Pembrolizumab in Combination With Platinum-Based Chemotherapy in Recurrent EGFR/ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

Pembrolizumab联合铂基化疗治疗复发性EGFR// alk阳性非小细胞肺癌

Introduction
介绍

Efficacy of single-agent immune checkpoint inhibitors is limited in patients with EGFR/ALK-altered NSCLC. We conducted a phase II study to assess the efficacy of pembrolizumab in combination with carboplatin and pemetrexed in these patients.

单药免疫检查点抑制剂在EGFR/ alk改变的NSCLC患者中的疗效有限。我们进行了一项II期研究，以评估派姆单抗联合卡铂和培美曲塞在这些患者中的疗效。

Methods
研究方法

Patients with recurrent EGFR-mutated or ALK-rearranged NSCLC, previously treated with targeted therapy, were eligible. Patients were treated with carboplatin AUC5, pemetrexed 500 mg/m²and pembrolizumab 200 mg I.V. every 3 weeks. After 4 cycles patients were maintained on pemetrexed and pembrolizumab for up to 2 years. Disease was assessed every 2 cycles for the first 6 cycles, then per investigator discretion. The primary end-point was RECIST 1.1 defined response rate. Secondary endpoints included PFS and OS. Tumor PD-L1 expression was assessed locally. Blood for circulating tumor cells (CTCs) was collected prior to the 1^stand 3^rdcycles. The plan was to enroll 28 evaluable patients in each of two separate cohorts of EGFR-mutated and ALK-rearranged NSCLC. Slow enrollment led to early termination of the trial.

复发性egfr突变或alk重排的NSCLC患者，之前接受过靶向治疗，符合条件。卡铂AUC5，培美曲塞500mg / m2，派姆单抗200mg，每3周静脉注射一次。4个周期后，患者继续使用培美曲塞和派姆单抗长达2年。在前6个周期中每2个周期评估一次疾病，然后由研究人员自行决定。主要终点为RECIST 1.1定义的应答率。次要终点包括PFS和OS。局部检测肿瘤PD-L1表达。循环肿瘤细胞(ctc)血液在1次循环前采集。该研究计划在egfr突变和alk重排NSCLC的两个独立队列中分别纳入28例可评估患者。缓慢的登记导致试验提前终止。

Results

结果

Of the 33 patients enrolled, 26 had EGFR-mutated NSCLC (13 del19, 9 L858R), 64% were female and median age was 67 years. The median number of prior treatments was 1 (range 1-3). 22 of 26 EGFR+ NSCLC patients had received prior osimertinib. Median number of cycles was 6 (2-24 cycles), with 4 patients, all EGFR+, still on therapy. Response rates (95%CI) were 42% (23%, 63%) and 29% (4%, 71%) among EGFR+ and ALK+ patients, respectively. Median duration of response was 6.1 months in all patients and in EGFR+ patients. Other efficacy results are provided below. Tumor PD-L1 expression was available for 30 patients and was ≥ 1% in 17. There was no difference in survival between patients with tumor PD-L1 <1% vs. ≥ 1%. The median CTC count at baseline in 15 EGFR+ patients in whom samples were available was 4/ml (0-23). Median overall survival among EGFR+ patients with decreased vs. increased CTC count during treatment was not reached vs. 18.5 months, respectively (p=0.52 for OS). The most common adverse events were fatigue, nausea, cytopenias, cough and dyspnea. The most common ≥ grade 3 toxicities were neutropenia, thrombocytopenia, thromboembolism, and AST/ALT elevation. One patient developed pneumonitis.

在纳入的33例患者中，26例为egfr突变的NSCLC (13 del19, 9 L858R)， 64%为女性，中位年龄为67岁。既往治疗的中位数为1例(范围1-3例)。26例EGFR+ NSCLC患者中有22例既往接受过奥西替尼治疗。中位周期数为6个(2-24个周期)，其中4例患者均为EGFR+，仍在治疗中。EGFR+和ALK+患者的缓解率(95%CI)分别为42%(23%，63%)和29%(4%，71%)。所有患者和EGFR阳性患者的中位缓解持续时间为6.1个月。其他疗效结果如下。肿瘤PD-L1表达有30例，其中17例≥1%。肿瘤PD-L1 <1%与≥1%患者的生存期无差异。在15例样本可用的EGFR+患者中，基线时中位CTC计数为4/ml(0-23)。治疗期间CTC计数减少与增加的EGFR+患者的中位总生存期分别为18.5个月(p=0.52 OS)。最常见的不良事件是疲劳、恶心、细胞减少、咳嗽和呼吸困难。最常见的≥3级毒性是中性粒细胞减少、血小板减少、血栓栓塞和AST/ALT升高。1名患者发展为肺炎。

Conclusion
结论

Pembrolizumab in combination with chemotherapy demonstrated a response rate of 42% and median survival of 22 months among patients with recurrent EGFR-mutated NSCLC. These results warrant further study of this combination in this patient population.

在复发性egfr突变NSCLC患者中，Pembrolizumab联合化疗的应答率为42%，中位生存期为22个月。这些结果为进一步研究该联合治疗提供了依据。