Pembrolizumab（商品名Keytruda，健痊得）是一種新型人源化單抗，通過作用於程序性細胞死亡1（PD-1）進行腫瘤免疫治療。Pembrolizumab（商品名Keytruda，健痊得）是一種新型治療癌症的藥物。

《壹篇》按

《柳葉刀腫瘤學分冊》2017年5月23日在線先發

http://thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30380-7/fulltext

在非小細胞肺癌治療中既往放療與派姆單抗的毒性、臨床療效間的關係：對KEYNOTE-001Ⅰ期臨床試驗的一項二次分析

背景

臨床前期研究已發現，放療可增強抗腫瘤免疫反應。在接受派姆單抗前既往已接受放療的非小細胞肺癌(NSCLC)患者中，我們旨在評估腫瘤控制和肺毒性情況。

方法

我們在一家單一醫療機構(美國加州大學洛杉磯分校)中，對KEYNOTE-001Ⅰ期臨床試驗中進行治療的晚期非小細胞肺癌(NSCLC)患者進行了評估。患者年齡≥18歲、東部腫瘤協作組（ECOG）體能狀態評分≤1、臟器功能佳、且無肺炎病史。患者接受派姆單抗治療直至疾病進展、或出現不可耐受毒性、或試驗方案界定的其它中止治療理由，治療劑量為2mg/Kg或10mg/Kg每3周重複，或10mg/Kg每2周重複。通過「不良事件免疫相關反應標準和常用術語標準4.0版」對腫瘤緩解和肺毒性情況進行前瞻性評估。KEYNOTE-001試驗的主要目的是評估派姆單抗的安全性、副作用和抗腫瘤活性。我們為了進行二次分析，將患者進行亞組分組，以對既往接受過放療的患者和未接受過放療的患者進行比較。我們的主要目的為在意向治療人群中，了解既往放療是否影響無進展生存、總生存和肺毒性。KEYNOTE-001試驗已在ClinicalTrials.gov網站註冊，註冊號NCT01295827。

結果

2012年5月22日至2014年7月11日，入組了98名患者，並接收了第一周期的派姆單抗治療，一名患者失訪。97名患者中42名(43%)在接受第一周期派姆單抗治療前已接受過針對非小細胞肺癌的放療。97名患者中38名（39%）接受過顱外放療，97名患者中24名（25%）接受過胸部放療。倖存患者中位隨訪時間為32.5個月（IQR，29.8-34.1）。派姆單抗治療的無進展生存期在既往接受過放療的患者中比既往未接受過放療的患者明顯長（風險比，0.56，95%CI，0.34-0.91，p=0.019，中位無進展生存期4.4個月[95%CI，2.1-8.6]VS2.1個月[1.6-2.3]），而且既往接受過顱外放療的患者與既往未接受過顱外放療的患者相比，使用派姆單抗治療的無進展生存期明顯長（HR，0.50[0.3-0.84]，p=0.0084；中位無進展生存期6.3個月[95%CI，2.1-10.4]VS2.0個月[1.8-2.1]）。既往接受過放療的患者與既往未接受過放療的患者相比，使用派姆單抗治療的總生存顯著延長（HR0.58，95%CI，0.36-0.94，p=0.026，中位總生存期10.7個月[95%CI，6.5-18.9]VS5.3個月[2.7-7.7]），而且既往接受過顱外放療的患者與既往未接受過顱外放療的患者相比，使用派姆單抗治療的總生存期明顯延長（0.59[0.36-0.96]，p=0.034；中位總生存期11.6個月[95%CI，6.5-20.5]VS5.3個月[3.0-8.5]）。既往接受過胸部放療的24名患者中15名(63%)有各種肺毒性的記錄，而既往為接受過胸部放療的73名患者中則有29名(40%)。既往胸部放療的3名患者(13%)出現治療相關性肺毒性，而既往沒有胸部放療的患者中則有1名(1%)，≥3級治療相關性肺毒性發生頻率相似(每組各有1名患者)。

推論

我們的數據表明，在晚期非小細胞肺癌患者中，與既往未接受過放療相比，既往放射治療使得派姆單抗治療的無進展生存期和總生存期延長，且安全性可接受。需要進一步的臨床試驗以研究這種組合，從而為晚期非小細胞肺癌患者確定最佳治療策略。

《壹篇》 孫莉

Previous radiotherapy and the clinical activity andtoxicity of pembrolizumab in the treatment of non-small-cell lungcancer: a secondary analysis of the KEYNOTE-001 phase 1trial

Background

Preclinical studies have found radiotherapy enhances antitumourimmune responses. We aimed to assess disease control and pulmonarytoxicity in patients who previously received radiotherapy fornon-small-cell lung cancer (NSCLC) before receivingpembrolizumab.

Methods

We assessed patients with advanced NSCLC treated on the phase 1KEYNOTE-001 trial at a single institution (University ofCalifornia, Los Angeles, CA, USA). Patients were aged 18 years orolder, had an Eastern Cooperative Oncology Group performance statusof 1 or less, had adequate organ function, and no history ofpneumonitis. Patients received pembrolizumab at a dose of either 2mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2weeks, until disease progression, unacceptable toxicity, or otherprotocol-defined reasons for discontinuation. Disease response andpulmonary toxicity were prospectively assessed by Immune-relatedResponse Criteria and Common Terminology Criteria for AdverseEvents version 4.0. The primary objective of the KEYNOTE-001 trialwas to assess the safety, side-effect profile, and antitumouractivity of pembrolizumab. For our secondary analysis, patientswere divided into subgroups to compare patients who previouslyreceived radiotherapy with patients who had not. Our primaryobjective was to determine whether previous radiotherapy affectedprogression-free survival, overall survival, and pulmonary toxicityin the intention-to-treat population. The KEYNOTE-001 trial wasregistered with ClinicalTrials.gov, number NCT01295827.

Findings

Between May 22, 2012, and July 11, 2014, 98 patients wereenrolled and received their first cycle of pembrolizumab. Onepatient was lost to follow-up. 42 (43%) of 97 patients hadpreviously received any radiotherapy for the treatment of NSCLCbefore the first cycle of pembrolizumab. 38 (39%) of 97 patientsreceived extracranial radiotherapy and 24 (25%) of 97 patientsreceived thoracic radiotherapy. Median follow-up for survivingpatients was 32·5 months (IQR 29·8–34·1). Progression-free survivalwith pembrolizumab was significantly longer in patients whopreviously received any radiotherapy than in patients withoutprevious radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34–0·91],p=0·019; median progression-free survival 4·4 months [95% CI2·1–8·6] vs 2·1 months [1·6–2·3]) and for patients who previouslyreceived extracranial radiotherapy compared with those withoutprevious extracranial radiotherapy (HR 0·50 [0·30–0·84], p=0·0084;median progression-free survival 6·3 months [95% CI 2·1–10·4] vs2·0 months [1·8–2·1]). Overall survival with pembrolizumab wassignificantly longer in patients who previously received anyradiotherapy than in patients without previous radiotherapy (HR0·58 [95% CI 0·36–0·94], p=0·026; median overall survival 10·7months [95% CI 6·5–18·9] vs 5·3 months [2·7–7·7]) and for patientswho previously received extracranial radiotherapy compared withthose without previous extracranial radiotherapy (0·59 [95% CI0·36–0·96], p=0·034; median overall survival 11·6 months [95% CI6·5–20·5] vs 5·3 months [3·0–8·5]). 15 (63%) of 24 patients who hadpreviously received thoracic radiotherapy had any recordedpulmonary toxicity versus 29 (40%) of 73 patients with no previousthoracic radiotherapy. Three (13%) patients with previous thoracicradiotherapy had treatment-related pulmonary toxicity compared withone (1%) of those without; frequency of grade 3 or worsetreatment-related pulmonary toxicities was similar (one patient ineach group).

Interpretation

Our data suggest that previous treatment with radiotherapy inpatients with advanced NSCLC results in longer progression-freesurvival and overall survival with pembrolizumab treatment thanthat seen in patients who did not have previous radiotherapy, withan acceptable safety profile. Further clinical trials investigatingthis combination are needed to determine the optimal treatmentstrategy for patients with advanced NSCLC.

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