First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer

SHAW A T, BAUER T M, DE MARINIS F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer [J]. N Engl J Med, 2020, 383(21): 2018-29.Correspondence to：[email protected].

BACKGROUND 背景

Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK-positive non–small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear.

勞拉替尼是間變性淋巴瘤激酶(ALK)的第三代抑制劑，對先前治療的ALK陽性非小細胞肺癌(NSCLC)患者具有抗腫瘤活性。與克唑替尼相比，勞拉替尼作為晚期ALK陽性非小細胞肺癌一線治療的療效尚不清楚。

METHODS 方法

We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred.

我們在296例ALK陽性的晚期非小細胞肺癌患者中進行了一項全球性的隨機3期試驗，比較了勞拉替尼和克唑替尼，這些患者之前沒有接受過轉移疾病的系統治療。主要終點是無進展存活期，次要終點包括獨立評估的客觀反應和顱內反應。在177例(75%)預期疾病進展或死亡事件中約133例(75%)發生後，計劃進行一項中期療效分析。

RESULTS 結果

The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia,edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively.

勞拉替尼組12個月無疾病進展的存活率為78%(95%可信區間，70~84)，克唑替尼組為39%(95%可信區間，30~48)(疾病進展或死亡的危險比為0.28；95%可信區間為0.19~0.41；P<0.001)。客觀反應在勞拉替尼組為76%(95%CI，68~83)，克唑替尼組為58%(95%CI，49~66)，可測量腦轉移的患者中，顱內反應分別為82%(95%CI，57~96)和23%(95%CI，5~54)，71%接受勞拉替尼治療的患者有顱內完全反應。勞拉替尼最常見的不良反應是高脂血症、水腫、體重增加、周圍神經病變和認知影響。與克唑替尼(72% VS 56%)相比，洛拉替尼有更多的3級或4級不良事件(主要是血脂水平改變)。分別有7%和9%的患者因不良事件而停止治療。

CONCLUSIONS 結論

In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.)

在對未經治療的晚期ALK陽性非小細胞肺癌患者進行的中期結果分析中，接受勞拉替尼治療的患者比接受克唑替尼治療的患者無進展生存期明顯更長，顱內反應的頻率更高。服用勞拉替尼的3級或4級不良事件的發生率比服用克唑替尼的高，因為經常發生脂質水平的改變。