Correlations between increasing concentrations of circulating tumor DNA (ctDNA) in plasma and disease progression have been shown. A nonlinear mixed effects model to describe the dynamics of epidermal growth factor receptor (EGFR) ctDNA data from patients with non‐small cell lung cancer (NSCLC) combined with a parametric survival model were developed to evaluate the ability of these modeling techniques to describe ctDNA data. Repeated ctDNA measurements on L858R, exon19del, and T790M mutants were available from 54 patients with EGFR mutated NSCLC treated with erlotinib or gefitinib. Different dynamic models were tested to describe the longitudinal ctDNA concentrations of the driver and resistance mutations. Subsequently, a parametric time‐to‐event model for progression‐free survival (PFS) was developed. Predicted L858R, exon19del, and T790M concentrations were used to evaluate their value as predictor for disease progression. The ctDNA dynamics were best described by a model consisting of a zero‐order increase and first‐order elimination (19.7/day, 95% confidence interval [CI] 14.9–23.6/day) of ctDNA concentrations. In addition, time‐dependent development of resistance (5.0 × 10 −4 , 95% CI 2.0 × 10 −4 –7.0 × 10 −4 /day) was included in the final model. Relative change in L858R and exon19del concentrations from baseline was identified as most significant predictor of disease progression ( p = 0.001). The dynamic model for L858R, exon19del, and T790M concentrations in ctDNA and time‐to‐event model adequately described the observed concentrations and PFS data in our clinical cohort. In addition, it was shown that nonlinear mixed effects modeling is a valuable method for the analysis of longitudinal and heterogeneous biomarker datasets obtained from clinical practice.
Purpose To investigate the influence of body mass index (BMI) on the tolerability and effectiveness of full-weight-based paclitaxel chemotherapy in early breast cancer patients. Methods Early-stage breast cancer patients who received (neo)adjuvant weekly paclitaxel 80 mg/m2 chemotherapy were included in this retrospective study. Patients were divided into three groups based on their BMI: lean, overweight, and obese. Logistic regression was used to assess for association between BMI with administered relative dose intensity (RDI) < 85%. The occurrence of treatment modifications and the pathological response on neoadjuvant chemotherapy were compared between BMI categories. Results Four hundred (400) patients were included in this study; 200 (50%) lean, 125 (31%) overweight, and 75 (19%) obese patients. The adjusted odds ratio to receive RDI < 85% for BMI was 1.02 (p value, .263). Treatment modifications occurred in 115 (58%), 82 (66%), and 52 (69%) patients in the respective BMI categories (p value = .132). Peripheral neuropathy was observed in 79 (40%), 58 (46%), and 41 (55%) patients in the lean, overweight, and obese group (p value = .069), whereas hematologic toxicity was observed in 31 (16%), 10 (8%), and 4 (5%) patients (p value = .025). Pathological complete response was observed in 22 (17%), 11 (14%), and 6 (13%) patients in the respective BMI categories (p value = .799). Conclusion BMI did not significantly influence the tolerability and effectiveness of full-weight-based paclitaxel chemotherapy. Therefore, the results of this study align with current guideline recommendations of using full-weight-based paclitaxel chemotherapy in obese patients.
Background: the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients. Methods:In this retrospective cohort study, patients with non-smallcell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups.Results: A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62
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Background Overall survival (OS) data of osimertinib in pretreated non-small-cell lung cancer (NSCLC) in real-world practice is limited, and treatment benefits for patients not represented in the pivotal trials (ineligible) are unclear. Objective To determine the representativeness of the AURA3 trial for NSCLC patients treated with osimertinib in a realworld setting and to determine outcomes of patients who were represented in the AURA3 trial (eligible) and those who were ineligible. Methods Advanced NSCLC patients receiving post first-line osimertinib were included in this retrospective study and were divided into two groups based on eligibility criteria of the AURA3 trial. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Cox models were used to estimate the association of eligibility criteria with OS. Results 328 patients were included; 126 (38%) patients were eligible and 202 (62%) patients were ineligible. The most common ineligibility reasons were the number of earlier treatment lines and an Eastern Cooperative Oncology Group performance status (ECOG PS) > 1. PFS of eligible and ineligible patients was not statistically different (8.0 vs. 5.8 months, p = 0.062). Eligible patients had a longer OS (24.0 vs. 15.4 months, p = 0.001) compared to ineligible patients. ECOG PS was the best predictor for OS. An ECOG PS of 1 was already associated with poorer survival compared to an ECOG PS of 0 (hazard ratio 1.54; p = 0.016). ConclusionThe majority of the study population was not represented in the AURA3 trial. Survival outcomes of eligible patients are in concordance with the AURA3 trial, while OS of ineligible patients was significantly shorter compared to eligible patients.
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