We observed that almonertinib was not inferior to osimertinib in terms of PFS, and OS and tumor response were also essentially the same for both drugs. Although, a recent meta-analysis of efficacy safety studies on first-line treatments for advanced NSCLC found that osimertinib had the most pronounced benefit on PFS, and almonertinib was the most effective on PFS for the subgroup with the EGFR-19del mutation[11]. To the best of our knowledge, this is the first retrospective study in the real-world setting to compare and evaluate the efficacy and safety of two molecularly targeted drugs in patients with advanced NSCLC.
Several studies have shown the association of EGFR-T790M mutant with better survival and better clinical response to third-generation EGFR-TKIs compared to EGFR-T790M wild-type[5, 12–14]. In the AURA (NCT01802632) trial[12], 253 patients were enrolled, who had developed acquired resistance to first- or second-generation EGFR-TKIs. Among them, a dose-escalation cohort comprised 31 patients who were treated with escalating doses (a daily dose of 20, 40, 80, 160, and 240 mg orally), while the remaining patients were included in the expansion cohort. Compared to patients without the EGFR-T790M mutation, those with T790M mutation had a better ORR (61% vs. 21%), DCR (95% vs. 61%), and median PFS (9.6 vs. 2.8 months). In our study, we found a greater proportion of objective responses in patients with EGFR-T790M mutation compared to those with wild-type EGFR-T790M, irrespective of their (osimertinib or almonertinib) treatment groups. On receiving treatment with a third-generation EGFR-TKI, patients with the EGFR-T790M mutation had considerably longer survival periods than those without the EGFR-T790M mutation. Therefore, when evaluating the efficacy of the two drugs, it is important to assess the efficacy of the entire patient population and to focus on the population that develops the EGFR-T790M mutation.
Currently, osimertinib is widely utilized as an initial or subsequent treatment option for patients with advanced NSCLC patients harboring EGFR mutations[9, 15]. Notably, among T790M-positive patients who have encountered resistance to first- or second-generation EGFR-TKIs, osimertinib exhibits a median PFS of 10.1 months, whereas almonertinib exhibits a longer PFS of 12.5 months[6, 16]. Similar to our results, the PFS in the almonertinib and osimertinib groups was 15.37 and 12.2 months, respectively, in the EGFR-T790M mutant population. The findings from our efficacy analysis indicated comparable clinical effectiveness of almonertinib to osimertinib in individuals with NSCLC who had received prior treatment with a first- or second-generation EGFR-TKI. Excluding the effect of the EGFR-T790M mutation, the median PFS in the almonertinib group was 15.37 months, which also did not differ significantly between the two groups, but was slightly higher than in the osimertinib group. These data further confirm the antitumor activity of almonertinib shown in previous clinical trials.
Patients with brain metastases and routinely treated with EGFR-TKIs, have a typically poorer prognosis[17, 18]. In the subset of patients with T790M mutation and resistance to initial or subsequent EGFR-TKIs, and also presenting with brain metastases, osimertinib demonstrated a PFS of 8.5 months and an OS of 19.2 months. The almonertinib group demonstrated a PFS of 8.3 months[6, 8, 16]. Our study also showed significantly lower PFS and OS compared to patients without CNS metastases. Similarly, we obsered a respective PFS of 7.55 and 10.3 months for almonertinib and osimertinib, in the EGFR-T790M mutant population (p = 0.53); this small variability may be related to the higher proportion of osimertinib combinations with intracranial localized radiotherapy. A current study reported that NSCLC patients with intracranial meningeal metastases had complete intracranial remission after almonertinib treatment[19], suggesting an antitumor effect of almonertinib on intracranial lesions that is not weaker than that of osimertinib.
Treatment-related toxicity of almonertinib was relatively less severe than that of osimertinib, particularly in terms of subjective patient perception of drug-related adverse reactions such as rash, diarrhea, oral ulcers, and paronychia. In this study, we observed a total of 21 grade 3/4 adverse events, with 7 in the almonertinib group and 14 in the osimertinib group. These results suggest that almonertinib is as effective as osimertinib in treating EGFR-mutated NSCLC and that toxicities are generally less severe. The toxicity distribution of our study aligns with the findings of other studies. No additional side effect related to either EGFR-TKI was observed during the course of treatment. Overall, tolerability profiles of both almonertinib and osimertinib were favorable among all patients diagnosed with NSCLC. Of the 182 patients investigated in this study, 5 discontinued the drug permanently due to side effects; 3 in the osimertinib group, respectively, had cardiac insufficiency, drug dermatitis, and diarrhea, and 2 in the almonertinib group, both of whom had markedly elevated serum creatine kinase, which normalized completely after discontinuation.
We believe that the better safety profile of almonertinib may be attributed to the introduction of a cyclopropyl group to osimertinib, leading to a significantly reduced metabolism on the indole side and a marked increase in selectivity for EGFR wild-type. However, due to the introduction of this structure, there also appeared a new safety signal, blood creatine kinase (CK) elevation; 26.6% of the patients in our study had blood CK elevation, and seven patients had grade 3/4 blood CK elevation; two of them discontinued the drug under the comprehensive consideration of the attending physician; the blood CK gradually returned to normal, and did not lead to any obvious damage to the organ function. Overall, compared to Osimertinib, new safety risks emerged with almonertinib, but there was no significant organ damage, and it was fully manageable.
In our study, female patients, those with a history of surgery, a history of radiotherapy, an EGFR-19del mutation, or an ECOG performance status score of 0–1 had an observed progression-free survival benefit, which occurred both in patients administered with almonertinib and in those receiving osimertinib. We also noticed a greater benefit of EGFR-TKI in the EGFR-19del compared to the EGFR-L858R mutant population, which also suggests the greater propensity of the EGFR-L858R mutant population to EGFR-TKI resistance[5, 20]. In a subgroup analysis, we reported shorter PFS with almonertinib compared to osimertinib in patients without the EGFR-T790M mutation but not in patients with the EGFR-T790M mutation. This may be because osimertinib and its metabolites have a better effect on certain rare mutation types, the ctDNA profile of the patients in the EGFR-T790M-negative group was not known, and a selection bias was observed in the small sample size of EGFR-T790M-negative patients, which needs to be further investigated.
To the best of our knowledge, this is the first real-world investigation of almonertinib and osimertinib in patients with advanced NSCLC who switched to third-generation EGFR-TKIs after developing resistance to previous first- or second-generation EGFR-TKIs. However, our study also had certain limitations. First, this was a retrospective study, therefore, it resulted in a relatively small sample size, especially when conducting subgroup analysis. Second, retrospective studies inevitably face collection bias, such as instances of short-term dose reductions when patients experience minor side effects during treatment, but fail to report them to their treating physician. Third, we included patients receiving third-generation EGFR-TKIs after progression on first- or second-generation targeted agents (icotinib, gefitinib, afatinib, and others), including a concurrent combination of vascular-targeted agents and chemotherapy. The pre- and post-treatment regimens of patients were not uniform, which may have affected the results. Fourth, not all patients included in this study had an EGFR-T790M mutation prior to treatment. Lastly, other strategies in the subsequent treatment of patients, such as immunotherapy, checkpoint inhibitors, topical treatments, or radiation therapy, was not evaluated, inevitably impacting the analysis of OS. Further investigation is necessary to identify effective approaches to guide precision and personalized medicine in future large-scale prospective studies.