Findings from our retrospective analysis comparing the efficacy of OSI versus AFA in patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment, showed that despite the short follow-up time, our finding confirmed similar results from prior reports[1, 22]with the same treatment regimen associated; we observed improved outcomes for patients with T790M-positive NSCLC and multiple CNS metastases, including similar survival benefit from OSI for such cohort. However, the shorter survival was detected in our study compared some previous studies[2, 6, 8]. The underlying background and reason of the shorter survival could be the fact that patients with T790M-positive NSCLC and multiple CNS metastases tend to have a worse prognosis than those who have no such metastases.
Previous reports of OSI or AFA in T790M-positive NSCLC have encountered unexpected obstacles, including non-uniform definitions of variables, undefined CNS metastases, and incoherent treatment regimens, which may lead to survival variability among patient reports[1, 2, 23-25]. Although the limited sample size makes it difficult to reach convincing conclusions in the current analysis, the survival advantage of OSI is more significant compared with that of AFA, but further validation of our findings is required. The key limiting factor for such cohort is to grasp the timing of multiple CNS metastases. For PFS, a well-defined finding favouring the OSI regimen was described[2, 25], although PFS was not the primary endpoint. The reason why PFS but not OS was affected could be associated with small cohort of research subjects with NSCLC progression who failed to undertake EGFR-TKI treatment.
A population-based study involving 15 medical institutes that cover a population of three million people indicated the disadvantages of pre-treatment before AFA in patients with NSCLC harboring an acquired EGFR T790M mutation[18]. However, the evidence-based trials regarding the optimal regimen in the management of cases with T790M-positive NSCLC and multiple CNS metastases remain controversial[23, 26]. Within this context, evidence has indicated that neither the first-generation nor second-generation EGFR-TKIs distinctly improve the OS among those cases with T790M-positive NSCLC[23, 27]. Nonetheless, whether there were multiple CNS metastases in the studied cohorts and whether CNS metastases offset some of the EGFR-TKI efficacy remain ambiguous[27, 28], which could obscure the facts. There is a significant difference in the composition ratio of patients with multiple CNS metastases in each group, possibly resulting from variability in the response to the EGFR-TKI in diverse reports[19, 29]. In the present study, the survival benefits of OSI over AFA were consistent with prospective randomized trials[22, 25, 30, 31]in which the composition ratio of multiple CNS metastases was assessed in subgroup analyses. Consequently, the between-group differences in survival benefits might be attributed to drug mechanistic differences[22, 32]. Additionally, analogous studies, which compared OSI with AFA in individuals with T790M-positive NSCLC following chemotherapy, also demonstrated similar findings[15, 33, 34].
However, consensus is lacking as to what is the optimal treatment regimen for such cohorts[5, 32, 35]. At present, patients with progressing NSCLC who received first- or second-generation EGFR-TKIs are best treated with OSI alone or in combination with chemotherapy, if possible[2, 5, 7]. Although OSI is not part of the current standard of care in China, it was approved by the FDA for the management of the T790M-positive NSCLC patients[22, 36]. Previous studies of cases with T790M-positive NSCLC have confirmed that the irreversible inhibitor OSI offers more survival benefits compared with other reversible EGFR-TKIs[4, 7]. Of note, those studies in which some subjects failed to be included based on the T790M mutation appear to have unclear data or to have restricted subjects according to the researcher's preference. Additionally, OSI has been less frequently used because the empirical use of drugs is common in clinical practice despite the lack of reliable supportive evidence in the first few years[2, 22, 27].
Although our analysis contributes to gaining a better understanding of the survival benefits of the continued OSI treatment in the setting of T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment, there are certain limitations to discuss. First, the level of evidence in the current study is limited due to the weaknesses inherent in a retrospective analysis including treatments, follow-up, and missing data. A number of cases were excluded at the final follow-up owing to imperfect follow-up data, which may introduce bias. Although the capacity to draw reliable conclusions may be reduced due to the biases that may have contributed to differences in outcomes, it is almost impossible for these issues to play a crucial role due to the baseline data and the contemporaneous methods following widespread standards. However, prospective studies are required to verify the survival benefit of OSI over AFA. Second, the current outcomes were limited by our follow-up protocol (i.e. frequency, length). Third, possible heterogeneity seems hard to avoid, even though considerable variables have been adjusted.