Treatment Approaches 治療手段
Human immune-checkpoint–inhibitor antibodies inhibit the PD-1 receptor or PD-L1, which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T-cells. Nivolumab and pembrolizumab inhibit PD-1 receptors. Atezolizumab inhibits PD-L1. Immune checkpoint inhibitors are associated with a delay in benefit when compared with targeted therapy or cytotoxic chemotherapy. Nivolumab, pembrolizumab, and atezolizumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). Pseudoprogression has been reported; therefore, traditional RECIST criteria may not be applicable.
The NCCN Panel recommends nivolumab (category 1) as subsequent therapy for patients with metastatic non-squamous NSCLC who have progressed on or after first-line chemotherapy based on data from a phase 3 randomized trial (CheckMate-057) and FDA approval. The NCCN Panel recommends immune checkpoint inhibitors as preferred agents for subsequent therapy based on improved overall survival rates, longer duration of response, and fewer adverse events when compared with cytotoxic chemotherapy.
The category 1 recommendation for nivolumab is based on the published data from CheckMate-057 and FDA approval of nivolumab for patients with metastatic non-squamous NSCLC. For patients receiving nivolumab, median overall survival was 12.2 months compared with 9.4 months for docetaxel (HR, 0.73; 95% CI, 0.59–0.89; P = .002). The median duration of response was 17.2 months with nivolumab compared with 5.6 months for docetaxel. At 18 months, the overall survival rate was 39% (95% CI, 34%–45%) with nivolumab compared with 23% (95% CI, 19%–28%) with docetaxel. Fewer grade 3 to 5 adverse events were reported for nivolumab (10%) when compared with docetaxel (54%) in the CheckMate-057 trial. Although many patients with metastatic non-squamous NSCLC benefit from nivolumab, those whose tumors have PD-L1 staining of 1% to 10% or more have overall survival of 17 to 19 months compared with 8 to 9 months for docetaxel. For patients who did not have PD-L1 expression, there was no difference in overall survival for nivolumab versus docetaxel; however, nivolumab was associated with a longer duration of response and fewer side effects.
根據CheckMate-057公布的數據和FDA對尼魯單抗的批準，對于轉移性非鱗NSCLC患者，尼魯單抗為1類推薦。對于接受尼魯單抗治療的患者，中位總生存期為12.2個月，而多西他賽為9.4個月（HR，0.73；95% CI, 0.59–0.89;P =0.002)。中位療效持續時間尼魯單抗是17.2個月，而多西他賽是5.6個月。在18個月時，總生存率尼魯單抗是39%（95% CI，34%–45%），而多西他賽是23%（95% CI，19%–28%）。在CheckMate-057試驗中報道的3至5度不良事件，尼魯單抗（10 %）比多西他賽（54%）更少。雖然許多轉移性非鱗NSCLC患者從尼魯單抗治療中獲益，但是那些腫瘤PD-L1染色1%-10%或更高的患者總生存期17-19個月，而多西他賽為8-9個月。對于那些無PD-L1表達的患者，與多西他賽相比，尼魯單抗總生存無差異；然而，尼魯單抗具有更長的應答持續時間和更少的副作用。
To help clinicians determine which patients with non-squamous NSCLC may benefit most from treatment with nivolumab, the FDA has approved a complementary diagnostic biomarker test to assess for PD-L1 protein expression. Testing for PD-L1 is not required for prescribing nivolumab but may provide useful information. Current or former smoking status correlated with the response rate to immune checkpoint inhibitors. Recent data suggest that mismatch repair deficiency is associated with response to immune checkpoint inhibitors.
The NCCN Panel also recommends (category 1) nivolumab as subsequent therapy for patients with metastatic squamous cell NSCLC who have progressed on or after first-line chemotherapy based on data from a phase 3 randomized trial (CheckMate-017), the recent FDA approval, and results of a phase 2 trial. In the CheckMate-017 trial, the median overall survival was 9.2 months with nivolumab compared with 6.0 months for docetaxel. Patients had a response rate of 20% with nivolumab compared with 9% for docetaxel (P = .008). PD-L1 expression was not associated with response to nivolumab in patients with squamous cell NSCLC. There were fewer grade 3 to 4 adverse events with nivolumab (7%) when compared with docetaxel (55%). No patients died in the nivolumab arm versus 3 deaths in the docetaxel arm. Immune-related adverse events, such as pneumonitis, may occur with nivolumab. Intravenous high-dose corticosteroids should be administered based on the severity of the reaction for patients with immune-mediated adverse events. Nivolumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information).
基于一項3期隨機試驗（CheckMate-017）的數據、最近FDA的批準以及一項2期試驗結果，對于在一線化療時或一線化療后進展的轉移性肺鱗癌患者，NCCN小組也推薦（1類）尼魯單抗作為后續治療。在CheckMate-017試驗中，尼魯單抗中位總生存期是9.2個月，而多西他賽是6.0個月。與多西他賽的有效率9%相比，尼魯單抗為20%（P = 0.008）。PD-L1表達與肺鱗癌患者對尼魯單抗的應答無關。與多西他賽（55%）相比，尼魯單抗具有較少的3-4度不良事件（7%）。尼魯單抗組沒有患者死亡而多西他賽組3人死亡。尼魯單抗可能會發生免疫相關不良事件如肺炎。對于具有免疫介導不良事件的患者，應該根據反應的嚴重程度給予靜脈注射大劑量皮質類固醇激素。對于重度或危及生命的肺炎患者，應該停止尼魯單抗，而對于其他嚴重或危及生命的免疫介導不良事件，當有指征時（見處方信息）應該拒絕或中止給藥。