The response rate, PFS and survival obtained with doublet chemotherapy, for NSCLC with EGFR mutation, were significantly improved with the first- and second-generation EGFR TKIs, including erlotinib, geftinib and afatinib. Studies reporting the use of EGFR-TKI in appropriate BM patients showed optimistic results (intracranial response rates of 75% -88%, median intracranial PFS and OS of 6.6–14.5 months and 15.9–21.8 months, respectively) [16]. More recently, Osimertinib emerged as an active third-generation EGFR TKI in the front-line setting as well as in patients with T790M mutation responsible for acquired resistance to the other EGFR-TKIs or with CNS lesions [17, 18].
As another third-generation EGFR-TKI, Almonertinib has high intracranial concentration and good blood-brain barrier penetration, which was confirmed to have a more prolonged survival and less toxicity in patients of brain metastases than Osimertinib [19]. In the annual meeting of the 2021 ASCO, a preliminary results of the phase III AENEAS study reported that Almonertinib significantly improved PFS compared with gefitinib (19.3 months vs. 9.9 months, hazard ratio: 0.46)[20]. As the first-line treatment of patients with advanced NSCLC of EGFR mutation, and the subgroup analyses showed that patients with brain metastases tended to benefit from Almonertinib treatment (hazard ratio = 0.38), which proved the adequate ability of Almonertinib to penetrate the blood-brain barrier. The phase I multi-center trial (NCT0298110) confirmed that Almonertinib is safe, effective, and tolerable in patients with locally advanced or metastatic NSCLC with EGFR T790M mutation[21].
In this study, we retrospectively analyzed 162 NSCLC patients with brain metastases and EGFR mutation, who were treated with Almonertinib. And we found that the intracranial ORR and DCR were 51.2% and 95.6% respectively. The extracranial ORR and DCR were 42.9% and 91.6% respectively. The median PFS was 15.0 months, and the 1- and 2-year PFS rates were 59.7% and 36.4%, respectively. Our results were consistent with the findings of James et al in a first-line trial of Almonertinib, with an ORR of 50% (95% CI: 41–59), a DCR of 89% (95% CI: 82–94), and the median DOR was 9.5 months (95% CI: 8.1-not reached) and PFS was 9.6 months (95% CI: 8.3–11.1) [12].
Previous study showed a relatively improved PFS in the combined therapy group with EGFR-TKI and other agents than EGFR-TKI mono-therapy in the treatment of NSCLC. The JO25567 trial (japicCT-111390) suggested that erlotinib in combination with bevacizumab significantly improved PFS (16.0 months vs 9.7 months) [21].The NEJ009 study (UMIN000006340) showed that the combination of gefitinib and chemotherapy significantly prolonged considerably PFS (20.9 months VS 11.9 months) and overall survival OS (50.9 months vs 38.8 months) compared with EGFR-TKI mono-therapy[22]. However, there was no statistic difference in PFS and OS in Almonertinib mono-therapy group and Almonertinib combined group in this study, which indicated the potential significance of Almonertinib mono-therapy in the treatment of locally advanced or metastatic NSCLC patients with EGFR-positive mutation.
In our study, the PFS in the Almonertinib group with prior TKI therapy (1-year PFS rates of 65.6% and 56.0%, respectively) and OS (1-year OS rates of 89.6% and 83.4%, respectively; 2-year OS rates of 77.1% and 59.5%, respectively) was superior to that in the Almonertinib group with no previous TKI therapy, but there was no statistical significance between the two groups. Whether to start with generation 1, 2 or generation 3 TKI in NSCLC with EGFR mutations has long been a controversial issue[23]. The National Comprehensive Cancer Network and European Society of Medical Oncology (ESMO) guidelines recommend first-line Osimertinib as the preferred regimen and other treatment strategies as alternative candidates [24]. A recent clinical study showed that Osimertinib was effective in patients with metastatic EGFR T790M-positive NSCLC who progressed during, or after first-line EGFRTKI therapy, with an ORR improvement from 61–71% and PFS extension from 9.6 months to 10.1 months[25]. In addition, the FLAURA Phase 3 trial reported an ORR of 80% and PFS of 18.9 months when using Osimertinib as a first-line agent in patients with EGFR mutation-positive NSCLC[26]. And lower response rates were reported for other third-generation EGFR TKIS, such as Lazertinib (54% response rate with EGFR mutations) and Avitinib (42.4% response rate with T790M mutations) [27, 28]. This study suggests no statistical difference between the first 1, 2, or 3 generations, so that we can choose the right drug according to the economic condition and adverse reaction.
PFS and OS in the combination group were higher than those in the mono-therapy group, but there were no statistical difference. It is suggested that combined brain radiotherapy may improve in local control. Zhang et al. [29] through mouse xenografts, confirmed that radiotherapy enhanced anti-tumor effects,by altering permeability of the blood-brain barrier, increasing the concentration of drugs entering the brain, And, in addition, Aumoltinib enhanced the efficacy of radiotherapy by inhibiting cell proliferation and survival, induction of apoptosis, alteration of cell cycle distribution, and inhibition of IR-induced DNA damage repair.
The overall AE probability was 21.6% (35/162) in this study, with the highest incidence of Rash (28.6%, 10/35) and Diarrhea (11.4%, 4/35). The overall safety was reliable, which was consistent with previous studies[30].
As to the limitations of our research, this is a single-center retrospective study, and inevitably there would be some biases. And we did not measure Almonertinib concentrations in cerebrospinal fluid and therefore we could not assess Almonertinib permeability to the blood-brain barrier. The OS data is not yet mature due to the short follow-up time. Finally, we did not evaluate the impact of quality of life or treatment on neurocognitive function.
In conclusion, Almonertinib mono-therapy is a safe and effective treatment for patients with locally advanced or metastatic NSCLC patients with EGFR positive mutation,which may reduce the cost burden of the patients. .