State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China.
Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, USA.
Ann Oncol. 2023 Apr;34(4):377-388. doi: 10.1016/j.annonc.2023.01.011. Epub 2023 Jan 25.
BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.
背景：我们评估了在 KEYNOTE-042 三期临床试验中，肿瘤组织突变负担（tTMB）和 STK11、KEAP1 和 KRAS 突变是否具有临床应用价值，可作为程序性死亡配体 1（PD-L1）阳性（肿瘤比例评分≥1%）的晚期/转移性非小细胞肺癌（NSCLC）患者接受派姆单抗单药治疗与铂类化疗的生物标志物，这些患者无 EGFR/ALK 改变。
方法：本回顾性探索性分析评估了通过肿瘤组织和匹配的正常 DNA 的全外显子测序确定的 tTMB 和 STK11、KEAP1 和 KRAS 突变的发生率，并分析了它们与 KEYNOTE-042 结果的相关性。使用 175 个突变/外显子的预设切点评估 tTMB 的临床应用价值。
结果：在 793 名患者中，345 名（43.5%）患者的 tTMB≥175 个突变/外显子，448 名（56.5%）患者的 tTMB＜175 个突变/外显子。PD-L1 表达与 tTMB 之间无相关性。在接受派姆单抗治疗的患者中，连续 tTMB 评分与总生存期（OS）和无进展生存期（PFS）的改善相关（Wald 检验，单侧 P＜0.001），而在接受化疗的患者中则无相关性（Wald 检验，双侧 P＞0.05）。tTMB≥175 个突变/外显子与派姆单抗相比化疗的疗效改善相关，而 tTMB＜175 个突变/外显子则不然[OS：风险比（HR），0.62（95%置信区间[CI]，0.48-0.80）和 1.09（95%CI，0.88-1.36）；PFS：0.75（0.59-0.95）和 1.27（1.04-1.55）]。无论 STK11 状态如何[STK11 突变（n=33）：0.37（0.16-0.86），STK11 野生型（n=396）：0.83（0.65-1.05）]；KEAP1 状态[KEAP1 突变（n=64）：0.75（0.42-1.35），KEAP1 野生型（n=365）：0.78（0.61-0.99）]；或 KRAS 状态[KRAS 突变（n=69）：0.42（0.22-0.81）；KRAS 野生型（n=232）：0.86（0.63-1.18）]，派姆单抗治疗的 OS 获益均观察到[HR（95%CI）]。
结论：以≥175 个突变/外显子为切点的 tTMB 是 PD-L1 肿瘤比例评分≥1%的晚期/转移性 NSCLC 患者接受派姆单抗单药治疗的潜在预测生物标志物。无论 STK11、KEAP1 或 KRAS 突变状态如何，派姆单抗都是该治疗方案的标准一线治疗药物。
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