基于KEYNOTE-059/061/062研究评估帕博利珠单抗治疗微卫星高度不稳定的胃癌或胃食管结合部癌的疗效

微卫星高度不稳定（microsatellite instability–high,MSI-H）表型是一种对免疫治疗高度敏感的特殊肿瘤亚型，对抗程序性死亡受体1(programmed cell death-1,PD-1)治疗反应较好。有5%～20%的胃癌属于MSI-H，需要进一步了解抗PD-1治疗在该亚组患者跨线治疗中的疗效。此事后分析纳入2期KEYNOTE-059临床研究7例（4.0%）、3期KEYNOTE-061和3期KEYNOTE-062临床研究27例（5.3%）、MSI-H晚期胃癌或胃食管结合部癌50例（7.3%）患者。三项研究中帕博利珠单抗组以及KEYNOTE-062研究中帕博利珠单抗联合化疗组患者的中位总生存期均未达到（not reached,NR）。KEYNOTE-059研究中帕博利珠单抗组中位无进展生存期（progression-free survival,PFS）和客观缓解率（objective response rate,ORR）为NR(95%CI:1.1个月至NR)和57.1%。KEYNOTE-061研究中帕博利珠单抗组和单纯化疗组的中位PFS分别为17.8个月（9...     

帕博利珠单抗对比化疗治疗微卫星高度不稳定或错配修复缺陷的转移性结直肠癌：KEYNOTE-177研究解读

摘 要：KEYNOTE-177研究是首个探索PD-1抑制剂（帕博利珠单抗）对比传统化疗一线治疗微卫星高度不稳定或错配修复缺陷（MSI-H/dMMR）转移性结直肠癌对总生存期（OS）及无进展生存期（PFS）影响的Ⅲ期随机对照研究。研究设计上，PFS和OS作为双主要研究终点，采用优效性设计，α控制在单侧0.025，其中PFS和OS初始α各分配50%比例。研究结果上，帕博利珠单抗组对比化疗组的OS没有达到显著性差异，但帕博利珠单抗组呈现出了PFS、客观缓解率及安全性方面的优势。尽管OS未达到其统计学预设终点，现有的数据仍支持帕博利珠单抗作为MSI-H/dMMR转移性结直肠癌患者的有效一线治疗方案。     

免疫相关中毒性表皮坏死松解症一例及文献复习

随着免疫检查点抑制剂（ICI）在临床越来越广泛的应用，ICI 治疗使肿瘤患者临床获益的同时，也会出现一些免疫相关 不良反应。本文报道了1 例晚期肺鳞癌男性患者使用替雷利珠单抗治疗后致免疫相关性皮肤毒性——史蒂文斯-约翰逊综合征（SJS）/中毒性表皮坏死松解症（TEN），主要表现躯干和四肢皮肤皮疹、红斑、瘙痒、脱皮等，经治疗后好转。通过复习替雷利珠单抗相关不良反应的文献，进一步分析了替雷利珠单抗所致皮肤毒性的临床特点和治疗方法，为提高免疫治疗药物临床应用的安 全性提供了参考。     

原发性肝细胞癌患者帕博利珠单抗治疗后发生致命性不良反应1例并文献复习

目的提高对原发性肝细胞癌患者帕博利珠单抗治疗后发生致命性不良反应的认识。方法回顾性分析莆田市第一医院2022年2月收治的1例帕博利珠单抗治疗后发生致命性不良反应的原发性肝细胞癌患者临床资料, 并复习相关文献。结果患者为72岁男性, 因原发性肝细胞癌接受综合治疗, 但在首次应用帕博利珠单抗1个周期内出现四肢酸痛无力、右眼睑下垂、视物重影、实验室指标、心电图异常。综合病史、临床表现及辅助检查结果, 经多学科会诊考虑该患者出现了免疫相关性心肌炎和肌炎, 不良反应分级为G4级。治疗方案总体上参照指南, 在持续抢救了近4个月后, 由于生命体征难以维持而自动出院。结论原发性肝癌患者应用帕博利珠单抗后发生免疫相关心肌炎和肌炎的情况是罕见且凶险的, 其早期表现没有特征性, 应做到早发现、早干预, 以期改善预后。     

帕博利珠单抗治疗晚期胃腺癌、胃食管结合部腺癌患者的疗效与安全性—Keynote-061/062研究阴性结果解读

摘 要：探索帕博利珠单抗（Pembrolizumab）与紫杉醇比较在PD-L1阳性晚期胃/胃食管结合部腺癌临床疗效和安全性的两项全球多中心、随机对照、Ⅲ期研究（Keynote-061和062）均以失败告终,导致FDA撤销了Keytruda（可瑞达）在该适应证上的应用。两项研究样本量分别为592例和763例,主要终点均为总生存（overall survival,OS）。结果显示：帕博利珠单抗单药对比紫杉醇二线治疗 PD-L1联合阳性分数（combined positive score,CPS）≥1患者中两组中位总生存期分别为9.1个月和8.3个月,风险比（hazard ratio,HR）为0.82（95%CI：0.66~1.03,P=0.042 1）,中位无进展生存期（progression-free survival,PFS）分别为1.5个月和4.1个月,风险比为1.27（95%CI：1.03~1.57）;一线治疗的患者（CPS1）帕博利珠单抗OS非劣效于化疗,HR为0.91（99.2%CI：0.69~1.18）,PFS风险比为1.66（95%CI：1.37~2.01）;帕博利珠单抗联合化疗组相比化疗疗效改善没有明显优势,OS风险比为0.85（95%CI：0.70~1.03）;PFS风险比为0.84（95%CI：0.70~1.02）。但在安全性方面,帕博利珠单抗相对于化疗均表现出较好的安全性。帕博利珠单抗单药在晚期胃/胃食管结合部腺癌的研究结果为阴性,其研究策略、方案设计、统计分析、后续布局等均值得进一步讨论和思考。     

PD-1 PD-L1单抗在复发转移性鼻咽癌中的研究进展

鼻咽癌患者经放疗及同步辅助化疗后,临床转归有所改善,但肿瘤复发及远处转移仍为一项难题。近些年,免疫检查点抑制剂的发现为肿瘤的免疫治疗提供了新的选择。其中,程序性细胞死亡受体1（programmed cell death protein-1,PD-1）/程序性死亡受体配体1（programmed cell death 1-ligand,PD-L1）单抗受到广泛关注且已应用于临床治疗。本文就帕博利珠单抗、纳武利尤单抗、卡瑞利珠单抗和特瑞普利单抗等PD-1/PD-L1单抗在复发/转移性鼻咽癌中的研究进展进行综述。      

帕博利珠单抗联合同步放化疗治疗不可切除的Ⅲ期NSCLC的疗效和安全性：KEYNOTE-799研究及2年随访数据解读

摘 要：KEYNOTE-799研究近期更新了2年生存结果。这是一个由10个国家52个研究中心参与的非随机Ⅱ期研究,旨在研究帕博利珠单抗联合同步放化疗治疗不可切除的Ⅲ期NSCLC的疗效,其主要研究终点为客观缓解率（ORR）和3级及以上肺炎的发生率。研究共纳入216例不可切除的局部晚期非小细胞肺癌（NSCLC）患者,其中112例患者进入A队列（鳞癌和非鳞NSCLC）,104例患者进入B队列（非鳞NSCLC）（2022ASCO更新时变为102例）。两组在给予帕博利珠单抗+化疗诱导治疗1个周期后行帕博利珠单抗联合同步放化疗,接着行帕博利珠单抗巩固治疗。结果显示,A队列ORR为71.4%,疾病控制率（DCR）达到88.4%;B队列ORR为75.5%,DCR达到93.1%。A队列中位PFS为 30.6 个月,2年PFS率55.3%;B队列中位PFS未达到,2年PFS率为60.6%。两队列的中位OS和缓解持续时间都未达到。KEYNOTE-799进行了免疫联合同步放化疗的尝试,有望使更多不可切除的局部晚期NSCLC患者接受免疫治疗。     

替雷利珠单抗联合化疗在尿路上皮癌中的疗效及不良反应分析

目的 评价真实世界中替雷利珠单抗联合化疗在治疗尿路上皮癌中的疗效及安全性。方法 纳入32例行替雷利珠单抗联合化疗（吉西他滨/顺铂或紫杉醇）的尿路上皮癌患者资料,统计分析治疗期间出现的治疗相关不良反应发生率及疗效评估。结果 患者分组：替雷利珠单抗联合紫杉醇组15例,替雷利珠单抗联合GC组17例。共24例患者获得有效疗效分析,总体的客观缓解率（ORR）为54.2%,疾病控制率（DCR）为83.3%。在替雷利珠单抗联合紫杉醇组和替雷利珠单抗联合GC组中ORR分别为50.0%与58.3%,DCR分别为75.0%和91.7%。32例患者常见的治疗相关不良反应包括贫血（56.3%）、食欲下降（53.1%）、皮肤瘙痒（50.0%）,3~4级不良反应发生率为21.8%。其中常见的免疫相关不良反应包括皮肤毒性（53.1%）、免疫性结肠炎（9.4%）。结论 替雷利珠单抗联合化疗治疗尿路上皮癌患者疗效显著,安全可控,但应注意免疫相关性不良反应。     

基于真实世界医药数据库的PD-1/PD-L1抑制剂相关不良反应信号挖掘

目的 利用真实世界中的医药大数据，挖掘肿瘤免疫治疗药物程序性死亡受体1/程序性死亡配体1(PD-1/PD-L1)抑制剂发生不良反应的风险信号，促进此类药物在临床安全合理使用。方法 收集美国食品与药品监督管理局(FDA)不良反应数据库中2014年9月1日至2022年9月30日的不良反应报告。经过数据标准化处理，使用报告比值比(ROR)法及数据交叉对比分析，对PD-1/PD-L1抑制剂的不良反应信号进行数据挖掘。结果 获得PD-1/PD-L1抑制剂的不良反应报告106 946份。经数据挖掘，有显著意义的不良反应风险信号2741个，其中帕博利珠单抗886个、纳武利尤单抗956个、阿替利珠单抗545个、度伐利尤单抗255个、阿维鲁单抗99个。全部风险信号共累及25个系统或器官，主要为神经系统疾病、胃肠系统疾病、感染类疾病等。报告数前20位的不良反应中未在说明书中出现的信号有22个。所有PD-1/PD-L1抑制剂均存在的风险信号包括自身免疫性结肠炎、肿瘤溶解综合征、血肌酸磷酸激酶升高、心肌病等。结论 临床使用PD-1/PD-L1抑制剂时，应关注患者的神经系统功能、胃肠道症状以及可能出现的感染，根...     

恩沃利单抗联合阿昔替尼治疗肾癌肺转移1例并文献复习

近年来,免疫治疗在转移性肾癌的治疗领域中取得了突破性进展,是目前晚期肾癌综合治疗体系中重要的组成部分。现报道1例右肾透明细胞癌根治术后出现双肺多发转移患者,一线使用培唑帕尼治疗进展,二线使用帕博利珠单抗联合阿昔替尼出现免疫检查点抑制剂相关性肺炎,经激素冲击治疗好转后,改用恩沃利单抗联合阿昔替尼治疗持续获益,以期为临床使用免疫治疗提供参考。     

Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m² every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m² (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5–24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5–not reached) versus 11.0 (8.6–19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27–1.15). Median PFS (95% CI) was 8.3 (6.1–13.0) versus 7.2 (3.9–8.8) months (HR 0.65; 95% CI, 0.35–1.23). Grade 3–5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.     

PD-1抑制剂治疗复发难治性胸腺瘤1例报道及文献复习

目的:探讨程序性细胞死亡蛋白1及其配体（PD-1/PD-L1）抑制剂在胸腺瘤治疗中的应用。方法:回顾性分析四川大学华西医院收治的1例晚期胸腺瘤患者使用PD-1抑制剂pembrolizumab的临床资料并对相关文献进行回顾。以“PD-1 inhibitor”、“PD-L1 inhibitor”、“pembrolizumab”、“nivolumab”或“atezolizumab”联合“thymoma”检索Pubmed数据库,检索时间截止至2019年9月30日。结果:患者男,26岁,B2/B3型胸腺瘤,在多次姑息性手术治疗,多线化疗,纵隔放疗后病情出现进展,后续使用PD-L1抑制剂pembrolizumab联合培美曲塞治疗,在第一次使用pembrolizumab治疗后患者出现免疫相关心肌炎,经甲基强的松龙治疗后好转,药物减停过程中患者出现心肌炎复燃,并伴随全身多器官功能障碍,最后在使用PD-1抑制剂后5个月死亡。在Pubmed数据库共检索到5篇文献共12例胸腺瘤患者使用免疫治疗,加上本例共13例。在这13例使用PD-1抑制剂的患者中,9例进行了疗效评价,3例患者达到部分缓解,6例患者疾病稳定;然而有11例患者出现免疫相关不良事件,6例患者死亡。结论:PD-1抑制剂在胸腺瘤中显示出良好的抗肿瘤活性,同时也具有很高的不良反应发生率及致死率,在临床应用中应慎重考虑患者的获益和风险。     

Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor

BackgroundDermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known.MethodsWe conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented.ResultsRash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab.ConclusionWe found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors.     

基于PD-1/PD-L1抑制剂联合疗法对比舒尼替尼治疗晚期肾细胞癌安全性和有效性的Meta分析

目的：系统评价基于PD-1/PD-L1抑制剂的免疫联合治疗（以下称“免疫联合治疗”）对比舒尼替尼治疗晚期肾细胞癌（RCC）的安全性和有效性。方法：检索PubMed、Embase、Cochrane Library及中国知网（CNKI）数据库，收集国内外公开发表的免疫联合治疗对比舒尼替尼应用于晚期RCC的随机对照试验（RCT），检索时间均为自建库时间至2022年10月。由两名研究者独立评价纳入研究的质量、提取资料并交叉核对，采用StataMP16.0软件进行Meta分析。结果：共纳入6项RCT,Meta分析结果显示，（1）有效性：与舒尼替尼相比，免疫联合治疗显著提高了晚期RCC患者的总生存期[OS,HR=0.74,95%CI(0.67,0.80),P<0.01]和无进展生存期[PFS,HR=0.66,95%CI(0.51,0.81),P<0.01](;2)安全性：两治疗组均有较高的不良反应（AE）发生率，差异无统计学意义。但免疫联合治疗组发生皮肤及内分泌系统AE显著高于舒尼替尼治疗组，而血液系统相关AE则明显低于舒尼替尼治疗组（；3）以1%为临界点，免疫联合治疗组的RCC患者，...     

化疗联合PD-1/PD-L1抑制剂治疗三阴性乳腺癌有效性和安全性的Meta分析

目的:利用循证医学手段,通过Meta分析评估化疗联合PD-1/PD-L1 抑制剂与单纯化疗治疗三阴性乳腺癌的安全性和有效性,从而为临床诊疗提供指导意见。方法:检索Pubmed、Embase、Cochrane图书馆、知网、万方、维普和CBM数据库从建库到2021年08月以来有关化疗联合PD-1/PD-L1 抑制剂治疗三阴性乳腺癌的文献。由两位研究者独立完成筛选文献、提取资料以及评估偏倚风险后,采用RevMan 5.3和STATA 15.1软件进行统计分析。结果:本次研究共纳入8篇文献。汇总结果表明联合治疗组患者的总生存期（overall survival,OS）和无进展生存期（progression-free survival,PFS）明显长于仅接受化疗的患者（HR=0.85,95%CI:0.75~0.96;HR=0.84,95%CI:0.73~0.97）。结果还表明联合治疗组患者的(complete remission rate,CRR)也显著高于仅接受化疗治疗的患者（RR=1.44,95%CI:1.10~1.89）。此外,联合治疗组的不良反应发生率高于单纯化疗组（RR=1.08,95%CI:1.03~1.14）。亚组分析的结果显示接受Atezolizumab联合化疗的患者的 OS 明显长于单独接受化疗的患者（HR=0.85,95%CI:0.75~0.96）,接受Atezolizumab或Pembrolizumab与化疗的联合治疗显著延长了患者的PFS（HR=0.80,95%CI:0.73~0.89;HR=0.79,95%CI:0.67~0.92）,然而接受Durvalumab联合化疗的患者OS和PFS较单纯化疗并无显著差异。结论:化疗联合 PD-1/PD-L1 抑制剂治疗三阴性乳腺癌比单独化疗更有效,但联合治疗有着更高的不良反应发生率。此外,Durvalumab与化疗药的联合使用并不能增加患者的OS和PFS。     

Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2)

IntroductionCheckpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2.MethodsCYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers.ResultsMedian follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5–2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54–1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708–3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3–5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519–1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772–4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms.ConclusionsDespite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs.     

Ipilimumab联合化疗治疗晚期肺鳞癌的单中心安全性观察

背景与目的：以检查点(checkpiont)为靶点的免疫治疗在实体瘤治疗领域有巨大的应用价值,引发了免疫靶向药物的研究热潮。一项研究结果为ipilimumab联合化疗治疗非小细胞肺癌(non-small cell lung can-cer,NSCLC)患者的后续研究提供了依据。该研究统计ipilimumab或安慰剂与紫杉醇和卡铂联合作为一线治疗方案治疗Ⅳ期或复发性、组织学为肺鳞状细胞癌的不良事件(adverse events,AEs),评价ipilimumab联合化疗治疗晚期肺鳞癌的安全性。方法：共入组13例经上海交通大学附属胸科医院收治的ⅣA期或ⅣB期ECOG评分标准均小于等于1的肺鳞癌患者。采用随机对照双盲试验,试验组方案为ipilimumab联合紫杉醇与卡铂,对照组方案为安慰剂联合紫杉醇与卡铂。统计治疗过程中发生的AEs。结果：最常见的AEs主要是1级和2级AEs。Ipilimumab单抗组出现的免疫相关AEs(immune-related AEs,irAEs)包括Ⅰ级的腹泻及皮肤瘙痒,Ⅱ级的皮疹及皮肤瘙痒和Ⅲ级的垂体炎。结论：Ipilimumab单抗的不良反应轻微,可耐受,可处理。     

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer

PurposeThe combination of an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibody with platinum-based chemotherapy can improve outcomes for patients with advanced non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC) compared with chemotherapy alone. For patients receiving these new treatment regimens, it is important that toxicities be managed effectively. A particular challenge can be determining the etiology of an event, especially when there are overlapping symptoms that can be attributed to either immunotherapy or to platinum-based chemotherapy. Here, we evaluate adverse events (AEs) reported in clinical trials of combination therapy with an anti-PD-1 or anti-PD-L1 (anti-PD-[L]1) immunotherapy and chemotherapy to provide information on toxicity management.MethodsWe performed a systematic review of the literature focused on randomized controlled trials of anti-PD-(L)1 therapy combined with platinum-based chemotherapy for advanced/metastatic NSCLC and SCLC.ResultsEleven reports from 9 randomized studies evaluating pembrolizumab, nivolumab, and atezolizumab combined with platinum-based chemotherapy in patients with advanced lung cancer were identified. Immune-mediated AEs and infusion reactions occurred more commonly in patients who received anti-PD-(L)1 immunotherapy with platinum-based chemotherapy compared with chemotherapy alone; however, there was no evidence of unexpected or unanticipated toxicity with these combinations.ConclusionCombinations of anti-PD-(L)1 immunotherapy with platinum-based chemotherapy regimens improve outcomes for patients with NSCLC and SCLC, and toxicity is generally manageable. Strategies for appropriate workup of AEs to allow clinicians to make informed decisions regarding causality and treatment modifications when appropriate are an important element of management of patients receiving an anti-PD-(L)1 agent combined with platinum-based chemotherapy.     

Clinical Benefit of Pembrolizumab in Advanced Urothelial Cancer Patients in Real-Life Setting: An Efficacy and Safety Monocentric Study

Background: Pembrolizumab is approved for patients with metastatic urothelial carcinoma (UC) who progressed under platinum therapy. The aim of this study was to assess the efficacy and safety of pembrolizumab in a cohort of real-life UC patients. Methods: This retrospective, observational study included advanced UC patients treated with pembrolizumab in a single institution in France. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS) at 6 months. Secondary endpoints were objective response rate (ORR), duration of response (DOR), disease control rate (DCR) and safety. Results: 78 patients were included in the study. The median OS was 7.3 months (3.8–12.2). The estimated OS rate at 6 months was 61.5% (50.5–72.6). The median PFS was 3.1 months (1.4–7.2). The estimated PFS rate at 6 months was 42.3% (31.1–53.5). The best ORR was 35.9%. The mean DOR was 95.5 days. The DCR was 30.8%. The most common treatment-related adverse events (AEs) of any grade were fatigue (46.2%), diarrhea (11.5%), pruritus (10.3%) and nausea (9.0%). There were no grade 3 AEs that occurred with an incidence of 5% or more. Conclusion: Our results confirmed those of randomized clinical trials concerning the treatment with pembrolizumab in patients with advanced UC that progressed after platinum-based chemotherapy.     

A Randomized,Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407

IntroductionIn the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment.MethodsEligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point.ResultsAfter median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.ConclusionsPembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.