Real-world experience of first-line afatinib in patients with EGFR-mutant advanced NSCLC: a multicenter observational study

Background: This study aimed to evaluate the efficacy, side-effects and resistance mechanisms of first-line afatinib in a real-world setting. Methods: This is a multicenter observational study of first-line afatinib in Malaysian patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). Patients’ demographic, clinical and treatment data, as well as resistance mechanisms to afatinib were retrospectively captured. The statistical methods included Chi-squared test and independent t-test for variables, Kaplan-Meier curve and log-rank test for survival, and Cox regression model for multivariate analysis. Results: Eighty-five patients on first-line afatinib from 1st October 2014 to 30th April 2018 were eligible for the study. EGFR mutations detected in tumors included exon 19 deletion in 80.0%, exon 21 L858R point mutation in 12.9%, and rare or complex EGFR mutations in 7.1% of patients. Among these patients, 18.8% had Eastern Cooperative Oncology Group performance status of 2–4, 29.4% had symptomatic brain metastases and 17.6% had abnormal organ function. Afatinib 40 mg or 30 mg once daily were the most common starting and maintenance doses. Only one-tenth of patients experienced severe side-effects with none having grade 4 toxicities. The objective response rate was 76.5% while the disease control rate was 95.3%. At the time of analysis, 56 (65.9%) patients had progression of disease (PD) with a median progression-free survival (mPFS) of 14.2 months (95% CI, 11.85–16.55 months). Only 12.5% of the progressed patients developed new symptomatic brain metastases. The overall survival (OS) data was not mature. Thirty-three (38.8%) patients had died with a median OS of 28.9 months (95% CI, 19.82–37.99 months). The median follow-up period for the survivors was 20.0 months (95% CI, 17.49–22.51 months). Of patients with PD while on afatinib, 55.3% were investigated for resistance mechanisms with exon 20 T790M mutation detected in 42.0% of them. Conclusions: Afatinib is an effective first-line treatment for patients with EGFR-mutant advanced NSCLC with a good response rate and long survival, even in patients with unfavorable clinical characteristics. The side-effects of afatinib were manageable and T790 M mutation was the most common resistance mechanism causing treatment failure

Whole blood transcriptome correlates with treatment response in nasopharyngeal carcinoma

<p>Abstract</p> <p>Background</p> <p>Treatment protocols for nasopharyngeal carcinoma (NPC) developed in the past decade have significantly improved patient survival. In most NPC patients, however, the disease is diagnosed at late stages, and for some patients treatment response is less than optimal. This investigation has two aims: to identify a blood-based gene-expression signature that differentiates NPC from other medical conditions and from controls and to identify a biomarker signature that correlates with NPC treatment response.</p> <p>Methods</p> <p>RNA was isolated from peripheral whole blood samples (2 x 10 ml) collected from NPC patients/controls (EDTA vacutainer). Gene expression patterns from 99 samples (66 NPC; 33 controls) were assessed using the Affymetrix array. We also collected expression data from 447 patients with other cancers (201 patients) and non-cancer conditions (246 patients). Multivariate logistic regression analysis was used to obtain biomarker signatures differentiating NPC samples from controls and other diseases. Differences were also analysed within a subset (n = 28) of a pre-intervention case cohort of patients whom we followed post-treatment.</p> <p>Results</p> <p>A blood-based gene expression signature composed of three genes — LDLRAP1, PHF20, and LUC7L3 — is able to differentiate NPC from various other diseases and from unaffected controls with significant accuracy (area under the receiver operating characteristic curve of over 0·90). By subdividing our NPC cohort according to the degree of patient response to treatment we have been able to identify a blood gene signature that may be able to guide the selection of treatment.</p> <p>Conclusion</p> <p>We have identified a blood-based gene signature that accurately distinguished NPC patients from controls and from patients with other diseases. The genes in the signature, LDLRAP1, PHF20, and LUC7L3, are known to be involved in carcinoma of the head and neck, tumour-associated antigens, and/or cellular signalling. We have also identified blood-based biomarkers that are (potentially) able to predict those patients who are more likely to respond to treatment for NPC. These findings have significant clinical implications for optimizing NPC therapy.</p

Real-world multicentre experience of first-line afatinib in patients with EGFR-mutant advanced non-small cell lung cancer

Background : Afatinib is an irreversible, second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has been shown to be more potent than platinum doublet chemotherapy as well as the firstgeneration EGFR-TKI in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the efficacy, side-effects and resistance mechanisms of first-line afatinib in a real-world setting. Method : This is a multicentre observational study of Malaysian patients with EGFR-mutant advanced NSCLC started on first-line afatinib from 1st October 2014 to 30th April 2018. Results : The demographic and clinical characteristics of 85 patients who met the study criteria are shown in Table 1. EGFR mutations harboured by the tumours included exon 19 deletion in 80.0%, exon 21 L858R point mutation in 12.9%, and rare or complex EGFR mutations in 7.1%. Of the patients. 18.8% of the patients had an ECOG performance status of 2-4, 29.4% had baseline symptomatic brain metastases and 17.6% had abnormal organ function. Table 2 shows the starting dose, dose adjustment and optimal dose of afatinib. Afatinib 40 mg or 30 mg once daily were the most common starting and maintenance doses. Treatment outcome (Tables 3, 4 and 5; Figures 1 and 2) Response to afatinib The objective response rate (ORR) was 76.5% while the disease control rate (DCR) was 95.3% on first-line afatinib (Table 3). Two (2.4%) patients had complete response. Patients without baseline brain metastases had a significantly higher ORR than those with baseline brain metastases (Table 4). There was a trend for patients in whom the dose of afatinib was reduced to experience higher ORR than those without dose adjustment. On multivariate subgroup analyses involving covariates shown in Table 4, patients without symptomatic brain metastases had significantly higher ORR than that of those with symptomatic brain metastases (81.7% versus 56.0%; OR, 4.51; 95% CI, 1.45–14.00; p = 0.009); while patients with afatinib dose reduction had significantly higher ORR than that of those without dose adjustment (88.5% versus 65.3%; OR, 5.53; 95% CI, 1.32–23.24; p = 0.019). Progression-free survival 56 (65.9%) patients had PD at the time of analysis with a mPFS of 14.2 (95% CI, 11.85 – 16.55) months (Figure 1) Conclusion : Afatinib is an effective first-line treatment for patients with EGFR-mutant advanced NSCLC with good response and disease control rates as well as long PFS even in patients with unfavourable clinical characteristics. The side-effects of afatinib were manageable and acquired T790M mutation was the acquired resistance mechanism in 42% of patients with PD who underwent rebiops