Treatment Patterns and Clinical Outcomes Among Patients With Metastatic Prostate Cancer Harboring Homologous Recombination Repair Mutations.

BACKGROUND: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations. METHODS: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014. RESULTS: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy. CONCLUSIONS: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.

Unique genomic alterations in the circulating tumor DNA of patients with solid tumors brain metastases.

Background: Although serum circulating tumor DNA (ctDNA) is routine, data from patients with brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients with solid tumor BrMs in 3 groups: Isolated BrMs with stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs (eCNS). We also compared ctDNA alterations between patients with and without BrMs. Methods: Patients with a Guardant360 ctDNA profile with (n = 253) and without BrMs (n = 449) from the Duke Molecular Registry between January 2014 and December 2020 were identified. Actionable alterations were defined as FDA-recognized or standard-of-care biomarkers. Disease status was determined via investigator assessment within 30 days of ctDNA collection. Results: Among the 253 patients with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. Breast (BC; 12.0%) and non-small cell lung cancer (NSCLC; 76.4%) were the most common tumor types. ESR1 (60% vs 25%, P < .001) and BRCA2 (17% vs 5%, P = .022) were more frequent in BC BrMs. In NSCLC BrMs, EGFR alterations were most frequent in the iCNS group (iCNS: 67%, cCNS: 40%, eCNS:37%, P = .08) and in patients with BrMs (36% vs 17%, P < .001). Sequencing from both brain tissue and ctDNA were available for 8 patients; 7 (87.5%) had identical alterations. Conclusions: This study illustrates the feasibility of detecting alterations from ctDNA among patients with BrMs. A higher frequency of actionable mutations was observed in ctDNA in patients with BrMs. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.

Transcatheter aortic valve implantation versus surgical aortic valve replacement in severe aortic stenosis patients at low surgical mortality risk: a cost-effectiveness analysis in Belgium.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) with the SAPIEN 3 device has recently shown significant clinical benefits, compared to surgical aortic valve replacement (SAVR), in patients at low risk for surgical mortality (PARTNER 3 trial, NCT02675114). Currently in Belgium, TAVI use is restricted to high-risk or inoperable patients with severe symptomatic aortic stenosis (sSAS). This cost-utility analysis aimed to assess whether TAVI with SAPIEN 3 could lead to potential cost-savings compared with SAVR, in the low-risk sSAS population in Belgium. METHODS: A previously published, two-stage, Markov-based cost-utility model was used. Clinical outcomes were captured using data from PARTNER 3 and the model was adapted for the Belgian context using cost data from the perspective of the Belgian National Healthcare System, indexed to 2022. A lifetime horizon was chosen. The model outputs included changes in direct healthcare costs, survival and health-related quality of life using TAVI versus SAVR. RESULTS: TAVI with SAPIEN 3 provides meaningful clinical and cost benefits over SAVR, in terms of an increase in quality-adjusted life years (QALYs) of 0.94 and cost-saving of €3 013 per patient. While initial procedure costs were higher for TAVI compared with SAVR, costs related to rehabilitation, disabling stroke, treated atrial fibrillation, and rehospitalization were lower. The cost-effectiveness of TAVI over SAVR remained robust in sensitivity analyses. CONCLUSION: TAVI with SAPIEN 3 may offer a meaningful alternative intervention to SAVR in Belgian low-risk patients with sSAS, showing both clinical benefits and cost savings associated with post-procedure patient management.

Cost-utility analysis of TAVI compared with surgery in patients with severe aortic stenosis at low risk of surgical mortality in the Netherlands.

BACKGROUND: There is growing evidence to support the benefits of transcatheter aortic valve implantation (TAVI) over surgical aortic valve replacement (SAVR) in patients with symptomatic severe aortic stenosis (sSAS) who are at high- or intermediate-risk of surgical mortality. The PARTNER 3 trial showed clinical benefits with SAPIEN 3 TAVI compared with SAVR in patients at low risk of surgical mortality. Whether TAVI is also cost-effective compared with SAVR for low-risk patients in the Dutch healthcare system remains uncertain. This article presents an analysis using PARTNER 3 outcomes and costs data from the Netherlands to inform a cost-utility model and examine cost implications of TAVI over SAVR in a Dutch low-risk population. METHODS: A two-stage cost-utility analysis was performed using a published and validated health economic model based on adverse events with both TAVI and SAVR interventions from a published randomized low risk trial dataset, and a Markov model that captured lifetime healthcare costs and patient outcomes post-intervention. The model was adapted using Netherlands-specific cost data to assess the cost-effectiveness of TAVI and SAVR. Uncertainty was addressed using deterministic and probabilistic sensitivity analyses. RESULTS: TAVI generated 0.89 additional quality-adjusted life years (QALYs) at a €4742 increase in costs per patient compared with SAVR over a lifetime time horizon, representing an incremental cost-effectiveness ratio (ICER) of €5346 per QALY gained. Sensitivity analyses confirm robust results, with TAVI remaining cost-effective across several sensitivity analyses. CONCLUSIONS: Based on the model results, compared with SAVR, TAVI with SAPIEN 3 appears cost-effective for the treatment of Dutch patients with sSAS who are at low risk of surgical mortality. Qualitative data suggest broader societal benefits are likely and these findings could be used to optimize appropriate intervention selection for this patient population.

Racial and ethnic disparities in genomic testing among lung cancer patients: a systematic review.

INTRODUCTION: Racial and ethnic disparities in genomic testing could exacerbate disparities in access to precision cancer therapies and survival-particularly in the context of lung cancer, where genomic testing has been recommended for the past decade. However, prior studies assessing disparities in genomic testing have yielded mixed results. METHODS: We conducted a systemic review to examine racial and ethnic disparities in the use of genomic testing among lung cancer patients in the U.S. Two comprehensive searches in PubMed, Embase, and Scopus were conducted (September 2022, May 2023). Original studies that assessed rates of genomic testing by race or ethnicity were included. Findings were narratively synthesized by outcome. RESULTS: The search yielded 2,739 unique records, resulting in 18 included studies. All but one study was limited to patients diagnosed with non-small cell lung cancer. Diagnosis years ranged from 2007-2022. Eleven of 18 studies found statistically significant differences in the likelihood of genomic testing by race or ethnicity; in seven of these studies, testing was lower among Black patients compared to White or Asian patients. However, many studies lacked adjustment for key covariates and included patients with unclear eligibility for testing. CONCLUSIONS: A majority of studies, though not all, observed racial and ethnic disparities in the use of genomic testing among patients with lung cancer. Heterogeneity of study results throughout a period of changing clinical guidelines suggests that minoritized populations-Black patients in particular-have faced additional barriers to genomic testing, even if not universally observed at all institutions.

Effects of Ataxia-Telangiectasia Mutated Variants on Radionecrosis and Local Control After Stereotactic Radiation Surgery for Non-Small Cell Lung Cancer Brain Metastases.

Purpose: Genetic variants affecting the radiation response protein ataxia-telangiectasia mutated (ATM) have been associated with increased adverse effects of radiation but also with improved local control after conventional radiation therapy. However, it is unknown whether ATM variants affect rates of radionecrosis (RN) and local intracranial progression (LIP) after stereotactic radiosurgery (SRS) for brain metastases. Methods and Materials: Patients undergoing an initial course of SRS for non-small cell lung cancer (NSCLC) brain metastases at a single institution were retrospectively identified. Kaplan-Meier estimates were calculated and Cox proportional hazards testing was performed based on ATM variant status. Results: A total of 541 patients completed SRS for brain metastasis secondary to NSCLC, of whom 260 completed molecular profiling. Variants of ATM were identified in 36 cases (13.8%). Among patients who completed molecular profiling, RN incidence was 4.9% (95% CI, 1.6%-8.2%) at 6 months and 9.9% (95% CI, 4.8%-15.0%) at 12 months. Incidence of RN was not significantly increased among patients with ATM variants, with an RN incidence of 5.3% (95% CI, 0.0%-15.3%) at both 6 and 12 months (P = .46). For all patients who completed genomic profiling, LIP was 5.4% (95% CI, 2.4%-8.4%) at 6 months and 9.8% (5.5%-14.1%) at 12 months. A significant improvement in LIP was not detected among patients with ATM variants, with an LIP incidence of 3.1% (0.0%-9.1%) at both 6 and 12 months (P = .26). Although differences according to ATM variant type (pathologic variant or variant of unknown significance) did not reach significance, no patients with ATM pathologic variants experienced LIP. Conclusions: We did not detect significant associations between ATM variant status and RN or LIP after SRS for NSCLC brain metastases. The current data set allows estimation of patient cohort sizes needed to power future investigations to identify genetic variants that associate with significant differences in outcomes after SRS.

Identification of an optimal mutant allele frequency to detect activating KRAS, NRAS, and BRAF mutations in a commercial cell-free DNA next-generation sequencing assay in colorectal and pancreatic adenocarcinomas.

Background: Evaluation for activating mutations in KRAS, NRAS, and BRAF in colorectal cancer (CRC) and in KRAS in pancreatic ductal adenocarcinoma (PDAC) is essential for clinical care. Plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) allows convenient assessment of a tumor's molecular profile, however low tumor DNA shedding limits sensitivity. We investigated mutant allele frequency (MAF) of other oncogenic dominant genes to identify a threshold for accurate detection of KRAS, NRAS, and BRAF (RAS/RAF) mutations in cfDNA. Methods: Molecular and clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA study. Patients with CRC or PDAC and a KRAS, NRAS, or BRAF activating single nucleotide variant (SNV) present on tissue NGS and with available cfDNA assays were included. Recursive partitioning and Wilcoxon-rank statistics methods identified potential cut-points for discriminative MAF values. Results: One hundred and thirty-five CRC and 30 PDAC cases with 198 total cfDNA assays met criteria. Greatest non-RAS/RAF dominant gene MAF of 0.34% provided maximum discrimination for predicting RAS/RAF SNV detection. Sensitivity for RAS/RAF SNVs increased with dominant gene MAF, with MAF ≥1% predicting sensitivity >98%, MAF between 0.34 and 1% predicting sensitivity of 84.0%, and MAF £0.34% predicting sensitivity of 50%. For 43 cfDNA assays that did not detect RAS/RAF SNVs, 18 assays detected 34 other oncogenic variants, of which 80.6% were not also detected on tissue. Conclusions: Non-RAS/RAF dominant oncogenic mutation MAF ≥1% on cfDNA NGS predicts high sensitivity to detect RAS/RAF oncogenic SNVs in CRC and PDAC. MAF £0.34% indicates an assay may not reliably detect RAS/RAF SNVs, despite detection on tissue testing. Most variants from assays that did not detect RAS/RAF had MAF <1% and were not detected on tissue, suggesting potential confounding. These data suggest a practical approach to determining cfDNA assay adequacy, with implications for guiding clinical decisions in CRC and PDAC.

Modeling of Proliferating CD4 and CD8 T-Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma.

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single-dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long-term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T-cell count was included in the final model. With the full covariate model, the half-maximal effective concentration (EC50 ) of tremelimumab was 6.10 µg/mL (standard error = 1.07 µg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 µg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death ligand-1 (anti-PD-L1) therapy primes an immune response that may then be sustained by anti-PD-L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti-CTLA-4 plus anti-PD-L1 combination strategies.

Circulating Tumor DNA Testing Overcomes Limitations of Comprehensive Genomic Profiling from Tumor Tissue.

"Liquid biopsy" is an established technique for examining circulating tumor DNA (ctDNA) from a routine blood draw and detecting actionable biomarkers. Nonetheless, ctDNA testing is rarely utilized for patients with newly diagnosed metastatic colorectal cancer (CRC). We report a case in which ctDNA testing uncovered an actionable biomarker that was not detected by comprehensive genomic profiling of tumor tissue. An 81-year-old woman with a remote history of non-Hodgkin's lymphoma presented with primary masses in the ascending colon and sigmoid colon. The ascending colon and sigmoid colon tumors were classified as microsatellite stable (MSS) and mismatch repair proficient (pMMR), and both ctDNA and tissue next-generation sequencing (NGS) from the ascending colon mass were ordered. Because tissue NGS results indicated that the ascending colon tumor was MSS, palliative 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy was started. However, the ctDNA NGS results that arrived after the start of FOLFOX found high microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) disease with a serine/threonine-protein kinase B-Raf (BRAF V600E ) mutation. To treat both her MSS/pMMR ascending colon and sigmoid colon tumors and MSI-H/dMMR metastatic disease, the immunotherapy nivolumab was added to FOLFOX. After 8 months of combined nivolumab and chemotherapy, the patient's metastatic disease had a complete clinical response. This case highlights the complementary role of ctDNA testing for biomarker identification. By performing simultaneous ctDNA testing at the time of diagnosis, an actionable biomarker was discovered that significantly altered this patient's prognosis and treatment options. Orthogonal testing of key molecular alterations offers significant advantages for identifying actionable biomarkers and improving management of metastatic CRC.

Sexually Dimorphic Adolescent Trajectories of Prefrontal Endocannabinoid Synaptic Plasticity Equalize in Adulthood, Reflected by Endocannabinoid System Gene Expression.

Introduction: How sex influences prefrontal cortexes (PFCs) synaptic development through adolescence remains unclear. Materials and Methods: In this study we describe sex-specific cellular and synaptic trajectories in the rat PFC from adolescence to adulthood. Results: The excitability of PFC layer 5 pyramidal neurons was lower in adult females compared with other developmental stages. The developmental course of endocannabinoid-mediated long-term depression (eCB-LTD) was sexually dimorphic, unlike long-term potentiation or mGluR3-LTD. eCB-LTD was expressed in juvenile females but appeared only at puberty in males. Endovanilloid TRPV1R or eCB receptors were engaged during LTD in a sequential and sexually dimorphic manner. Gene expression of the eCB/vanilloid systems was sequential and sex specific. LTD-incompetent juvenile males had elevated expression levels of the CB1R-interacting inhibitory protein cannabinoid receptor interacting protein 1a and of the 2-arachidonoylglycerol-degrading enzyme ABHD6. Pharmacological inhibition of ABHD6 or MAGL enabled LTD in young males, whereas inhibition of anandamide degradation was ineffective. Conclusions: These results reveal sex differences in the maturational trajectories of the rat PFC.

Cost-Effectiveness of SAPIEN 3 Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in German Severe Aortic Stenosis Patients at Low Surgical Mortality Risk.

INTRODUCTION: In the randomized PARTNER 3 trial, transcatheter aortic valve implantation (TAVI) with the SAPIEN 3 device significantly reduced a composite of all-cause death, stroke, and rehospitalization, compared with surgical aortic valve replacement (SAVR), in patients with severe symptomatic aortic stenosis and low risk of surgical mortality. Furthermore, TAVI has been shown to be cost-effective in low-risk patients, compared with SAVR, in a number of countries. This study aimed to determine the cost-effectiveness of TAVI with SAPIEN 3 versus SAVR in Germany. METHODS: A previously published two-stage Markov-based model that captured clinical outcomes from the PARTNER 3 trial was adapted for the German context using the German Statutory Health Insurance perspective. The model had a lifetime horizon. The cost-utility analysis estimated changes in direct healthcare costs as well as survival and health-related quality of life using TAVI with SAPIEN 3 compared with SAVR. RESULTS: TAVI with SAPIEN 3 increased quality-adjusted life years (QALYs) by + 0.72 at an increased cost of €8664 per patient. The incremental cost-effectiveness/QALY ratio was €12,037, which fell below that of other cardiovascular interventions in use in Germany. The cost-effectiveness of TAVI over SAVR remained robust across multiple challenging scenarios and was driven by lower longer-term management costs compared with SAVR. CONCLUSIONS: TAVI with SAPIEN 3 appears to be a clinically meaningful, cost-effective treatment option over SAVR for patients with severe symptomatic aortic stenosis and low risk for surgical mortality in Germany. CLINICAL TRIAL REGISTRATION NUMBER: www. CLINICALTRIALS: gov identifier: NCT02675114.

Concordance Between Genomic Alterations Detected by Tumor and Germline Sequencing: Results from a Tertiary Care Academic Center Molecular Tumor Board.

OBJECTIVE: The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results. METHODS: A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status. RESULTS: A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin. CONCLUSIONS: Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making.

A population pharmacokinetic-pharmacodynamic model of navtemadlin, its glucuronide metabolite (M1) and serum macrophage inhibitory cykokine-1 (MIC-1).

Navtemadlin is a potent, selective, orally available inhibitor of murine double minute 2 that restores p53 activity to induce apoptosis in TP53 wild-type malignancies. Using richly sampled pharmacokinetic (PK) and pharmacodynamic (PD) data from healthy volunteers, a population PK/PD model was developed.A population PK (PPK) model described the PK characteristics of navtemadlin and its major metabolite acyl glucuronide (M1) and quantified enterohepatic recirculation (EHR). Post hoc individual PK parameters from this model were coupled with PD data for serum macrophage inhibitory cytokine-1 (MIC-1, GDF15), a cytokine biomarker of p53 activation, to construct a population PK/PD model that described plasma concentration-driven MIC-1 excursions and enabled simulation of the extent and duration of navtemadlin PD effects.The median apparent clearance (CL/F) and apparent central volume (V2/F) of navtemadlin were 36.4 L/hr and 159 L. The typical maximum stimulatory effect (Smax) was close to the median maximum MIC-1 ratio to baseline of 7.29 in observed data.Simulation revealed a dose-dependent increase of MIC-1 with steady state attained in approximately 7 days, in a 7-day-on/21-day-off dose regimen. Elevated MIC-1 concentrations persist through 17-19 days, leaving about 9-11 PD-free days in a 28-day cycle.

AACR Project GENIE: 100,000 Cases and Beyond.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from the United States, Canada, the United Kingdom, France, the Netherlands, and Spain. Here, we demonstrate the use of these real-world data, harmonized through a centralized data resource, to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharmaceutical collaborations and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledge base of increasing impact to inform clinical decision-making and bring together cancer researchers internationally. SIGNIFICANCE: AACR Project GENIE has now accrued data from >110,000 tumors, placing it among the largest repository of publicly available, clinically annotated genomic data in the world. GENIE has emerged as a powerful resource to evaluate genome-guided clinical trial design, uncover drivers of cancer subtypes, and inform real-world use of genomic data. This article is highlighted in the In This Issue feature, p. 2007.

Cost-Effectiveness Analysis of SAPIEN 3 Transcatheter Aortic Valve Implantation Procedure Compared With Surgery in Patients With Severe Aortic Stenosis at Low Risk of Surgical Mortality in France.

OBJECTIVES: The clinical and cost-saving benefits of transcatheter aortic valve implantation (TAVI) over surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis who are at high or intermediate risk of surgical mortality are supported by a growing evidence base. The PARTNER 3 trial (Placement of AoRTic TraNscathetER Valve Trial) demonstrated clinical benefits with SAPIEN 3 TAVI compared with SAVR in selected patients at low risk of surgical mortality. This study uses PARTNER 3 outcomes in combination with a French national hospital claim database to inform a cost-utility model and examine the cost implications of TAVI over SAVR in a low-risk population. METHODS: A 2-stage cost-utility analysis was developed to estimate changes in both direct healthcare costs and health-related quality of life using TAVI with SAPIEN 3 compared with SAVR. Early adverse events associated with TAVI were captured using the PARTNER 3 data set. These data fed into a Markov model that captured longer-term outcomes of patients, after TAVI or SAVR intervention. RESULTS: TAVI with SAPIEN 3 offers meaningful benefits over SAVR in providing both cost saving (€12 742 per patient) and generating greater quality-adjusted life-years (0.89 per patient). These results are robust with TAVI with SAPIEN 3 remaining dominant across several scenarios and deterministic and probabilistic sensitivity analyses. CONCLUSIONS: This model demonstrated that TAVI with SAPIEN 3 was dominant compared with SAVR in the treatment of patients with severe symptomatic aortic stenosis who are at low risk of surgical mortality. These findings should help policy makers in developing informed approaches to intervention selection for this patient population.

Population pharmacokinetics of rucaparib in patients with advanced ovarian cancer or other solid tumors.

PURPOSE: To develop a population pharmacokinetics (PPK) model for rucaparib, an oral poly(ADP-ribose) polymerase inhibitor. METHODS: The PPK analysis used PK data from patients in Study 1014 (NCT01009190, n = 35), Study 10 (NCT01482715, n = 123), and ARIEL2 (NCT01891344, n = 300), including intensive intravenous data (12-40 mg), intensive and sparse oral data (12-360 mg single-dose, 40-500 mg once daily, and 240-840 mg twice daily [BID]), and intensive single-dose oral data under fasted conditions and after a high-fat meal (40, 300, and 600 mg). RESULTS: Rucaparib PK was well described by a two-compartment model with sequential zero-order release and first-order absorption and first-order elimination. A high-fat meal slightly increased bioavailability at 600 mg but not at lower doses; this is not considered clinically significant, and rucaparib can be taken with or without food. Covariate effects of baseline creatinine clearance and albumin on rucaparib clearance were identified. Despite numerical increases in exposure with renal impairment, no dose adjustment is recommended for patients with mild or moderate renal impairment. No statistically significant relationships were detected for demographics, hepatic function (normal versus mild impairment), CYP1A2 and CYP2D6 phenotypes, or strong CYP1A2 or CYP2D6 inhibitors. Concomitant proton pump inhibitors showed no clinically significant effect on absorption. External validation of the model with data from ARIEL3 (NCT01968213) and TRITON2 (NCT02952534) studies showed no clinically meaningful PK differences across indications or sex. CONCLUSION: The PPK model adequately described rucaparib PK, and none of the covariates evaluated had a clinically relevant effect. CLINICALTRIALS: GOV: Study 1014 (NCT01009190), Study 10 (NCT01482715), ARIEL2 (NCT01891344), ARIEL3 (NCT01968213), and TRITON2 (NCT02952534).

Model-informed drug development of voxelotor in sickle cell disease: Population pharmacokinetics in whole blood and plasma.

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.

Model-informed drug development of voxelotor in sickle cell disease: Exposure-response analysis to support dosing and confirm mechanism of action.

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p < 0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents.

Cost-effectiveness of transcatheter aortic valve implantation versus surgical aortic valve replacement in low surgical risk aortic stenosis patients.

BACKGROUND: The PARTNER 3 trial demonstrated clinical benefits of transcatheter aortic valve implantation (TAVI) with the SAPIEN 3 device, over surgical aortic valve replacement (SAVR) in patients with severe symptomatic aortic stenosis (sSAS) at low risk of surgical mortality. Using PARTNER 3 outcomes and Italy-specific costs data, this cost-utility analysis from the perspective of the Italian National Health System aimed to determine the cost-effectiveness of SAPIEN 3 TAVI versus SAVR in low risk sSAS patients in Italy. METHODS: A two-stage cost-utility model was developed to estimate changes in both direct healthcare costs and health-related quality of life using TAVI with SAPIEN 3 compared with SAVR. Early adverse events associated with TAVI were captured utilising the PARTNER 3 dataset. These data fed into a Markov model that captured longer-term outcomes of patients, following TAVI or SAVR intervention. RESULTS: Analysis findings estimated that TAVI with SAPIEN 3 offers benefits over SAVR in terms of increased quality-adjusted life years (QALYs) with only a small increase in costs, representing an incremental cost-effectiveness ratio/QALY gained of €2989 per patient. The results were robust, with TAVI with SAPIEN 3 remaining cost-effective across several scenarios and in probabilistic sensitivity analyses. CONCLUSIONS: This model demonstrated that TAVI with SAPIEN 3 is likely to be cost effective compared with SAVR for the treatment of patients with sSAS who are at low risk of surgical mortality. These findings can inform policy makers to facilitate policy development in Italy on intervention selection for this patient population.

An early cost analysis of magnetic bone growth stimulation in England.

BACKGROUND: Fracture nonunions impact on morbidity and health care costs and are associated with substantial pain, reduced mobility, prolonged morbidity, and a lower quality of life. CMF OrthoLogic 1000 (OL1000) is a bone growth stimulator used to promote fracture healing potentially reducing the need for surgical intervention. A cost analysis comparing CMF OL1000 versus surgical care for patients with nonunion tibial fractures was conducted. METHODS: A Markov model was developed to compare the difference in costs between CMF OL1000 versus surgical care within the English National Health Service over a 2-year time horizon. The effectiveness of CMF OL1000 was based on recently published registry data. Cost data were derived from published sources and national cost databases. Sensitivity and scenario analyses were conducted. RESULTS: The use of CMF OL1000 is estimated to lead to cost-savings of £1,104 per patient, a reduction in average healing time of 2.1 months and a relative risk of infection of 0.19 compared to immediate surgical intervention (standard of care). The results of the model are robust to most changes in input parameters and scenarios considered. CONCLUSIONS: This early analysis shows cost-savings for CMF OL1000 compared with surgical intervention for individuals with nonunion tibial fractures.