This multicenter phase-II trial aimed to investigate the efficacy, safety, and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC. Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled. Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles, followed by the maintenance of toripalimab and pemetrexed. The primary endpoint was objective-response rate (ORR). Integrated biomarker analysis of PD-L1 expression, tumor mutational burden (TMB), CD8 + tumor-infiltrating lymphocyte (TIL) density, whole-exome, and transcriptome sequencing on tumor biopsies were also conducted. Forty patients were enrolled with an overall ORR of 50.0% and disease-control rate (DCR) of 87.5%. The median progression free survival (PFS) and overall survival were 7.0 and 23.5 months, respectively. The most common treatment-related adverse effects were leukopenia, neutropenia, anemia, ALT/AST elevation, and nausea. Biomarker analysis showed that none of PD-L1 expression, TMB level, and CD8 + TIL density could serve as a predictive biomarker. Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type. Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC. DSPP mutation might serve as a potential biomarker for this combination. A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing (NCT03924050).

这项多中心 II 期试验旨在研究特瑞普利单抗联合化疗作为EGFR患者二线治疗的疗效、安全性和预测性生物标志物-突变晚期NSCLC。入组一线 EGFR-TKI 治疗失败且没有 T790M 突变的患者。托瑞普利单抗加卡铂和培美曲塞每三周给药一次，最多六个周期，然后维持特瑞普利单抗和培美曲塞。主要终点是客观反应率（ORR）。还对肿瘤活检的 PD-L1 表达、肿瘤突变负荷 (TMB)、CD8 + 肿瘤浸润淋巴细胞 (TIL) 密度、全外显子组和转录组测序进行了综合生物标志物分析。40 名患者入组，总体 ORR 为 50.0%，疾病控制率 (DCR) 为 87.5%。中位无进展生存期 (PFS) 和总生存期分别为 7.0 个月和 23.5 个月。最常见的治疗相关不良反应是白细胞减少、中性粒细胞减少、贫血、ALT/AST 升高、和恶心。生物标志物分析表明，PD-L1 表达、TMB 水平和 CD8 + TIL 密度均不能作为预测生物标志物。全外显子组和转录组测序数据的综合分析显示，患有DSPP突变的 M2 巨噬细胞浸润减少，并且与野生型相比 PFS 更长。特瑞普利单抗联合化疗显示出有希望的抗肿瘤活性，并且作为EGFR突变 NSCLC 患者的二线治疗具有可接受的安全性。DSPP突变可能作为这种组合的潜在生物标志物。在这种情况下，一项比较特瑞普利单抗与安慰剂联合化疗的 III 期试验正在进行中（NCT03924050）。