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Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance. Methods In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naive patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR). Results At the start of afatinib treatment, median age (range) was 62 years (34–88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0–30.2) and median OS was 36.5 months (95% CI: 32.9–41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups. Conclusion Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.

This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) in mitotic checkpoint-related genes and clinical outcomes of surgically resected non-small cell lung cancer (NSCLC). A total of 766 patients with NSCLC who underwent curative surgery were enrolled. 73 SNPs form 25 mitotic checkpoint-related genes were genotyped and their associations with survival outcomes were analyzed. Among the 73 SNPs evaluated, BUB3 rs7897156C>T and AURKB rs1059476G>A were significantly associated with overall survival under a recessive model (adjusted hazard ratio [aHR] = 1.58, 95% confidence interval [CI] = 1.07–2.33, P = 0.02 and aHR = 0.64, 95% CI = 0.41–0.99, P = 0.05, respectively). PTTG1 rs1895320T>C and RAD21 rs1374297C>G were associated with worse disease-free survival (under a recessive model, aHR = 2.46, 95% CI = 1.43–4.23, P = 0.001 and under a codominant model, aHR = 1.18, 95% CI = 1.01–1.38, P = 0.04, respectively). In the functional study, relative luciferase activities were higher at the BUB3 rs7897156T allele compared to that at the C allele in H1299 and A549 cell lines ( P = 0.02 and 0.003, respectively). BUB3 mRNA expression was also higher in the rs7897156CT or TT genotypes than in the rs7897156CC genotype ( P = 0.04). The three-dimensional model of Aurora kinase indicates that AURKB rs1059476G>A leads to increased hydrophobicity of Aurora kinases B. We found that four SNPs of mitotic checkpoint-related genes were associated with survival outcomes in patients with surgically resected NSCLC. Particularly, our results suggest that BUB3 rs7897156C>T and AURKB rs1059476G>A are funcitional SNPs.

This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNPs) in genes in DNA repair and apoptosis pathways and determine the relationship between polymorphisms and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with first-line paclitaxel-cisplatin chemotherapy. Three hundred eighty two patients with NSCLC were enrolled. Seventy-four SNPs in 48 genes (42 SNPs in 27 DNA repair pathway genes and 32 SNPs in 21 apoptotic pathway genes) were genotyped and their associations with chemotherapy response and overall survival (OS) were analyzed. Among SNPs in DNA repair genes, BRCA1 rs799917 was significantly associated with both chemotherapy response and OS. XRCC1 rs25487 exhibited a significant association with chemotherapy response and ERCC2 rs1052555 with OS. Four SNPs in apoptotic genes ( TNFRSF1B rs1061624, BCL2 rs2279115, BIRC5 rs9904341, and CASP8 rs3769818) were significantly associated with OS, but not with response to chemotherapy. When the six SNPs which were associated with OS in individual analysis were combined, OS decreased as the number of bad genotypes increased ( P trend =2×10 −6 ). Patients with 3, and 4–6 bad genotypes had significantly worse OS compared with those carrying 0–2 bad genotypes (adjusted hazard ratio [aHR]=1.54, 95% CI=1.14–2.08, P =0.005; aHR=2.10, 95% CI=1.55–2.85, P =2×10 −6 , respectively). In conclusion, these findings suggest that the six SNPs identified, particularly their combined genotypes, could be used as biomarkers predicting chemotherapy response and survival of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.