BACKGROUND:The evaluation of innovative oncology medicines presents significant challenges related to the selection of appropriate clinical endpoints and the sufficiency of evidence, particularly in therapeutic areas, such as immunotherapies, targeted treatments, single-arm trials, and tumor-agnostic therapies. In these contexts, the added value of new treatments is often not adequately captured by traditional clinical trial endpoints, such as overall survival (OS), which remains the gold standard in oncology assessment. This article aims to analyze the main sources of uncertainty in the value assessment of oncology therapies in Spain, with a focus on the limitations of current endpoints and evidence-generation processes, and to provide recommendations for enhancing the recognition and assessment of additional clinical benefit. METHODS:A multidisciplinary expert panel composed of twelve professionals, including medical oncologists, hospital pharmacists, health economists, and patient representatives, was convened to identify and discuss key sources of uncertainty in the value assessment of oncology treatments, particularly those related to clinical endpoint selection and evidence generation. The panel participated in three structured plenary sessions. Additional external experts were engaged to provide complementary input in areas, such as tumor-specific characteristics and statistical methodology. Consensus statements were developed through an iterative process of discussion, critical appraisal, and refinement across and between sessions. RESULTS:The expert panel issued twelve recommendations to improve value assessment in oncology. These include tailoring clinical endpoints to treatment type, tumor characteristics, and stage; complementing overall survival with milestone analysis and quality-of-life measures; and standardizing real-world evidence collection across the healthcare system. The panel advocated for a national portfolio of prioritized endpoints, appropriate statistical methods by context, and the conditional use of early-phase data for decision-making. Additional recommendations addressed the use of synthetic control arms, flexible reimbursement models, advanced analytics (e.g., AI and Big Data), evaluator expertise, and the promotion of stakeholder training and transparency. CONCLUSIONS:Addressing the challenges of clinical endpoint selection and evidence generation is essential to reduce uncertainty in the value assessment of innovative oncology treatments. The twelve expert recommendations outlined in this study provide a structured roadmap to improve methodological consistency, enhance the relevance and robustness of clinical and real-world data, and promote a more adaptive and transparent evaluation framework. These proposals aim to support more evidence-based, equitable, and sustainable decision-making within the Spanish healthcare system, while aligning with broader European initiatives in oncology drug assessment.
This update and revision of the international guideline for urticaria was developed in accordance with the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is an initiative of the Global Allergy and Asthma Excellence Network (GA2LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), with the participation of 210 delegates from 107 national and international societies, from 59 countries. The consensus conference was held on December 6th, 2024. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, defined by a rapid appearance of wheals, angioedema, or both. The lifetime prevalence of acute urticaria is estimated to be approximately 20%. Chronic urticaria, categorized as either chronic spontaneous urticaria or chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school, however, novel therapies are available. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
Abstract Introduction: In RRMM, increasing rates of pt attrition and decreasing durability of responses with each line of therapy (LOT) necessitate early treatment (tx) with the most effective therapies. Immunotherapies that are widely accessible across different MM tx settings have the potential to change the trajectory of RRMM. Teclistamab (Tec), the first approved BCMA×CD3 bispecific antibody (BsAb) for heavily pretreated RRMM, provided deep, durable responses in MajesTEC-1, with improved efficacy and safety in earlier LOTs. Daratumumab (Dara), a standard-of-care (SoC) foundational CD38 targeted therapy with direct on-tumor activity, has been shown to deplete immunosuppressive T-cells and expand cytotoxic T-cells, creating an immune-permissive microenvironment for synergistic Tec-mediated killing of MM cells. MajesTEC-3 (NCT05083169) evaluates Tec-Dara vs SoC DPd/DVd in RRMM. We report initial results for this first phase 3 study of BsAb therapy in MM. Methods: Eligible pts had 1-3 prior LOTs including a PI and lenalidomide (Len; pts with 1 prior LOT must have been Len-refractory) with progressive disease (PD) on or after the last LOT. Pts with prior BCMA-directed therapy or refractory to anti-CD38 were excluded; prior anti-CD38 exposure was permitted. Pts were randomized 1:1 to Tec-Dara or DPd/DVd. The Tec-Dara group received 28-day cycles (C) of Tec (1.5 mg/kg QW in C1-2 [C1 preceded by the approved step-up dose schedule]; 3 mg/kg Q2W in C3-6; and 3 mg/kg Q4W in C7+) with Dara; steroids were not required after C1 Day 8. Tec and Dara dosing were aligned with the approved Dara schedule. DPd/DVd were administered per approved schedules. Progression-free survival (PFS) by IRC was the primary endpoint; secondary endpoints included complete response or better (≥CR), overall response, minimal residual disease (MRD) negativity (10–5; next-generation sequencing), overall survival (OS), time to worsening of symptoms (MySIm-Q), and safety. Results: 587 pts were randomized (Tec-Dara, n=291; DPd/DVd, n=296). Median (range) age was 64 (25-88) yrs, median number of prior LOTs was 2 (1-3). With 34.5-mo median follow-up, Tec-Dara significantly improved PFS vs DPd/DVd (HR, 0.17; 95% CI, 0.12-0.23; P<0.0001); mPFS was NR and 18.1 mo, and 36-mo PFS rate was 83.4% and 29.7%, respectively. PFS benefit was consistent across all prespecified and clinically relevant pt subgroups, including age ≥75 yrs, Len-refractory, high-risk cytogenetics, ≥60% bone marrow plasma cells, soft-tissue plasmacytomas, and anti-CD38 exposed. Significantly higher rates of ≥CR (81.8% vs 32.1%; OR, 9.56; 95% CI, 6.47-14.14), overall response (89.0% vs 75.3%; OR, 2.65; 95% CI, 1.68-4.18), and MRD-negativity (58.4% vs 17.1%; OR, 6.78; 95% CI, 4.53-10.15) were observed with Tec-Dara (P<0.0001). There were 45 deaths with Tec-Dara and 96 with DPd/DVd, primarily due to PD (4.6%; 20.3%). OS significantly favored Tec-Dara (HR, 0.46; 95% CI, 0.32-0.65; P<0.0001), including across all prespecified subgroups. The 36-mo OS rates were 83.3% and 65.0%, respectively and >90% of Tec-Dara pts alive at 6 mo were also alive at 30 mo. Median time to worsening of MM symptoms was NR with Tec-Dara vs 39.9 mo with DPd/DVd (HR, 0.50; 95% CI, 0.34-0.72; P=0.0002). At data cutoff, 49.4% of pts remained on study tx (Tec-Dara, 71.0%; DPd/DVd, 28.3%). Median tx duration was twice as long with Tec-Dara vs DPd/DVd (32.4 vs 16.1 mo). Frequency of grade 3/4 (Tec-Dara, 95.1%; DPd/DVd, 96.6%) and grade 5 (7.8%; 6.2%) treatment-emergent adverse events (TEAEs), were comparable (safety set: Tec-Dara, n=283; DPd/DVd, n=290). Serious TEAEs occurred in 70.7% Tec-Dara and 62.4% DPd/DVd pts; tx discontinuations due to TEAEs were low (4.6% vs 5.5%). Any grade infections occurred in 96.5% and 84.1% of Tec-Dara and DPd/DVd pts, respectively; grade 3/4 infections occurred in 54.1% and 43.4%. New onset grade ≥3 infections decreased over time, coinciding with transition to Q4W dosing and supported by antimicrobial and Ig prophylaxis guidance. CRS rate was 60.1% (grade 1/2: 44.2%/15.9%) and ICANS was 1.1% with Tec-Dara. Conclusion: We demonstrate the clinically remarkable and statistically significant PFS and OS benefits of Tec-Dara vs SoC triplets in RRMM, with 83.4% of Tec-Dara pts alive and progression-free at 3 yrs. Infections with Tec-Dara were well managed with established protocols. This highly effective, off-the-shelf, immunotherapy combination represents a new SoC for RRMM as early as first relapse.
3004 Background: Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC). Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that targets DLL3-positive (DLL3+) tumors. NCT04429087 is an ongoing, Phase (Ph) I dose-escalation trial of obrixtamig in patients (pts) with DLL3+ pulmonary and extrapulmonary NEC (epNEC), who had failed to respond to standard treatment (Tx). This analysis examined the efficacy and safety of obrixtamig in pts with epNEC with high vs low DLL3 expression. Methods: Obrixtamig was given IV in 4 dose-escalation regimens (R): RA (fixed dose q3w); RB1 (fixed dose qw); RB2 (step-up dose, then qw) and RB3 (step-up dose, then qw for 3 weeks, then q3w), until disease progression or unacceptable toxicity. Efficacy was assessed through objective response rate (ORR) and disease control rate (DCR) using RECIST v1.1. Results are reported for pts who received obrixtamig RB2 or RB3, categorized as having high vs low DLL3, using a threshold of ≥50% of tumor cells stained with an investigational antibody for DLL3 (SP347, Roche Diagnostics). Results: As of June 21, 2024, 60 pts with epNEC were included (gastroenteropancreatic [GEP]: 45.0%, genitourinary [GU]: 30.0%, other/unknown primary site: 25.0%); 30 each DLL3-high and DLL3-low. Mean age: 63.9 years in DLL3-high; 59.1 in DLL3-low pts. Baseline characteristics were well-balanced across DLL3 groups. All pts had received prior systemic therapy; 30.0% of DLL3-high and 50.0% of DLL3-low pts had received > 2 lines of prior Tx. Efficacy data are shown in the Table. After obrixtamig Tx, pts with high DLL3 expression had greater ORR, DCR, and duration of response (DoR) than DLL3-low pts. Responses were seen most frequently amongst pts with DLL3-high GEP (50.0%) or GU (60.0%) epNECs. Seven DLL3-high pts are still receiving Tx. Most treatment-related AEs (TRAEs) were mild to moderate for both groups (Table). Conclusions: Analyses from this ongoing Ph I study show greater obrixtamig efficacy in patients with epNEC with high DLL3 expression compared with low DLL3 expression, with a manageable safety profile that is comparable across both groups. The ORR of 40.0% and median DoR of 7.9 months in heavily pretreated epNEC tumors with DLL3 high expression are encouraging, and support further development of obrixtamig for this subgroup. Clinical trial information: NCT04429087 . Efficacy/safety parameter DLL3-high (n=30) DLL3-low (n=30) ORR, % (95% CI) 40.0 (24.6–57.7) 3.3 (0.6–16.7) DCR, % (95% CI) 66.7 (48.8–80.8) 26.7 (14.2–44.4) Median DoR (95% CI), months 7.9 (6.2–NC) 2.8 (NC–NC) TRAEs, all G/G ≥3, (%) 100.0/23.3 90.0/20.0 Cytokine release syndrome, all G/G ≥3, (%) 70.0/3.3 60.0/3.3 Neurotoxicity, including immune effector cell-associated neurotoxicity syndrome*, all G/G ≥3, (%) 16.7/6.7 10.0/3.3 *Evaluated with a customised MedDRA query. CI, confidence interval; NC, not calculable.
Objective: While microballoon interventions (MBIs) have emerged as a safe treatment for hepatocellular carcinoma, they also lead to blood flow alterations that are not well understood and could decrease the treatment's effectiveness. In this study, we developed patient-inspired in vitro and in silico models (IVM and ISM). The IVM was used to study the influence of using a microballoon vs. a standard catheter on the tumor targeting and to validate the ISM; the ISM was used to study the influence of the size of a communicating arcade on the tumor targeting. Methods: Two IVM (with a literature-based collateral artery and without collateral artery), two catheter modes (a microballoon catheter with inflated and deflated balloon), and three occlusion locations were combined to conduct an experimental, parametric analysis. Furthermore, the ISM was validated and used to study four collateral artery diameters. Results: The IVM generated realistic hemodynamic alterations, and the ISM replicated the experimental results with an average difference of 4 percent points on the flow distribution per outlet. The designed collateral artery did not affect the simulated intervention negatively. Conclusion: Patient-inspired IVMs and ISMs can be used to better understand the complex hemodynamic phenomena after balloon occlusion and help determine collateral artery sizes that generate successful MBIs. Significance: Combined patient-inspired IVM and ISM of the hepatic artery hemodynamics during MBIs were developed for the first time. This modeling approach could potentially lead to a better assessment of patients with liver cancer not eligible for standard chemoembolization or radioembolization.
