The Hospital Clínico San Carlos is a hospital located at the Ciudad Universitaria neighborhood in Madrid, Spain, part of hospital network of the Servicio Madrileño de Salud (SERMAS).It is one of the healthcare institutions associated to the Complutense University of Madrid (UCM) for the purpose of clinical internship.
Immunotherapy (IO) has improved prognosis of non-small cell lung cancer (NSCLC); however, some patients experience primary IO resistance (PIR). CXCL13 could be a promising PIR biomarker due to its role in antitumor immune responses. 177 patients with stage IV NSCLC receiving IO from the observational, multicenter, real-world study BLI-O were included from 15 centers in Spain. CXCL13 and 39 other cytokines were measured in 158 baseline (BS1) and 98 post-first-cycle of IO (BS2) plasma samples. Additionally, peripheral T and B cell BS2 immunophenotypes were determined. CXCL13 levels were also measured in plasma samples from 38 stage IIIA NSCLC patients treated with neoadjuvant chemoimmunotherapy from the NADIM II trial (NCT03838159). PIR was defined as disease progression within 3 months in non-surgical cases or incomplete pathological response in surgical cases. Metastatic PIR patients had higher CXCL13 plasma levels compared to non-PIR patients, especially in BS2 samples, and exhibited a greater increase of CXCL13 levels after the first cycle of IO. Patients with high BS2 CXCL13 levels showed shorter PFS (p = 0.0002) and OS (p = 0.0007). Females showed a lower percentage of high CXCL13 cases compared to male cases. CXCL13 did not influence the growth of NSCLC cell lines in vitro. Moreover, the expression of the CXCL13/CXCR5 axis was restricted to the immune compartment of tumors. Plasmatic CXCL13 levels were not associated with PD-L1 TPS expression nor TLS density in tumor tissue. However, at systemic level, patients with high CXCL13 levels exhibited impaired B and T cell phenotypes, along with elevated levels of inflammatory cytokines, after first IO cycle. Finally, high BS2 CXCL13 levels in resectable cases were also associated with PIR. Elevated CXCL13 levels after the first cycle of IO are associated with PIR and an altered peripheral immune profile in NSCLC, supporting its potential as a prognostic biomarker in these patients.
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.
Resumen es: El sindrome de Tako-Tsubo, tambien conocido como cardiopatia de estres o apical ballooning, representa una entidad recientemente descripta que mimetiza m...
