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Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. 洛拉替尼与克唑替尼在 ALK 阳性晚期非小细胞肺癌患者中的应用:III 期 CROWN 研究的 5 年结果。
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-05-31 DOI: 10.1200/JCO.24.00581
Benjamin J Solomon, Geoffrey Liu, Enriqueta Felip, Tony S K Mok, Ross A Soo, Julien Mazieres, Alice T Shaw, Filippo de Marinis, Yasushi Goto, Yi-Long Wu, Dong-Wan Kim, Jean-François Martini, Rossella Messina, Jolanda Paolini, Anna Polli, Despina Thomaidou, Francesca Toffalorio, Todd M Bauer

Purpose: Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up.

Methods: Two hundred ninety-six patients with ALK-positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses.

Results: With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment.

Conclusion: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.

目的:在III期CROWN研究中,对于既往未经治疗的晚期ALK阳性非小细胞肺癌(NSCLC)患者,与克唑替尼相比,洛拉替尼可改善患者的无进展生存期(PFS)和颅内活动度。在此,我们报告 CROWN 5 年随访后的长期结果:296名ALK阳性NSCLC患者按1:1比例随机分配,接受lorlatinib 100毫克,每天一次(149人)或克唑替尼250毫克,每天两次(147人)。这份事后分析报告介绍了研究者评估的最新疗效结果、安全性和生物标志物分析:中位随访PFS分别为60.2个月和55.1个月,lorlatinib的中位PFS未达到(NR [95% CI, 64.3 to NR]),克唑替尼的中位PFS为9.1个月(95% CI, 7.4 to 10.9)(危险比[HR],0.19 [95% CI, 0.13 to 0.27]);5年PFS分别为60%(95% CI, 51 to 68)和8%(95% CI, 3 to 14)。洛拉替尼中位颅内进展时间为NR(95% CI,NR至NR),克唑替尼为16.4个月(95% CI,12.7至21.9)(HR,0.06 [95% CI,0.03至0.12])。安全性与之前的分析结果一致。在罗拉替尼治疗结束时收集的循环肿瘤DNA中未检测到新的ALK耐药突变:结论:经过5年的随访,lorlatinib组的中位生存期尚未达到,这是晚期NSCLC单药分子靶向治疗和所有转移性实体瘤中有报道的最长生存期。这些结果加上延长的颅内疗效和无新的安全性信号,代表了晚期ALK阳性NSCLC患者前所未有的治疗结果,为癌症靶向治疗树立了新的标杆。
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引用次数: 0
Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer. 萨妥珠单抗戈维替康对晚期实体瘤患者的疗效和安全性(TROPiCS-03):晚期子宫内膜癌患者分析。
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-07-31 DOI: 10.1200/JCO.23.02767
Alessandro D Santin, Bradley R Corr, Alexander Spira, Lyndsay Willmott, James Butrynski, Ka Yu Tse, Jilpa Patel, Sabeen Mekan, Tia Wu, Kai-Wen Lin, Peiwen Kuo, Ecaterina E Dumbrava

Purpose: Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC.

Methods: TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry.

Results: At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG.

Conclusion: Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.

目的:晚期子宫内膜癌(EC)患者在接受铂类治疗和免疫治疗后病情进展,预后较差。我们报告了滋养层细胞表面抗原2(Trop-2)导向的抗体-药物共轭物sacituzumab govitecan(SG)在晚期子宫内膜癌患者中的疗效和安全性:TROPiCS-03(ClinicalTrials.gov标识符:NCT03964727)是一项针对转移性实体瘤患者的多队列、开放标签、II期篮子研究。符合条件的EC队列患者在第1天和第8天接受SG 10 mg/kg,每3周一次。主要终点是研究者根据 RECIST v1.1 评估的客观反应率(ORR)。次要终点包括临床获益率(CBR;完全和部分应答,疾病稳定≥6个月)、应答持续时间(DOR)、研究者评估的无进展生存期(PFS)、总生存期和安全性。通过免疫组化分析档案或基线肿瘤标本中Trop-2的表达情况:截至数据提取日,共有41名患者入组。中位随访时间为5.8个月(0.7-19.3个月);中位既往治疗时间为3个月(1-6个月);85%的患者接受过化疗和免疫治疗。ORR为22%(95% CI,11-38);CBR为32%(95% CI,18-48)。中位DOR为8.8个月(95% CI,2.8至无法估计);中位PFS为4.8个月(95% CI,2.8至9.8)。对39名患者进行了Trop-2探索性分析。肿瘤Trop-2蛋白在EC中高表达,但与疗效的相关性有限。73%的患者发生了≥3级治疗相关不良事件(TRAE)。因 TRAEs 而停药的患者占 5%。有2例死亡病例被认为与SG无关:TROPiCS-03的研究结果表明,SG在晚期EC重度预处理人群中具有令人鼓舞的疗效和可控的毒性。安全性研究结果与已知的 SG 安全性特征一致。
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引用次数: 0
Results From First-in-Human Phase I Dose-Escalation Study of a Novel Bicycle Toxin Conjugate Targeting EphA2 (BT5528) in Patients With Advanced Solid Tumors. 靶向 EphA2 的新型自行车毒素共轭物 (BT5528) 在晚期实体瘤患者中的首次人体 I 期剂量放大研究结果。
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-09-04 DOI: 10.1200/JCO.23.01107
Babar Bashir, Judy S Wang, Gerald Falchook, Elisa Fontana, Hendrik-Tobias Arkenau, Louise Carter, Rachel Galot, Bristi Basu, Alastair Greystoke, Vivek Subbiah, Debra L Richardson, Hanna Orr, Gavin Bennett, Rajiv Sharma, Hongmei Xu, Paola Paganoni, Cong Xu, Carly Campbell, Meredith McKean

Purpose: BT5528 is a Bicycle Toxin Conjugate, a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting EphA2 tumor antigen, linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is overexpressed in many solid tumors and contributes to oncogenesis, tumor-associated angiogenesis, and metastasis.

Materials and methods: The primary objectives were to investigate the safety and tolerability of BT5528 and to define the maximum-tolerated dose, if observed, and recommended phase II dose (RP2D)/expansion dose. Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a Bayesian logistic regression model. Secondary and exploratory end points included preliminary efficacy and the pharmacokinetics of BT5528 and MMAE.

Results: Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m2 once every week to 10.0 mg/m2 once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m2 once every 2 weeks was selected as a RP2D. At 6.5 mg/m2 once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proportional. BT5528 has a short half-life (0.4-0.7 hours), and the half-life of MMAE is longer (35-47 hours).

Conclusion: BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m2 once every 2 weeks.

目的:BT5528 是一种自行车毒素共轭物,它是一类化学合成的新型分子,由靶向 EphA2 肿瘤抗原的双环肽与细胞毒素(单甲基乌司他丁 E [MMAE])连接而成。EphA2 在许多实体瘤中过度表达,有助于肿瘤发生、肿瘤相关血管生成和转移:主要目的是研究BT5528的安全性和耐受性,并确定最大耐受剂量(如果观察到)和II期推荐剂量(RP2D)/扩大剂量。剂量升级探索每周一次或每两周一次服用BT5528,前两个剂量水平采用3 + 3剂量升级设计,然后采用贝叶斯逻辑回归模型。次要和探索性终点包括初步疗效以及 BT5528 和 MMAE 的药代动力学:45名患者入组,在研究的剂量递增阶段,他们接受的BT5528剂量从每周一次的2.2 mg/m2到每两周一次的10.0 mg/m2不等。最常见的BT5528相关不良事件(AEs)是恶心(44.4%)、腹泻(35.6%)和疲劳(33.3%),最常见的≥3级BT5528相关AE是中性粒细胞减少/中性粒细胞计数减少(22.2%)。剂量水平为 6.5 mg/m2,每 2 周一次,被选为 RP2D。6.5毫克/平方米、每两周一次的剂量水平下,总反应率为6.7%,疾病控制率为20.0%。BT5528 和 MMAE 的药代动力学一般与剂量成正比。BT5528的半衰期较短(0.4-0.7小时),而MMAE的半衰期较长(35-47小时):BT5528的耐受性良好,并显示出良好的初步抗肿瘤活性。我们相信,这些数据初步验证了针对 EphA2 肿瘤抗原的 "自行车毒素共轭物 "方法。这项研究正在进行中,目前正在评估 BT5528 作为单药治疗的效果,RP2D 为 6.5 mg/m2,每 2 周一次。
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引用次数: 0
Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial. 人表皮生长因子受体 2 引导的抗体-药物共轭物 SHR-A1811 在表达或变异的人表皮生长因子受体 2 晚期实体瘤中的安全性、有效性和药代动力学:全球 I 期试验。
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-06-20 DOI: 10.1200/JCO.23.02044
Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, John J Park, Jee Hyun Kim, Yahua Zhong, Yiming Zhao, Mark Voskoboynik, Yongmei Yin, Kan Liu, Andreas Kaubisch, Caigang Liu, Jian Zhang, Shouman Wang, Seock-Ah Im, Vinod Ganju, Minal Barve, Hui Li, Changsheng Ye, Amitesh C Roy, Li-Yuan Bai, Chia-Jui Yen, Shanzhi Gu, Yung-Chang Lin, Lingying Wu, Lequn Bao, Kaijing Zhao, Yu Shen, Shangyi Rong, Xiaoyu Zhu, Erwei Song

Purpose: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors.

Methods: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose.

Results: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors.

Conclusion: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

目的:SHR-A1811是一种抗体-药物共轭物,由抗人表皮生长因子受体2(HER2)抗体曲妥珠单抗、可裂解连接体和拓扑异构酶I抑制剂有效载荷组成。我们评估了SHR-A1811在重度预处理的HER2表达或突变晚期实体瘤中的安全性、耐受性、抗肿瘤活性和药代动力学:这项全球性、多中心、首次人体I期试验在33个中心进行。入组患者均为HER2表达或突变的不可切除、晚期或转移性实体瘤患者,且对标准疗法难治或不耐受。SHR-A1811 以 1.0 至 8.0 mg/kg 的剂量静脉注射,每 3 周一次。主要终点为剂量限制毒性、安全性和II期推荐剂量:2020年9月7日至2023年2月27日,307名既往接受过中位数为3种(IQR,2-5种)转移性治疗方案的患者接受了SHR-A1811治疗。截至数据截止日(2023 年 2 月 28 日),6.4 mg/kg 组的一名患者出现了剂量限制性毒性反应(泛发性泛肾炎和结肠炎)。最常见的 3 级或以上不良事件(AEs)包括中性粒细胞计数减少(119 例 [38.8%])和白细胞计数减少(70 例 [22.8%])。仅有 8 例(2.6%)患者出现间质性肺病。70名患者(22.8%)和13名患者(4.2%)分别出现严重AE和死亡。SHR-A1811使59.9%的患者(184/307)、76.3%的HER2阳性乳腺癌患者(90/118)、60.4%的HER2低表达乳腺癌患者(55/91)以及98例非乳腺肿瘤患者中的45.9%(39/85有可评估的肿瘤反应)产生了客观反应:结论:SHR-A1811在重度预处理的晚期实体瘤中表现出可接受的耐受性、有希望的抗肿瘤活性和良好的药代动力学特征。针对不同肿瘤类型,II期推荐剂量为4.8或6.4 mg/kg。
{"title":"Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial.","authors":"Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, John J Park, Jee Hyun Kim, Yahua Zhong, Yiming Zhao, Mark Voskoboynik, Yongmei Yin, Kan Liu, Andreas Kaubisch, Caigang Liu, Jian Zhang, Shouman Wang, Seock-Ah Im, Vinod Ganju, Minal Barve, Hui Li, Changsheng Ye, Amitesh C Roy, Li-Yuan Bai, Chia-Jui Yen, Shanzhi Gu, Yung-Chang Lin, Lingying Wu, Lequn Bao, Kaijing Zhao, Yu Shen, Shangyi Rong, Xiaoyu Zhu, Erwei Song","doi":"10.1200/JCO.23.02044","DOIUrl":"10.1200/JCO.23.02044","url":null,"abstract":"<p><strong>Purpose: </strong>SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors.</p><p><strong>Methods: </strong>This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose.</p><p><strong>Results: </strong>From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors.</p><p><strong>Conclusion: </strong>SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reply to C.T. Matava et al. 对 C.T. Matava 等人的答复
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-07-24 DOI: 10.1200/JCO-24-01244
Sarah Alexander, John A Kairalla, Sumit Gupta, Emily Hibbitts, Hannah Weisman, Doralina Anghelescu, Naomi J Winick, Kevin R Krull, Wanda L Salzer, Michael J Burke, Lia Gore, Meenakshi Devidas, Leanne Embry, Elizabeth A Raetz, Stephen P Hunger, Mignon L Loh, Kristina K Hardy
{"title":"Reply to C.T. Matava et al.","authors":"Sarah Alexander, John A Kairalla, Sumit Gupta, Emily Hibbitts, Hannah Weisman, Doralina Anghelescu, Naomi J Winick, Kevin R Krull, Wanda L Salzer, Michael J Burke, Lia Gore, Meenakshi Devidas, Leanne Embry, Elizabeth A Raetz, Stephen P Hunger, Mignon L Loh, Kristina K Hardy","doi":"10.1200/JCO-24-01244","DOIUrl":"10.1200/JCO-24-01244","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11458345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia. 急性淋巴细胞白血病预后的基因组决定因素
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-08-09 DOI: 10.1200/JCO.23.02238
Ti-Cheng Chang, Wenan Chen, Chunxu Qu, Zhongshan Cheng, Dale Hedges, Abdelrahman Elsayed, Stanley B Pounds, Mary Shago, Karen R Rabin, Elizabeth A Raetz, Meenakshi Devidas, Cheng Cheng, Anne Angiolillo, Pradyuamna Baviskar, Michael Borowitz, Michael J Burke, Andrew Carroll, William L Carroll, I-Ming Chen, Richard Harvey, Nyla Heerema, Ilaria Iacobucci, Jeremy R Wang, Sima Jeha, Eric Larsen, Leonard Mattano, Kelly Maloney, Ching-Hon Pui, Nilsa C Ramirez, Wanda Salzer, Cheryl Willman, Naomi Winick, Brent Wood, Stephen P Hunger, Gang Wu, Charles G Mullighan, Mignon L Loh

Purpose: Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease.

Materials and methods: To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years.

Results: Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL.

Conclusion: Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

目的:尽管儿童急性淋巴细胞白血病(ALL)的治愈率超过90%,但ALL仍是儿童癌症死亡的主要原因。一半的复发发生在最初被归类为标准风险(SR)疾病的儿童身上:为了确定SR ALL患儿复发的基因组决定因素,我们对参加儿童肿瘤学组试验的SR患儿(n = 1,381)或具有良好细胞遗传学特征的高危B-ALL患儿(n = 115)的诊断样本和缓解样本进行了基因组和转录组测序。我们采用病例对照研究设计,分析了439名复发患者和1057名完全缓解至少5年的患者:结果:基因组亚型与复发有关,约50%的PAX5改变ALL病例出现复发(几率比[OR],3.31 [95% CI,2.17至5.03];P = 3.18 × 10-8)。在高超二倍体 ALL 中,10 号染色体增益伴 7 号染色体切除与良好预后相关(OR,0.27 [95% CI,0.17 至 0.42];P = 8.02 × 10-10;圣裘德儿童研究医院验证队列:OR,0.22[95%CI,0.05至0.80];P = .009),10号和17号染色体切除伴6号染色体增益与复发相关(OR,7.16[95%CI,2.63至21.51];P = 2.19 × 10-5;验证队列:OR,21.32[95%CI,3.62至119.30];P = .0004)。基因组改变以亚型依赖的方式与复发相关,包括ETV6::RUNX1 ALL中INO80的改变、高超二倍体ALL中IKZF1和CREBBP的改变以及BCR::ABL1样ALL中FHIT的改变。基因组改变也与存在极小残留病有关,包括高超二倍体ALL中的NRAS和CREBBP:结论:基因亚型、非整倍体模式和继发性基因组改变决定了儿童 ALL 的复发风险。最佳风险分层需要全面的基因组分析。
{"title":"Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.","authors":"Ti-Cheng Chang, Wenan Chen, Chunxu Qu, Zhongshan Cheng, Dale Hedges, Abdelrahman Elsayed, Stanley B Pounds, Mary Shago, Karen R Rabin, Elizabeth A Raetz, Meenakshi Devidas, Cheng Cheng, Anne Angiolillo, Pradyuamna Baviskar, Michael Borowitz, Michael J Burke, Andrew Carroll, William L Carroll, I-Ming Chen, Richard Harvey, Nyla Heerema, Ilaria Iacobucci, Jeremy R Wang, Sima Jeha, Eric Larsen, Leonard Mattano, Kelly Maloney, Ching-Hon Pui, Nilsa C Ramirez, Wanda Salzer, Cheryl Willman, Naomi Winick, Brent Wood, Stephen P Hunger, Gang Wu, Charles G Mullighan, Mignon L Loh","doi":"10.1200/JCO.23.02238","DOIUrl":"10.1200/JCO.23.02238","url":null,"abstract":"<p><strong>Purpose: </strong>Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease.</p><p><strong>Materials and methods: </strong>To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years.</p><p><strong>Results: </strong>Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of <i>PAX5</i>-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; <i>P =</i> 3.18 × 10<sup>-8</sup>). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; <i>P</i> = 8.02 × 10<sup>-10</sup>; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; <i>P</i> = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; <i>P</i> = 2.19 × 10<sup>-5</sup>; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; <i>P</i> = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of <i>INO80</i> in <i>ETV6::RUNX1</i> ALL, <i>IKZF1</i>, and <i>CREBBP</i> in high-hyperdiploid ALL and <i>FHIT</i> in <i>BCR::ABL1</i>-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including <i>NRAS</i> and <i>CREBBP</i> in high-hyperdiploid ALL.</p><p><strong>Conclusion: </strong>Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11458106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Propofol, Anesthesia, and Neurocognitive Outcomes in Patients With Pediatric Leukemia: Are We Missing the Forest for the Trees? 丙泊酚、麻醉和小儿白血病患者的神经认知结果:我们是否只见树木,不见森林?
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-07-24 DOI: 10.1200/JCO.24.00856
Clyde T Matava, James Peyton, Britta S von Ungern-Sternberg, Caleb Ing
{"title":"Propofol, Anesthesia, and Neurocognitive Outcomes in Patients With Pediatric Leukemia: Are We Missing the Forest for the Trees?","authors":"Clyde T Matava, James Peyton, Britta S von Ungern-Sternberg, Caleb Ing","doi":"10.1200/JCO.24.00856","DOIUrl":"10.1200/JCO.24.00856","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years. 肺癌靶向治疗的新基准:洛拉替尼(Lorlatinib)治疗晚期ALK+非小细胞肺癌的中位无进展生存期超过5年。
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-09-04 DOI: 10.1200/JCO.24.01147
Christine M Lovly
{"title":"New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years.","authors":"Christine M Lovly","doi":"10.1200/JCO.24.01147","DOIUrl":"10.1200/JCO.24.01147","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reply to Y.-Y. Qiu et al. 对 Y.-Y. Qiu 等人的答复Qiu et al.
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-07-24 DOI: 10.1200/JCO-24-01217
Huabin Hu, Jianwei Zhang, Lishuo Shi, Meijin Huang, Jianping Wang, Yanhong Deng
{"title":"Reply to Y.-Y. Qiu et al.","authors":"Huabin Hu, Jianwei Zhang, Lishuo Shi, Meijin Huang, Jianping Wang, Yanhong Deng","doi":"10.1200/JCO-24-01217","DOIUrl":"10.1200/JCO-24-01217","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evaluation of CD3 and CD8 T-Cell Immunohistochemistry for Prognostication and Prediction of Benefit From Adjuvant Chemotherapy in Early-Stage Colorectal Cancer Within the QUASAR Trial. 在 QUASAR 试验中评估 CD3 和 CD8 T 细胞免疫组化对早期结直肠癌辅助化疗获益的预后和预测作用
IF 42.1 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 Epub Date: 2024-07-31 DOI: 10.1200/JCO.23.02030
Christopher J M Williams, Richard Gray, Robert K Hills, Michael Shires, Liping Zhang, Zuo Zhao, Tracie Gardner, Nancy Sapanara, Xiao-Meng Xu, Isaac Bai, Dongyao Yan, Andrea Muranyi, Sarah Dance, Faranak Aghaei, Gemma Hemmings, Michael Hale, Uday Kurkure, Christoph Guetter, Susan D Richman, Gordon Hutchins, Jenny F Seligmann, Nicholas P West, Shalini Singh, Kandavel Shanmugam, Philip Quirke

Purpose: High densities of tumor infiltrating CD3 and CD8 T-cells are associated with superior prognosis in colorectal cancer (CRC). Their value as predictors of benefit from adjuvant chemotherapy is uncertain.

Patients and methods: Tumor tissue from 868 patients in the QUASAR trial (adjuvant fluorouracil/folinic acid v observation in stage II/III CRC) was analyzed by CD3 and CD8 immunohistochemistry. Pathologists, assisted by artificial intelligence, calculated CD3 and CD8 cell densities (cells/mm2) in the core tumor (CT) and invasive margin (IM). Participants were randomly partitioned into training and validation sets. The primary outcome was recurrence-free interval (RFI), 2-year RFI for assessment of biomarker-treatment interactions. Maximum-likelihood methods identified optimal high-risk/low-risk group cutpoints in the training set. Prognostic analyses were repeated in the validation set.

Results: In the training set, the recurrence rate in the high-risk group was twice that in the low-risk group for all measures (CD3-CT: rate ratio [RR], 2.00, P = .0008; CD3-IM: 2.38, P < .00001; CD8-CT: 2.17, P = .0001; CD8-IM: 2.13, P = .0001). This was closely replicated in the validation set (RR, 1.96, 1.79, 1.72, 1.72, respectively). In multivariate analyses, prognostic effects were similar in colon and rectal cancers, and in stage II and III disease. Proportional reductions in recurrence with adjuvant chemotherapy were of similar magnitude in the high- and low-recurrence risk groups. Combining information from CD3-IM and CD3-CT (CD3 Score) generated high-, intermediate-, and low-risk groups with numbers needed to treat (NNTs) to prevent one disease recurrence being 11, 21, and 36, respectively.

Conclusion: Recurrence rates in the high-risk CD3/CD8 groups are twice those in the low-risk groups. Proportional reductions with chemotherapy are similar, allowing NNTs derived in QUASAR to be updated using contemporary, nonrandomized data sets.

目的:高密度的肿瘤浸润CD3和CD8 T细胞与结直肠癌(CRC)的良好预后有关。它们作为辅助化疗获益预测因子的价值尚不确定:通过 CD3 和 CD8 免疫组化对 QUASAR 试验(II/III 期 CRC 的氟尿嘧啶/叶酸辅助化疗与观察)中 868 例患者的肿瘤组织进行了分析。病理学家在人工智能的辅助下计算核心肿瘤(CT)和浸润边缘(IM)的 CD3 和 CD8 细胞密度(细胞/平方毫米)。参与者被随机分为训练集和验证集。主要结果是无复发间隔期(RFI)和用于评估生物标记物与治疗相互作用的两年无复发间隔期(RFI)。最大似然法确定了训练集中最佳的高风险/低风险组切点。在验证集中重复进行预后分析:在训练集中,就所有指标而言,高风险组的复发率是低风险组的两倍(CD3-CT:比率比 [RR],2.00,P = .0008;CD3-IM:2.38,P < .00001;CD8-CT:2.17,P = .0001;CD8-IM:2.13,P = .0001)。这一结果在验证组中得到了很好的重复(RR 分别为 1.96、1.79、1.72、1.72)。在多变量分析中,结肠癌和直肠癌以及 II 期和 III 期疾病的预后效果相似。在高复发风险组和低复发风险组中,辅助化疗降低复发的比例相似。结合CD3-IM和CD3-CT(CD3评分)的信息,得出了高、中、低风险组,预防一次疾病复发所需的治疗次数(NNT)分别为11、21和36:结论:CD3/CD8高风险组的复发率是低风险组的两倍。结论:高风险 CD3/CD8 组的复发率是低风险组的两倍,化疗的比例降低率相似,因此可以利用当代非随机数据集更新 QUASAR 中得出的 NNT。
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Journal of Clinical Oncology
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