First-line Use Research Articles

Real-World Survival of First-Line Immune Checkpoint Inhibitor Treatment Versus Chemotherapy in Older Patients With Non-Small-Cell Lung Cancer and Synchronous Brain Metastases.

This study assessed real-world survival among older patients with non-small-cell lung cancer (NSCLC) and brain metastases (BMs) at diagnosis (synchronous BM [SBM]) receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy only. Patients with NSCLC and SBM age 65 years or older at diagnosis from 2010 to 2019 SEER-Medicare database and received US Food and Drug Administration-approved ICIs (pembrolizumab/nivolumab/ipilimumab/atezolizumab/durvalumab/cemiplimab) and/or chemotherapy (platinum-based doublets/taxane/pemetrexed/gemcitabine) as first-line systemic treatment were included, excluding those with no cranial radiation or ever being treated with targeted therapies. Overall survival time was from the start of systemic treatment (ICI/chemotherapy) to death, censored at disenrollment from Medicare part A/B, enrollment in part C, or end of the study period (December 31, 2019). Kaplan-Meier (KM) survival curves were compared between treatment groups using the log-rank test. Multivariable Cox proportional hazards (CPH) model was used to estimate hazard ratio (HR) between groups, adjusting for patients' sociodemographic and clinical characteristics. The study included 1,481 patients (1,303 chemotherapy and 178 ICI). The median (range) age was 71 (65-91) years. First-line ICI patients were more likely to be older, live in urban areas, and less likely to be non-White than the chemotherapy group. KM estimates showed that survival curves initially overlapped but diverged approximately 6 months after initiating first-line systemic treatment (median survival [95% CI]: ICI, 190 [131 to 303] days versus chemotherapy, 189 [177 to 201] days), with ICI showing a better survival than the chemotherapy group (log-rank test P < .0001). First-line ICI was associated with a lower risk of death compared with chemotherapy in adjusted CPH model (HR [95% CI], 0.67 [0.55 to 0.80]; P < .0001). Among older patients with NSCLC and SBM, first-line ICI use was associated with improved survival occurring 6 months after treatment initiation compared with chemotherapy only.

First-line versus second-line use of pralsetinib in treatment of rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer: a cost-effectiveness analysis.

The ARROW study demonstrated favorable clinical efficacy and safety of pralsetinib (PRL) in treating rearranged during transfection (RET) fusion positive non-small cell lung cancer (NSCLC) in clinical trials. However, due to the high cost of PRL, evaluating its cost-effective characteristics is crucial. Currently, there has been no cost-effectiveness analysis specifically for PRL. Therefore, the aim of this study was to assess the cost-effectiveness characteristics of using PRL as a first-line therapy versus reserving it until the second-line versus solely relying on chemotherapy from the perspective of payers in the United States. A Markov model was developed to evaluate the 3 above mentioned PRL-based treatment strategies. Clinical data from the ARROW trial were incorporated into the model, and costs and utilities values were obtained through previously published literature and public databases, with both being discounted at 3% per year. To ensure the robustness of the model, both probabilistic and univariate sensitivity analyses were performed. The primary endpoints included quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). Compared to chemotherapy, the use of PRL in the first-line therapy resulted in an additional 0.07 QALYs at a cost of $133,561, with an ICER of $1,353,849.65 per QALY. Similarly, when used in the second-line setting, PRL led to an additional 0.09 QALYs at a cost of $92,797, with an ICER of $559,232.70 per QALY. The ICER value in the first-line or in the second-line therapy strategy was higher than the US willingness-to-pay (WTP) threshold of $150,000 per QALY. Univariable sensitivity analyses revealed that the cost of PRL and the utility of progressed disease had the most significant impact on the ICER. To be considered cost-effective at a WTP threshold of $150,000 per QALY, the cost of PRL would need to be reduced by 71.34% in first-line treatment or 84.49% in second-line treatment. Based on current pricing, neither PRL as first-line nor second-line therapy was found to be cost-effective for patients with RET fusion-positive advanced NSCLC compared to chemotherapy. Reserving PRL until second-line therapy may be a compromise approach to maintaining control over healthcare expenses yet still achieving favorable clinical outcomes.

Efficacy and safety of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma patients with esophageal-gastric varices.

Bevacizumab inhibits vascular endothelial growth factor-A (VEGF-A), though is known to increase bleeding risk as an adverse event (AE). This study examined whether atezolizumab/bevacizumab (Atez/Bev) for unresectable hepatocellular carcinoma (uHCC) can be used for patients with esophageal-gastric varices (EGV). From October 2020 to December 2022, 506 uHCC patients (median 74years) underwent an upper gastrointestinal endoscopy examination were enrolled, after exclusion of those with portal vein tumor thrombus (PVTT). Patients with EGV (≧ F1) were defined as EGV positive, and the cohort was divided into non-EGV (n = 355) and EGV (n = 151). Before introducing Atez/Bev, endoscopic treatment was performed, when necessary. Prognosis was evaluated, retrospectively. The EGV group had significantly worse hepatic function, lower platelet count, elevated alpha-fetoprotein, and lower rate of extrahepatic metastasis, and lower rate of first-line use (each P < 0.05) than the other. However, progression-free survival (PFS) was also not a significantly difference between the EGV and non-EGV groups in analyses with (PFS rate at 6/12/18 months: 60%/38%/30% vs. 65%/46%/34%, P = 0.29) or without inverse probability weighting adjustment [median: 10.6months (95% CI 8.3-14.0) vs. 10.5months (95% CI 7.8-13.7), P = 0.79]. As for AEs, diarrhea was more frequent in the EGV group (≧ G3: 2.0% vs. 0.3%, P = 0.036), while no significant difference was noted for EGV hemorrhage (≧ G3: 1.3% vs. 0.6%, P = 0.345). Of 28 patients who underwent endoscopic treatments before introducing Atez/Bev, none showed EGV-associated hemorrhage. Atez/Bev might be an effective therapeutic option in patients with EGV, when appropriate endoscopic treatment for EGV is performed.

Glioma angiogenesis is boosted by ELK3 activating the HIF-1alpha/VEGF-A signaling axis

BackgroundClinical studies have shown that first-line use of anti-angiogenetic therapy can prolong progression-free survival but little progress has been made in extending the overall survival of the patients. We explored the role of ELK3 in glioma angiogenesis to improve and design more efficacious therapies.MethodsA tissue microarray and immunohistochemistry analysis were used to determine the expression of ELK3 protein in 400 glioma patients. Cell proliferation, metastasis, cell cycle, and apoptosis were monitored in U87 and U251 cells using CCK-8, EdU, transwell assays, and flow cytometry. A tube-formation assay, a rat aorta ring sprouting assay, and a matrigel plug assay were performed to examine the antiangiogenic activity of ELK3. An ELISA, Western blot, and correlation analysis of the CGGA dataset were used to detect the association between ELK3 and VEGF-A or ELK3 and HIF-1alpha. Besides, orthotopic transplantation in nude mice and histopathological and immunological analysis of in vitro tumors were used to explore the effect of ELK3 on tumor progression and median survival.ResultsELK3 was upregulated in glioma tissues and associated with a poor prognosis. In vitro, ELK3 promoted cell proliferation and cell cycle progression, induced metastasis, and suppressed apoptosis. Then, silencing ELK3 inhibited VEGF-A expression and secretion by facilitating HIF-1alpha degradation via ubiquitination. Finally, knockdown ELK3 inhibited tumor progression and angiogenesis in vitro and in vivo, as well as prolonged nude mice’s median survival.ConclusionsOur findings first evidenced that ELK3 is crucial for glioma because it promotes angiogenesis by activating the HIF-1alpha/VEGF-A signaling axis. Therefore, we suggest that ELK3 is a prognostic marker with a great potential for glioma angiogenesis and ELK3-targeted therapeutic strategies might hold promise in improving the efficacy of anti-angiogenic therapies.

First-line diuretics versus other classes of antihypertensive drugs for hypertension.

First-line diuretics versus other classes of antihypertensive drugs for hypertension.

Trends in antihypertensive drug utilization in British Columbia, 2004-2019: a descriptive study.

Clinical guidelines for hypertension were updated with lower blood pressure targets following new studies in 2015; the real-world impact of these changes on antihypertensive drug use is unknown. We aimed to describe trends in antihypertensive drug utilization from 2004 to 2019 in British Columbia. We conducted a longitudinal study to describe the annual prevalence and incidence rate of use of 5 antihypertensive drug classes (thiazides, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], calcium channel blockers and β-blockers) among BC residents aged 30-75 years. We also conducted a cohort study to compare the risk of discontinuation and switch or add-on therapy between incident users of the above drug classes. We used linkable administrative health databases from BC. We performed a Fine-Gray competing risk analysis to estimate subhazard ratios. Among BC residents aged 30-75 years (population: 2 376 282 [2004] to 3 014 273 [2019]), the incidence rate of antihypertensive drug use decreased from 23.7 per 1000 person-years in 2004 to 18.3 per 1000 person-years in 2014, and subsequently increased to 22.6 per 1000 person-years in 2019. The incidence rate of thiazide use decreased from 8.9 per 1000 person-years in 2004 to 3.2 per 1000 person-years in 2019, and incidence rates for the other drug classes increased. Incident users receiving thiazide monotherapy had an increased risk of discontinuing any antihypertensive treatment compared with ACE inhibitor monotherapy (subhazard ratio 0.96, 95% confidence interval [CI] 0.95-0.97), ARB monotherapy (subhazard ratio 0.84, 95% CI 0.81-0.87) and thiazide combination with ACE inhibitor or ARB (subhazard ratio 0.86, 95% CI 0.84-0.88), and had the highest risk of switching or adding on. First-line use of thiazides continued to decrease despite a marked increase in incident antihypertensive therapy following updated guidelines; incident users receiving ARB monotherapy were least likely to discontinue, and incident users receiving thiazide monotherapy were more likely to switch or add on than users of other initial monotherapy or combination. Further research is needed on the factors influencing treatment decisions to understand the differences in trends and patterns of antihypertensive drug use.

P48 Clinical update: ivermectin access for scabies improved through the pharmaceutical benefits scheme change in Australia

Abstract Scabies is estimated to affect 455 million people worldwide and is a neglected tropical disease that is endemic in northern Australia. Indigenous communities in northern Australia are reported to have some of the highest rates of scabies in the Pacific, with recent prevalence reported to be as high as 25%, with secondary complications including rheumatic heart disease and poststreptococcal glomerulonephritis. However, the high burden of skin disease is still under-reported and under-represented on the national policy agenda. It is essential to consider public health strategies and therapeutic opportunities to address the high burden of disease and minimize serious secondary complications that contribute to the health and life expectancy gap that exists between aboriginal and Torres Strait Islander people and other Australians. Considering the clinical need of the patient population, the management of scabies in northern Australia highlights the impracticality and tolerability issues experienced, with topical permethrin 5% cream as the sole first-line treatment option and use of ivermectin only as a second-line treatment after treatment failure with permethrin cream. This is especially important as poor medication access and treatment failure are well known to perpetuate a cycle of health inequity in northern Australia. A multistakeholder submission to the Pharmaceutical Benefits Advisory Committee was developed to support a change to the listing of ivermectin on the Pharmaceutical Benefits Scheme (PBS) in Australia, and to recommend ivermectin as a first-line treatment option for the management of scabies in aboriginal and Torres Strait Islander people in Australia. The PBS listing was successfully changed after 9 months of review, and from 1 April 2022, oral ivermectin has been listed as a first-line treatment for the management of scabies in aboriginal and Torres Strait Islander people in Australia. It is anticipated that the change in national prescribing will have a large impact on a small number of Australians who face significant disadvantages and health inequity and will improve access of treatment to manage effectively a condition that disproportionately affects First Nations people in Australia. The successful PBS listing change occurred ahead of the release of the new edition of the Australian clinical guidelines, which at the time of writing are scheduled to be released in early 2023. The updated guidelines will include ivermectin as a co-first-line treatment alongside topical permethrin 5% cream for the management of scabies, in addition to considering an ivermectin-based mass-drug administration programme for endemic regions in which the burden of scabies is estimated to be &amp;gt; 10%, as recommended by the World Health Organization.

Removal of incorrect penicillin allergy labels in a UK hospital

ObjectivesPenicillin allergy records are common, often incorrect and are associated with broad spectrum antibiotic use. We piloted a pharmacist-led multidisciplinary penicillin allergy de-labelling daily ward round to determine the opportunity for penicillin allergy de-labelling in a UK hospital. MethodsA daily ward round, delivered by antibiotic pharmacists or junior doctors, identified adult medical and surgical patients between 7 November 2022 and 31 January 2023 with a penicillin allergy record that was preventing first-line penicillin use. An allergy history was taken before risk stratifying likelihood of future harm from penicillin re-exposure and an allergy testing method was determined (direct de-label on history alone or after direct drug provocation testing). After successful allergy de-label, the antibiotic was switched to a penicillin antibiotic. ResultsOf 7214 inpatients during the study period, 1133 (15.7%) had a penicillin allergy record. Of 285 allergy histories taken, 105 (36.8%) met high-risk criteria, 45 (15.8%) met low-risk criteria eligible for direct de-label and 73 (25.6%) met criteria eligible for direct drug provocation testing. We were unable to obtain a history for 61 (21.4%) patients. Of 45 low-risk patients eligible for direct de-label, 40 (88.9%) were de-labelled of whom 24 (53.3%) were switched to a penicillin antibiotic. Of 73 patients with a low-risk allergy history eligible for direct drug provocation testing, 16 (21.9%) received direct drug provocation testing, of whom 9 were switched to a penicillin antibiotic. Two direct de-label patients experienced harm (thrush within 5 days and delayed skin reaction after day 5); none of the direct drug provocation testing patients had a reaction by day 5. The switches resulted in reduced alternative antibiotic use by 173 Daily Defined Doses (DDDs). DiscussionPenicillin allergy de-labelling patient pathway delivered by pharmacists and junior doctors was safe and effective and well accepted by patients and the wider clinical teams.

Efficacy and Tolerability of Ramucirumab Plus Erlotinib in Taiwanese Patients with Untreated, Epidermal Growth Factor Receptor-Mutated, Stage IV Non-small Cell Lung Cancer in the RELAY Study.

In RELAY, a randomized, double-blind, phase III trial investigating the efficacy and safety of ramucirumab+erlotinib (RAM+ERL) or ERL+placebo (PBO) in patients with untreated, stage IV, epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), RAM+ERL demonstrated superior progression-free survival (PFS) versus PBO+ERL, with no new safety signals. The aim of this paper was to report efficacy and tolerability findings for the Taiwanese participants of RELAY. Patients were randomized 1:1 to RAM+ERL or ERL+PBO. Primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and tolerability. Data for the current analysis are reported descriptively. In RELAY, 56 Taiwanese patients were enrolled; 26 received RAM+ERL, 30 received ERL+PBO. The demographic profile of the Taiwanese subgroup was consistent with that of the overall RELAY population. Median PFS for RAM+ERL/ERL+PBO, respectively, was 22.05 months/13.40 months (unstratified hazard ratio 0.4; 95% confidence interval 0.2-0.9); ORR was 92%/60%; median DoR was 18.2 months/12.7 months. All patients experienced one or more treatment-emergent adverse events (TEAEs); those most commonly reported were diarrhea and dermatitis acneiform (58% each) for RAM+ERL and diarrhea (70%) and paronychia (63%) for PBO+ERL. Grade ≥3 TEAEs were experienced by 62%/30% of RAM+ERL/PBO+ERL patients, respectively, and included dermatitis acneiform (19%/7%), hypertension (12%/7%), and pneumonia (12%/0%). PFS for the Taiwanese participants of RELAY receiving RAM+ERL versus ERL+PBO was consistent with that in the overall RELAY population. These results, together with no new safety signals and a manageable safety profile, may support first-line use of RAM+ERL in Taiwanese patients with untreated EGFR-mutant stage IV NSCLC. www. gov , NCT02411448.

Risk comparison of osteonecrosis of the jaw in osteoporotic patients treated with bisphosphonates vs. denosumab: a multi-institutional retrospective cohort study in Taiwan.

To compare the long-term risk of osteonecrosis of the jaw (ONJ) between osteoporotic patients treated with bisphosphonates (BPs) and denosumab. This multi-institutional retrospective cohort study included patients aged > 40years with osteoporosis between January 2010 and December 2018. Patients who met the eligibility criteria were divided into BPs and denosumab groups by propensity score matching (PSM). The risk of ONJ of denosumab vs. BPs was estimated using a Cox proportional hazards model and was described by the cumulative incidence rate using the Kaplan-Meier method. A total of 84,102 patients with osteoporosis were enrolled, among whom, 8962 were eligible for inclusion based on their first-line drug use (denosumab, n = 3,823; BPs, n = 5,139). Following PCM matching (1:1), the BPs and denosumab groups included 3665 patients each. The incidence density of ONJ in the denosumab and BPs matching groups was 1.47 vs. 2.49 events (per 1000 person-years), respectively. The hazard ratio of ONJ in the denosumab vs. BPs group was estimated as 0.581 (95% confidence interval: 0.33-1.04, p = 0.07). The cumulative incidence rates of ONJ in both groups were similar for the first and second years of drug use (p = 0.062), but significantly different from the third year onwards (p = 0.022). The severity of ONJ was not significantly different between the two groups. In osteoporotic patients, after 2years of use, the likelihood of ONJ being induced by denosumab is lower than that of BPs, and the difference increases with time.

First-Line Versus Second-Line Use of Reslizumab in Severe Uncontrolled Asthma.

First-Line Versus Second-Line Use of Reslizumab in Severe Uncontrolled Asthma.

Cost analysis for mirabegron use in the treatment of children with neurogenic bladder

Mirabegron is a beta-3 adrenergic receptor agonist that received FDA approval in 2021 to treat neurogenic detrusor overactivity (NDO) in children ages three years and older. Despite its safety and efficacy, access to mirabegron frequently remains restricted by payor coverage policies. This cost minimization study sought to determine the cost implications from a payor perspective of mirabegron use at different points in the treatment pathway for pediatric NDO. A Markov decision analytic model was constructed to assess the costs for eight treatment strategies over a 10-year period, using six-month cycles (Table). Five strategies involve mirabegron use as first-, second-, third-, or fourth-line therapy. Two strategies, including the "base case," entail use of anticholinergic medications followed by onabotulinum toxin type A (Botox) injection and augmentation cystoplasty. A strategy involving first-line Botox was also modeled. The effectiveness, adverse event rates, attrition rates, and costs associated with each treatment option were obtained from the clinical literature and adjusted to a six-month cycle. Costs were adjusted to 2021-dollar value. A discount rate of 3% was used. To quantify uncertainty, costs and treatment transition probabilities were modeled as gamma and PERT distributions, respectively. One-way sensitivity analyses were performed. Probabilistic sensitivity analysis (PSA) was conducted using a Monte Carlo simulation with 100,000 iterations. Analyses were performed using Treeage Pro (Healthcare Version). The least costly strategy involved first-line mirabegron (expected cost $37,954). All strategies involving mirabegron were less costly than the base case ($56,417). On PSA, first-line mirabegron was the least costly strategy in 88.9% of cases (mean $37,604, 95% CI: $37,579-37,628); in 100% of cases, the least costly strategy involved mirabegron use. Cost savings associated with mirabegron use were attributable to decreased use of augmentation cystoplasty and Botox injections. This is the first study to compare costs across multiple strategies involving mirabegron to treat pediatric NDO. Mirabegron use likely yields cost savings for the payor: the least costly strategy involved first-line mirabegron, and all pathways incorporating mirabegron were less costly than those without mirabegron use. These findings provide an updated cost analysis for the treatment of NDO by investigating mirabegron use alongside more established treatment options. Use of mirabegron for the treatment of pediatric NDO is likely associated with cost savings as compared to treatment pathways without mirabegron. Expansion of payor coverage for mirabegron, as well as clinical studies to study first-line mirabegron use, should be considered.

P09 Non-allergist Removal of Incorrect Penicillin Allergy Labels (RIPAL) in a UK hospital

Abstract Objectives We piloted a pharmacist-led multidisciplinary penicillin allergy de-labelling (PADL) daily ward round to determine the opportunity for PADL in a UK hospital. Methods A daily ward round, delivered by either an antibiotic pharmacist or a junior doctor, identified adult medical and surgical patients between 7 November 2022 and 31 January 2023 with a penicillin allergy (penA) record that was preventing first-line penicillin use. An allergy history was taken before risk stratifying likelihood of future harm from penicillin re-exposure and an allergy testing method was determined [de-label on history (DOH) or after direct drug provocation testing (DDPT)]. Following successful de-label, in agreement with the responsible clinician, the antibiotic was switched to a penicillin antibiotic. Results Of 7214 inpatients during the study period, 1133 (15.7%) had a penA record. Of 285 allergy histories taken, 105 (36.8%) met high-risk criteria, 45 (15.8%) met low-risk criteria eligible for DOH, 73 (25.6%) met low-risk criteria eligible for DDPT and we were unable to obtain a history from 62 (21.8%) patients. Of 45 low-risk patients eligible for DOH, 40 (88.9%) were de-labelled of which 24 (53.3%) were switched to a penicillin antibiotic. Of 73 patients with a low-risk allergy history eligible for DOC, 16 (21.9%) received DDPT, of which nine were switched to a penicillin antibiotic to complete their antibiotic course. Two DOH patients experienced harm (thrush within the first 5 days and delayed skin reaction after day 5), none of the DPTs had a reaction by day 5. The switches resulted in 170 DDDs of penicillin use (predominantly amoxicillin) and reduced alternative antibiotic use by 174 DDDs (predominantly meropenem and levofloxacin). Conclusions Penicillin allergy de-labelling patient pathway delivered by pharmacists and junior doctors was safe and effective and well accepted by patients and the wider clinical teams. Further work is required to optimize and streamline these patient pathways to maximize patient and health system benefit.

Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC).

LBA1000 Background: The phase-3, randomized, investigator-initiated, nationwide SONIA trial is evaluating the efficacy, safety and cost-effectiveness of CDK4/6i added to either first- or second-line endocrine therapy (ET) in patients with HR+, HER2- ABC who have received no prior therapy for ABC. The addition of CDK4/6i to ET improves progression-free (PFS) and overall survival (OS) in HR+, HER2- ABC, as initial treatment (first-line) and after prior endocrine monotherapy (second-line). Most international guidelines advice first-line use, despite prolonged toxicity and a steep increase in costs compared to use in second-line. Evidence of superiority of first-line use over second-line based on a head-to-head comparison is lacking. Methods: Pre- and postmenopausal women (N=1050), who received no prior therapy for ABC, with measurable or evaluable disease and WHO performance status 0-2 were enrolled in 74 Dutch hospitals. (Neo)adjuvant therapy was allowed (disease-free interval after non-steroidal aromatase inhibitor (NSAI) &gt;12 months). Patients were randomized 1:1 to receive strategy A (first-line treatment with an NSAI + CDK4/6i, followed on progression by fulvestrant (F)) or strategy B (first-line treatment with an NSAI, followed on progression by F + CDK4/6i). Choice between one of the available CDK4/6i (abemaciclib, palbociclib, ribociclib) was a stratification factor and left to the discretion of the treating physician. The primary endpoint is time from randomization to second objective disease progression, as assessed by local investigators, or death (PFS2). Secondary endpoints include OS, safety, quality of life, and cost-effectiveness. Results: After a median follow-up of 37.3 months (data cut-off 1 December 2022), median PFS2 was 31.0 months in strategy A versus 26.8 months in strategy B (hazard ratio 0.87; 95% confidence interval, 0.74 to 1.03; P=0.10). The treatment effect was consistent across the levels of pre-defined subgroups. The safety profile was characteristic for ET + CDK4/6i. Median time on CDK4/6i was 24.64 months in strategy A and 8.08 months in strategy B (Δ 16.56 months). The number of grade ≥3 adverse events was 2782 for strategy A and 1620 for strategy B. Conclusions: First-line use of CDK4/6i + ET does not provide statistically significant, nor clinically meaningful PFS benefit compared to second-line use in women with HR+, HER2- ABC. Use in first-line prolongs the time on CDK4/6i by 16.56 months and increases toxicity and costs. Second-line use may thus be a preferred option for the majority of patients. (Funded by The Netherlands Organisation for Health Research and Development and Dutch Health Insurers; ClinicalTrials.gov number, NCT03425838). Clinical trial information: NCT03425838 .

Next-generation sequencing in the diagnosis of neurobrucellosis: a case series of eight consecutive patients

BackgroundNeurobrucellosis (NB) presents a challenge for rapid and specific diagnosis. Next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has showed power in detection of causative pathogens, even some infrequent and unexpected pathogens. In this study, we presented 8 cases of NB diagnosed by the NGS of CSF.MethodsBetween August 1, 2018 and September 30, 2020, NGS was used to detect causative pathogens in clinically suspected central nervous system (CNS) infections. Data on demographics, clinical features, and laboratory tests, imaging results and NGS results were collected and reviewed.ResultsAmong the presented 8 patients, Brucella was rapidly detected using NGS of CSF within 1–4 days, despite those eight patients had variable medical history, disease course, clinical manifestations, laboratory tests and imaging findings. NGS showed the sequence reads corresponded to Brucella species were 8 to 448, with genomic coverage of 0.02 to 0.87%. The relative abundance was 0.13% to 82.40% and sequencing depth was 1.06 to 1.24. Consequently, patients were administered with 3 to 6 months of doxycycline, ceftriaxone and rifampicin, double or triple combination, supplemented with symptomatic therapy and were fully recovered except for case 1.ConclusionNGS of CSF provides a powerful tool in detection of Brucella in a prompt and specific manner, and can be considered for first-line diagnostic use in practice.

Time to treatment initiation in a retrospective cohort of patients with advanced lung cancer treated with an immune checkpoint inhibitor.

e21199 Background: Advanced lung cancer is diagnosed by imaging through screening, incidental findings, or during the workup of symptoms. Historically, there was no apparent benefit in expediting the times to biopsy, staging, and chemotherapy initiation. However, the widespread first-line use of immune checkpoint inhibitors (ICIs) can introduce delays such as biomarker testing and financial approval. We aimed to test whether the time to ICI treatment initiation was associated with worse clinical outcomes. Methods: We created a retrospective registry of all patients with advanced lung cancer who received at least one dose of an ICI for any first-line indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics and made a validated database. We defined the time to biopsy as the interval between the initial diagnostic imaging of the index cancer and the biopsy. We defined time to treatment initiation (TTI) as the interval between initial imaging and the first dose of ICI. Overall survival was the interval from the biopsy date to death. We used a Cox multivariate regression to model the continuous association of each additional month of TTI with survival. Confidence intervals (CI) were calculated to 95%, and p-values &lt; 0.05 were considered significant. The study had institutional IRB approval. Results: Our cohort consisted of 472 patients diagnosed with advanced lung cancer and treated with first-line ICI. The median time to biopsy was 15.5 days with an interquartile range (IQR) of 5-29 days, median TTI was 51 days (IQR 35-79), and median overall survival was 14.3 months (CI 11.5-16.6). TTI was not associated with survival by unadjusted or multivariate analysis (HR 0.98, CI 0.95-1.01 and HR 1.02, CI 1.00-1.05, respectively). Smoking history (HR 1.011, CI 1.00-1.02 per pack-year) and higher pre-treatment ECOG performance scores (p &lt; 0.01) were associated with worse survival. Tumor histologic subtype, autoimmune comorbidities, and toxic dust exposure were not associated with survival. The time to biopsy was not associated with survival by unadjusted or multivariate analysis (HR 0.97, CI 0.95-1.01, and HR 1.02, CI 0.97-1.07, for each additional week). Among the subset of patients with a symptomatic presentation of cancer (n = 363, 77%), longer TTI was associated with improved survival, but this effect became non-significant in multivariate analysis (HR 0.94, CI 0.89-0.99 and HR 0.96, CI 0.86-1.08, respectively). Conclusions: We did not find evidence that a shorter TTI is associated with improved survival among patients with advanced lung cancer starting first-line ICI. Additional studies are needed to test if baseline disease burden or other clinical factors can identify patients who would benefit from expedited initiation of treatment.

Clinical efficacy of frontline immunotherapy (IO) in ethnic-minority patients (pts) with metastatic NSCLC.

e21063 Background: Since minority pts have been historically underrepresented in key IO trials, knowledge on the clinical use of IO in ethnic-minority pts with non-small cell lung cancer (NSCLC) remains limited. This study aims to evaluate race/ethnicity and other demographic, socioeconomic and clinical factors of pts with metastatic NSCLC treated with first-line IO. Methods: A retrospective cohort study of 5920 pts diagnosed with lung cancer within the Montefiore Health system from 1/1/2013 to 6/1/2022 was conducted. Pts with metastatic NSCLC without EGFR or ALK alterations and underwent first-line IO use were identified. The primary endpoint was overall survival (OS) with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of IO. Results: In total, 248 pts were identified with median follow-up time of 10.7 months (mons), median age of 66 years and 39.1% as Non-Hispanic Black (NHB), 30.2% as Hispanic and 30.7% as non-Hispanic White (NHW). OS (p = 0.39), PFS (p = 0.29) and TTD (p = 0.98) were similar among races/ethnic groups. ECOG &lt; 2 at the start of IO was associated with longer OS summarized in Table 1. Significantly higher PFS and TTD were noted respectively in pts with Medicare insurance and PD-L1 status (TPS&gt;1), while lower PFS and TTD with lower BMI. These results were remained after adjusting for biological sex, smoking status, histology, and IO regimen. Conclusions: Our study demonstrates that race/ethnicity does not impact the benefits of IO. However, factors such as ECOG status impact OS, and BMI, insurance and PD-L1 significantly impact PFS and TTD. These findings help identify potential factors that can be addressed to optimize outcomes and supportive care while undergoing IO.[Table: see text]

Characteristics and clinical outcome of BRCA germline mutation carriers with advanced breast cancer treated with PARP (poly ADP-ribose polymerase) inhibitors: A single institution experience.

10587 Background: About 5-10% of breast cancers (BC) are related to germline BRCA 1/2 pathogenic variants (PV). Several studies have demonstrated the effectiveness of PARP inhibitors (PARPi) in this population. However, BC patients with BRCA PVs remain a challenge to treat. In this report, we aim to characterize the clinical characteristics and outcome of a single institution cohort of advanced BC patients with a BRCA PV and who received PARPi therapy. Methods: Patients with BRCA 1/2 germline PVs who presented to the University of Texas MD Anderson Cancer Center Breast Medical Oncology clinics and were treated with PARPi between 2008-2022 as part of their treatment for metastatic or recurrent disease were included in the analysis. Variables included in this analysis included age at diagnosis, family history of BC and ovarian cancer, treatment details, tumor characteristics including histological type, receptor status and clinical outcome. Descriptive statistics, the Kaplan-Meier method, and The Cox proportional hazards regression model were used to report patient characteristics and outcomes. Progression free survival (PFS) was defined as the time from treatment initiation of PARPi to disease progression or death. Overall survival (OS) was defined as the time from treatment initiation of PARPi to death of any cause. Results: One hundred and seven patients were treated with PARPi. Median age at diagnosis was 38 years (23-73). Forty-eight (44.9%) and 59 (55.1%) patients had BRCA1 and BRCA2 mutations, respectively. Ninety-seven (90.7%) had invasive ductal carcinoma and 42 (39.3%) had triple negative BC. Nineteen (17.8%) patients were de novo metastatic BC (Stage IV). Sixty-two (57.9%) patients received one or more prior lines of chemotherapy before being treated with PARPi; 24 (22.4%) patients received prior platinum. In 91 patients evaluable for clinical response, the overall response rate (ORR) was 59.4% and the duration of response (DoR) was 7 months (2.1-96.2). In platinum-naïve patients ORR was 70.4% and DoR 7.4 months (2.1-96.2). Median PFS was 8.9 months (95% CI 6.3-10.3) and median OS 25.8 mo (95% CI 18.3-30.9). In univariate analysis, first-line PARPi use (p = 0.0274) and no previous use of platinum (p = 0.0121) were statistically significant for better PFS. Hormone receptor positive BC (p = 0.0105) was statistically significant for better OS. Conclusions: In this real-world single institution cohort of advanced BC patients with BRCA germline PVs who were treated with PARPi, the ORR and outcome of patients is similar to those reported in the previous clinical trials. Platinum naïve and patients who received PARPi as 1st line therapy had a better ORR. Further studies of predictive markers of response and resistance as well as sequencing with platinums are needed to optimize the use of PARPi in this patient population.

Clinical factors associated with prescribing patterns of bone modifying agents in men with metastatic castration-resistant prostate cancer.

e18878 Background: Bone metastases occur in up to 90% of men with metastatic prostate cancer and cause skeletal-related events (SREs) such as fracture and spinal cord compression. Although bone modifying agents (BMAs) have been shown to decrease the risk of SREs in men with metastatic castration-resistant prostate cancer (mCRPC), BMAs are not widely used in this patient population. In this retrospective study, we report the prescribing patterns of BMAs and predictors of BMA use in a large national cohort. Methods: We used the VA corporate data warehouse to identify patients with mCRPC who were treated with first-line mCRPC therapy (abiraterone, enzalutamide, docetaxel, or ketoconazole) between 2010 and 2017. BMA prescribing frequency and patterns were analyzed. Multivariable regression analysis was used to evaluate clinical and disease-specific factors associated with BMA use which are presented as adjusted odds ratios (OR) with 95% confidence intervals (CI). Results: In the final cohort of 4,079 patients, the median age at mCRPC diagnosis was 73 years (IQR 66-81). 29% of patients in the cohort were Black. Diagnosis codes identified bone metastases at mCRPC diagnosis in 48% of the cohort (ICD-9 and 10 coding for sites of metastases are known to underestimate the actual incidence of metastases). Only 48% of patients received a BMA following initiation of treatment for mCRPC, 47% of which had already received a BMA 6 months prior to mCRPC diagnosis. For those who were new BMA starts, the median time to BMA administration from mCRPC treatment was 3.4 months (IQR 1.2-8.8). Factors associated with BMA use were having an ICD-9 or 10 diagnosis code for bone metastases at time of mCRPC treatment (OR 1.28, 95% CI 1.10-1.48), concurrent corticosteroid use (OR 1.90, 95% CI 1.53-2.38), and docetaxel use as first-line mCRPC therapy (OR 1.78, 95% CI 1.45-2.18). Factors associated with decreased BMA use were Charlson comorbidity index score of ≥ 2 (OR 0.75, 95% CI 0.62-0.90), advancing age (OR 0.86 per 10 years, 95% CI 0.79-0.94), and decreased eGFR (eGFR 30-59, OR 0.81, 95% CI 0.68-0.96; eGFR 0-29, OR 0.23, 95% CI 0.14-0.37). Having a diagnosis code for a SRE before mCRPC diagnosis (e.g., bone fracture and cord compression) did not impact BMA use, but the incidence of those events was low. Conclusions: Less than half of this VA cohort received a BMA after starting therapy for mCRPC. Key factors associated with BMA use were corticosteroid use and first-line docetaxel use, which likely represented more aggressive disease. Notably, patients who were older and had more comorbid conditions were less likely to receive a BMA despite being highest risk for frailty and SREs. Future quality improvement efforts aimed at increasing BMA use may address the needs of the geriatric mCRPC patient population.

THE IMPACT OF COVID-19 PANDEMIC ON BLOOD PRESSURE CONTROL IN PATIENTS WITH TREATED HYPERTENSION. RESULTS OF EUROPEAN SOCIETY OF HYPERTENSION STUDY (ESH ABPM COVID-19 STUDY)

Objective: We aimed to assess the impact of the COVID-19 pandemic on blood pressure (BP) control assessed by office and ambulatory blood pressure monitoring (ABPM) in patients with treated hypertension. Design and method: Clinical and BP data were collected from 32 centres including Excellence Centres of the European Society of Hypertension. Two groups of patients were compared. Group1 (‘pandemic’) consisting of participants who have undergone two ABPM recordings (visits): visit-2 during the COVID-19 pandemic, and visit-1 performed 9 - 15 months prior to visit-2. Participants in Group2 (‘pre-pandemic’) had two repeated ABPMs, both performed before the pandemic within 9 - 15 months interval between visits. Results: Overall, 3384 ABPMs were collected from 1692 patients (50.5% men). 759 patients constituted Group1 and 933 patients Group2. Study groups did not differ regarding sex, age, or body weight. The duration of hypertension and frequency of first-line antihypertensive drug use at visit-1 were also similar in both groups. Beta-blockers were the only class of drugs with a significant decrease between visits (difference between visit-2 and visit-1) in Group1. At visit-1, there were no differences in all BP phenotypes (office and ABPM values) or hypertension control rates (27% vs 26.6%; p = 0.62) between study groups. At visit-2 significantly higher office BP was observed in Group1 compared to Group2, with a mean difference of +2.09 mmHg (p = 0.028) and +1.39 mmHg (p = 0.026) for systolic (SBP) and diastolic (DBP) BP, respectively. Moreover, on visit-2, higher 24-hour daytime and nighttime SBP and DBP were observed in Group1 as compared to Group2. Of note, the prevalence of uncontrolled hypertension (when considering both office and ABPM) was also higher at visit-2 in Goup1 than in Group2 (25.8% vs 20.0%; p = 0.005). Both SBP and DBP, regardless of the measurement method, dropped between visit-1 to visit-2, but to a lesser extent in Group1. Thus, the magnitude of BP decrease between visits was smaller in Group1 (delta24SBP: -1.04 vs -3.2 mmHg; p &lt; 0.001 and delta24DBP: -1.22 vs -1.93 mmHg; p = 0.038). Conclusions: The results of the study indicate a negative impact of the COVID-19 pandemic on BP control both in office and during ABPM.