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

Pembrolizumab聯合鉑基化療治療複發性EGFR// alk陽性非小細胞肺癌

Introduction
介紹

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.

單藥免疫檢查點抑製劑在EGFR/ alk改變的NSCLC患者中的療效有限。我們進行了一項II期研究，以評估派姆單抗聯合卡鉑和培美曲塞在這些患者中的療效。

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/m² and 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^st and 3^rd cycles. 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.

複發性egfr突變或alk重排的NSCLC患者，之前接受過靶向治療，符合條件。卡鉑AUC5，培美曲塞500mg / m2，派姆單抗200mg，每3周靜脈注射一次。4個周期後，患者繼續使用培美曲塞和派姆單抗長達2年。在前6個周期中每2個周期評估一次疾病，然後由研究人員自行決定。主要終點為RECIST 1.1定義的應答率。次要終點包括PFS和OS。局部檢測腫瘤PD-L1表達。循環腫瘤細胞(ctc)血液在1次循環前采集。該研究計劃在egfr突變和alk重排NSCLC的兩個獨立隊列中分別納入28例可評估患者。緩慢的登記導致試驗提前終止。

Results

結果

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.

在納入的33例患者中，26例為egfr突變的NSCLC (13 del19, 9 L858R)， 64%為女性，中位年齡為67歲。既往治療的中位數為1例(範圍1-3例)。26例EGFR+ NSCLC患者中有22例既往接受過奧西替尼治療。中位周期數為6個(2-24個周期)，其中4例患者均為EGFR+，仍在治療中。EGFR+和ALK+患者的緩解率(95%CI)分別為42%(23%，63%)和29%(4%，71%)。所有患者和EGFR陽性患者的中位緩解持續時間為6.1個月。其他療效結果如下。腫瘤PD-L1表達有30例，其中17例≥1%。腫瘤PD-L1 <1%與≥1%患者的生存期無差異。在15例樣本可用的EGFR+患者中，基線時中位CTC計數為4/ml(0-23)。治療期間CTC計數減少與增加的EGFR+患者的中位總生存期分別為18.5個月(p=0.52 OS)。最常見的不良事件是疲勞、惡心、細胞減少、咳嗽和呼吸困難。最常見的≥3級毒性是中性粒細胞減少、血小板減少、血栓栓塞和AST/ALT升高。1名患者發展為肺炎。

Conclusion
結論

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.

在複發性egfr突變NSCLC患者中，Pembrolizumab聯合化療的應答率為42%，中位生存期為22個月。這些結果為進一步研究該聯合治療提供了依據。