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Insight into the development of treatment resistance can support the optimization of anticancer treatments. This study aims to characterize the tumor dynamics and development of drug resistance in patients with non-small cell lung cancer treated with erlotinib, and investigate the relationship between baseline circulating tumor DNA (ctDNA) data and tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics' parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (<20.0 kg/m 2 ) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (C min,SS ; >271 ng/mL) had shorter PFS compared to a low C min,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high C min,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objectives: In patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung (NSCLC) chemotherapy remains standard of care after progression on EGFR-tyrosine kinase inhibitors (TKIs). With the development of anti-angiogenic agents and immune checkpoint inhibitors the landscape of systemic regimens has changed significantly. This cohort study aims to evaluate the efficacy of chemotherapy regimens after progression on EGFR-TKI in a European population., Material and Methods: All consecutive patients treated with chemotherapy after progression on EGFR-TKI for EGFR-mutated NSCLC, were identified in two tertiary centers in the Netherlands. Data on best response, progression free survival (PFS) and overall survival (OS) were extracted from medical records., Results: In total, 171 lines of chemotherapy were identified: platinum/pemetrexed (PP, n = 95), carboplatin/paclitaxel/bevacizumab/atezolizumab (CPBA, n = 32), paclitaxel/bevacizumab (PB, n = 36) and carboplatin/paclitaxel/bevacizumab (CPB, n = 8). Of the 171 lines, 106 were given as first-line after EGFR-TKI. Median PFS did not differ significantly between the first-line regimens (p = 0.50), with the highest PFS in PP (5.2 months [95% CI 4.5-5.9]) and CPBA (5.9 months [95% CI 3.8-80]). The majority of the PB group (n = 32) received this regimen in a second- or later line with a median PFS of 4.9 months (95% CI 3.3-6.6). First-line regimens had a median OS of 15.3 months (95% CI 11.6-18.9) with no significant difference between regimens (p = 0.85)., Conclusion: After progression on EGFR-TKI, patients with EGFR-mutated NSCLC show substantial benefit on different chemotherapy regimens. In particular, favorable outcomes were seen in patients treated with PP and CPBA as first-line chemotherapy, and PB in further lines of chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.M.J. Steendam reports receiving institutional fees from Boehringer Ingelheim, Roche and Eli Lilly; outside the current work. S.K. Badrising reports receiving institutional fees from Pfizer; outside the current work. M.S. Paats reports receiving institutional fees from AstraZeneca, Bayer, Eli Lilly, Janssen, Novartis, Pfizer, Roche and Takeda; outside the current work. J.G.J.V. Aerts reports receiving advisory board and speakers fees from Eli-Lilly, BMS, MSD, Astra-Zeneca, Bayer, Amphera and is a stock owner of Amphera; outside the current work. A.J. de Langen reports institutional fees from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Merus; outside the current work. A.C Dingemans reports receiving institutional fees from Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Janssen, Chiezi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, Sanofi and Daiichi; outside the current work. S.M. Ernst reports no disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC)., Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m 2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m 2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2-16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity., Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5-7.1) versus 1.9 months (95% CI 1.4-3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16-5.43). Corresponding median OS was 10.6 months (95% CI: 7.0-8.6) versus 4.7 months (95% CI: 3.2-8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46-9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia., Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Erlotinib's gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crossover study to investigate the influence of cow's milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison., Method: Pharmacokinetic sampling was performed on days 7 and 14 during 24 consecutive hours. During the 7 days prior to pharmacokinetic sampling, erlotinib was taken daily with 250 mL of either water or milk. In the PPI arm, esomeprazole (40 mg once daily 3 h prior to erlotinib) was taken for 3 days., Results: Erlotinib area under the curve from time zero to 24 h (AUC 24 ) did not significantly change when administered with milk, compared with water, in both non-PPI users (n = 14; - 3%; 95% confidence interval [CI] - 12 to 8%; p = 0.57) and patients who used esomeprazole (n = 15; 0%; 95% CI - 15 to 17%; p = 0.95). Esomeprazole decreased erlotinib AUC 24 by 47% (n = 9; 95% CI - 57 to - 34%; p < 0.001) and C max by 56% (95% CI - 64 to - 46%; p < 0.001). No differences in toxicities were observed between milk and water., Conclusion: Milk with 3.9% fat has no effect on the exposure to erlotinib in NSCLC patients, independent of PPI use. The combination with milk is safe and well tolerated. Concomitant esomeprazole treatment strongly decreased both erlotinib AUC 24 and C max and should be avoided if possible.