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  • br The PolyPhen analysis we


    The PolyPhen-2 analysis we performed predicted damaging ef-fects for 43 of the 45 rare point EGFR mutations we found (similar to the known pathologically relevant mutations p.G719A, p.L858R, and p.T790M). Thus, almost all EGFR mutations we found affect the stability of the protein. Previous studies also used 3-dimensional drugeprotein interaction modeling to better understand changes in protein structures caused by mutations in the EGFR gene and their variable drug response.98-101 Sickmier et al,101 for instance, demonstrated that the resistance Protease Inhibitor Cocktail p.S468R directly blocks the EGFR domain III, where cetuximab binds to the EGF receptor. These data suggest that poor response to TKI therapy for the rare oncogenic EGFR mutations we found are likely associated with steric changes preventing the binding of the drug.
    Thus, most patients with rare EGFR mutations have disease that does not respond to first-generation TKIs. Still, with more than 50% of the patients harboring a common sensitizing mutation, a
    secondary resistance mutation (eg, p.T790M, p.L747S, p.D761Y, or p.T854A) occurs.43,102 Also, primary resistance in patients with a sensitizing mutation can be possible, caused by the presence of a secondary resistance mutation in Kirsten rat sarcoma viral oncogene (KRAS ),27,103-105 PIK3CA,27,106 or v-Raf murine sarcoma viral oncogene homolog B (BRAF ),107 or a mesenchymaleepithelial transition (MET ) gene amplification.106,108 Consequently, a rare EGFR mutation should not be a criterion to exclude these patients from receiving TKI therapy in general.
    Today, many different treatment options for patients with EGFR-mutated NSCLC are available. Afatinib, a second-generation TKI, is associated with better response rates for patients with rare mutations of the EGFR gene,65,80 but it also shows good therapeutic efficacy in patients with common EGFR mutations.109 Further-more, combination therapies are also possible. Girard4 in 2018 re-ported that first- or second-generation TKIs followed by osimertinib, an irreversible third-generation TKI, may improve survival outcome compared to osimertinib alone. Further, pozioti-nib may be a new potent TKI for exon 20 mutations in gen-eral.110,111 However, discussions about whether patients benefit most from “best therapy first” (based on overall survival) or com-bination therapy are ongoing. Thus, personalized medicine for NSCLC patients with rare or compound mutations of the EGFR gene needs more individual assessment, and it is likely that future TKIs will provide benefit for patients with rare mutations. There-fore, we encourage all clinicians to publish their data on the clinical outcomes of patients with rare and compound EGFR mutations.
    Our study expands the knowledge about the clinical response behavior to first- or second-generation TKIs for 8 single rare and 7 compound mutation of the EGFR gene. Additionally, we report for the first time the clinical outcome after TKI treatment for 2 rare EGFR mutations (p.A702T and p.G874D).
    Patients with a rare EGFR mutation had disease that did not respond to first-generation TKIs in our cohort, except for a patient harboring the mutation p.G874D. In contrast, compound muta-tions consisting of a rare and a common sensitizing mutation responded to first- or second-generation TKIs.
    The increasing landscape of EGFR mutations, including possible resistance mutations to different TKIs, the amount of different available TKIs, and many other factors influencing the response behavior (eg, additional mutation in KRAS, PIK3CA, BRAF ), in-dicates that the clinical outcome of all patients with an EGFR-mutated NSCLC treated with first-, second-, or third-generation TKIs should be reported and collected in a free, accessible data-base for a better understanding of the clinical evidence.
    Clinical Practice Points
    In our cohort, only one patient with a rare EGFR mutation (p.G874D) had disease that responded to TKI therapy with erlotinib, whereas the disease of all other patients with rare EGFR mutations did not respond to first-generation TKI therapy. In contrast, all patients with compound mutations, consisting of a common and a rare EGFR mutation, had disease that responded to first- or second-generation TKI therapy.