Concurrent EGFR L858R and K860I mutations: PCR-negative but NGS-positive alterations that respond to EGFR inhibitors in non-small cell lung cancer

Introduction: Clinical routine amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and next generation sequencing (NGS) are able to identify sensitizing EGFR mutations of non-small cell lung cancer (NSCLC) patients. Nevertheless, the detection and treatment response of NSCLC patients with concurrent L858R and uncommon EGFR exon 21 mutations remain unclear. Methods: Concurrent NGS and ARMS-PCR were performed to identify EGFR mutations in 5033 NSCLC cases. Results: Totally, EGFR L858R mutations were identified in 1024 (20.3%) cases, among which 54 concurrent L858R and uncommon EGFR exon 21 mutations were identified by NGS but not ARMS-PCR. The most common concurrent pathogenic mutations in EGFR exon 21 were V834L, K860I and L833V. Of those, 23 patients received EGFR-TKIs as the first-line treatment with median progression-free survival (PFS) of 16.7 months (95% CI: 12.8–20.7 months) and objective response rate (ORR) of 38.9% (95% CI: 9.1% – 46.9%). Interestingly, concurrent L858R and K860I mutations were observed in 10 cases by NGS, while ARMS-PCR showed completely negative results in EGFR mutations. Of those, three patients received EGFR-TKIs as the first-line treatment, with median PFS of 11.0 months and ORR of 100.0%. Furthermore, three patients with concurrent L858R and K860I mutations identified by NGS received adjuvant targeted therapy after surgery with median disease free survival of 10.0 months. Conclusion: NSCLC patients with concurrent EGFR L858R and K860I mutations are able to benefit from EGFR-TKIs, which can be detected by NGS but not by ARMS-PCR.