通過sotorasib抑制KRASG12C治療晚期實體瘤
KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors
背景
目前尚無任何靶向癌症KRAS突變的療法通過審批。KRAS p.G12C突變發生於13%的非小細胞肺癌（NSCLC）以及1%~3%的結直腸癌和其他癌症。sotorasib是選擇性、不可逆性靶向KRASG12C的小分子。
No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non–small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.方法
我們在攜帶KRAS p.G12C突變的晚期實體瘤患者中對sotorasib開展了一項1期試驗。患者每日1次口服sotorasib。主要終點是安全性。關鍵次要終點包括藥代動力學和根據《實體瘤療效評價標準》（Response Evaluation Criteria in Solid Tumors RECIST）1.1版評估的客觀緩解。
We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.結果
共計129例患者（59例NSCLC患者、42例結直腸癌患者和28例其他腫瘤患者）被納入了劑量遞增和擴展隊列。患者因轉移性疾病接受過的抗癌治療的線數中位數為3（範圍，0~11）。本研究未觀察到劑量限制性毒性作用或與治療相關的死亡。共計73例患者（56.6%）發生了與治療相關的不良事件；15例患者（11.6%）發生了3級或4級事件。在NSCLC患者亞組中，32.2%（19例患者）達到了經證實的客觀緩解（完全或部分緩解），88.1%（52例患者）達到了疾病控制（客觀緩解或疾病穩定）；中位無進展生存期為6.3個月（範圍，0.0+~14.9[+號表示數值包括在數據截止時刪失的患者數據]）。在結直腸癌患者亞組中，7.1%（3例患者）達到了經證實的緩解，73.8%（31例患者）達到了疾病控制；中位無進展生存期為4.0個月（範圍，0.0+~11.1+）。在胰腺癌、子宮內膜癌、闌尾癌和黑色素瘤患者中也觀察到了緩解。
Result
A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.
結論
在既往接受過大量治療，攜帶KRAS p.G12C突變的晚期實體瘤患者中，sotorasib表現出令人鼓舞的抗癌活性。11.6%的患者發生了與治療相關的3級或4級毒性作用。（由安進等資助；CodeBreaK100在ClinicalTrials.gov註冊號為NCT03600883。）
Conclusions
Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)
David S. Hong, Marwan G. Fakih, John H. Strickler, et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. DOI:10.1056/NEJMoa1917239本周五 中午十二點 app和官網發布全文中譯
阿維魯單抗用於晚期或轉移性尿路上皮細胞癌的維持治療
Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma
背景
鉑類化療是晚期尿路上皮細胞癌的標準一線治療。然而，無進展生存期和總生存期受到化療耐藥的限制。
Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.方法
在一項3期試驗中，我們將患不可切除的局部晚期或轉移性尿路上皮細胞癌，並且一線化療（吉西他濱+順鉑或卡鉑治療4~6個周期）後未出現疾病進展的患者隨機分組，兩組分別接受最佳支持性治療或最佳支持性治療聯合阿維魯單抗[avelumab]維持治療。主要終點是在以下兩個人群中評估的總生存期：被隨機分組的所有患者（全部人群），以及程序性細胞死亡受體配體1（PD-L1）陽性的腫瘤患者。次要終點包括無進展生存期和安全性。
In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.
結果
在被隨機分組的全部700例患者中，與單獨採用最佳支持性治療（對照）相比，最佳支持性治療加用阿維魯單抗維持性治療顯著延長了總生存期。在阿維魯單抗組和對照組中，1年總生存率分別為71.3%和58.4%（中位總生存期，21.4個月vs. 14.3個月；死亡的風險比，0.69；95%置信區間[CI]，0.56~0.86；P=0.001）。阿維魯單抗還顯著延長了PD-L1陽性人群的總生存期；在阿維魯單抗組和對照組中，1年總生存率分別為79.1%和60.4%（風險比，0.56；95% CI，0.40~0.79；P<0.001）。在整個人群中，阿維魯單抗組和對照組的中位無進展生存期分別為3.7個月和2.0個月（疾病進展或死亡的風險比，0.62；95% CI，0.52~0.75）；在PD-L1陽性人群中，兩組的中位無進展生存期分別為5.7個月和2.1個月（風險比，0.56；95% CI，0.43~0.73）。在阿維魯單抗組和對照組中，全因不良事件發生率分別為98.0%和77.7%；3級或更高級別不良事件發生率分別為47.4%和25.2%。
Result
Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P=0.001). Avelumab also significantly prolonged overall survival in the PD-L1–positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1–positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.結論
在一線化療後未發生疾病進展的尿路上皮細胞癌患者中，與單獨採用最佳支持性治療相比，最佳支持性治療+阿維魯單抗維持治療顯著延長了總生存期。（由輝瑞和默克[德國達姆施塔特]資助；JAVELIN Bladder 100在ClinicalTrials.gov註冊號為NCT02603432。）
Conclusions
Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.)Thomas Powles, Se Hoon Park, Eric Voog, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. DOI: 10.1056/NEJMoa2002788
小劑量鋅劑治療兒童腹瀉的隨機多中心試驗
Lower-Dose Zinc for Childhood Diarrhea — A Randomized, Multicenter Trial
背景
世界衛生組織建議給急性腹瀉患兒每日使用20 mg鋅劑，持續用藥10~14天；在之前的試驗中，這一劑量減少了腹瀉，但增加了嘔吐。
The World Health Organization recommends 20 mg of zinc per day for 10 to 14 days for children with acute diarrhea; in previous trials, this dosage decreased diarrhea but increased vomiting.方法
我們將印度和坦尚尼亞4500名6~59個月齡的急性腹瀉患兒隨機分組，兩組分別接受5 mg、10 mg或20 mg的硫酸鋅治療，持續用藥14天。三項主要結局包括腹瀉持續時間超過5天和排便次數（在非劣效性分析中評估），以及鋅劑用藥後30分鐘內發生嘔吐（在優效性分析中評估）。
We randomly assigned 4500 children in India and Tanzania who were 6 to 59 months of age and had acute diarrhea to receive 5 mg, 10 mg, or 20 mg of zinc sulfate for 14 days. The three primary outcomes were a diarrhea duration of more than 5 days and the number of stools (assessed in a noninferiority analysis) and the occurrence of vomiting (assessed in a superiority analysis) within 30 minutes after zinc administration.結果
在20 mg組、10 mg組和5 mg組中，腹瀉超過5天的患兒百分比分別為6.5%、7.7%和7.2%。20 mg組和10 mg組之間的差異為1.2個百分點（98.75%置信區間[CI]上限，3.3），20 mg組和5 mg組之間的差異為0.7個百分點（98.75% CI上限，3.0），這兩項差異均低於4個百分點的非劣效性界值。在20 mg組、10 mg組和5 mg組中，發生腹瀉的平均排便次數分別為10.7次、10.9次和10.8次。20 mg組和10 mg組之間的差異為0.3次排便（98.75% CI上限，1.0），20 mg組和5 mg組之間的差異為0.1次排便（98.75% CI上限，0.8），這兩項差異均低於非劣效性界值（2次排便）。在20 mg、10 mg和5 mg組中，分別19.3%、15.6%和13.7%的患者在給藥後30分鐘內發生嘔吐；10 mg組的嘔吐風險顯著低於20 mg組（相對危險度，0.81；97.5% CI，0.67~0.96），5 mg組的嘔吐風險也顯著低於20 mg組（相對危險度，0.71；97.5% CI，0.59~0.86）。較小的劑量還與給藥後30分鐘之後較少的嘔吐次數相關。
Result
The percentage of children with diarrhea for more than 5 days was 6.5% in the 20-mg group, 7.7% in the 10-mg group, and 7.2% in the 5-mg group. The difference between the 20-mg and 10-mg groups was 1.2 percentage points (upper boundary of the 98.75% confidence interval [CI], 3.3), and that between the 20-mg and 5-mg groups was 0.7 percentage points (upper boundary of the 98.75% CI, 3.0), both of which were below the noninferiority margin of 4 percentage points. The mean number of diarrheal stools was 10.7 in the 20-mg group, 10.9 in the 10-mg group, and 10.8 in 5-mg group. The difference between the 20-mg and 10-mg groups was 0.3 stools (upper boundary of the 98.75% CI, 1.0), and that between the 20-mg and 5-mg groups was 0.1 stools (upper boundary of the 98.75% CI, 0.8), both of which were below the noninferiority margin (2 stools). Vomiting within 30 minutes after administration occurred in 19.3%, 15.6%, and 13.7% of the patients in the 20-mg, 10-mg, and 5-mg groups, respectively; the risk was significantly lower in the 10-mg group than in the 20-mg group (relative risk, 0.81; 97.5% CI, 0.67 to 0.96) and in the 5-mg group than in the 20-mg group (relative risk, 0.71; 97.5% CI, 0.59 to 0.86). Lower doses were also associated with less vomiting beyond 30 minutes after administration.
結論
當用於治療兒童腹瀉時，較小劑量鋅劑的療效不劣於20 mg標準劑量，並且與較少的嘔吐相關。（由比爾及梅林達·蓋茨基金會資助；ZTDT在ClinicalTrials.gov註冊號為NCT03078842。）
Conclusions
Lower doses of zinc had noninferior efficacy for the treatment of diarrhea in children and were associated with less vomiting than the standard 20-mg dose. (Funded by the Bill and Melinda Gates Foundation; ZTDT ClinicalTrials.gov number, NCT03078842.)Usha Dhingra, Rodrick Kisenge, Christopher R. Sudfeld, et al. Lower-Dose Zinc for Childhood Diarrhea — A Randomized, Multicenter Trial. DOI:10.1056/NEJMoa1915905通過反義抑制前激肽釋放酶控制遺傳性血管性水腫
Antisense Inhibition of Prekallikrein to Control Hereditary Angioedema
遺傳性血管性水腫的典型表現是反覆發生不可預測且可能危及生命的皮下和黏膜腫脹發作。IONIS-PKK-LRx是一種配體結合型反義寡核苷酸，其設計目標是在受體介導下向肝細胞遞送。在一項同情用藥的先導性研究中，兩例緩激肽介導的重度血管性水腫患者首先接受了為期12~16周的非結合型原型藥物IONIS-PKKRx每周皮下注射給藥，之後接受了為期7~8個月的IONIS-PKK-LRx給藥（每3~4周給藥1次，每次80 mg）。治療伴有血管性水腫發作率降低。（由阿姆斯特丹大學醫學中心[Amsterdam UMC]資助。）Hereditary angioedema is characterized by recurrent and unpredictable episodes of subcutaneous and mucosal swelling that can be life threatening. IONIS-PKK-LRx is a ligand-conjugated antisense oligonucleotide designed for receptor-mediated delivery to hepatocytes. In a compassionate-use pilot study, two patients with severe bradykinin-mediated angioedema were initially administered weekly subcutaneous injections of the unconjugated parent drug, IONIS-PKKRx, for 12 to 16 weeks, after which they received IONIS-PKK-LRx at a dose of 80 mg every 3 to 4 weeks for 7 to 8 months. Treatment was accompanied by a reduction in the angioedema attack rate. (Funded by Amsterdam UMC.)
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