Co-occurring MET amplification predicts inferior clinical response to first line erlotinib in advanced stage EGFR-mutated NSCLC patients

Abstract Background: Intrinsic resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC) patients with an activating mutation in the epidermal growth factor receptor (EGFR). We investigated co-occurring genetic alterations in circulating tumor DNA (ctDNA) from pretreatment plasma samples as predictive markers of clinical response to first line erlotinib. Methods: Pretreatment plasma samples were collected from 76 EGFR-mutated, advanced-stage NSCLC patients treated with first line erlotinib. ctDNA was isolated from plasma and subjected to next generation sequencing. Results: Co-occurring oncogenic drivers were detected in 21% of pretreatment samples (16/76) and correlated with reduced progression free survival (PFS) (6.9 months vs. 14.4 months, HR=2.088 [95% CI:0.8119-5.370], p=0.0355). Concurrent MET amplification was identified in 9 samples (12%) and predicted inferior PFS (5.5 months vs. 14.4 months, HR=4.750 [95% CI:0.5923-38.10], p=0.0007) and overall survival (7.6 months vs. 28.3 months, HR=3.952 [95% CI:0.8441-18.50], p=0.0005). Co-occurring oncogenic alterations other than MET amplification showed a tendency to be associated with shorter PFS (9.9 months vs. 14.4 months, HR=1.199 [95% CI:0.3373-4.265], p=0.7586). Clearing of EGFR-mutated ctDNA during erlotinib treatment is a positive predictor of clinical outcome. Among patients who cleared the EGFR-mutation 12% (7/57) had a co-occurring oncogenic driver which associated with a tendency to inferior PFS (8.7 months vs. 16.1 months, HR=1.703 [95% CI:0.5347-5.424], p=0.2508). Conclusion: Co-occurring MET amplification in pretreatment ctDNA samples predict inferior clinical response to first line erlotinib in advanced-stage, EGFR-mutated NSCLC patients. Other co-occurring oncogenic alterations were associated with inferior response and may also be potential predictors of clinical outcome. Micro Abstract Co-occurring genetic alterations could play an important role in intrinsic resistance in EGFR-mutated NSCLC patients. The predictive potential of co-occurring genetic alterations on response to first-line erlotinib was evaluated in 76 EGFR-mutated patients by next generation sequencing of ctDNA from pretreatment blood samples. We demonstrate that co-occurring oncogenic alterations, and in particular MET amplification, predict inferior response to first-line erlotinib.