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  • Osimertinib re administration also showed excellent tolerabi


    Osimertinib re-administration also showed excellent tolerability. The AEs of all patients except one were grade 2 or lower (Table 2). One patient had a grade 3 platelet decrease, which was deemed by the attending physician to be caused by the progression of the disease itself, not by osimertinib. This study had some limitations. First, we retrospectively analyzed heterogeneous data with a small sample size, such that the results are somewhat speculative, rather than definitive. In fact, the ORR and median PFS of initial osimertinib treatment in our cohort were worse than those of the historical control [17]. Given that osimertinib has been clinically available for only 2 years in our country, and that many patients remain on initial osimertinib treatment, more patients with shorter response times may have been included in this Dihexa (PNB-0408) analysis. Dihexa (PNB-0408) Second, this study was conducted only in patients with T790M-positive NSCLC after acquired resistance to first- or second-generation EGFR TKIs. The recent FLAURA trial showed that osimertinib for treatment-naïve EGFR-mutant NSCLCs can extend PFS compared to first-generation EGFR TKIs [6]. Osimertinib is now among the most potent first-line treatments for treatment-naïve EGFR-mutant NSCLC. Further extensive investigations are needed to determine whether re-administration is also effective for NSCLCs that progressed after first-line osimertinib treatment. Third, actual resistance mechanisms to initial osimertinib therapy were not determined in the 17 re-challenged cases and, therefore, further investigation is needed to determine the type of resistance mechanisms for which osimertinib re-challenge would be effective. Thus, our results should be interpreted cautiously. In conclusion, osimertinib re-administration had modest activity and low toxicity in the treatment of EGFR-mutant NSCLC that had acquired resistance to osimertinib.
    Conflict of interest statement
    Introduction The emergence of immune checkpoint inhibitors (ICI) has significantly influenced clinical therapeutic strategies for most cancer subtypes, notably in advanced non-small-cell lung cancer (aNSCLC). Programmed cell death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, and programmed cell death ligand-1 (PD-L1) inhibitors (e.g. atezolizumab) have significantly improved progression-free survival (PFS) and overall survival (OS) of patients with aNSCLC, achieving outstanding duration of disease control compared to standard platinum-based frontline chemotherapy or second-line docetaxel chemotherapy [[1], [2], [3]]. However, only 20 to 25% of patients treated with immunotherapy derive bona fide benefit from this therapy, and determinants of response remain desperately elusive. To date, the only approved predictive biomarkers of ICI efficacy are microsatellite instability status [4,5] and strong PD-L1 expression, assessed by immunohistochemical analysis for pembrolizumab in aNSCLC in first line [3]. Nonetheless, although PD-L1 tumor cell expression appears positively correlated to ICI efficacy [6], a significant proportion of selected patients with positive PD-L1 expression do not respond to ICI, or even show disease hyper-progression under treatment [7]. Conversely, patients with PD-L1- negative tumors can surprisingly also manifest significant response to ICI. Thus, identifying more robust predictive tools of response to ICI in NSCLC patients is an urgent need that still has yet to be met. Recently, several studies provided compelling evidence that tumor mutational burden (TMB) could predict the potential activity of immunotherapy in numerous tumor types, including NSCLC [8,9]. By generating impaired cellular proteins recognized as neo-antigens by immune cells, the resulting genetic instability can enhance tumor immunogenicity, thereby optimizing the antitumor cytotoxicity of T lymphocytes, reinstated by ICI therapy. As such, it has been suggested that mutations in oncogenes such as K-RAS are associated with favorable outcomes under ICI therapy in NSCLC patients [10,11], though this effect is thought to be merely mediated through high TMB [12], while, conversely, EGFR mutations were associated with low mutational burden and lower rates of response to ICI [9]. Hailed as a historic “guardian of genome integrity”, the TP53 gene may also constitute a relevant tool to indirectly quantify TMB [13]. Moreover, several studies demonstrated that PD-L1 expression was boosted in TP53-mutated tumors, whether TP53 status was assessed indirectly by immunohistochemistry analysis [14] or directly using whole-exome sequencing (WES) [11]. Thus, in a recent study, Dong et al. retrospectively showed in 30 aNSCLC patients treated with pembrolizumab that median PFS was significantly longer in the TP53-mutated group than in the TP53- wild-type group (14.5 versus 3.5 months, p = 0.042) [11]. However, these interesting results were not adjusted for the clinical and pathological features likely to influence response to ICI. Finally, using WES, the influence of individual genes within the TMB variable was analyzed to identify whether a limited number of mutational events could drive the predictive effect of TMB on PFS in patients treated with combined PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade [15]. TP53 mutations were identified as key events driving this predictive effect, while STK11 and PTEN mutations were associated with worse response to this combined ICI treatment, suggesting that a mutational signature incorporating these alterations with positive and negative values should be assessed, since it is easier by far to obtain tumor specimens from patients, to perform targeted NGS assessing such genes, than generating the expensive and complicated TMB in routine practice.