State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China.
The Medical Department, 3D Medicines, Inc., Shanghai, P. R. China.
J Thorac Oncol. 2020 Apr;15(4):556-567. doi: 10.1016/j.jtho.2019.12.001. Epub 2019 Dec 12.
Blood-based tumor mutational burden (bTMB) has been studied to identify patients with NSCLC who would benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration.
Three independent cohorts of patients with NSCLC treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N = 211, and OAK, N = 462) and further validated in the third National Cancer Center (NCC) cohort (N = 64).
bTMB-H (bTMB ≥ cutoff point) was not associated with favorable OS after immunotherapy regardless of the cutoff points in either the POPLAR and OAK or the NCC cohorts (p > 0.05) owing to its correlation with the amount of circulating tumor DNA, which was associated with poor OS. In the POPLAR and OAK cohorts, with allele frequency (AF) adjustment, a high AF bTMB (HAF-bTMB, mutation counts with an AF > 5%) was strongly correlated with the amount of circulating tumor DNA (Pearson r = 0.65), whereas a low AF bTMB (LAF-bTMB, mutation counts with an AF ≤ 5%) was not (Pearson r = 0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.52-0.95, p = 0.02), progression-free survival (PFS; HR = 0.62, 95% CI: 0.47-0.80, p < 0.001), and objective response rate (ORR) (p < 0.001) after immunotherapy but not chemotherapy, with a cutoff point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR = 0.20, 95% CI: 0.05-0.84, p = 0.02), PFS (HR = 0.30, 95% CI: 0.13-0.70, p = 0.003), and ORR (p = 0.001).
We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and ORR after anti-PD-(L)1 therapies in patients with NSCLC, which needs to be prospectively validated.
血液肿瘤突变负荷（bTMB）已被研究用于识别可能从抗程序性细胞死亡蛋白 1（抗 PD-1）或抗程序性死亡配体 1（抗 PD-L1）治疗中获益的 NSCLC 患者。然而，它未能预测总生存期（OS）获益，这需要进一步探索。
本研究使用了三个接受免疫治疗的 NSCLC 患者独立队列。首先在两个独立队列（POPLAR，N=211；OAK，N=462）中开发了新的 bTMB 算法，并在第三个国家癌症中心（NCC）队列（N=64）中进一步验证。
bTMB-H（bTMB≥截止值）与免疫治疗后的有利 OS 无关，无论是在 POPLAR 和 OAK 队列还是在 NCC 队列中，这是由于它与循环肿瘤 DNA 的数量相关，而循环肿瘤 DNA 与不良 OS 相关。在 POPLAR 和 OAK 队列中，在等位基因频率（AF）调整后，高 AF bTMB（HAF-bTMB，AF>5%的突变计数）与循环肿瘤 DNA 的数量密切相关（Pearson r=0.65），而低 AF bTMB（LAF-bTMB，AF≤5%的突变计数）则不然（Pearson r=0.09）。LAF-bTMB-H 与免疫治疗后的有利 OS（风险比[HR]为 0.70，95%置信区间[CI]为 0.52-0.95，p=0.02）、无进展生存期（PFS；HR 为 0.62，95%CI：0.47-0.80，p<0.001）和客观缓解率（ORR）（p<0.001）相关，但与化疗无关，POPLAR 队列中确定的截止值为 12，并在 OAK 队列中得到验证。LAF-bTMB 算法在 NCC 队列中进一步验证，LAF-bTMB-H 与 OS（HR 为 0.20，95%CI：0.05-0.84，p=0.02）、PFS（HR 为 0.30，95%CI：0.13-0.70，p=0.003）和 ORR（p=0.001）相关。
我们开发并验证了一种新的 LAF-bTMB 算法，作为 NSCLC 患者接受抗 PD-（L）1 治疗后 OS、PFS 和 ORR 的可行预测因子，这需要前瞻性验证。
