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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) as predictive markers of clinical response to first-line erlotinib., Methods: Pretreatment plasma samples were collected from 76 patients with EGFR-mutated, advanced-stage NSCLC treated with first-line erlotinib. We isolated ctDNA from plasma for next-generation sequencing., Results: Co-occurring oncogenic drivers were detected in 21% of pretreatment samples and correlated with decreased progression-free survival (PFS) (6.9 months vs 14.4 months; hazard ratio [HR], 2.088; 95% confidence interval [CI], 0.8119-5.370; P = .0355). Concurrent MET amplification was identified in 9 samples (12%), predicting inferior PFS (5.5 months vs 14.4 months; HR, 4.750; 95% CI, 0.5923-38.10; P = .0007) and overall survival (7.6 months vs 28.3 months; HR, 3.952; 95% CI, 0.8441-18.50; P = .0005). Co-occurring non-MET-amplification oncogenic alterations showed a tendency for shorter PFS (9.9 months vs 14.4 months; HR, 1.199; 95% CI, 0.3373-4.265; P = .7586). Clearing EGFR-mutated ctDNA during erlotinib treatment is a positive predictor of clinical outcomes. Among patients who cleared the EGFR mutation, 12% had a co-occurring oncogenic driver, with a tendency toward inferior PFS (8.7 months vs 16.1 months; HR, 1.703; 95% CI, 0.5347-5.424; P = .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. Co-occurring oncogenic alterations were associated with inferior response and may be potential predictors of clinical outcome., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with advanced-stage non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations are successfully treated with tyrosine kinase inhibitors (TKIs). However, treatment outcome varies significantly. Previously, we found the polymorphism 181946C>T (rs2293347) located in exon 25 of the EGFR gene to be a predictor of improved outcome. However, these data were based on a subgroup analysis. Furthermore, other minor studies have found conflicting data. Thus, the aim of this study was to demonstrate the association of 181946C>T with clinical outcome in an independent cohort of EGFR-mutated patients treated with erlotinib., Patients and Methods: Seventy-five patients were prospectively enrolled. Blood samples were collected, and genotype for 181946C>T was determined by allele-specific polymerase chain reaction. Genotype was correlated with outcome., Results: In 73 patients, 181946C>T was successfully measured. Patients harboring the 181946CT genotype had a significantly longer median progression-free survival compared with patients harboring the 181946CC genotype (49.9 months [95% confidence interval (CI), 5.9-93.9 months] versus 11.1 months (95% CI, 7.4-14.9 months); P = .020). Moreover, a significantly longer median overall survival of 65.6 months (95% CI, 11.0-120.3 months) versus 31.2 months (95% CI, 10.9-51.6 months) was found (P = .019). Both results remained significant in a multivariate analysis adjusting for potential confounders., Conclusion: We demonstrate that the 181946C>T polymorphism is a significant predictor of prolonged progression-free survival and overall survival in an independent cohort of EGFR mutation-positive patients treated with erlotinib. The polymorphism could be an important predictor of treatment response in these patients. A large multicenter cohort study involving other concurrent genetic alterations is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The purpose of this study was to determine which method for early response evaluation with 18 F-FDG PET/CT performed most optimally for the prediction of response on a later CT scan in erlotinib-treated non-small cell lung cancer patients. Methods: 18 F-FDG PET/CT scans were obtained before and after 7-10 d of erlotinib treatment in 50 non-small cell lung cancer patients. The scans were evaluated using a qualitative approach and various semiquantitative methods including percentage change in SUVs, lean body mass-corrected (SUL) SUL peak , SUL max , and total lesion glycolysis (TLG). The PET parameters and their corresponding response categories were compared with the percentage change in the sum of the longest diameter in target lesions and the resulting response categories from a CT scan obtained after 9-11 wk of erlotinib treatment using receiver-operating-characteristic analysis, linear regression, and quadratic-weighted κ. Results: TLG delineation according to the PERCIST showed the strongest correlation to sum of the longest diameter ( R = 0.564, P < 0.001), compared with SUL max ( R = 0.298, P = 0.039) and SUL peak ( R = 0.402, P = 0.005). For predicting progression on CT, receiver-operating-characteristic analysis showed area under the curves between 0.79 and 0.92, with the highest area under the curve of 0.92 (95% confidence interval [CI], 0.84-1.00) found for TLG (PERCIST). Furthermore, the use of a cutoff of 25% change in TLG (PERCIST) for both partial metabolic response and progressive metabolic disease, which is the best predictor of the CT response categories, showed a κ-value of 0.53 (95% CI, 0.31-0.75). This method identifies 41% of the later progressive diseases on CT, with no false-positives. Visual evaluation correctly categorized 50%, with a κ-value of 0.47 (95% CI, 0.24-0.70). Conclusion: TLG (PERCIST) was the optimal predictor of response on later CT scans, outperforming both SUL peak and SUL max The use of TLG (PERCIST) with a 25% cutoff after 1-2 wk of treatment allows us to safely identify 41% of the patients who will not benefit from erlotinib and stop the treatment at this time., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: The central immune co-inhibitory programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway plays a key role in tumor immune evasion in non-small cell lung cancer (NSCLC). Soluble PD-1 (sPD-1) can be detected in the blood, and preclinical evidence suggests that sPD-1 blocks PD-1/-L1 interaction and improves anti-tumor immunity. The present study compares the concentration of sPD-1 in the serum of advanced NSCLC patients with Epidermal Growth Factor Receptor (EGFR) mutation prior to erlotinib treatment and at the time of progression and correlates these results to patient outcome., Materials and Methods: Blood samples from 38 patients with EGFR-mutated advanced NSCLC treated with erlotinib were analyzed for sPD-1 by sandwich ELISA. EGFR mutational status was assessed in circulating tumor DNA (ctDNA) and tumor biopsies., Results: sPD-1 could be detected in 21% of patients prior to erlotinib treatment, and at disease progression in 37% (p=0.015). An increase in sPD-1 during erlotinib therapy was found in 34%, a decrease in 8% and no change in 58% of patients. An increase in sPD-1 during treatment was associated with prolonged progression-free (adjusted HR 0.32, p=0.013) and overall survival (adjusted HR 0.33, p=0.006), but not associated with the emergence of EGFR T790M mutation in ctDNA at progression or any clinicopathological factors., Conclusion: Patients with an increase in sPD-1 during erlotinib treatment have a more favorable outcome. Our results emphasize the vast clinical impact of the PD-1/PD-L1 axis, and support the existing preclinical evidence in the bioactive function of sPD-1., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line., Materials and Methods: Four hundred and eighty eight patients with advanced NSCLC were included. The mutation status was assessed using the cobas EGFR Mutation Test. Erlotinib was administrated (150 mg/d) until disease progression or unacceptable toxicities occurred. The primary endpoint was progression-free survival. Secondary endpoints were overall survival and response., Results: Biopsies were retrieved from 467 patients, and mutation results obtained for 462. We identified 57 (12%) patients with EGFR mutations: 33 exon 19 deletions, 13 exon 21 mutations, 5 exon 18 mutations, 3 exon 20 insertions, 1 exon 20 point mutation (S768I), and two complex mutations. Seven percent of the patients were never smokers. The differences in median progression-free survival and overall survival between the mutated group and the wild-type group were 8.0 vs. 2.5 months, p<0.001 and 12.1 vs. 3.9 months, p<0.001. Performance status (0-1 vs. 2-3) and line of treatment (1st vs. 2nd and 3rd) had no influence on outcome in EGFR-mutated patients., Conclusion: We found a higher frequency of EGFR mutations than expected in a cohort with less than 10% never smokers. The outcome after treatment with erlotinib was much better in patients with EGFR mutations than in patients with wild-type EGFR and was independent of performance status and treatment line in EGFR-mutated patients., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)