帕博利珠单抗治疗高肿瘤突变负荷肿瘤的疗效：MyPathway 多中心、开放标签、Ⅱa 期多篮子研究。

Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study.

机构信息

Memorial Sloan Kettering Cancer Center, New York, New York.

Weill Medical College at Cornell University, New York, New York.

出版信息

Cancer Discov. 2022 Mar 1;12(3):654-669. doi: 10.1158/2159-8290.CD-21-0450.

UNLABELLED

High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)-certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and <16 mut/Mb were also evaluated. Ninety patients with 19 tumor types and F1(CDx) TMB ≥10 mut/Mb were efficacy evaluable. In 42 patients with F1(CDx) TMB ≥16 mut/Mb, confirmed ORR was 38.1% [16/42; 95% confidence interval (CI), 23.6-54.4], and disease control rate was 61.9% (26/42; 95% CI, 45.6-76.4) versus 2.1% (1/48; 95% CI, 0.1-11.1) and 22.9% (11/48; 95% CI, 12.0-37.3) for 48 patients with TMB ≥10 and <16 mut/Mb. Responses were observed in nine different tumor types (47%; 9/19).

SIGNIFICANCE

Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and <16 mut/Mb. See related commentary by Maron and Klempner, p. 602. This article is highlighted in the In This Issue feature, p. 587.

背景

高肿瘤突变负担（TMB-H）与免疫治疗反应改善相关。我们评估了 atezolizumab 1200mg 每 3 周用于 MyPathway（NCT02091141）中的 TMB-H 肿瘤，这是一项 IIa 期多篮子研究。121 名患有高级实体瘤的患者的 TMB 通过任何临床实验室改进修正案（CLIA）认证的检测为≥10 mut/Mb。主要的预先计划终点是 TMB 检测结果为≥16 mut/Mb 肿瘤患者的客观缓解率（ORR）[FoundationOne TMB 检测（F1（CDx）]。F1（CDx）TMB≥10 且<16 mut/Mb 的患者也进行了评估。有 19 种肿瘤类型的 90 名患者和 F1（CDx）TMB≥10 mut/Mb 为疗效可评估。在 42 名 F1（CDx）TMB≥16 mut/Mb 的患者中，确认的 ORR 为 38.1%（16/42；95%置信区间[CI]，23.6-54.4），疾病控制率为 61.9%（26/42；95%CI，45.6-76.4），而 48 名 TMB≥10 且<16 mut/Mb 的患者为 2.1%（1/48；95%CI，0.1-11.1）和 22.9%（11/48；95%CI，12.0-37.3）。在 9 种不同的肿瘤类型中观察到 9 例（47%；9/19）有反应。

意义

在缺乏其他合适治疗选择且入组时免疫治疗初治的 TMB≥16 mut/Mb 肿瘤患者中，atezolizumab 单药治疗具有令人鼓舞的、持久的临床活性，且涵盖了多种高级实体瘤类型，无论微卫星不稳定性状态如何。在 TMB≥10 且<16 mut/Mb 的肿瘤中观察到有限的活性。详见 Maron 和 Klempner 的相关评论，第 602 页。本文在本期特色栏目中重点介绍，第 587 页。