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早期三阴性乳腺癌患者接受帕博利珠单抗治疗的总生存期
Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer
背景
在早期三阴性乳腺癌患者中，3期KEYNOTE-522试验显示，在铂类化疗基础上加用帕博利珠单抗可显著提高病理学完全缓解率和无事件生存率。本文报告总生存率的最终结果。
In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival.
方法
我们以2:1比例将既往未经治疗的Ⅱ期或Ⅲ期三阴性乳腺癌患者随机分组，分别接受以下新辅助治疗：一组接受帕博利珠单抗（剂量200 mg，每3周用药一次，用药4个周期）联合紫杉醇和卡铂治疗，之后接受帕博利珠单抗（用药4个周期）联合多柔比星-环磷酰胺或表柔比星-环磷酰胺治疗，另一组接受安慰剂（每3周用药一次，用药4个周期）联合紫杉醇和卡铂治疗，之后接受安慰剂（用药4个周期）联合多柔比星-环磷酰胺或表柔比星-环磷酰胺治疗。确定性手术后，两组患者分别接受帕博利珠单抗（帕博利珠单抗-化疗组）或安慰剂（安慰剂-化疗组）辅助治疗，每3周用药一次，最多用药9个周期。主要终点是病理学完全缓解率和无事件生存率。总生存率是次要终点。
We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab–chemotherapy group) or placebo (placebo–chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point.
结果
在接受随机分组的1174例患者中，784人被分配到帕博利珠单抗-化疗组，390人被分配到安慰剂-化疗组。截至数据截止日（2024年3月22日），中位随访时间为75.1个月（范围，65.9~84.0）。帕博利珠单抗-化疗组的60个月总生存率估计值为86.6%（95%置信区间[CI]，84.0~88.8），而安慰剂-化疗组为81.7%（95% CI，77.5~85.2）（P=0.002）。不良事件与帕博利珠单抗和化疗已知安全性相符。
Result
Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab–chemotherapy group and 390 to the placebo–chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab–chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo–chemotherapy group (P=0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy.
结论
对于早期三阴性乳腺癌患者，与单纯新辅助化疗相比，新辅助帕博利珠单抗联合化疗及后续帕博利珠单抗辅助治疗可显著提高总生存率。（由默沙东[默克的子公司，默克位于美国新泽西州拉威市]资助；KEYNOTE-522在ClinicalTrials.gov注册号为NCT03036488）。
Conclusions
Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)
PCV10减剂次接种方案对越南肺炎球菌携带率的影响
Effect of a Reduced PCV10 Dose Schedule on Pneumococcal Carriage in Vietnam
背景
通过疫苗接种方案控制肺炎球菌疾病和定植后，肺炎球菌结合疫苗（PCV）减剂次接种方案 可能足以以较低成本维持上述控制效果。
我们研究了10价PCV（PCV10）单剂基础免疫和加强免疫（1p+1）在持续控制疫苗所含肺炎球菌血清型的携带率方面是否不劣于其他接种方案。在越南芽庄这一既往未使用过PCV的地区实施PCV10补种计划，为3岁以下儿童提供接种PCV10的机会，之后开展整群随机试验，儿童分别在以下时间点接种PCV10：2、3和4月龄（3p+0组）；2、4和12月龄（2p+1组）；2和12月龄（1p+1组）；或12月龄（0p+1组）。2016—2020年期间每年对婴儿（4~11月龄）和幼儿（14~24月龄）进行携带率调查。主要终点是引入疫苗后3.5年时，在非劣效性分析中评估1p+1组与2p+1和3p+0组相比，对疫苗血清型携带情况的防护作用（非劣效性界值，5个百分点）。此外还评估了0p+1方案的非劣效性。
Methods
We investigated whether a single primary dose and booster dose (1p+1) of the 10-valent PCV (PCV10) would be noninferior to alternative dose schedules in sustaining control of carriage of pneumococcal serotypes included in the vaccine. In Nha Trang, Vietnam, an area in which PCV had not been used previously, a PCV10 catch-up campaign was conducted in which the vaccine was offered to children younger than 3 years of age, after which a cluster-randomized trial was conducted in which children received PCV10 at 2, 3, and 4 months of age (3p+0 group); at 2, 4, and 12 months of age (2p+1 group); at 2 and 12 months of age (1p+1 group); or at 12 months of age (0p+1 group). Annual carriage surveys in infants (4 to 11 months of age) and toddlers (14 to 24 months of age) were conducted from 2016 through 2020. The primary end point was protection against carriage of vaccine serotypes, evaluated in a noninferiority analysis in the 1p+1 group as compared with the 2p+1 and 3p+0 groups, 3.5 years after vaccine introduction (noninferiority margin, 5 percentage points). Noninferiority of the 0p+1 schedule was also evaluated.
在引入PCV10之前的2016年，1363名婴儿中的160名（11.7%）被发现携带疫苗血清型，2020年，1p+1组333名婴儿中的6名（1.8%）、2p+1组340名婴儿中的5名（1.5%）和3p+0组313名婴儿中的4名（1.3%）被发现携带疫苗血清型，表明1p+1与2p+1（差异，0.3个百分点；95%置信区间[CI]，－1.6~2.2）以及1p+1与3p+0（差异，0.5个百分点；95% CI，－1.4~2.4）相比具有非劣效性。同样，对于幼儿，在对疫苗血清型携带情况的防护作用方面，1p+1与2p+1以及1p+1与3p+0相比具有非劣效性。2016年，1363名婴儿中的99名（7.3%）携带血清型6A；2020年，1p+1组333名婴儿中的12名（3.6%）、2p+1组340名婴儿中的10名（2.9%）和3p+0组313名婴儿中的3名（1.0%）携带血清型6A。在婴儿和幼儿中，0p+1接种方案也不劣于其他三种接种方案，但与其他接种方案相比，0p+1接种方案对血清6A型的交叉防护作用较弱。未观察到与PCV10相关的重度不良反应。
Result
In 2016, before the introduction of PCV10, vaccine-serotype carriage was found in 160 of 1363 infants (11.7%); in 2020, vaccine-serotype carriage was found in 6 of 333 (1.8%), 5 of 340 (1.5%), and 4 of 313 (1.3%) infants in the 1p+1, 2p+1, and 3p+0 groups, respectively, indicating noninferiority of 1p+1 to 2p+1 (difference, 0.3 percentage points; 95% confidence interval [CI], −1.6 to 2.2) and to 3p+0 (difference, 0.5 percentage points; 95% CI, −1.4 to 2.4). Similarly, 1p+1 was noninferior to 2p+1 and 3p+0 for protection against vaccine-serotype carriage among toddlers. In 2016, carriage of serotype 6A was found in 99 of 1363 infants (7.3%); in 2020, it was found in 12 of 333 (3.6%), 10 of 340 (2.9%), and 3 of 313 (1.0%) infants in the 1p+1, 2p+1, and 3p+0 groups, respectively. The 0p+1 schedule was also noninferior to the other three dose schedules among infants and toddlers, although cross-protection against serotype 6A was less common than with the other vaccination schedules. No PCV10-associated severe adverse effects were observed.
结论
在保护婴儿和幼儿免于携带疫苗血清型方面，减剂次接种方案（单剂PCV10基础免疫和加强免疫）不劣于其他接种方案。（由比尔及梅琳达-盖茨基金会[Bill and Melinda Gates Foundation]等资助；在ClinicalTrials.gov注册号为NCT02961231）。
部分剂量肺炎球菌结合疫苗接种——非劣效性试验
Fractional Doses of Pneumococcal Conjugate Vaccine — A Noninferiority Trial
背景
肺炎球菌结合疫苗是常规免疫计划中价格比较昂贵的一种疫苗。部分剂量接种方案可能是提高疫苗计划可持续性的一种选择。
我们评估了部分剂量10价和13价肺炎球菌结合疫苗（分别为PCV10[GSK]和PCV13[辉瑞]）的免疫原性是否不劣于全剂量的免疫原性，并分析了疫苗血清型携带率。我们将肯尼亚健康婴儿随机分配到七个相同人数的试验组之一。A组至F组参与者被分配接种部分剂量或全剂量PCV10或PCV13，接种方式是两剂基础免疫和一剂加强免疫。在A组中，参与者接种了全剂量PCV13；B组接种了40%剂量PCV13；C组接种了20%剂量PCV13；D组接种了全剂量PCV10；E组接种了40%剂量PCV10；F组接种了20%剂量PCV10。第七组（G组）参与者接种了全剂量PCV10，接种方式为三剂基础免疫，无加强免疫。在完成基础免疫后4周和完成加强免疫后4周评估免疫原性。如果在完成基础免疫后4周，达到阈值应答的参与者百分比差异不超过10%，并且在完成加强免疫后4周，IgG的几何平均浓度（GMC）比值超过0.5，则可宣布达到非劣效性。如果PCV10组10种疫苗血清型中的至少8种达到非劣效性标准，或PCV13组13种疫苗血清型中的至少10种达到非劣效性标准，则将该疫苗剂量预设为非劣效性。在参与者9月龄和18月龄时评估携带率。
Methods
We assessed whether the immunogenicity of fractional doses of the 10-valent and 13-valent pneumococcal conjugate vaccines (PCV10 [GSK] and PCV13 [Pfizer], respectively) would be noninferior to that of the full doses and analyzed the prevalence of vaccine-serotype carriage. We randomly assigned healthy infants in Kenya to one of seven equal-sized trial groups. Participants in groups A through F were assigned to receive either a fractional or full dose of PCV10 or PCV13, administered as two primary doses plus one booster dose. In group A, participants received a full dose of PCV13; group B, a 40% dose of PCV13; group C, a 20% dose of PCV13; group D, a full dose of PCV10; group E, a 40% dose of PCV10; and group F, a 20% dose of PCV10. Participants in the seventh group (group G) received a full dose of PCV10 as three primary doses without a booster. Immunogenicity was assessed 4 weeks after the primary series of doses and 4 weeks after the booster dose. Noninferiority could be declared 4 weeks after the primary series if the difference in the percentage of participants with a threshold response was not more than 10% and 4 weeks after administration of the booster if the ratio of the geometric mean concentration (GMC) of IgG was more than 0.5. A vaccine dose was prespecified as noninferior if it met the noninferiority criterion for at least 8 of the 10 vaccine types in the PCV10 groups or at least 10 of the 13 vaccine types in the PCV13 groups. Carriage was assessed when participants were 9 months and 18 months of age.
在符合方案分析中，基础免疫后对于13种血清型中的12种，加强免疫后对于13种血清型中的13种，40%剂量PCV13达到了非劣效性标准。20%剂量CV13以及40%和20%剂量PCV10的免疫原性不劣于全剂量。9月龄和18月龄时，各PCV13组的疫苗血清型携带率相似。
Result
In the per-protocol analysis, 40% of a full dose of PCV13 met the noninferiority criterion for 12 of 13 serotypes after the primary series and for 13 of 13 serotypes after the booster. The immunogenicity of the 20% dose of PCV13 and of the 40% and 20% doses of PCV10 was not noninferior to that of the full doses. Vaccine serotype-type carriage prevalence was similar across the PCV13 groups at 9 months and 18 months of age.
结论
在三剂接种方案（两剂基础免疫和一剂加强免疫）中，对于包含的所有血清型，40%剂量PCV13均不劣于全剂量PCV13。更低剂量PCV13和PCV10未达到非劣效性标准。（由比尔及梅琳达-盖茨基金会[Bill and Melinda Gates Foundation]等资助；在ClinicalTrials.gov注册号为NCT03489018；在泛非临床试验注册系统注册号为PACTR202104717648755）。
纳武利尤单抗联合伊匹木单抗治疗微卫星不稳定性高的转移性结直肠癌
Nivolumab plus Ipilimumab in Microsatellite-Instability–High Metastatic Colorectal Cancer
背景
微卫星不稳定性高（MSI-H）或错配修复缺陷（dMMR）型转移性结直肠癌患者接受标准化疗（联合或不联合靶向治疗）的结局不良。在对MSI-H或dMMR转移性结直肠癌开展的非随机研究中，纳武利尤单抗联合伊匹木单抗显示出临床疗效。
在此项3期、开放标签试验中，我们将当地检测结果显示MSI-H或dMMR的不可切除或转移性结直肠癌患者以2:2:1比例随机分组，分别接受纳武利尤单抗联合伊匹木单抗治疗、纳武利尤单抗单药治疗或化疗（联合或不联合靶向治疗）。在集中确认MSI-H或dMMR状态的患者中评估的双重主要终点是为作为一线治疗，纳武利尤单抗联合伊匹木单抗治疗与化疗相比的无进展生存期，以及不论患者既往是否因转移性疾病接受过全身性治疗，纳武利尤单抗联合伊匹木单抗治疗与纳武利尤单抗单药治疗相比的无进展生存期。此次预设的期中分析对第一项主要终点（纳武利尤单抗联合伊匹木单抗治疗 vs. 化疗）进行了评估。
Methods
In this phase 3 open-label trial, we randomly assigned patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary end points, assessed in patients with centrally confirmed MSI-H or dMMR status, were progression-free survival with nivolumab plus ipilimumab as compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab as compared with nivolumab alone in patients regardless of previous systemic treatment for metastatic disease. At this prespecified interim analysis, the first primary end point (involving nivolumab plus ipilimumab vs. chemotherapy) was assessed.
共计303例既往未因转移性疾病接受过全身性治疗的患者被随机分配接受接受纳武利尤单抗联合伊匹木单抗治疗或化疗；255例患者被集中确认为MSI-H或dMMR肿瘤。中位31.5个月（范围，6.1~48.4）随访时，纳武利尤单抗联合伊匹木单抗组的无进展生存期结局（主要分析）显著优于化疗组（使用双侧分层时序检验法计算出无进展生存期组间差异P<0.001）；纳武利尤单抗联合伊匹木单抗组的24个月无进展生存率为72%（95%置信区间[CI]，64~79），而化疗组为14%（95% CI，6~25）。24个月时，纳武利尤单抗联合伊匹木单抗组的限制性平均生存时间比化疗组长10.6个月（95% CI，8.4~12.9），这一结果与无进展生存期的主要分析结果一致。纳武利尤单抗联合伊匹木单抗组23%的患者和化疗组48%的患者发生了3级或4级治疗相关不良事件。
Result
A total of 303 patients who had not previously received systemic treatment for metastatic disease were randomly assigned to receive nivolumab plus ipilimumab or chemotherapy; 255 patients had centrally confirmed MSI-H or dMMR tumors. At a median follow-up of 31.5 months (range, 6.1 to 48.4), progression-free survival outcomes (the primary analysis) were significantly better with nivolumab plus ipilimumab than with chemotherapy (P<0.001 for the between-group difference in progression-free survival, calculated with the use of a two-sided stratified log-rank test); 24-month progression-free survival was 72% (95% confidence interval [CI], 64 to 79) with nivolumab plus ipilimumab as compared with 14% (95% CI, 6 to 25) with chemotherapy. At 24 months, the restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer with nivolumab plus ipilimumab than with chemotherapy, a finding consistent with the primary analysis of progression-free survival. Grade 3 or 4 treatment-related adverse events occurred in 23% of the patients in the nivolumab-plus-ipilimumab group and in 48% of the patients in the chemotherapy group.
结论
在既往未因MSI-H或dMMR转移性结直肠癌接受过全身性治疗的患者中，纳武利尤单抗联合伊匹木单抗治疗的无进展生存期超过化疗。（由百时美施贵宝和小野制药资助；CheckMate 8HW在ClinicalTrials.gov注册号为NCT04008030）。
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