Clinical Impact Of Uncommon Exon 19deletion Variants On TKI Efficacy In Non-Small-Cell Lung Cancer

Objectives: Our study aimed to evaluate the efficacy and resistance mechanisms of first-line epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)in advanced non-small cell lung cancer(NSCLC)patients with uncommon EGFR exon 19 deletion insertion(delins)variants.Methods: We screened 1,530 lung cancer patients using next-generation sequencing(NGS)from Jan,2015 to Aug,2018.We then reviewed the outcomes of forty-nine patients with uncommon EGFR exon 19delins(Cohort A)and 98 patients with common EGFR exon 19 deletion selected through propensity score matching with a ratio of 1:2(Cohort B).All patients were treated with front-line gefitinib or erlotinib(gefitinib 250 mg orally once daily,erlotinib 150 mg orally once daily),received at least two cycles of standard dosing EGFR-TKI and having at least one radiological response evaluation according to Response Evaluation Criteria in Solid Tumor(RECIST)version 1.1.Majorexclusion criteria included baseline EGFR T790 M mutation and other previous systemic therapy.Patients with T790 M mutation after acquired resistance were treated with Osimertinib.The primary observational endpoint was median PFS and secondary observational endpoint was safety.Results: In 49 EGFR rare exon 19 deletion insertion mutation subtype analysis,we identified 19 EGFR 19 exon deletion insertion variants.L747-A750 delinsP and L747-P753 delinsS were the most frequent variants,accounting for 24.5%(12/49)and 22.4%(11/49)of the cases,respectively.TP53 missense mutation is the most common concomitant mutation in both groups.There were no differences in baseline characteristics,treatment drugs and response rates between cohorts A and B;however,the median progression-free survival(mPFS)of cohort A was significantly longer than cohort B(19.0 months vs.12.0months;p=0.006).At disease progression from first-line EGFR-TKI therapy,fewer patients from cohort A acquired T790 M than cohort B(28.9% vs 45.2%).Other resistance mechanisms identified from our cohort included histological Transformation and MET amplification.For patients whose tumors acquired EGFR T790 M and were treated with Osimertinib,the mPFS in cohort A(n=11)was significantly shorter than cohort B(n=33)(4 months vs.10 months;p=0.003).The commonadverse reactions after taking the first generation egfr-tki in the two groups were mild to moderate rash and diarrhea,53% and 47%,respectively.Conclusion: Patients with uncommon EGFR exon 19 delins have better efficacy with first-generation EGFR TKI,but inferior outcomes with third-generation EGFR TKI upon development of T790 M resistance mutations.