◥Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFR L858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo.Significance: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance.
Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.
Summary Background In 2019, the United States Food and Drug Administration detected above‐regulation levels of the human carcinogen N‐nitrosodimethylamine (NDMA) in ranitidine, resulting in a complete removal of the medication from the market. NDMA is known to cause gastrointestinal malignancies in animal models. Aim To determine if patients who were receiving ranitidine have a higher risk of developing cancers of the digestive tract compared to patients taking other anti‐reflux medications. Methods Using the nationwide database IBM Explorys, patients taking ranitidine were compared to patients on either famotidine or omeprazole. Incidence data of new malignancies of the oesophagus, stomach, liver, pancreas, and colon/rectum were obtained in 1‐year intervals for up to 10 years. Two multivariable logistic regression models were used to calculate odds ratios (ORs), one adjusting for common risk factors for each cancer studied, and the other for demographic factors. Results Patients on ranitidine who were compared to patients on famotidine had ORs of 0.51(95% CI 0.43‐0.60), 0.43(95% CI 0.36‐0.51), 0.39(95% CI 0.36‐0.41), 0.54(95% CI 0.49‐0.62), and 0.46(95% CI 0.43‐0.49) of developing oesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers, respectively (P < 0.001). Patients on ranitidine compared to omeprazole had ORs of 0.62(95% CI 0.52‐0.72), 0.58(95% CI 0.49‐0.68), 0.81 (95% CI 0.76‐0.86), 0.68(95% CI 0.60‐0.76), and 0.66(95% CI 0.62‐0.70) of developing oesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers respectively (P < 0.001). Conclusions Use of ranitidine was not associated with an increased odds of developing gastrointestinal malignancies compared to omeprazole or famotidine use.
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