MK-226 GDC68 Key to achieving a response? CRC = colorectal cancer 21

22 Trastuzumab and everolimus combination in mbc Trastuzumab and everolimus are both active in gastric cancer in vitro and in vivo Trastuzumab + everolimus + paclitaxel activity in breast cancer: HER2/neu overexpressing breast cancer patients resistant to trastuzumab (n=31) Varied everolimus doses: 5 mg daily (n=6); 1 mg daily (n=15); 3 mg weekly (n=1) RR: 83% (5 mg); 13% (1 mg); 3% (3 mg) DCR: 83% (5 mg); 88% (1 mg); 8% (3 mg) RR, response rate; DCR, disease control rate 5 Lesson from AVAGAST trial Regional difference cannot be ignored. Median survival time in developed countries is around one year. Thus, it is very difficult to show survival benefit in the 1 st line setting for all gastric cancers; > 2M difference is necessary to get a hazard ratio of.8 (11 vs 14M). Bevacizumab has no killing activity by itself. Because gastric cancers are very heterogeneous; There may be specific types of gastric cancer to some molecular target agents. Enriched population selected by bio marker, like Herceptin. Single target such as Bevacizumab may not be sufficient; Multiple target TKI? Or Combination of molecular target agents?? 22

23 Lesson 3: Bevacizumab has no killing activity by itself Region XP + Placebo Median, mo XP + Bev Median, mo mo Hazard Ratio 95% CI OS Asia Europe America PFS Asia Europe America RR Asia 45.5% 47.9% 2.4% Europe 28.2% 41.3% 13.1% America 36.4% 5.% 13.6% Ohtsu A, et al. WCGIC, 21 Another angiogenesis inhibitor: ramucirumab (anti-vegfr2 Ab) VEGFR-2 appears to be the most responsible for the mitogenis and angiogenic effect of VEGF DC11= murine anti-vegfr2 antibody 23

24 Response in phase I study of ramucirumab (anti-vegfr2 Ab) Response rate = 15% Disease control rate = 62% Spratlin JL et al. J Clin Oncol 21 Ramucirumab (anti-vegfr2) for mgc: RAINBOW: second-line setting Metastatic GC refractory to Fus and platinum Randomize W-paclitaxel + placebo W-paclitaxel + Ramucirumab Primary endpoint: Overall survival Study rationale: single agent anti-tumor activity for GC (in vitro, clinial) synergism between ramcirumab and taxane second-line setting 24

25 5 Lesson from AVAGAST trial Regional difference cannot be ignored. Median survival time in developed countries is around one year. Thus, it is very difficult to show survival benefit in the 1 st line setting for all gastric cancers; > 2M difference is necessary to get a hazard ratio of.8 (11 vs 14M). Bevacizumab has no killing activity by itself. Because gastric cancers are very heterogeneous; There may be specific types of gastric cancer to some molecular target agents. Enriched population selected by bio marker, like Herceptin. Single target such as Bevacizumab may not be sufficient; Multiple target TKI? Or Combination of molecular target agents?? Blood plasma VEGF-A analysis in the AVAGAST randomized study of first-line bevacizumab + capecitabine/cisplatin in patients with advanced gastric cancer MA Shah 1, YK Kang 2, A Ohtsu 3, L Roman 4, J Nunes 5, CP Li 6, P Delmar 7, B Langer 8, SJ Scherer 9, E Van Cutsem 1 1 Memorial Sloan Kettering Cancer Center, New York, USA; 2 Asan Medical Centre, Seoul, Korea; 3 National Cancer Center Hospital East, Kashiwa, Japan; 4 Leningrad Regional Oncology Centre, St Petersburg, Russian Federation; 5 Hospital Do Cancer de Barretos, Barretos, Brazil; 6 Veterans General Hospital Cancer Center, Taipei, Taiwan; 7 F. Hoffmann-La Roche, Basel, Switzerland; 8 F. Hoffmann-La Roche, Basel, Switzerland; 9 Genentech Inc, South San Francisco, USA; 1 University Hospital Gasthuisberg, Leuven, Belgium 25

26 Samples Samples and pvegf-a levels Overall, 774 patients participated in the AVAGAST study Baseline pvegf-a samples were available for 712 (92%) of these patients Baseline characteristics of the biomarker population were similar to the overall population pvegf-a The median plasma levels of VEGF-A at baseline was 111 ng/l (range ng/l) in the overall population Baseline pvegf-a levels were higher in patients from non-asian regions than in Asian patients (median 147 vs. 94 ng/l; p<.1; Mann-Whitney U test), and in patients with a poorer Eastern Cooperative Oncology Group performance status (p<.1; Mann-Whitney U test) Kaplan-Meier estimates of overall survival by baseline pvegf-a level and treatment group Overall survival rate (%) XP + placebo ( median) XP + placebo (>median) XP + bev ( median) XP + bev (>median) No. at risk XP + placebo ( median) XP + placebo (>median) XP + bev ( median) XP + bev (>median) Study month

27 Overall survival by baseline pvegf-a level and treatment group in non-asian / Asia-Pacific patients Overall survival rate (%) Non-Asian patients Study month XP + placebo ( median) XP + placebo (>median) XP + bev ( median) XP + bev (>median) Asia-Pacific patients Overall survival rate (%) Study month XP + placebo ( median) XP + placebo (>median) XP + bev ( median) XP + bev (>median) No. at risk XP + placebo ( median) XP + placebo (>median) XP + bev ( median) XP + bev (>median) No. at risk XP + placebo ( median) XP + placebo (>median) XP + bev ( median) XP + bev (>median) pvegf-a at baseline and OS and PFS (biomarker population, quartile analysis) Total group Subgroup 25 th percentile 25 5 th percentile 5 75 th percentile > 75 th percentile Non-Asian group Subgroup 25 th percentile 25 5 th percentile 5 75 th percentile > 75 th percentile Asia-Pacific group Subgroup 25 th percentile 25 5 th percentile 5 75 th percentile > 75 th percentile Overall survival Progression-free survival Hazard ratio* Hazard ratio* *Hazard ratio of <1 denotes benefit for bevacizumab + chemotherapy; hazard ration >1 denotes benefit for chemotherapy 27

28 Evaluation of plasma VEGF-A as a potential predictive pan-tumour biomarker for bevacizumab Gordon C Jayson on behalf of: de Haas S, Delmar P, Miles DW, Shah MA, Van Cutsem E, Carmeliet P, Hegde P, Wild N, Scherer SJ Background A novel ELISA-based assay favouring shorter isoforms (VEGF-A 121 and VEGF-A 11 ), was used to assess the predictive value of VEGF-A in 6 different bevacizumab trials CRC NSCLC BC RCC AVF217g 1 OS: HR=.66 p<.1 (n=923) AVAiL 2 PFS: HR=.75/.82 p=.3/.3 (n=143) AVADO 3 PFS: HR=.67 p=.2 (n=736) AVOREN 4 PFS: HR=.63 p=.1 (n=649) GC PC AVAGAST 5 OS: HR=.87 p=.12 (n=774) AViTA 6 OS: HR=.89 p=.287 (n=67) 1. Hurwitz et al. NEJM 24; 2. Reck et al. JCO 29; 3. Miles et al. JCO 21; 4. Escudier et al. Lancet 27; 5. Ohtsu et al. JCO, 211; 6. Van Cutsem et al. JCO 29 28

29 29

30 3

31 EGFR Inhibitor 31

32 EGFR-expression rates in human cancers Colorectal EGFR is expressed in a variety of solid tumors Lung (NSCLC) Head and neck (SCCHN) Colorectal cancer, % Head and neck cancer, % 95 1 Lung cancer (NSCLC), % 4 8 Gastric cancer % 33-7 Breast cancer, % Ovarian cancer, % 35 7 Renal cell cancer, % 5 9 Cunningham et al. N Engl J Med 24;351: ; Grandis et al. Cancer 1996;78: ; Salomon et al. Crit Rev Oncol Hematol 1995;19: ; Walker & Dearing. Breast Cancer Res Treat 1999;53: ; Folprecht et al. ASCO 24 (Abstract #283). 63 Cetuximab combinations for GC: first-line phase II Agents n RR M-PFS(M) MST(M) FOLFIRI+cetux % Iri/FU (AIO)+cetux % 8 16 mfolfox6+cetux 4 5 % FUFOX+cetux % XELOX+cetux % CDDP/doce +cetux % Pinto,et al. Ann Oncol, 27; Moehler et al, ASCO-GI 28; Han SW, et sl. ASCO-GI 28; Lordick et al. ASCO 27; Kim C, et al ASCO-GI, 29; Pinto et al. ASCO 28 32

33 Cetuximab for gastric cancer:expand study Metastatic gastric cancer Cape + CDDP Cape + CDDP + cetuximab Required sample size = 87 Primary endpoint; Progression-free survival Participants; EU (Germany, France, Italy,, etc), Asia (Japan, Korea, China etc) Pts accrual have been completed 33

34 Super-responder を探せ ( 個別化医療 ) 34

35 Imatinib for GIST Sunitinib for GIST 35

36 Cetuximab for Colon Cancer 36

37 Erlotinib for Pancreatic Cancer Sorafenib for HCC 37

38 5 Lesson from AVAGAST trial Regional difference cannot be ignored. Median survival time in developed countries is around one year. Thus, it is very difficult to show survival benefit in the 1 st line setting for all gastric cancers; > 2M difference is necessary to get a hazard ratio of.8 (11 vs 14M). Bevacizumab has no killing activity by itself. Because gastric cancers are very heterogeneous; There may be specific types of gastric cancer to some molecular target agents. Enriched population selected by bio-marker, like Herceptin. Single target such as Bevacizumab may not be sufficient; Multiple target TKI? Or Combination of molecular target agents?? Lesson 5: Single target such as Bevacizumab may not be sufficient; Multiple target TKI? or Combination of molecular target agents?? ESMO 21 38

39 New agents for HER2: pertuzumab and TDM-1 neoadjuvant: pcr rate in taxane (T)+ herceptin(h) + pertuzumab (P) Efficacy of TDM-1 in pts failed to taxane, trastuzumab, lapatinb, cape 現在の消化器領域における分子標的薬の限界 : 私見消化器がんで Addiction になっている遺伝子異常はあるのか? 著効を示す分子標的薬は開発可能か? 肺癌においても Oncogene Addiction を起こしているのは 喫煙歴のない きれいな肺癌 きれいながん vs きたないがん GIST > pnet > GI Cancers 単純な発がん vs 多段階発がん vs 無秩序発がん GIST > pnet > Pancreatic, Colorectal, HCC > Gastric きたない胃がんには きれいな個別化よりも きたなく攻める??? 分子標的治療薬も併用すれば Cytotoxic と同じ????? 39

40 ご清聴ありがとうございました ACTS-GC Eligibility criteria: Histologically proven gastric carcinoma D 2 lymph node dissection, R resection Stage II/III (Japanese classification) Negative peritoneal cytology Age 2-8 years No prior adjuvant therapy Adequate organ function Written informed consent Central Randomization (dynamic balancing) Adjustment factors : Stage*(II, IIIA, IIIB), Institution S mg/day** 4 weeks administration with 2weeks off in each course for 12 months Surgery only (No further therapy) Primary endpoint: Overall Survival Secondary endpoint: Relapse-free survival, Safety of S-1 * Japanese Classification of Gastric Carcinoma, 13th ed,1999 ** Body surface area (m 2 ) < 1.25 m 2 : 8mg/day, < 1.5 m 2 1mg/day, >= 1.5 m 2 12mg/day M Sasako et al, ESMO 21 (#79PD) 4

41 Overall Survival Stage IIIB in ACTS-GC trial Overall Survival (%) Overall Survival HR =.791 [ ] 3 5 年 OS 2 S-1 5.2% 1 手術単独 44.1% Relapse-free Survival (%) ( 適格例 ) Relapse-free Survival 4 HR =.788 [ ] 3 5 年 RFS 2 S % 1 手術単独 34.4%

42 CLASSIC study design Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization No prior chemotherapy or radiotherapy n=135 R A N D O M I Z A T I O N 1:1 n=52 Capecitabine: 1,mg/m 2 bid, d1 14, q3w Oxaliplatin: 13mg/m 2, d1, q3w n=515 8 cycles of XELOX (6 months) Observation: No adjuvant therapy Primary endpoint: 3-year DFS Secondary endpoints: overall survival and safety profile Stratified by stage and country with age, sex, and nodal status as covariates GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 29 42

43 Primary endpoint (3-year DFS) met at interim analysis 3-year DFS No. left XELOX Observation HR=.56 (95% CI.44.72) P<.1 Time (months) 74% 6% XELOX, n=52 Observation, n=515 ITT population; DFS = disease-free survival Median follow-up 34.4 months (range 16 51) XELOX では S-1 に 簡単には 勝てないですよ!! ACTS-GC Classic HR n 観察期間 24M 34M DFS All Stage II Stage IIIa Stage IIIb

44 A phase II study of preoperative chemotherapy with S-1 (S) and cisplatin (P) followed by D3 gastrectomy for gastric cancer with extensive lymph node metastasis (ELM): -Survival results of JCOG45 T. Yoshikawa, K. Nakamura, A. Tsuburaya, T. Sano, J. Mizusawa, H. Katai, A. Kurita, I. Uyama, E. Nomura, M. Sasako, T Definition of extensive lymph node metastases Bulky N2 : >3cm or >1.5cm x 2 #16 : >1cm paraaortic JCOG 1 44

45 Radiological tumor response by RECIST ver 1. *Central review Response CR PR SD PD NE N % ( / 51) % 64.7% 27.5% 7.8% % Response rate was 64.7% (95%CI; %). Pathological response in the lymph node Grade* 1a 1b 2 3 Degeneration None 1/3> 1/3-2/3 >2/3 1% area n % ( / 51**) 7.8% 33.3% 13.7% 21.6% 15.7% * Grading due to the proportion of degeneration area in the primary tumor by the Japanese Classification of Gastric Carcinoma ** All eligible. Data is missing in 4 patients (3 no surgery, 1 data not available) Pathological response rate of the lymph node was 51.% (95%CI; %). Overall survival (n=51, all eligible) Cumulative overall survival Median overall survival time; not reached 3-year overall survival ; 58.8% (95% CI, %) Time (years) 45

46 Modified DCF with bi-weekly 5-FU/LV, CDDP and DTX 46

47 mdcf is more active and feasible than original DCF CDDP と L-OHP 同じではない 基礎実験での交差耐性 CDDP 投与後の L-OHP Kim (23) Seo (29) Kim (21) L-OHP 5FU LV q2w /48h 15/48h q2w 1 24/48h 1/2h q2w(folfox4) /48h 2/2h N 26 Phase II Pre-treatment Platinum 5FU 1% 1% 62 Retro 68% 84% 42 Phase II 6% 91% RR DCR PFS (M) OS (M) 26%* (26%*) 35% % (25%*) 58% % (29%*) 55% *CDDP 耐性後に限ったRR CDDPとOHPは 臨床的には 交差耐性はない と考えていい 94 効果のある症例に違いがある?

48 かなり無茶のようですが すべて外来で可能術前は強力なtriplet(3ヶ月 ) 術後はfeasibility(3ヶ月) CDDP OHP( 感受性 毒性 ) S-1 Cape( 毒性 ) Clinical Stageによる再発高危険群の選定 Neoadjuvant Cx 2w 2w 2w 2w 2w 2w S-1(4mg/m 2 ) x2, 7days LV (25mg/body) x2, 7days CDDP (4mg/m 2 ) Doce (4mg/m 2 ) Herceptin if Her-2(+) Surgery Adjuvant Cx 3w 3w 3w 3w Cape(1g/m 2 ) x2, 14days OHP (13mg/m 2 ) Herceptin if Her-2(+) 48