Discussion
NSCLC, tumor, EGFR-mutant NSCLC, cancer, tumors, TRAEs
CANCER, TUMOR, TUMORS, NSCLC
EGFR TKIs are recommended as the standard first-line treatment for NSCLC with EGFR-sensitizing mutations with the third-generation EGFR TKIs being the preferred agents nowadays. Nevertheless, the FLAURA Asian subgroup analysis revealed no statistically significant OS benefit with the curve crossing at approximately 39 months (hazard ratio [HR] = 1.00, 95%CI: 0.75–1.32) [Median PFS in this trial was 15.1 months, corroborating other studies of EGFR-TKIs combined with anti-angiogenic drugs. Indeed, in a study by Zhang et al. [In a study by Zhang et al. [This work showed that anlotinib plus icotinib could achieve promising ORR and PFS in patients with concomitant mutations. Although first line osimertinib may bring better PFS, patients harboring concurrent mutations such as TP53 still have shorter PFS than reported in the present trial [Based on existing data, we recognize that the complexity of the tumor genome determines the treatment of tumors rather than single gene targeting. The occurrence of concurrent mutations is likely to completely change the biological properties of the original tumor through synergistic effects, conferring new biological features to the tumor and leading to drug resistance. These concurrent mutations are likely to occur gradually during the treatment process. Although existing studies have suggested a value for concurrent mutations, most of them did not statistically analyze the associations of specific mutation sites with tumor cell functions. In addition to some common mutations, mutations in non-hotspot genes may also play important roles in tumor development. Therefore, further investigation is urgently required to identify the regularity of the occurrence and development of concurrent mutations in NSCLC as well as their impacts on clinical prognosis. Predicting deleterious mutations is widely used in the era of precision therapy in cancer. In this study, we established gene mutation profiles through the NGS technology, used bioinformatics to predict the pathogenicity of non-hot-spot variants with unknown biological significance, searched for clinically relevant concurrent mutations, and examined the effects of concurrent mutations on the efficacy of TKIs and their relationships with drug resistance. For missense mutations in non-hotspot genes, we applied three recognized prediction software (MutationTaster, Polyphen-2 and PROVEAN), elucidating the pathogenic potential of the mutations through DNA sequencing and amino acid alterations. In the era of precision tumor therapy, these methods for predicting deleterious mutations have been widely used [TP53, a widely studied and critical tumor suppressor in tumor development, also plays a significant role in the efficacy of EGFR TKI treatment. Previously, the effect of TP53 mutation within a certain exon (e.g., exon 8) on TKI has been studied but inconsistent conclusions were obtained. Therefore, the concept of disruptive/non-disruptive was introduced [In the present study, five patients discontinued the combined therapy due to TRAEs. No grade 5 AEs occurred, and no new safety signals were observed the present study. As to anlotinib, dose interruption and dose reduction due to TRAEs occurred in 23 and 15 patients, respectively, and two patients had a starting dose of 8 mg. The dosing of anlotinib combined with EGFR-TKIs deserves further investigation.Major limitations of the present study included the limited sample size, the single-arm design, and the inconsistency of serial biopsies. Additionally, distinct detection platforms as well as panel sizes and depths may represent an underestimation of concomitant mutations. Compared to previous studies, survival and response rate in patients without concurrent mutations did not seem to increase in this study, likely due to the following reasons: (1) limited sample size; (2) false negatives due to limited sequencing depth and panel size; (3) the dual inhibition regimen may not be applicable to cases without concurrent mutations; (4) the first-generation TKI icotinib was applied in this study, whose efficacy is lower compared with a third generation TKI.In conclusion, anlotinib combined with icotinib is effective and tolerable in the first-line treatment of EGFR mutated advanced NSCLC with or without concurrent mutations. These results call for further large-scale randomized controlled trials. According to the findings of this study, patients harboring pathogenic concurrent mutations are more suitable for the anlotinib + icotinib regimen option. Our team is now conducting a multicenter, phase III RCT clinical trial in EGFR-mutant NSCLC patients with pathogenic concurrent mutations, comparing anlotinib combined with icotinib vs. icotinib (NCT04797806). It is expected that further analysis of patients harboring concurrent mutations will be further studied with the aim of achieving better outcomes.