First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non–small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC. Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m and investigator’s choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB. 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0–35.5). ORR was 40.2 % (95 % CI 31.2–49.6 %), median PFS was 7.2 months (95 % CI 5.6–9.8) and median OS was 18.1 months (95 % CI 13.5–25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3–5, = 56 [47.9 %]). Of patients with evaluable bTMB ( = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36–0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively). AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy.

中文翻译：

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非小细胞肺癌的血液肿瘤突变负荷和对派姆单抗联合化疗的反应：KEYNOTE-782

无论组织肿瘤突变负荷 (tTMB) 状态如何，一线派姆单抗联合化疗已显示出对转移性非小细胞肺癌 (NSCLC) 患者的临床益处。使用血浆来源的循环肿瘤 DNA (ctDNA) 评估的血液肿瘤突变负荷 (bTMB) 可能是 tTMB 的替代品。 KEYNOTE-782 研究评估了 bTMB 与一线派姆单抗联合化疗治疗 NSCLC 疗效的相关性。既往未经治疗的 IV 期非鳞状 NSCLC 患者接受帕博利珠单抗 200 mg 加培美曲塞 500 mg/m2 治疗，研究者选择卡铂曲线下面积 5 mg/mL/min 或顺铂 75 mg/m2，持续 4 个周期，然后帕博利珠单抗加培美曲塞治疗≤31每 3 周增加一个周期。研究目标是评估基线 bTMB 与客观缓解率 (ORR)（研究者评估的 RECIST v1.1；主要）、无进展生存期（PFS；研究者评估的 RECIST v1.1）、总生存期 (OS) 的关联和不良事件（AE；均为次要）。使用下一代测序测定 (GRAIL LLC) 和 ctDNA 组合（包括肺癌相关基因和免疫基因靶标）来测量 bTMB。 117名患者入组；从第一次给药到数据截止的中位时间为 19.3 个月（范围，1.0-35.5）。 ORR 为 40.2%（95% CI 31.2–49.6%），中位 PFS 为 7.2 个月（95% CI 5.6–9.8），中位 OS 为 18.1 个月（95% CI 13.5–25.6）。 113 名患者发生了与治疗相关的 AE（96.6%；3-5 级，= 56 [47.9%]）。在具有可评估 bTMB 的患者 (= 101) 中，连续 bTMB 区分反应的受试者工作特征曲线下面积为 0.47 (95 % CI 0.36–0.59)。基线 bTMB 与 PFS 或 OS 无关（正相关的后验概率：分别为 16.8 % 和 7.8 %）。 AE 与 NSCLC 一线派姆单抗联合化疗的既定安全性一致。基线 bTMB 没有显示与疗效相关的证据。