Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide

In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (-driven), SCLC-N (-driven), SCLC-P (-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival.Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS.More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 ( < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm.These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen.ClinicalTrial.govIdentifier: NCT02763579.

在I/III期IMpower133研究中，对于广泛期小细胞肺癌（ES - SCLC），一线阿替利珠单抗联合卡铂和依托泊苷（CP/ET）治疗相比安慰剂联合CP/ET显著提高了总生存期（OS）和无进展生存期。我们探究了IMpower133研究中与长期生存相关的患者和疾病特征，以及差异基因表达以及小细胞肺癌 - A（驱动型）、小细胞肺癌 - N（驱动型）、小细胞肺癌 - P（驱动型）和小细胞肺癌炎症型（SCLC - I）转录亚型与长期生存的关联。 既往未经治疗的ES - SCLC患者按1∶1随机分组，分别接受阿替利珠单抗或安慰剂联合CP/ET进行4个21天周期的治疗。长期生存者（LTS）定义为随机分组后存活≥18个月的患者。采用广义线性模型评估存活≥18个月的几率。利用LTS和非LTS的RNA测序数据分析差异基因表达。通过T效应细胞和B细胞基因特征表达评估总生存期。评估LTS和非LTS中小细胞肺癌转录亚型的分布。 阿替利珠单抗组的长期生存者比例（34%）高于安慰剂组（20%）。阿替利珠单抗组相较于安慰剂组存活≥18个月的优势比为2.1（P < 0.03）。两组的长期生存者中均可见免疫相关信号增强。探索性总生存期分析显示，在T效应细胞和B细胞基因特征表达亚组中，阿替利珠单抗治疗相比安慰剂均有获益。两组中具有SCLC - I亚型的长期生存者比例均高于非长期生存者；这种差异在阿替利珠单抗组中尤为显著。 这些探索性分析表明，在ES - SCLC中，使用阿替利珠单抗比使用安慰剂更有可能实现长期生存，证实了IMpower133方案的治疗益处。 临床试验政府识别码：NCT02763579