Amgen (Germany)

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.

Bispecific T-cell engagers have revolutionized the treatment and management of hematological malignancies and more recently have started making similar strides for solid tumor indications, with opportunities to become best-in- class therapeutics for cancer. Xaluritamig is a novel bivalent XmAb® 2+1 T cell engager with two STEAP1 binding sites and one CD3 binding site being developed for solid tumors with the primary indication of metastatic castrate resistant prostate cancer (mCRPC). The First-In-Human (FIH) study showed promising anti-tumor activity in mCRPC patients, and the program is currently in late phase clinical development. Xaluritamig was administered as an intravenous infusion once weekly (QW) or once every other week (Q2W) in the dose escalation of the FIH study at dose levels ranging from 0.001 to 2 mg. Initial pharmacokinetic (PK) characterization of xaluritamig exhibited approximately dose-proportional increase in exposures over the dose levels explored, with an estimated terminal half-life of ≈9 days, assuming subjects had no anti-drug antibodies, calculated via the population PK model. The time at which maximum concentration (Cmax) occurred was typically at the end of infusion (median ≈ 1 h), as expected with IV administration. Additionally, thorough dose-exposure-response analyses integrated observed data and model-based simulations of PK, key efficacy endpoints, and safety events to support the evaluation of the target doses 0.75 mg QW, 1.5 mg QW, and 1.5 mg Q2W in dose expansion. This work provides the framework for which modeling and simulations can be used to guide dose selection for dose expansion at an early stage of development adhering to the recent principles of Project Optimus.

To document the decision-making criteria physicians use when selecting regimens for second- and third-line therapy for patients with relapsed and/or refractory multiple myeloma (RRMM) in Germany. Experienced multiple myeloma (MM) physicians extracted data from medical records from 30 June to 8 September 2023 for patients who initiated approved second- and third-line therapy for MM in 2021. Regimens, most important treatment goal, and key reasons for prescribing were reported in addition to patient characteristics. All data were summarised descriptively. MM physicians (33 hospital-based, 16 office-based) with a median of 17years of treatment experience extracted data from a total of 268 patient records (second-line, n=170; third-line, n=98). In second- and third-line, 17 and 16 different regimens were documented, respectively. The most utilized second-line regimens were: daratumumab (D), lenalidomide (R) and dexamethasone (d) (DRd 16.5%); carfilzomib (K), d and D (KdD 12.4%); Kd (11.2%); KRd; (10.0%); D, bortezomib (V) and d (DVd 9.4%); and V with cyclophosphamide (C) and d (VCd 7.1%). The main reasons for selecting the regimen were treatment effectiveness, patient characteristics/status, and relapse. Inducing deepest possible response and prolonging survival or symptom control were the most important treatment goals for triplet regimens. The main third-line regimens were: pomalidomide (P) and d (Pd 15.3%); DRd (13.3%); Rd (13.3%); elotuzumab (E) and Pd (EPd 12.2%); isatuximab (Isa) and Kd or KdD (10.2%); and ixazomib (I) and Rd (IRd 8.2%). The main reasons for selecting the regimens varied for third-line regimens but primarily focused on treatment effectiveness, patient characteristics/status, and prior therapy response or mechanism of action. The most important treatment goal was prolongation of survival. The results suggest that in the absence of a single standard of care for RRMM, prescribers made patient-centred choices of regimens with efficacy as the main goal of therapy.

Although survival rates for patients with newly diagnosed multiple myeloma (NDMM) have improved over recent decades, multiple myeloma (MM) remains without a cure for most. There is increasing consensus that achievement of deep remissions, especially minimal residual disease negativity (MRD −), in frontline treatment is crucial and translates into improved survival. The standard of care (SOC) for NDMM consists at minimum of a triplet regimen of therapies, with or without an autologous stem cell transplant, or a doublet regimen for certain ineligible, particularly frail patients who may have specific limitations. Recently, anti-CD38 monoclonal antibodies (mAbs), such as daratumumab (Dara) or isatuximab (Isa), have been integrated into frontline SOC regimens. Seeking to further deepen and prolong responses, several clinical trials have commenced investigating the addition of anti-CD38 mAbs to carfilzomib, lenalidomide, and dexamethasone (KRd). These quadruplet regimens (Isa/Dara-KRd) are being evaluated in the context of evolving treatment considerations for the heterogeneous population of patients with NDMM. In clinical trials, the addition of Isa/Dara to KRd achieved high rates of deep responses and MRD − . Favorable outcomes were observed in patients with NDMM independent of age, transplant eligibility, and cytogenetic risk, while these treatments did not result in unexpected or emergent safety risks. The efficacy observed with intensified, yet well-tolerated therapy may offer further development of risk- and response-adapted therapy for individualized patient needs. This review summarizes the clinical outcomes of quadruplet-based therapy with Isa/Dara-KRd in NDMM.

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BackgroundDespite the success of bispecific T-cell recruiting antibody constructs (BsAbs) in B-cell malignancies, the translation to a myeloid setting has been less successful so far, independently of the target antigen. Several reports demonstrate that the diverse genetic makeup of AML confers resistance to T-cell based immunotherapy. Mutations of TP53 occur in 5–10% of patients with de novo AML and up to 50% in older patients with tAML, highlighting its role as a potential resistance mechanism. We hypothesize, that genetic aberrations of TP53 in AML contribute to cell intrinsic and extrinsic resistance against T-cell based immunotherapy.MethodsTo study the impact of TP53 aberrations on T-cell based immunotherapy, MV4-11 p53 WT or p53 KD were cocultured with healthy donor T cells at an effector to target ratio of 1:6 with or without BsAbs.ResultsAs expected, BsAb-mediated cytotoxicity was reduced against p53 KD vs p53 WT MV4-11. However, BsAb-mediated T-cell proliferation was also significantly decreased in cocultures with p53 KD. In line with this, we observed a significant decrease in secretion of the proinflammatory cytokines IFN-γ, TNF and IL-2. RNA-Seq analysis of T cells after coculture with MV4-11 p53 KD vs WT revealed a decrease in the expression of genes associated with mitosis, providing a potential explanation for the reduction in T-cell proliferation after coculture with p53 KD. To dissect if the observed effects were due to the AML surfacome or secretome, transwell assays were performed. Indeed, the negative impact of p53 KD AML cells on T-cell function was also observed without direct cell-cell contact. To gain further insights into the secretome, coculture supernatant was analyzed using the Olink® proteomics platform. The analysis revealed significantly higher secretion of IL-18 and LAP TGF-β1 (TGF-β1 latency associated protein, cleaved from TGF-β before its activation) in the coculture with p53 KD vs p53 WT. The relevance of TGF-β on T-cell fitness was confirmed, as addition of TGF-β to the coculture with p53 WT decreased the specific lysis significantly and was now comparable to the lysis of p53 KD. Confirmatory studies in primary AML samples with or without p53 aberrations further validated our findings with a reduction of BsAb-mediated cytotoxicity, T-cell proliferation and secretion of proinflammatory cytokines.ConclusionsWe demonstrated that AML cells with p53 aberrations are less susceptible to BsAb-mediated cytotoxicity. Surprisingly, immune evasion was mediated by the AML secretome, which reduced T-cell proliferation and cytokine secretion. Secretome analysis identified TGF-β as a cytokine impairing T-cell function.Ethics ApprovalSamples from healthy donors and samples from AML patients were collected with written consent in accordance with the Declaration of Helsinki and with approval from the Institutional Review Board of LMU Munich.

ObjectiveThe aim of this study was to assess the utilization of surgical interventions in patients diagnosed with superficial vein thrombosis (SVT) and its potential association with the occurrence of venous thromboembolism (VTE) and bleeding events. MethodsINSIGHTS-SVT, a prospective, non-interventional, multicenter study in Germany, investigated the management and outcomes of patients with acute SVT who received conservative and/or invasive treatments at the discretion of the treating physician. ResultsAmong the 872 patients with 12-month data, 657 had medical therapy only, and 215 patients underwent vascular surgery (70 within 3 months of SVT diagnosis, 136 between months 4 and 12, and nine had an intervention in both periods). The most commonly performed procedures included endovenous thermal ablation, ligation of the saphenofemoral or saphenopopliteal junction, and vein stripping. The primary outcome of symptomatic VTE was observed in 5.8% of conservatively treated patients and 6.3% of those who underwent surgical intervention. Additionally, the secondary outcome of recurrent or extended SVT was documented in 4.7% of conservatively treated patients and 5.3% of invasively treated patients. Bleeding events occurred in 1.4% of conservatively treated patients and 2.1% of surgically treated patients. These differences were statistically not significant. Furthermore, our analysis indicated a potential protective effect associated with surgical treatments, such as ligation of the saphenofemoral or saphenopopliteal junction, stripping and endovenous thermal ablation, concerning the endpoint of VTE for patients when applied after 3 months from the index SVT event. ConclusionsIn line with previous research, our study suggests that surgical interventions are not frequently employed in the management of SVT, although they may be warranted in select cases. Nevertheless, additional research is essential to gain a deeper understanding of the indications, criteria, and benefit of surgical interventions in the treatment of SVT.

SummaryOsteoporosis is the most common bone disorder. Our data gives an estimate of around 5.87 million cases of osteoporosis in the general German population in 2018. Only 30% of insured individuals who suffered an osteoporotic fracture and/or had a confirmed diagnosis of osteoporosis, received an appropriate prescription.PurposeOsteoporosis is the most common bone disorder. It particularly affects elderly people and increases the risk of atraumatic fractures. The aim of this study was to estimate the prevalence of osteoporosis in the general German population aged ≥ 50 years and to collect data on the frequency of prescription of osteoporosis-specific medication in order to assess the treatment gap.MethodsRetrospective analysis of anonymized data of individuals aged ≥ 50 years insured under statutory healthcare schemes from the database of the Institute for Applied Health Research Berlin (InGef) for 2018 (study population). Insured individuals with osteoporosis were identified based on osteoporosis diagnoses, osteoporosis-specific prescriptions, or osteoporotic fractures. Thus, we estimated the prevalence of osteoporosis in the general German population aged ≥ 50 years. The prevalence of diagnoses, fractures, and prescriptions was determined for the study population and stratified by age and gender.ResultsWithin the study population of 1,599,299 insured individuals, a prevalence of osteoporosis of 15.9% was determined. This estimated approximately 5.87 million cases of osteoporosis for the general German population. 81.6% of the cases were women. Osteoporosis-specific prescriptions were received by 30.0% of the insured individuals in the study population who had been diagnosed with osteoporosis and/or suffered an osteoporotic fracture.ConclusionsGermany has a high prevalence of osteoporosis. Only a small portion of individuals who may require osteoporosis-specific treatment actually receive it.