周彩存 周彩存，医学博士，博士生导师，主任 医师，教授；上海市领军人才，享受国 务院特殊津贴 现任同济大学附属上海市肺科医院肿瘤 科主任，医学院肿瘤研究所所长 中国医促会胸部肿瘤分会主委，中国抗 癌协会肺癌专业委员会常委，上海市抗 癌协会肺癌分子靶向和免疫治疗专业委 员会主委，中国抗癌协会肿瘤药物临床 研究专业委员会副主任委员，上海市医 学会分子诊断专委会副主任委员，中国 医师协会肿瘤分会常委，上海市医师协 会肿瘤分会副会长 晚期非小细胞肺癌的精准治疗 Caicun Zhou Shanghai Pulmonary Hospital, Shanghai Tongji University, P.R.China 肺癌是我国发病率和死亡率最高的恶性肿瘤，5年生存率仅为16 发病率和死亡率仍在上升 肺癌对患者、家庭、国家都是一种灾难 生存期短 过度治疗 无效治疗 患 者家 庭国 家 失去家庭成员的巨大痛苦 高昂治疗费用的压力 治与不治的艰难选择 不断增加的高 昂医疗负担 高加索肺腺癌驱动基因图谱亚裔肺腺癌驱动基因图谱 Sholl LM, et al. J Thorac Oncol. 2015;10(5):768-777 Seo JS, Genome Res. 2012, 22(11):2109-2119 肺癌驱动基因谱明确，精准治疗条件最成熟 KRAS 25% 无已知 的肿瘤 驱动 基因 36% EGFR 23% ALK 7.9% MEK1 0.3% ERBB2 2.7% BRAF 2.6% PIK3CA 0.8% NRAS 0.7%MET 0.7% 融合 基因 点突变 未知 肺腺癌 （n=200） 外显子 跳跃 精准治疗，路在何方？ Precision Medicine in Advanced NSCLC Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science Transl. Med. 2013 Target therapy (1st, 2nd, and 3rd generation) New targets Increase of biomarker testing Immunotherapy 1 50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma No actionable driver mutation AvastinChemo Non-squamous NSCLC Adeno Ca Squamous Ca. SCLC NOS Large cell US Lung Cancer Mutational Consortium (LCMC) Collaboration of 14 US Cancer Centers Multiplex genotyping of 1007 adenocarcinomas (full genotyping 733) Close link to clinical trial platform Kris et al., ASCO 2011, # 7506, Kris et al., JAMA 2014 LCMC: Benefit in overall survival for personalized treatment Kris et al., ASCO 2011, # 7506, Kris et al., JAMA 2014 IPASS开启了EGFR-TKI的肺癌精准医学时代 04812162024 0.0 0.2 0.4 0.6 0.8 1.0 Gefitinib EGFR M+ (n=132) Gefitinib EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) Probability of PFS EGFR M+ HR (95% CI) 0.48 (0.36, 0.64), p50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma No actionable driver mutation AvastinChemo Non-squamous NSCLC Adeno Ca Squamous Ca. SCLC NOS Large cell E4599：贝伐珠单抗一线联合卡铂/紫杉醇 显著延长PFS、OS及ORR ECOG 4599 HR=0.66, p200 Squamous Carcinoma Smoking adenocarcinoma No actionable driver mutation AvastinChemo Non-squamous NSCLC Adeno Ca Squamous Ca. SCLC NOS Large cell Activity in pretreated patients NivolumabPembrolizumabAtezolizumabDurvalumabAvelumab N129475175228184 RR 鳞鳞癌 非鳞鳞癌 17% 18% 23.5% 19% 27% 21% 21% 13% 14% 药药物相关 AE 所有级别级别 级级 41% 4.7% 71% 9.5% 66% 11% 50% 8% 77% 12% RR PDL-1 阳性 PDL-1 阴性 16% 13% 42% (50%) 10% (1%) 34% IC2/3 or TC 2/3 (half if 3 used) Gettinger S, J Clin Oncol 2015; 33: 2004-2012; Herbst R, Nature 2014; 515: 563-7; Soria JC, ESMO 2013 ; Garon E, NEJM 2015; 372: 2018-28; Rizvi N, ASCO 2015; Guley LJ, ASCO 2015 Nivolumab vs docetaxel in advanced NSCLC Overall survival Sqamous Adenocarcinoma HR 0.59 (95% CI 0.44-0.79) HR 0.73 (95% CI 0.59-0.89) P0.001p=0.002 Brahmer J et al. NEJM 2015, 373, 123Borghaei H et al. NEJM 2015 Pembrolizumab (2 or 10 mg/kg) versus docetaxel in advanced NSCLC: Overall Survival Herbst R et al. Lancet Oncology 2015, online December 18 PD-L1 50% or more Pembrolizumab 10 mg /kg every 3 weeks: HR 0.50 (95% CI 0.36-0.70) p0.0001 Pembrolizumab 2 mg/kg every 3 weeks: HR 0.54 (95% CI 0.38-0.77) p=0.0002 Total Pembrolizumab 10 mg /kg every 3 weeks: HR 0.61 (95% CI 0.49-0.75) p=0.0001 Pembrolizumab 2 mg /kg every 3 weeks: HR 0.71 (95% CI 0.58-0.88) p=0.0008 Slide 16 Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting 探索性汇总无进展生存K-M曲线 Slide 17 Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting 探索性汇总总 生存K-M曲线 一线策略？ Monotherapy High PD-L1 expression In combination with chemotherapy Low PD-L1 expression In combination with other agents Targeted therapies？ Bevacizumab Immune checkpoint inhibitors Other immunotherapies 免疫治疗一线研发策略 Primary endpoint: Progression-free survival (independent radiology review committee) in patients with strongly PD-L1 positive tumors 535 patients Nivolumab 3 mg/kg i.v. every 2 weeks (until disease progression, unacceptable toxicity, withdrawal of consent or study closure) Chemotherapy (investigators choice, up to 6 cycles) vs Pembrolizumab as first-line therapy in patients with high levels of PD-L1 KEYNOTE-024 Mercks KEYTRUDA (pembrolizumab) demonstrates superior -progression-free survival and overall survival compared to chemotherapy as first-line therapy in patients with advanced non-small cell lung cance.r Press release, Thursday, June 16, 2016 6:45 am EDT 34% of Patients were TPS1% KEYNOTE-021(phase /):study design Stage IIIB/IV NSCLC No systemic therapy for recurrent disease ECOG PS 0-1(n=308) Cohort A: Pembrolizumab+carboplatin+paclitaxel (n=25) Cohort B: Pembrolizumab+carboplatin+paclitaxel +bevacizumab (n=25) Cohort C: Pembrolizumab+carboplatin+ pemetrexed (n=25) Maintenance pembrolizumab Maintenance pembrolizumab+ bevacizumab Maintenance pembrolizumab+ pemetrexed Pembrolizumab dose: 2 or 10mg/kg i.v. q3w; Carboplatin dose: AUC 6 i.v.(cohort A and B), AUC 5 i.v.(cohort C); Paclitaxel dose: 200mg/m2 i.v. q3w; Bevacizumab dose:15mg/kg i.v.q3w; Pemetrexed dose: