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| 1 | 帕博利珠单抗单用或与放疗联用治疗转移性非小细胞肺癌:两个随机试验的汇总分析显示文摘背景放疗可以提高整个机体对免疫治疗的应答。在Ⅱ期PEMBRO-RT研究和Ⅰ/Ⅱ期MDACC研究中,患有转移性非小细胞肺癌(NSCLC)的患者被随机分配入组,接受免疫治疗(帕博利珠单抗)+放疗联合疗法,或免疫治疗单一疗法。当上述2个研究单独分析时,联合疗法组显示出潜在获益。由于每个研究的样本量较小,缓解率和结局并未显示出统计学意义,然而却有显著的临床获益。因此,本研究进行汇总分析,来判断放疗是否会改善转移性NSCLC患者的免疫治疗应答。方法PEMBRO-RT和MDACC研究纳入标准:患者年龄≥18岁,患有转移性NSCLC,且有≥1处未经放疗照射的病灶,以便进行射野外应答监测。PEMBRO-RT研究纳入曾接受过化疗患者,MDACC研究纳入曾接受过治疗或新诊断患者。2个研究中的患者均未接受过免疫治疗。在PEMBRO-RT研究中患者被等比例随机分配入组,并根据吸烟状态进行分层(分为<10年组和≥10年组)。MDACC研究的患者根据放疗计划可行性被等比例随机分配入2个受试组。由于联合治疗组的干预本质,每个研究中的放疗均不适用盲法。在2个研究中,不论是否进行放疗,均静脉滴入帕博利珠单抗(每3周200 mg)。在PEMBRO-RT研究中,在放疗(24 Gy 3次分割照射)结束后1周给予第1剂帕博利珠单抗。在MDACC研究中,在第1次放疗(50 Gy 4次分割照射或45 Gy 15次分割照射)同时给予帕博利珠单抗。仅检测未经照射病灶的应答。本研究的终点为最佳射野外(远隔)应答率(ARR)、最佳射野外疾病控制率(ACR)、12周时ARR、12周时ACR、无进展生存期(PFS)和总生存期(OS)。2个研究的意向治疗(ITT)人群均纳入分析。PEMBRO-RT研究(NCT02492568)和MDACC研究(NCT02444741)均在ClinicalTrials.gov上注册。发现纳入148例患者,76例接受帕博利珠单抗治疗,72例接受帕博利珠单抗+放疗治疗。所有患者随访时间中位数为33个月[四分位距(IQR):32.4~33.6]。148例患者中124例(84%)组织学特征为非鳞癌,111例(75%)患者曾经接受过化疗。组间没有基线特征差异,包括PD-L1表达状态和转移灶体积。最常见的照射部位为肺转移灶(39%,28/72)、胸腔内淋巴结(21%,15/72)和非原发灶(17%,12/72)。帕博利珠单抗组和联合治疗组的最佳ARR分别为19.7%(15/76)和41.7%(30/72),OR=2.96,95%CI:1.42~6.20,P=0.0039;最佳ACR分别为43.4%(33/76)和65.3%(47/72),OR=2.51,95%CI:1.28~4.91,P=0.0071;PFS中位数分别为4.4(IQR:2.9~5.9)和9.0个月(IQR:6.8~11.2),HR=0.67,95%CI:0.45~0.99,P=0.045;OS中位数分别为8.7(IQR:6.4~11.0)和19.2个月(IQR:14.6~23.8),OR=0.67,95%CI:0.54~0.84,P=0.0004。在汇总分析中没有发现新的安全问题。解读帕博利珠单抗免疫疗法+放疗显著提高转移性NSCLC患者的应答和改善治疗结局。这些结果需要在三期临床试验中进行验证。 | 陈大卫(翻译) 于金明(校对) Willemijn S M E Theelen Vivek Verma Brian P Hobbs Heike M U Peulen Joachim G J V Aerts Idris Bahce Anna Larissa N Niemeijer Joe Y Chang Patricia M de Groot Quynh-Nhu Nguyen Nathan I Comeaux George R Simon Ferdinandos Skoulidis Steven H Lin Kewen He Roshal Patel John Heymach Paul Baas James W Welsh | 2021 | 中华肿瘤防治杂志2021，28，24： | 49 |
| 2 | Predictive biomarkers in precision medicine and drug development against lung cancer显示文摘The molecular characterization of various cancers has shown that cancers with the same origins,histopathologic diagnoses,and clinical stages can be highly heterogeneous in their genetic and epigenetic alterations that cause tumorigenesis.A number of cancer driver genes with functional abnormalities that trigger malignant transformation and that are required for the survival of cancer cells have been identified.Therapeutic agents targeting some of these cancer drivers have been successfully developed,resulting in substantial improvements in clinical symptom amelioration and outcomes in a subset of cancer patients.However,because such therapeutic drugs often benefit only a limited number of patients,the successes of clinical development and applications rely on the ability to identify those patients who are sensitive to the targeted therapies.Thus,biomarkers that can predict treatment responses are critical for the success of precision therapy for cancer patients and of anticancer drug development.This review discusses the molecular heterogeneity of lung cancer pathogenesis;predictive biomarkers for precision medicine in lung cancer therapy with drugs targeting epidermal growth factor receptor(EGFR),anaplastic lymphoma kinase(ALK),c-ros oncogene 1 receptor tyrosine kinase[ROSl),and immune checkpoints;biomarkers associated with resistance to these therapeutics;and approaches to identify predictive biomarkers in anticancer drug development.The identification of predictive biomarkers during anticancer drug development is expected to greatly facilitate such development because it will increase the chance of success or reduce the attrition rate.Additionally,such identification will accelerate the drug approval process by providing effective patient stratification strategies in clinical trials to reduce the sample size required to demonstrate clinical benefits. | Bingliang Fang Reza J Mehran John V Heymach Stephen G Swisher | 2015 | Chinese Journal of Cancer2015，34，7： | 5 |
| 3 | Lung Cancer显示文摘 | Herbst RS Heymach JV | 2008 | N Engl J Med2008，359，13： | 1 |
| 4 | 7_2)6474 in combination with carboplatin and paclitaxel as first-line treatment in patients with NSCLC:Results of the run-in phase of a two-part randomized phase Ⅱ study显示文摘 | Heymach J West H Kerr R | 2005 | Lung Cancer2005，49，2： | 1 |
| 5 | ZD6474 in combination with carboplatin and paclitaxel as first line treatment in patients with NSCLC :Results of the run - in phase of a two - part randomized phase Ⅱ study显示文摘 | Heymach J West H Kerr R | 2005 | Lung Cancer2005，49，12： | 1 |
| 6 | A randomized,placebo-controlled phasc Ⅱ study of vandctanib plus docetaxel in previously treated non-small-cell lung cancer显示文摘 | Heymach JV Johnson BE Parger D | | 0，，11： | 1 |
| 7 | Randomized, placebo controlled phase Ⅱ study of vandetanib plus docetaxel in previously treated non small-cell lung cancer 显示文摘 | Heymach JV Johnson BE Prager D | 2007 | J Clin Oncol2007，25，27： | 1 |
| 8 | The tyrosine kinase inhibitor cediranib for non-small cell lung cancer and other thoracic malignancies显示文摘 | Nikolinakos P Heymach J V | 2008 | J Thorac Oncol2008，3，6： | 1 |
| 9 | Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and an- giogenesis显示文摘 | Herbst RS Heymach JV O'Reilly MS | 2007 | Expert 0pin Investig Drugs2007，16，2： | 1 |
| 10 | EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase Ⅲ study of second-line treatment of patients with advanced non-small cell lung cancer 显示文摘 | Heymach JV Lockwood SJ Herbst RS | 2014 | Ann Oncol2014，25，10： | 1 |
| 11 | Lung cancer 显示文摘 | Herbst RS Heymach JV Lippman SM | 2008 | N EnglJ Med2008，359，13： | 1 |
| 12 | Phase Ⅱ study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung eancer显示文摘 | Heymach JV Johnson DH Khuri FR | 2004 | Ann Oncol2004，15，8： | 1 |
| 13 | Lung cancer显示文摘 | Herbst RS Heymach JV Lippman SM | 2008 | N Engl J Med2008，359，13： | 1 |
| 14 | ZD6474 in combination with carboplatin and paclitaxel as first-line treatment in patients with NSCLC:Results of the run in phase of a two part randomized phase II study显示文摘 | Heymach J West H Kerr R | 2005 | Lung Cancer2005，49，2： | 1 |
| 15 | Lung cancer显示文摘 | Herbst RS Heymach JV Lippman SM | 2008 | N Engl J Med2008，359，13： | 1 |
| 16 | Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer显示文摘 | Heymach JV Johnson BE Prager D | 2007 | J Clin Oneol2007，25，27： | 1 |
| 17 | Molecular origins of cancer: Lung cancer显示文摘 | Herbst RS Heymach JV Lippman SM | 2008 | N Engl J Med2008，359，13： | 1 |
| 18 | Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-celllung cancer显示文摘 | Heymach JV Johnson BE Prager D | 2008 | Clin Oneol2008，26，1： | 1 |
| 19 | Two conserved domains in the NGF propeptide are necessary and sufficient for the biosynthesis of correctly processed and biologically active NGF显示文摘 | Suter U Heymach JV Jr Shooter EM | 1991 | EMBO J1991，10，9： | 1 |
| 20 | Molecular origins of cancer: lung cancer显示文摘 | Herbst RS Heymach JV Lippman SM | 2008 | N Engl J Med2008，359，13： | 1 |
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