br Conclusion br Acknowledgment The authors
Acknowledgment The authors would like to thank “Science and Engineering Research Board (SERB) of Department of Science and Technology (DST) Govt. of India” (Grant No.YSS/2015/002017) for funding the project.
Introduction Mutations occurring within EGFR exons 18 to 21 are present in approximately 10% to 15% of Caucasian and up to 50% of Asian patients with advanced or metastatic NSCLC and are strongly associated with adenocarcinoma histology, female sex, and no-smoking status.1, 2, 3, 4, 5, 6 Most patients present with either EGFR 99 8 19 deletions (50%-55%) or exon 21 (L858R) substitution (30%-35%), considered as common mutations,2, 3, 4, 5, 6 showing significant improvements of efficacy outcomes when treated with first- or second-generation tyrosine kinase inhibitors (TKIs).7, 8, 9, 10, 11, 12, 13, 14 Beyond classical mutations, the remaining 10% to 15% of patients present uncommon EGFR mutations, being part of a very heterogeneous group including exon 18 point mutations (3%-4%) and exon 20 insertions and point mutations, that account for approximately 8% to 10% of all EGFR-positive NSCLCs. Uncommon mutations can appear in a single form or in combination with another classical or nonclassical EGFR mutation.15, 16, 17, 18 The efficacy of first- or second-generation EGFR-TKIs in NSCLC harboring uncommon mutations is not yet well established.4, 16, 17 Only a few small retrospective studies and a post hoc analysis from 3 trials of the LL (LUX-lung) program (LL2, LL3, and LL6) evaluated the activity of EGFR TKIs in exon 20 insertions and point mutations.16, 17, 18, 19 Point mutations, such as S768I, showed partial sensitivity to EGFR TKIs (overall response rate [ORR], 20%-100%) and median progression-free survival (mPFS) (1.6-14.7 months), with inferior outcomes for a single mutation, compared with combinations comprising exon 20 point mutations. Instead, the exon 20 insertion group, including V769_D770insASV, D770_N771insSVD, D770_N771insNPG, A763_Y764insFQEA, and H773_V774insH, appear heterogeneous with primary resistance to first- and second-generation EGFR TKIs; third-generation TKIs showed some promising activity and are now under investigation.16, 17, 18, 19 Exon 18 point mutations account for 3% to 4% of all EGFR mutations and include G719X mutation with a substitution of glycine at position 719 to alanine (G719A), cysteine (G719C), or serine (G719S), and E709A/E790K mutations. In the exon 18 mutations, the G719X presents the highest frequency among all rare mutations and seems to have an outcome comparable with common mutations (deletion 19 and L858R), although data are not homogeneous despite being evaluated in a retrospective experience, and an individual patient data meta-analysis comprising data from ATLAS, BeTa, FASTACT-2, SATURN, TITANT, and TRUST clinical trials.16, 17, 18 Despite these limited data, the results from post hoc analysis from LL trials previously mentioned more recently led to broadening the afatinib indication by the US Food and Drug Administration in the naive population with tumors harboring uncommon EGFR alterations in L861Q, G719X, and/or S768I. Among the uncommon single mutations, the EGFR baseline complex mutations (CMs), excluding exon 20 T790M, present a high incidence, up to 14%. CMs showed different patterns of presentations including co-occurring classical mutations (del19 and L858R), classical with uncommon (del19/L858R and exon 18/20) and double nonclassical (exon 18 and exon 20). Data about the clinical activity of EGFR TKIs in CMs are difficult to compare because of the heterogeneity of the different groups; however, they present sensitivity to EGFR TKIs with an ORR of approximately 50% to 70%. In this group, there is persistent interest on exon 20 mutations and their role on sensitivity or resistance where they co-occur with other EGFR mutations.
Patients and Methods