Exploring the Role of Target Expression in Treatment Efficacy of Antibody-Drug Conjugates (ADCs) in Solid Cancers: A Comprehensive Review.

PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) offer a promising path for cancer therapy, leveraging the specificity of monoclonal antibodies and the cytotoxicity of linked drugs. The success of ADCs hinges on precise targeting of cancer cells based on protein expression levels. This review explores the relationship between target protein expression and ADC efficacy in solid tumours, focusing on results of clinical trials conducted between January 2019 and May 2023. RECENT FINDINGS: We hereby highlight approved ADCs, revealing their effectiveness even in low-expressing target populations. Assessing target expression poses challenges, owing to variations in scoring systems and biopsy types. Emerging methods, like digital image analysis, aim to standardize assessment. The complexity of ADC pharmacokinetics, tumour dynamics, and off-target effects emphasises the need for a balanced approach. This review underscores the importance of understanding target protein dynamics and promoting standardized evaluation methods in shaping the future of ADC-based cancer therapies.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

Patients with advanced cancer, previously treated with immune checkpoint blockade therapy, may retain residual treatment when undergoing the initial infusion of experimental monotherapy in phase 1 clinical trials. ANV419, an antibody-cytokine fusion protein, combines interleukin-2 (IL-2) with an anti-IL-2 monoclonal antibody, aiming to stimulate the expansion of CD8 T and natural killer lymphocytes while restricting regulatory T lymphocytes. In the recent publication of the phase 1 dose escalation study of ANV419, a notable gap exists in detailed information regarding patients' prior antitumoral treatments, specifically programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) targeted monoclonal antibodies. Some patients likely retained residual anti-PD-1/PD-L1 monoclonal antibodies, potentially influencing the outcomes of ANV419. In a separate clinical cohort, we retrospectively measured the residual concentration of nivolumab and pembrolizumab, revealing persistent serum concentrations of anti-PD-1/PD-L1 antibodies even months after treatment cessation. This underscores the importance of comprehensively documenting prior immunotherapy details in clinical trials. Such information is crucial for understanding potential interactions that may impact both immunological and clinical effects.

Impact of Clonal Hematopoiesis-Associated Mutations in Phase I Patients Treated for Solid Tumors: An Analysis of the STING Trial.

PURPOSE: With liquid biopsy's widespread adoption in oncology, an increased number of clonal hematopoiesis-associated mutations (CHm) have been identified in patients with solid tumors. However, its impact on patient outcomes remains unclear. This study aimed to analyze and describe CHm in a cohort of phase I patients. METHODS: Retrospective data collection from medical records and molecular profiles (Foundation One Liquid CDx Assay) was performed before first study drug administration at the Drug Development Department of Gustave Roussy (France) within the STING trial (ClinicalTrials.gov identifier: NCT04932525). CHm prevalence was assessed using any and ≥1% variant allele frequency (VAF) in epigenetic modifier genes (DNMT3A, TET2, and ASXL1). RESULTS: From January 2021 to December 2022, 255 patients were enrolled in a phase I clinical trial. A total of 55% were male, with a median age of 62 years (24-86). Principal tumor locations were GI (27%) and genitourinary (21%). Overall, 104 patients (41%) had at least one CHm in liquid biopsy, with 55 patients (22%) having a VAF of ≥ 1%. The most frequent mutation was DNMT3A 73% at any VAF (n = 76) and 22% at 1% VAF (n = 23). Median progression-free survival (PFS) and overall survival were 3.8 months (m) for the CHm group versus 3.2 m for nonclonal hematopoiesis (CH; P = .08) and 18.26 m CHm versus 15.8 m non-CH (P = .9), respectively. PFS increased in the CHm population treated with targeted therapy (hazard ratio, 0.6 [95% CI, 0.42 to 0.84]; P = .004). CONCLUSION: CHm was commonly found in patients with solid tumors treated in phase I trials, with a prevalence of 41% in our cohort. The most frequently mutated gene was DNMT3A. The presence of CHm had no impact on the population of patients treated in the phase I trials.

Genomic landscape of liquid biopsy mutations in TP53 and DNA damage genes in cancer patients.

Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.

Association Between Lung Immune Prognostic Index and Durvalumab Consolidation Outcomes in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. MATERIAL AND METHODS: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). RESULTS: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. CONCLUSION: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC.

BRAF mutational status is associated with survival outcomes in locally advanced resectable and metastatic NSCLC.

BACKGROUND: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown. MATERIALS AND METHODS: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing. RESULTS: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001). CONCLUSION: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.

Las epistemologías sordas pensadas desde las experiencias con la otredad / Deaf epistemologies from the experiences with the otherhood

Objetivo: El presente artículo tiene como finalidad reflexionar, desde una perspectiva crítica, el cómo se han pensado los procesos de subjetivación de lo que se ha denominado sordedad, a partir de la construcción del otro en el contexto de la modernidad. Estructura: Se plantea la alteridad y alteridad sorda explicitando que la sordedad es una forma más de otredad y que en este sentido, obedece a una misma matriz de inteligibilidad que opera sobre la idea de cuerpos normativizados. Posteriormente, se plantean las miradas de la sordera, se analizan los dispositivos de saber-poder que están a la base de cada modelo de conceptualización de la sordedad, con el propósito de conocer los presupuestos que los sustentan. Conclusión: En este contexto, se concluye el riesgo que implica perpetuar los discursos referidos a la sordedad desde el dispositivo de normalidad de la cultura oyente y que, en consecuencia, la sitúan en un "estatus especial de inferioridad" que termina discriminando y excluyendo; como propuesta se presenta la consideración de las epistemologías sordas.

Aim: The purpose of this article is to propose, from a critical perspective, that the processes of subjectivation of what has been called deafhood have been thought, of from the construction of the other in the context of modernity. Structure: Alterity and deaf alterity are considered, explaining that deafhood is another form of otherhood and that, in this sense; it obeys the same matrix of intelligibility which operates on the idea of normativised bodies. Subsequently, the views of deafness are raised; the knowledge-power devices that are at the base of each model of conceptualization of deafhood are analyzed, in order to understand the assumptions that support them. Conclusion: In this context, the discussion is based on the risk involved in perpetuating the discourse regarding deafness from the normality device of the hearing culture. And conclusions are places it in a "special status of inferiority" that ends up discriminating and excluding. As a proposal, deaf epistemologies are introduced.Dra Karina Andrea Muñoz VilugrónORCID: 0000-0003-3938-2758Source | Filiacion:Universidad Austral de Chile. Sede Puerto MonttBIO:Profesora de Educación Diferencial/Magister en Educación /Doctor en Ciencias de la EducaciónCity | Ciudad:Puerto Monnt (Chile)e-mail:karina.munoz@uach.clDr Santiago Leonardo Rodríguez PonceORCID: 0000-0002-6644-6676 Source | Filiacion:Universidad Austral de Chile. Sede Puerto MonttBIO:Magister en Cultura y Educación / Doctorado en Inclusión y DiscapacidadCity | Ciudad:Puerto Monnt (Chile)e-mail:santiago.rodriguez@uach.clDra Daniela Andrea Bachmann VeraORCID: 0000-0003-3757-3817Source | Filiacion:Universidad Austral de Chile. Sede Puerto MonttBIO:Psicóloga / Magister en Educación / Doctora en Ciencias de la EducaciónCity | Ciudad:Puerto Monnt (Chile)e-mail:daniela.vera@uach.clCitar como:Muñoz Vilugrón, K. A., Rodríguez Ponce, S. L., y Bachmann Vera, D. A. (2023). Las epistemologías sordas pensadas desde las experiencias con la otredad. Areté, 23 (2), 1-7. Obtenido de: https://arete.ibero.edu.co/article/view/26922Para su más amplia difusión, esta obra y sus contenidos se distribuyen bajo licencia: Creative Commons Atribución-NoComercial-SinDerivadas 4.0 InternationalSe autoriza cualquier tipo de reproducción y sus diferentes usos, siempre y cuando se preserve la integridad del contenido y se cite la fuente.ARETÉARETÉFonoaudiologíaRevistaISSN-l: 1657-2513 | e-ISSN:2463-2252

Tratamiento del carcinoma broncogénico de célula no pequeña en estadios precoces / Treatment of non-small cell lung carcinoma in early stages

El tratamiento del carcinoma brongénico es multidisciplinar. Se dispone de diferentes estrategias terapéuticas, siendo la cirugía la que presenta mejores resultados en aquellos pacientes con carcinoma broncogénico en estadios precoces. Otras opciones como la radioterapia estereotáctica quedan relegadas a pacientes con pequeños tumores y mala reserva cardiopulmonar, o a aquellos que rechacen la cirugía. La quimioterapia adyuvante no está justificada en pacientes con enfermedad en estadio i , planteándose doble quimioterapia adyuvante basada en cisplatino tras la cirugía en aquellos con estadios ii y III A (AU)

Treatment of lung carcinoma is multidisciplinary. There are different therapeutic strategies available, although surgery shows the best results in those patients with lung carcinoma in early stages. Other options such as stereotactic radiation therapy are relegated to patients with small tumors and poor cardiopulmonary reserve or to those who reject surgery. Adjuvant chemotherapy is not justified in patients with stage i of the disease and so double adjuvant chemotherapy should be considered. This adjuvant chemotherapy should be based on cisplatin after surgery in those patients with stages ii and IIIA (AU)