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2016 ESMO大会中肺癌免疫治疗领域取得了重要的进展，不仅有PD-1抑制剂首次进入一线梯队，还有对应的配体PD-L1抑制剂在二线治疗中胜出化疗。在多药组合战场，PD-1抑制剂Pembrolizumab联合一线化疗治疗晚期非小细胞肺癌（NSCLC）的KEYNOTE-021研究中，患者的无进展生存和缓解率得到明显提升。
主要研究者，来自美国宾夕法尼亚大学Abramson癌症中心的Corey Langer教授说：“Pembrolizumab使T细胞重新获得活性，促进杀伤肿瘤细胞。”
在KEYNOTE-021Ⅱ期研究中，纳入的患者为ⅢB/Ⅳ期未接受化疗的非鳞癌NSCLC，共123例。随机将入组患者分配进4周期的卡铂+培美曲塞（500mg/m2）联合±Pembrolizumab（200mg）治疗。
中位随访10.6个月，Pembrolizumab联合化疗组的客观缓解率（ORR）为55%，单用化疗组则只有29%。虽然通过PD-L1表达水平筛选患者，但研究结果显示，在免疫联合化疗治疗下，的确存在高表达人群（≥50%）缓解率更高（约80%）的现象。
在无进展生存方面，Pembrolizumab联合化疗组中位PFS为13.0个月，而单纯化疗组为8.9个月。两干预组患者的早期总生存数据相似，6个月生存率均为92%。
不良反应方面，与单独化疗相比，Pembrolizumab联合化疗组≥3级以上不良事件发生率更高（26% vs 39%），但对治疗中断率（13% vs 10%）和治疗相关死亡无影响。最常见的治疗相关不良事件是疲乏和恶心，多见于Pembrolizumab联合化疗组，而贫血更多见于单独化疗组。
“这是首个对比免疫联合化疗和单独化疗的Ⅱ期临床研究，如果前者的临床获益结果能在已经开展的Ⅲ期研究中得到证实，可能会从根本上改变晚期非小细胞肺癌的治疗模式。”
英国南曼彻斯特大学医院的Raffaele Califano教授在评论该研究时说：“Pembrolizumab联合化疗的数据令人鼓舞。在化疗基础上增加免疫治疗的毒性可控，并未增加治疗相关不良事件或死亡的发生率，这一点比较让人放心。”
“需要注意的是，标准化疗组的无进展生存期比往常的数据好很多，几乎加倍。这可能是对患者的选择或其他可能的临床/分子特征。如果要在临床实践中应用这样的联合方案，那么还要设计类似的Ⅲ期临床试验进一步评估，使PFS更有效力以及患者报告结局的评价更加充分。” Califano教授补充道。
信源：First-line Pembrolizumab Plus Chemotherapy Significantly Improves Outcomes in Advanced NSCLC.ESMO 2016 Press Release.
摘要原文
Abstract：LBA46
Title：Randomized,phase 2 study of carboplatin and pemetrexed with or without pembrolizumab asfirst-line therapy for advanced NSCLC: KEYNOTE-021 cohort G
Background: Pembrolizumab (pembro) monotherapy exhibits robustantitumor activity in PD-L1─expressing advanced NSCLC. Cohort G of themulticenter, open-label, phase 1/2 KEYNOTE-021 study (NCT02039674) evaluatedthe efficacy and safety of pembro + carboplatin and pemetrexed (CP) vs CP aloneas first-line therapy for advanced nonsquamous NSCLC.
Methods: Key eligibility criteria were stage IIIB/IV,chemotherapy-naive, nonsquamous NSCLC, ECOG PS 0-1, and no EGFR mutation or ALKtranslocation. Patients (pts) were randomized to 4 cycles of carboplatin AUC 5+ pemetrexed 500 mg/m2 Q3W ± 24 mo of pembro 200 mg Q3W; maintenance pemetrexedwas allowed in both arms. Randomization was stratified by PD-L1 tumorproportion score ≥1% vs <1%. Eligible pts with radiologic progression on CPcould crossover to pembro monotherapy. Primary end point was ORR, with PFS asthe key secondary end point; both were assessed per RECIST v1.1 by blindedindependent central review. ORR and PFS superiority thresholds were one-sided α= 0.025.
Results: 123 pts were enrolled: 60 in the pembro + CP arm,63 in the CP arm. Demographics were generally balanced between treatment arms.As of Aug 8, 2016, median follow-up was 10.6 mo (range, 0.8-19.3); medianexposure was 8.0 mo for pembro + CP and 4.9 mo for CP. In the CP arm, 43 ptsdiscontinued therapy; 32 received subsequent anti–PD-1 therapy as part ofcrossover (n = 20) or off study (n = 12). Pembro + CP significantly improvedORR (55% vs 29%; P = 0.0016) and PFS (HR 0.53, 95% CI 0.31-0.91, P = 0.0102;median 13.0 vs 8.9 mo). Overall survival was similar; 6-mo survival rates were92% in each arm. Without adjusting for exposure, for pembro + CP vs CP,treatment-related AEs led to discontinuation in10% vs 13%, were of grade ≥3severity in 39% vs 26%, and led to death in 2% (sepsis, n = 1) vs 3% (sepsisand pancytopenia, n = 1 each). The most common any-grade treatment-related AEswere fatigue (64% vs 40%), nausea (58% vs 44%), and anemia (32% vs 53%).
Conclusions: Pembro 200 mg Q3W + CP demonstrated a statisticallysignificant, clinically relevant ORR and PFS benefit over CP alone and had amanageable, safety profile as first-line therapy in patients with advancednonsquamous NSCLC.
