Abstract
The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively. Immunohistochemistry was used to evaluate the activation of associated proteins. We found that nine in ten patients with EGFR/ALK co-alterations had good response with first-line EGFR TKI, and the objective response rate (ORR) of EGFR TKIs was 80% (8/10) for EGFR/ALK co-altered and 65.5% (55/84) for EGFR-mutant (P = 0.57), with a median progression-free survival (PFS) of 11.2 and 13.2 months, (hazard ratio [HR]=0.95, 95% [CI], 0.49-1.84, P= 0.87). ORR of crizotinib was 40% (2/5) for EGFR/ALK co-altered and 73.9% (17/23) for ALK-rearranged (P= 0.29), with a median PFS of 1.9 and 6.9 months (hazard ratio [HR], 0.40; 95% [CI] 0.15-1.10, P = 0.08). The median overall survival (OS) was 21.3, 23.7, and 18.5 months in EGFR-mutant, ALK-rearranged, and EGFR/ALK co-altered (P= 0.06), and there existed a statistically significant difference in OS between ALK-rearranged and EGFR/ALK co-altered (P=0.03). Taken together, the first-line EGFR-TKI might be the reasonable care for advanced NSCLC harbouring EGFR/ALK co-alterations, whether or nor to use sequential crizotinib should be guided by the status of ALK rearrangement and the relative level of phospho-EGFR and phospho-ALK.
Highlights
Lung cancer is the leading cause of cancer-related death in the world [1]
84 advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations treated with first-line EGFR tyrosine kinase inhibitors (TKIs), and 23 with only anaplastic lymphoma kinase (ALK) rearrangements treated with second or further-line crizotinib, were retrospectively enrolled to investigate overall survival (OS) in the present study during the same period of time
It seemed that first-line EGFR TKI was a reasonable regimen for most of the subgroup, but single ALK TKI was excluded from the following eligible treatment
Summary
Lung cancer is the leading cause of cancer-related death in the world [1]. recent discovery of oncogenic drivers has transformed the care of lung adenocarcinomas dramatically [2]. Isolated cases with concomitant EGFR and ALK alterations have been reported [7,8,9,10,11,12,13,14,15,16,17,18,19,20], and the co-occurrence of multiple oncogenic drivers was published [21, 22] These two oncogenic drivers might overlap, and little has been known on both molecular biology and the role of EGFR or ALK inhibitors in such EGFR/ALK co-altered NSCLC. Little has been known about the overall survival (OS) and molecular mechanisms of resistance to EGFR or ALK inhibitors in EGFR/ALK co-altered NSCLC To address these issues, we performed a retrospective investigation in a cohort of EGFR mutation, ALK rearrangement and EGFR/ALK coaltered patients.
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