Amgen (United States)

BackgroundChemotherapy-induced thrombocytopenia (CIT) is a common complication of chemotherapy that is associated with bleeding, reduced relative dose intensity, and potentially worse outcomes. No widely available therapies are approved for CIT.MethodsWe conducted a phase 3, international, double-blind, randomized, placebo-controlled trial involving patients with persistent CIT (platelet count, ≤85×109 per liter on trial day 1) who were receiving oxaliplatin-based multiagent cytotoxic chemotherapy for gastrointestinal cancers. Patients were randomly assigned in a 2:1 ratio to receive romiplostim or placebo for three chemotherapy cycles. The primary end point was the absence of CIT-induced modifications of the chemotherapy dose (reduction, delay, omission, or discontinuation) in both the second and third chemotherapy cycles.ResultsOf the 165 patients who underwent randomization (109 in the romiplostim group and 56 in the placebo group), 75% had colorectal cancer, 13% had gastroesophageal cancer, and 12% had pancreatic cancer; 72% of the patients in the romiplostim group and 61% of those in the placebo group had stage 4 disease. The percentage of patients with no CIT-induced modifications of the chemotherapy dose was 84% (92 of 109 patients) with romiplostim and 36% (20 of 56 patients) with placebo, which corresponded to an odds ratio of 10.16 (95% confidence interval [CI], 4.44 to 23.72; P<0.001) and a risk ratio of 2.77 (95% CI, 1.78 to 4.30; P<0.001). Adverse events of grade 3 or higher occurred in 37% of the patients who received romiplostim and in 22% of those who received placebo, which primarily reflected chemotherapy effects. Adverse events that were considered by the investigator to be related to romiplostim or placebo occurred in 12% of patients who received romiplostim and in 7% who received placebo, with the most frequent being nausea (2% in each group) and headache (2% in the romiplostim group); none were serious or led to death or discontinuation of romiplostim, placebo, or chemotherapy. Thromboembolic events occurred in 2% of patients who received romiplostim and in no patients who received placebo.ConclusionsIn this phase 3, placebo-controlled trial, romiplostim was efficacious in treating CIT. (Funded by Amgen and the Biomedical Advanced Research and Development Authority; RECITE ClinicalTrials.gov number, NCT03362177.)

Abstract Background The first-line standard of care (SOC) for patients (pts) with estrogen receptor-positive, HER2-negative advanced breast cancer (ER+, HER2- aBC) is CDK4/6 inhibitor (i) + endocrine therapy (ET) but effective post-CDK4/6i options remain limited. Giredestrant (GIRE) targets the ER pathway while everolimus (E) targets the PI3K/AKT/mTOR pathway; both of which are implicated in driving resistance in the post-CDK4/6i setting. evERA BC (NCT05306340) is the first Phase III trial to demonstrate statistically significant and clinically meaningful improvement in investigator-assessed progression-free survival (INV-PFS) with an all-oral selective ER antagonist and degrader combination of GIRE + E vs SOC ET + E in pts with ER+, HER2- aBC post-CDK4/6i + ET, both in pts whose tumors had a detectable ESR1 mutation (m) and in the intent-to-treat (ITT) population (Mayer ESMO 2025). The safety profile of GIRE + E was manageable with no unexpected findings (Mayer ESMO 2025). We report results from prespecified exploratory subgroup analyses. Methods Pts who had ER+, HER2- aBC with disease progression (PD) post-CDK4/6i + ET in the aBC setting, or relapse during/after CDK4/6i + ET in the adjuvant setting, were randomized 1:1 to once-daily oral 30 mg GIRE + 10 mg E or SOC ET (exemestane, fulvestrant, or tamoxifen) + E until PD or unacceptable toxicity. Mutational status was determined using circulating tumor DNA at baseline. The co-primary endpoints were INV-PFS per Response Evaluation Criteria in Solid Tumors v1.1 in pts whose tumors had detectable ESR1m and in the ITT population. INV-PFS was assessed by subgroup analyses. Results Three-hundred-and-seventy-three pts were randomized; 183 pts were randomized to GIRE + E and 190 to SOC ET + E. A total of 207 pts (55%) had tumors with ESR1m, 115 (31%) had PIK3CAm, and 137 (37%) had alterations (alt) in the PI3K pathway genes (PIK3CA/AKT1/PTEN). Sixty-four pts (17%) had both ESR1m and PIK3CAm; 76 (20%) had both ESR1m and PIK3CA/AKT1/PTEN alt. Ninety-eight percent of pts received a CDK4/6i in the metastatic setting. INV-PFS benefit was observed for GIRE + E vs SOC ET + E regardless of PIK3CAm status or PIK3CA/AKT1/PTEN alt in both the ESR1m and ITT populations (Table). Consistent benefit was observed regardless of duration of prior CDK4/6i (Table). Data for additional subgroup analyses for prior therapy will be presented. Conclusions GIRE + E led to clinically meaningful improvements in INV-PFS vs SOC ET + E irrespective of PIK3CAm and PIK3CA/AKT1/PTEN alt, and other key relevant subgroups, regardless of ESR1m status. These data support the use of GIRE + E vs SOC ET + E in pts with ER+, HER2- aBC post-CDK4/6i + ET. Citation Format: H. S. Rugo, S. M. Tolaney, K. L. Jhaveri, M. Martin, G. A. Vidal, L. Moscetti, A. Brufsky, W. J. Gradishar, A. Schneeweiss, N. Niikura, A. Favret, M. Alfie, K. S. Lee, S. Khan, M. Feldman, B. M. Day, L. H. Lam, W. C. Darbonne, T. M. Fernando, P. Perez-Moreno, E. L. Mayer.Clinical and biomarker subgroup analysis of evERA Breast Cancer: A Phase III trial of giredestrant plus everolimus in patients with estrogen receptor-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS3-09.

Small-cell lung cancer (SCLC) is associated with poor survival and is accompanied by symptoms that impact patients' quality of life. Although quality of life can be assessed by the EORTC 30-item core questionnaire (QLQ-C30) and 13-item lung cancer (QLQ-LC13) module, interpretation of meaningful improvement or deterioration within and between individuals is challenging. The objective of this study was to derive thresholds for interpretation of changes over time for the key scales of Coughing, Chest Pain, Dyspnea, Physical Functioning, and Global Health Status (GHS). Anchor- and distribution-based analyses were used to derive meaningful within-patient change (MWPC) and meaningful between-group difference (MBGD) thresholds using data from the phase II DeLLphi-301 trial in patients with previously treated SCLC. Methods included estimating mean change scores, mixed models for repeated measures, classification statistics, receiver operating characteristic curves, alongside calculating half standard deviation and standard error of measurement. MWPC recommendations were ±33.3 for single-item scales QLQ-LC13 Chest Pain and Coughing, ±16.7 for both QLQ-LC13 Dyspnea and QLQ-C30 GHS, and ±20.0 for QLQ-C30 Physical Functioning. Estimated MBGD thresholds ranged from ±6 for GHS to ±22 for Coughing. To our knowledge, this study is the first to estimate MWPC and MBGD thresholds specifically in patients with relapsed SCLC. Estimated threshold ranges are considered robust given the comprehensive considerations and triangulation of various methods and can help clinicians, researchers, and healthcare decision makers to evaluate the clinical meaningfulness to patients of changes in key SCLC scales over time.

The SOURCE phase 3 oral corticosteroid (OCS)-sparing study of tezepelumab indicated an OCS-sparing effect with tezepelumab versus placebo in patients with OCS-dependent asthma and baseline blood eosinophil counts (BECs) of at least 150 cells per μL. The WAYFINDER study aimed to further evaluate the ability of tezepelumab to reduce or discontinue OCS use in a larger cohort of patients with OCS-dependent severe, uncontrolled asthma. WAYFINDER was a phase 3b, multicentre, single-arm, open-label, OCS-sparing study. Adults (aged 18-80 years) with severe, uncontrolled asthma receiving a maintenance OCS dose of 5-40 mg per day (or equivalent) of prednisone or prednisolone were recruited from 68 clinical centres across 11 countries (Argentina, Belgium, Bulgaria, France, Germany, Latvia, Mexico, Poland, Spain, UK, and USA). Participants received tezepelumab 210 mg subcutaneously once every 4 weeks for up to 52 weeks. The co-primary endpoints, assessed at weeks 28 and 52, were the proportion of participants who reduced their prescribed maintenance OCS dose to 5 mg per day or less without loss of asthma control and the proportion of participants who discontinued OCS without loss of asthma control. OCS dose reductions to below 5 mg per day were contingent on participants demonstrating preserved adrenal function. This completed study was registered with ClinicalTrials.gov (NCT05274815). WAYFINDER was conducted between May 17, 2022, and Sept 9, 2024. Overall, 382 participants were enrolled and 298 participants (206 female [69·1%]) received tezepelumab and were included in the efficacy and safety analyses. The mean baseline maintenance OCS dose was 10·8 (SD 6·5) mg per day. The proportion of participants who had a maintenance OCS dose of 5 mg per day or less without loss of asthma control was 265 of 298 (88·9% [95% CI 84·8-92·3]) at week 28 and 268 of 298 (89·9% [85·9-93·1]) at week 52. The proportion of participants who discontinued OCS without loss of asthma control was 96 of 298 (32·2% [26·9-37·8]) at week 28 and 150 of 298 (50·3% [44·5-56·2]) at week 52. OCS reduction and discontinuation were achieved across pre-specified subgroups based on baseline BEC, fractional exhaled nitric oxide level, or allergy status. Serious adverse events were reported in 28 (9·4%) of 298 participants (asthma [13 participants] and pneumonia [three participants] were the most common), and four participants (1·3%) had adverse events leading to tezepelumab discontinuation. Two participants died during the study but neither death was considered to be causally related to tezepelumab treatment. After 52 weeks of open-label tezepelumab treatment, nearly 90% of patients with OCS-dependent severe, uncontrolled asthma had a maintenance OCS dose of 5 mg per day or less and more than 50% completely discontinued OCS, while maintaining asthma control. These findings indicate that tezepelumab treatment can help enable patients with severe asthma to reduce their OCS use and its associated burden, with broad applicability across patient phenotypes. AstraZeneca and Amgen.

Vascular smooth muscle cell (VSMC) diversification drives atherosclerotic coronary artery disease (CAD). Mechanisms governing these cell state transitions remain unclear. We applied multiomic single-cell profiling, epitope mapping, and spatial transcriptomics across 27 human coronary arteries, identifying fibroblast activation protein (FAP) as a marker of modulated VSMCs. Lineage tracing in mice indicated that FAP+ cells originate from Myh11+ VSMCs, and FAP PET imaging in CAD patients showed plaque uptake. FAP+ cells states resided in the macrophage-rich neo-intima. Therapeutically, we developed an anti-FAP bispecific T-cell engager, which reduced plaque burden and remodeled the stromal-immune microenvironment through T-cell clonal expansion. Our study delivers a single-cell and spatial atlas of human CAD, establishes FAP as a marker of modulated VSMCs, and highlights immunotherapy for lipid-independent targets.

The German national psoriasis registry PsoBest collects long-term data on the effectiveness, safety, and tolerability of systemic treatments for psoriatic disease. Here, we describe patient characteristics and the safety and effectiveness of apremilast for the treatment of psoriatic disease in Germany based on data from PsoBest. This was a descriptive analysis of observational data collected from PsoBest using cross-sectional (baseline characteristics) and longitudinal (outcomes, safety) designs. PsoBest recruits patients with moderate to severe plaque psoriasis or psoriatic arthritis who initiate a new systemic psoriasis treatment. Adverse events (AEs) and sociodemographic descriptors were reported for patients exposed to apremilast during the study period (safety cohort). Clinical and patient-reported outcomes were collected 3, 6, and 12months after the initiation of apremilast monotherapy (outcomes cohort). From January 15, 2015 to June 30, 2020, 595 registry patients were exposed to apremilast; 417 were treated with apremilast monotherapy. Patients taking apremilast had a higher mean age and higher proportions of comorbidities such as cardiovascular or metabolic disease compared with those taking other nonbiologic systemic or biologic drugs. The most common nonserious AEs were drug ineffectiveness (14.1%), diarrhea (9.4%), nausea (7.1%), and headache (6.1%). The highest incidence rates of nonserious and serious AEs of special interest were for infections and infestations per system organ class (8.03/100 patient-years) and malignant or unspecified tumors (2.50/100 patient-years), respectively. Improvements in Dermatology Life Quality Index, patient-defined treatment benefits (Patient Benefit Index), body surface area, and Psoriasis Area and Severity Index were observed after 3, 6, and 12months of apremilast treatment. Patients in routine care treated with apremilast in the German PsoBest registry experienced treatment benefits and improved skin, psoriasis severity, and quality of life. Safety was consistent with the established safety profile. Apremilast is safe and effective for treating moderate to severe psoriatic disease.

In clinical trials, it is often valuable to borrow information from external data sources. Unfortunately, when the external data are fully or partially incompatible with the current trial data, type I error rates can be highly inflated under traditional blanket discounting schemes such as power priors, commensurate priors, and meta-analytic predictive priors. However, such inflation of the probability of a false positive can be necessary, as the alternative is to have an underpowered study. For clinical trials with time-to-event (TTE) outcomes, this problem is exacerbated since many observations are censored. In this paper, we develop the latent exchangeability prior for TTE data. We also present a novel framework to borrow information about the treatment effect between groups as well as incorporate information from external controls. Simulation results suggest that, although efficiency gains can be achieved by borrowing information among external controls, operating characteristics in general can be quite poor under a lack of exchangeability. We apply our approach to a real clinical trial in second-line metastatic colorectal cancer.

Extrachromosomal DNAs (ecDNAs) are circular DNA molecules prevalent in human cancers that drive tumor evolution and drug resistance. Their circular topology, which disrupts topological domains and rewires regulatory circuits, has typically been studied via pairwise interactions. Here we develop ec3D, a computational method for reconstructing three-dimensional ecDNA structures from Hi-C data. Given a candidate ecDNA sequence and whole-genome Hi-C data, ec3D reconstructs spatial structures by maximizing the Poisson likelihood of observed interactions. We validate ec3D using simulated structures, previously characterized cancer cell lines, and microscopy imaging. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range regulatory interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex structures with duplicated segments, identify multi-way interactions, and identify potential intermolecular (trans) interactions. Our findings provide insights into how ecDNA’s spatial organization bypasses normal chromosomal constraints and contributes to increased oncogene expression.