Haratake Naoki, Misumi Toshihiro, Yamanaka Takeharu, Seto Takashi
Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan.
JTO Clin Res Rep. 2020 Aug 21;1(4):100085. doi: 10.1016/j.jtocrr.2020.100085. eCollection 2020 Nov.
The mutation rate of T790M might change the effective therapeutic sequence of EGFR tyrosine kinase inhibitors (TKIs). This simulation estimates the T790M positivity rate required for first-line first- or second-generation EGFR TKI to exceed overall progression-free survival (PFS) of first-line osimertinib.
The PFS of each treatment with EGFR TKIs as first-line treatment, with osimertinib as second-line treatment among T790M-positive cases, and chemotherapy as second-line treatment among T790M-negative cases was set based on phase 3 trials. Overall PFS A of "upfront osimertinib" and overall PFS B of "first- or second-generation EGFR TKIs followed by osimertinib or chemotherapy" were simulated at different T790M mutation rates, to estimate the T790M mutation rate at which PFS B exceeds PFS A.
Upfront osimertinib: In the setting of PFS of 19 months with first-line osimertinib, the median overall PFS A was 24.8 months (95% confidence interval [CI]: 21.6-28.0 mo). Upfront first- or second-generation EGFR TKI: When the T790M positivity rate was set to 50% and the PFS of second-line osimertinib was 10 months, the total median PFS (PFS B) was 20.2 months (95% CI: 17.5-22.9 mo). Even at a T790M mutation rate of 100%, PFS B (24.7 mo; 95% CI: 21.9-27.9 mo) was shorter than PFS A.
Even with a T790M mutation rate of 100%, upfront osimertinib treatment is associated with better median PFS than the upfront treatment with first- or second-generation EGFR TKIs. Consistent with the results of the FLAURA trial, with regard to EGFR TKI monotherapy in the first-line treatment, upfront osimertinib would contribute to good prognosis.
T790M的突变率可能会改变表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的有效治疗顺序。本模拟研究估算了一线使用第一代或第二代EGFR-TKI时，T790M阳性率需达到何种程度才能超过一线使用奥希替尼时的总体无进展生存期（PFS）。
基于3期试验设定以EGFR-TKIs作为一线治疗、T790M阳性病例中以奥希替尼作为二线治疗以及T790M阴性病例中以化疗作为二线治疗时每种治疗的PFS。在不同的T790M突变率下模拟“一线使用奥希替尼”的总体PFS A以及“第一代或第二代EGFR-TKIs序贯奥希替尼或化疗”的总体PFS B，以估算PFS B超过PFS A时的T790M突变率。
一线使用奥希替尼：在一线使用奥希替尼时PFS为19个月的情况下，总体PFS A的中位数为24.8个月（95%置信区间[CI]：21.6 - 28.0个月）。一线使用第一代或第二代EGFR-TKI：当T790M阳性率设定为50%且二线使用奥希替尼时的PFS为10个月时，总PFS中位数（PFS B）为20.2个月（95%CI：17.5 - 22.9个月）。即使T790M突变率为100%，PFS B（24.7个月；95%CI：21.9 - 27.9个月）仍短于PFS A。
即使T790M突变率为100%，一线使用奥希替尼治疗的PFS中位数仍优于一线使用第一代或第二代EGFR-TKIs治疗。与FLAURA试验结果一致，在一线治疗的EGFR-TKI单药治疗方面，一线使用奥希替尼有助于获得良好预后。
