Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer.

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/m2 ) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS ; >271 ng/mL) had shorter PFS compared to a low Cmin,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 Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.

Proactive monitoring of drug-drug interactions between direct oral anticoagulants and small-molecule inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Small-molecule inhibitors (SMIs) have revolutionised the treatment of non-small cell lung cancer (NSCLC). However, SMI-induced drug-drug interactions (DDIs) with frequently co-administered direct oral anticoagulants (DOACs), increase thromboembolic and bleeding risks. This study investigated and proactively managed the consequences of DOAC-SMI DDIs. METHODS: This prospective, observational study enrolled patients with NSCLC concomitantly using a DOAC and SMI. The primary outcome was the proportion of patients with DOAC plasma trough (Ctrough) and peak (Cpeak) concentrations outside expected ranges. Secondary outcomes included DOAC treatment modifications, incidence of bleeding and thromboembolic events and feasibility evaluation of pharmacokinetically guided DOAC dosing. RESULTS: Thirty-three patients were analysed. Thirty-nine percent (13/33) had DOAC Ctrough and/or Cpeak were outside the expected ranges in 39% (13/33). In 71% (5/7) of patients with DOAC concentrations quantified before and during concurrent SMI use, DOAC Ctrough and/or Cpeak increased or decreased >50% upon SMI initiation. In all patients in whom treatment modifications were deemed necessary, DOAC concentrations were adjusted to within the expected ranges. CONCLUSION: Proactive monitoring showed that a substantial proportion of patients had DOAC concentrations outside the expected ranges. DOAC concentrations were successfully normalised after treatment modifications. These results highlight the importance of proactive monitoring of DOAC-SMI DDIs to improve treatment in patients with NSCLC.

Development and validation of an HPLC-MS/MS method to simultaneously quantify brigatinib, lorlatinib, pralsetinib and selpercatinib in human K2-EDTA plasma.

A liquid chromatography-tandem mass spectrometry method was developed and validated to quantify the small-molecule inhibitors (SMIs) brigatinib, lorlatinib, pralsetinib and selpercatinib, which are used in patients with oncogenic-driven non-small cell lung cancer. Chromatographic separation was performed on a HyPURITY® C18 analytical column with a gradient elution using ammonium acetate in water and in methanol, both acidified with formic acid 0,1%. Detection and quantification were performed using a triple quad mass spectrometer with an electrospray ionization interface. The assay was validated over a linear range of 50-2,500 ng/ml for brigatinib, 25-1,000 ng/ml for lorlatinib, 100-10,000 ng/ml for pralsetinib and 50-5,000 ng/ml for selpercatinib. All four SMIs were stable for at least 7 days under cool conditions (2-8°C), and at least 24 h at room temperature (15-25°C) in K2-EDTA plasma. Under freezing conditions (-20°C), all SMIs were stable for at least 30 days, except for the lowest quality control (QCLOW ) of pralsetinib. The QCLOW of pralsetinib was stable for at least 7 days at -20°C. This method provides an efficient and simple way to quantify four SMIs with a single assay in clinical practice.

Hyperhydration with cisplatin does not influence pemetrexed exposure.

Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Survival before and after the introduction of pertuzumab and T-DM1 in HER2-positive advanced breast cancer, a study of the SONABRE Registry.

PURPOSE: Immediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to examine whether the real-world overall survival (OS) has improved in patients with human epidermal growth factor receptor 2-positive (HER2 +) advanced breast cancer (ABC) since the market release of pertuzumab and T-DM1. Furthermore, we aimed to assess the implementation and survival rates per hormone receptor (HR) subtype. PATIENTS AND METHODS: We included 493 systemically treated patients consecutively diagnosed with HER2 + ABC in 2008-2017 from the SOutheast Netherlands Advanced BREast cancer (SONABRE) Registry. Median OS was obtained using the Kaplan-Meier method and differences between periods (2008-2012 versus 2013-2017) were tested using multivariable Cox proportional hazards regression modeling. The 3-year implementation rates were estimated for any HER2-targeted therapy, pertuzumab, and T-DM1 by using the competing risk method and calculated from the date of diagnosis of ABC to start of HER2-targeted therapy of interest. RESULTS: The median OS in 2008-2012 versus 2013-2017 was 28.3 versus 39.7 months in all patients (adjusted hazard ratio (adjHR) 0.85, 95%CI 0.66-1.08), 29.9 versus 36.3 months in patients with HR + /HER2 + disease (adjHR 0.97, 95%CI 0.72-1.32), and 22.7 versus 40.9 months in patients with HR-/HER2 + disease (adjHR 0.59, 95%CI 0.38-0.92). Any HER2-targeted therapy was used in 79% of patients in 2008-2012 and in 84% in 2013-2017. The use of pertuzumab and T-DM1 in 2013-2017 was 48% and 29%, respectively. For patients diagnosed with HR + /HER2 + and HR-/HER2 + disease, implementation rates in 2013-2017 were , respectively, 77% and 99% for any HER2-targeted therapy, 38% and 69% for pertuzumab, and 24% and 40% for T-DM1. CONCLUSION: The survival of patients with HER2 + ABC improved since the introduction of pertuzumab and T-DM1. There is room for improvement in implementation of these HER2-targeted therapies, especially in patients with HR + /HER2 + disease.

Ultra-performance liquid chromatography for quantification of amphotericin B plasma concentrations after use of liposomal amphotericin B.

OBJECTIVES: Liposomal amphotericin B is widely used to treat life-threatening invasive fungal infections and has replaced conventional amphotericin B deoxycholate due to its more favourable toxicity profile. Despite the fact that liposomal amphotericin B has been licensed for several decades, there is still a paucity of clinical pharmacokinetic data. An assay for the quantification of amphotericin B is necessary to allow the study of its pharmacokinetics. METHODS: A UPLC-photodiode array (PDA) analytical method was developed and validated (linearity, accuracy, precision, dilution integrity, carry-over, selectivity and stability) in accordance with EMA requirements. RESULTS: The analytical method was validated over a concentration range of 0.5-50.0 mg/L. Accuracy ranged from 97.6% to 112.1% and within-day repeatability and between-day reproducibility from 1.0% to 6.6% and from 0.4% to 4.6%, respectively, dependent on the concentration. Originally, the goal was to develop an analytical method to separate the liposomal and free amphotericin B fractions, but this was not achieved. Difficulties and bottlenecks encountered are presented. CONCLUSIONS: A UPLC-PDA analytical method was developed to quantify total amphotericin B in plasma after the use of liposomal amphotericin B.

Development and validation of an HPLC-MS/MS method to simultaneously quantify alectinib, crizotinib, erlotinib, gefitinib and osimertinib in human plasma samples, using one assay run.

A liquid chromatography-tandem mass spectrometry method was developed and validated to quantify alectinib, crizotinib, erlotinib and gefitinib. This assay can be combined with our method for osimertinib, allowing quantification of the most used ALK- and EGFR-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer with a single-assay setup. Chromatographic separation was performed on a HyPurity® C18 analytical column using an elution gradient of ammonium acetate in water and in methanol, both acidified with formic acid 0.1%. Detection and quantification were performed using a triple quad mass spectrometer with an electrospray ionization interface. This method led to robust results, as the selectivity, carryover, precision and accuracy met all pre-specified requirements. The assay was validated over a linear range of 100-2,000 ng/ml for alectinib and erlotinib and 50-1,000 ng/ml for crizotinib and gefitinib. Alectinib, crizotinib, erlotinib and gefitinib were all stable for at least 4 h in whole blood (at room temperature and at 4°C) and for at least 1 month in EDTA plasma when stored at -80°C, while osimertinib proved to be unstable at room temperature. Although high-performance liquid chromatography was used, the run time was short and comparable with other methods using ultra-high performance liquid chromatography.

Simple and Rapid Quantification of the Multi-Enzyme Targeting Antifolate Pemetrexed in Human Plasma.

BACKGROUND: Pemetrexed is an antifolate cytostatic drug that targets multiple enzymes involved in folate biosynthesis and is indicated for treatment of non-small-cell lung cancer and malignant pleural mesothelioma. As evidence for an exposure-response/toxicity relationship is accumulating, dose individualization using therapeutic drug monitoring may be a feasible strategy to optimize treatment. The purpose of this study was to develop a simple, sensitive, high-performance liquid chromatography method with UV detection for quantification of pemetrexed levels in human plasma. METHOD: The method involves a simple protein precipitation, followed by ultra-performance liquid chromatography with ultraviolet detection at a wavelength of 254 nm. Pemetrexed was separated using a mobile phase with a linear gradient and a run time of only 7 minutes. RESULTS: The assay has been validated over the concentration range 0.25-500 mg/L of pemetrexed. Accuracy for this assay ranged from -4.50% to 1.78%, and the within- and between-run coefficients of variation were <3.57%. Pemetrexed in plasma was proven to be stable for 8 months at -40°C. CONCLUSIONS: The bioanalytical method we developed proved to be simple, accurate, precise, and fast. This analytical method is successfully in use for therapeutic drug monitoring and will be used for pharmacokinetic studies.

Validation of an analytical method using HPLC-MS/MS to quantify osimertinib in human plasma and supplementary stability results.

A new method for quantification of osimertinib (OSIM) in human plasma using a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated. Methanol was used for protein precipitation and pazopanib as internal standard. Separation was performed on a HyPURITY®C18 analytical column (50 × 2.1 mm; 3 µm) using a gradient elution of ammonium acetate in water and ammonium acetate in methanol, both acidified with formic acid 0.1%. Detection and quantification of OSIM and pazopanib was performed using a triple quadruple mass spectrometer after electrospray ionization. This method led to robust results, as the selectivity, carryover, precision and accuracy all met pre-specified requirements. OSIM was stable in human serum when stored at -80°C. Reduced stability was found when stored at 2-4°C or room temperature. Degradation of OSIM slowed down in EDTA-plasma and acidified human serum. The limited stability of OSIM at room temperature should be considered for transport and sample preparation. Plasma samples should be frozen as soon as possible and sample preparation should be performed on dry-ice. In the future, EDTA-plasma and sample acidification may be used to improve OSIM stability at room temperature. However, more research and validation of such an approach are required.

Use of Systemic Therapy Concurrent With Cranial Radiotherapy for Cerebral Metastases of Solid Tumors.

The incidence of brain metastases of solid tumors is increasing. Local treatment of brain metastases is generally straightforward: cranial radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) or resection when feasible. However, treatment becomes more complex when brain metastases occur while other metastases, outside of the central nervous system, are being controlled with systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies). It is known that some anticancer agents can increase the risk for neurotoxicity when used concurrently with radiotherapy. Increased neurotoxicity decreases quality of life, which is undesirable in this predominantly palliative patient group. Therefore, it is of utmost importance to identify the compounds that should be temporarily discontinued when cranial radiotherapy is needed.This review summarizes the (neuro)toxicity data for combining systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies) with concurrent radiotherapy of brain metastases. Because only a limited amount of high-level data has been published, a risk assessment of each agent was done, taking into account the characteristics of each compound (e.g., lipophilicity) and the microenvironment of brain metastasis. The available trials suggest that only gemcitabine, erlotinib, and vemurafenib induce significant neurotoxicity when used concurrently with cranial radiotherapy. We conclude that for most systemic therapies, the currently available literature does not show an increase in neurotoxicity when these therapies are used concurrently with cranial radiotherapy. However, further studies are needed to confirm safety because there is no high-level evidence to permit definitive conclusions. The Oncologist 2017;22:222-235Implications for Practice: The treatment of symptomatic brain metastases diagnosed while patients are receiving systemic therapy continues to pose a dilemma to clinicians. Will concurrent treatment with cranial radiotherapy and systemic therapy (chemotherapeutics, molecular targeted agents, and monoclonal antibodies), used to control intra- and extracranial tumor load, increase the risk for neurotoxicity? This review addresses this clinically relevant question and evaluates the toxicity of combining systemic therapies with cranial radiotherapy, based on currently available literature, in order to determine the need to and interval to interrupt systemic treatment.

Use of incretin agents and risk of acute and chronic pancreatitis: A population-based cohort study.

AIM: To determine the association between the use of incretin agents (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) for the treatment of type 2 diabetes mellitus (T2DM) and the risk of any, acute and chronic pancreatitis. RESEARCH DESIGN AND METHODS: A population-based cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD 2007-2012). A total of 182 428 adult patients with ≥1 non-insulin antidiabetic drug (NIAD) prescription were matched to control subjects without diabetes. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of pancreatitis in incretin-users (N = 28 370) compared with controls and with other NIAD users. Adjustments were made for lifestyle, disease and drug history. In a sensitivity analysis, a new-user design was used. RESULTS: Current incretin users had a 1.5-fold increased risk of any pancreatitis compared with NIAD users (adjusted HR 1.47, 95% CI 1.06-2.04). In incident current incretin users the risk of any and acute pancreatitis was increased 2.1- and 2.0-fold compared with NIAD users (adjusted HR 2.12, 95% CI 1.31-3.43 and adjusted HR 1.96, 95% CI 1.13-3.41), whereas there was no increased risk found for chronic pancreatitis. CONCLUSIONS: Incretin use was associated with an increased risk of any pancreatitis. Moreover, risk of any and acute pancreatitis was higher when applying a new-user design. We were not able to detect an association with chronic pancreatitis, but the number in this subgroup was small.

Dried Blood Spot Sampling for Tacrolimus and Mycophenolic Acid in Children: Analytical and Clinical Validation.

BACKGROUND: Tacrolimus and mycophenolic acid (MPA) are the backbone of immunosuppressive therapy after pediatric kidney transplantation. Dosing of these drugs is individualized by therapeutic drug monitoring. Dried blood spot (DBS) sampling may prove beneficial over conventional venous sampling. We aimed to develop and clinically validate a DBS method for tacrolimus and MPA in children. METHODS: A joint DBS liquid chromatography-mass spectrometry assay for tacrolimus and MPA was developed. DBS-specific items included the hematocrit effect and influence of spot volume. Subsequently, a clinical validation study among children aged 2-18 years was performed to assess the agreement between observed and DBS-predicted venous concentrations. Agreement of the methods was assessed with Passing-Bablok regression, Bland-Altman plots, and quantification of the DBS predictive performance in terms of bias (median percentage prediction error) and precision (median absolute percentage prediction error), both should be <15%. RESULTS: A total of 40 tacrolimus and 32 MPA samples were available from 28 children. Conversion factors were used to predict venous concentrations from DBS. For tacrolimus, 95% of the individual ratios of predicted and observed concentrations were within a range of 0.74-1.28, with 85% of these ratios between 0.80 and 1.20 (Bland-Altman plots). For MPA, the 95% limits of agreement represented a broader range of 0.49-1.49%, and 72% of individual ratios were between the 0.80 and 1.20 limits. Median percentage prediction error and median absolute percentage prediction error were less than 15% for both drugs. CONCLUSIONS: A DBS assay was developed for tacrolimus and MPA. Tacrolimus venous concentrations could be adequately predicted from DBS. DBS analysis of MPA seemed to be a semiquantitative measurement at the most when compared with conventional plasma analysis, considering the high variability between observed and predicted concentrations. Next, home-based DBS sampling of tacrolimus for the purpose of therapeutic drug monitoring will be implemented into routine clinical care.

Evaluation of Vancomycin Prediction Methods Based on Estimated Creatinine Clearance or Trough Levels.

BACKGROUND: The aim of this study was to investigate whether vancomycin clearance (CLva) can be adequately predicted with CLva prediction methods. Additionally, other covariates influencing the CLva were investigated and predictivity of monitoring of only trough levels to 24-hour area under the curve (AUC24) was evaluated. METHODS: Routine vancomycin plasma levels were measured with a fluorescence polarization immunoassay. Pharmacokinetic (PK) parameters of individual patients, that is, CLva and volume of distribution, were determined with maximum a posteriori Bayesian estimation. CLva was calculated with the 3 prediction methods, which are solely based on creatinine clearance (CLcr) estimated with Cockcroft and Gault formula and was compared with the calculated CLva with maximum a posteriori Bayesian estimation. Prediction errors were calculated. Correlations between CLva and CLcr, creatinine, age, weight, sex, and neutropenia were made. Furthermore, correlations between trough levels and AUC24 were evaluated. RESULTS: A total of 171 patients were included. Prediction errors and absolute prediction errors of the 3 methods ranged from 28% to 80% and 39% to 83%, respectively. In the multivariate analysis, CLva was significantly associated with CLcr, creatinine, age, weight, sex, and neutropenia. Linear correlation between AUC24 and trough levels was R(2) 0.38. CONCLUSIONS: Large prediction errors make the CLva algorithms based on estimated plasma CLcr unsuitable for use in patient care. Additionally, other factors, which are not accounted for in the current algorithms, influence the CLva individually. Owing to low association of AUC24 and trough levels, the AUC24 cannot be predicted with through levels. For a reliable AUC24 guided vancomycin dosing, therapeutic drug monitoring is necessary.

Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Several population pharmacokinetic (popPK) studies have been reported that can guide the prediction of osimertinib plasma concentrations in individual patients. It is currently unclear which popPK model offers the best predictive performance and which popPK models are most suitable for nonadherence management and model-informed precision dosing. Therefore, the objective of this study was to externally validate all osimertinib popPK models available in the current literature. METHODS: Published popPK models for osimertinib were constructed using NONMEM version 7.4.4. The predictive quality of the identified models was assessed with goodness-of-fit (GoF) plots, conditional weighted residuals (CWRES) plots and a prediction-corrected visual predictive check (pcVPC) for osimertinib and its active metabolite AZ5104. A subset from the Dutch OSIBOOST trial, where 11 patients with low osimertinib exposure were included, was used as evaluation cohort. RESULTS: The population GoF plots for all four models poorly followed the line of identity. For the individual GoF plots, all models performed comparable and were closely distributed among the line of identity. CWRES of the four models were skewed. The pcVPCs of all four models showed a similar trend, where all observed concentrations fell in the simulated shaded areas, but in the lower region of the simulated areas. CONCLUSION: All four popPK models can be used to individually predict osimertinib concentrations in patients with low osimertinib exposure. For population predictions, all four popPK models performed poorly in patients with low osimertinib exposure. A novel popPK model with good predictive performance should be developed for patients with low osimertinib exposure. Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known. CLINICAL TRIALS REGISTRATION: NCT03858491.

Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC.

Introduction: Brain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (Cmin,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib Cmin,SS and BM development or progression. Methods: A prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib Cmin,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group. Results: A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) Cmin,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6-49.0), 31% (95% CI:10.6-53.9), and 31% (95% CI:10.8-54.5) per Cmin,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6-49.0), 52% (95% CI:23.8-74.2), and 57% (95% CI:24.9-79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within Cmin,SS subgroups. Conclusions: No relation was found between osimertinib Cmin,SS and BM development or progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.

Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan.

BACKGROUND: The antibody-drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality. OBJECTIVE: The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access. PATIENTS AND METHODS: Exposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9-1.11 boundaries for area under the concentration-time curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios. RESULTS: Dosing regimens of sacituzumab govitecan for the EU (< 50 kg: 400 mg, 50-80 kg: 600 mg, and > 80 kg: 800 mg) and US population (< 40 kg: 360 mg, 40-65 kg: 540 mg, 65-90 kg: 720 mg, and > 90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and 19.0% lower for the EU and US scenarios, respectively. CONCLUSIONS: With the alternative dosing proposal, an approximately 20% reduction in drug expenses for sacituzumab govitecan can be realized while maintaining an equivalent and more evenly distributed exposure throughout the body weight range, without notable increases in pharmacokinetic variability.

Incidence of Bone Metastases and Skeletal-Related Events in Patients With EGFR-Mutated NSCLC Treated With Osimertinib.

Introduction: Bone metastases are frequent in patients with EGFR-mutated (EGFR+) NSCLC. Skeletal-related events (SREs) are common in these patients; however, no data on SRE in osimertinib-treated patients are reported. We investigated the development of bone metastases and SREs in patients with EGFR+ NSCLC treated with osimertinib. Methods: This is a retrospective multicenter cohort study that included patients with metastatic EGFR+ NSCLC who were treated with osimertinib between February 2016 and September 2021. Demographics, bone metastases-related outcomes, SREs, treatment efficacy, and overall survival (OS) were collected. Results: In total, 250 patients treated with osimertinib (43% first line) were included. Of the patients, 51% had bone metastases at initiation of osimertinib. Furthermore, 16% of the patients with bone metastases used bone-targeted agents. Median follow-up from initiation of osimertinib was 23.4 months (95% confidence interval [CI]: 19.9-26.9 mo). During osimertinib treatment, 10% developed new bone metastases or bone progression. Of the patients with bone metastases, 39% had more than or equal to one SREs: 28% developed first SRE before osimertinib treatment, 1% after, and 11% during. Median OS post-bone metastasis was 30.8 months (95% CI: 21.9-39.7). Median OS after first SRE was 31.1 months (95% CI: 15.8-46.5). Conclusions: Bone metastases and SREs are frequent before and during treatment with osimertinib in EGFR+ NSCLC. Because of these findings and the long OS post-bone metastases, we advocate prescription of bone-targeted agents in these patients and recommend adding bone-specific end points in clinical trials.

Durvalumab after chemoradiotherapy in patients with stage III non-small-cell lung cancer: real-world outcomes versus clinical trial results.

Aim: We investigated the effectiveness of durvalumab post-concurrent CRT (cCRT) and post-sequential CRT (sCRT) versus cCRT and sCRT alone and compared these outcomes with the PACIFIC trial. Methods: Four cohorts of stage III NSCLC patients who received CRT were included: cCRT with and without durvalumab, sCRT with and without durvalumab. PFS and OS were analyzed using Cox regression. Results: Durvalumab improved PFS (cCRT: aHR = 0.69, sCRT: aHR = 0.71) and OS (cCRT: aHR = 0.71, sCRT: aHR = 0.32), although not all results were significant. PFS was longer in the real-world than in the trial, while OS did not differ. Conclusion: Durvalumab after CRT improved the survival outcomes. The difference between PFS in our study and the trial may be due to differences in follow-up methods.

We assessed a medicine called durvalumab on patients with non-small cell lung cancer who received chemoradiotherapy in a real-world setting. We compared their outcomes with those from a clinical trial. Patients who received two types of chemoradiotherapy with or without durvalumab were included, and their progression-free survival (PFS) and overall survival (OS) outcomes were analyzed. We found that patients treated with durvalumab had better PFS and OS than those treated without durvalumab. PFS was longer in the real-world than in the clinical trial, but OS was similar. The difference in PFS may be due to differences in measuring PFS.