RESUMEN
INTRODUCTION: The effect of change in sodium (Na) in critically ill patients undergoing slow low-efficiency dialysis (SLED) is unclear. METHODS: Prospective observational study enrolled dysnatremic critically ill adult patients with acute kidney injury (AKI) undergoing the first SLED as cases and normonatremic patients as controls. Baseline and SLED-related parameters, and 30-day mortality were noted. RESULTS: 100 dysnatremic and 51 normonatremic patients were included, with a median age of 31(25-52) years and median admission SOFA scores of 10 (9-12). Patients with dysnatremia at study inclusion had a mortality of 53%, with the highest mortality in severe hypernatremia (Na > 160 mEq/L: 75%), followed by those with severe hyponatremia (Na < 120 mEq/L: 68.6%). SLED-associated natremia change > 10 mEq/L was significantly associated with mortality, in patients with mild dysnatremia and normonatremia (Na:130-150) (p<0.001), and not in those with moderate to severe dysnatremia (Na < 130 and Na >150) (p=0.72). Upon multivariate logistic regression analysis, a model with pre-SLED pH, dialysate-pre-SLED Na difference, and duration of SLED significantly predicted SLED-associated natremia change (R2 0.18, p=0.001). CONCLUSIONS: Na change can be more than 10 meq/L in one-third of critically ill patients, subjected to first SLED session, which is associated with poor outcome in mild dysnatremics and normonatremics.
RESUMEN
Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.
RESUMEN
Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.
Asunto(s)
Cromatina , Neoplasias , Animales , Humanos , Ratones , Cromatina/genética , Mutación , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Empalme del ARN/genética , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismoRESUMEN
Cancer immunotherapy has transformed the clinical approach to patients with malignancies, as profound benefits can be seen in a subset of patients. To identify this subset, biomarker analyses increasingly focus on phenotypic and functional evaluation of the tumor microenvironment to determine if density, spatial distribution, and cellular composition of immune cell infiltrates can provide prognostic and/or predictive information. Attempts have been made to develop standardized methods to evaluate immune infiltrates in the routine assessment of certain tumor types; however, broad adoption of this approach in clinical decision-making is still missing. We developed approaches to categorize solid tumors into 'desert', 'excluded', and 'inflamed' types according to the spatial distribution of CD8+ immune effector cells to determine the prognostic and/or predictive implications of such labels. To overcome the limitations of this subjective approach, we incrementally developed four automated analysis pipelines of increasing granularity and complexity for density and pattern assessment of immune effector cells. We show that categorization based on 'manual' observation is predictive for clinical benefit from anti-programmed death ligand 1 therapy in two large cohorts of patients with non-small cell lung cancer or triple-negative breast cancer. For the automated analysis we demonstrate that a combined approach outperforms individual pipelines and successfully relates spatial features to pathologist-based readouts and the patient's response to therapy. Our findings suggest that tumor immunophenotype generated by automated analysis pipelines should be evaluated further as potential predictive biomarkers for cancer immunotherapy. © 2024 The Pathological Society of Great Britain and Ireland.
Asunto(s)
Automatización , Antígeno B7-H1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Inmunofenotipificación , Neoplasias de la Mama Triple Negativas , Humanos , Inmunoterapia , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Inmunofenotipificación/métodos , Terapia Molecular Dirigida , Automatización/métodos , Estudios de Cohortes , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Biomarcadores de Tumor/análisis , Resultado del TratamientoRESUMEN
Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
Asunto(s)
Anticuerpos Monoclonales , Antineoplásicos , Antígeno B7-H1 , Células Mieloides , Neoplasias , Receptores Inmunológicos , Linfocitos T Reguladores , Animales , Humanos , Ratones , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Quimioterapia Combinada , Inhibidores de Puntos de Control Inmunológico/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Activación de Macrófagos , Células Mieloides/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptores de IgG/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunologíaRESUMEN
Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses.
Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Neoplasias Pulmonares/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/genética , Carboplatino/uso terapéutico , Etopósido/uso terapéutico , InmunoterapiaRESUMEN
BACKGROUND: In children with cerebral palsy (CP), fine motor skills limit forearm supination and active extension of the elbow, wrist, or fingers. Therapeutic interventions focusing on improving the ranges at these joints while facilitating active movements are the key to augmenting fine motor skills. OBJECTIVE: This pilot study examines if children with CP (with UE involvement) exposed to the Novel Hand Rehabilitation (NHR) Board will demonstrate 1) changes in spasticity and passive ROM of forearm and wrist/finger muscles, and 2) improvement in fine motor abilities. METHODS: The forearm and wrist/fingers of children with spastic CP (Nâ=â15; Mâ=â7, Fâ=â8) aged 49-72 months (65.33±6.355 months) were positioned on the NHR board till their tolerance limit or a minimum duration of 30 minutes. The outcome measures, i.e., spasticity (Modified Ashworth Scale), passive range of motion (PROM) of wrist and fingers, and fine motor skills (PDMS-2 - Fine motor scale), were recorded. RESULTS: The spasticity of forearm pronators (0.001) and wrist flexors (0.008) reduced significantly, but not in wrist extensors. Post-intervention improvements in wrist extension (pâ=â0.005) and ulnar deviation ROM (pâ=â0.007) were significant. In thumb, changes were non-significant for the CMC flexion, but extension (0.003) and abduction (0.001) as well as MCP extension (0.004) were significant. The post-intervention MCP extension ROM for the 2nd (0.001), 3rd (0.007), and 4th fingers (0.014) were also substantial, but not for PIP and DIP joints. The post-intervention percentage change in the Grasping and Visual-motor integration subtests of PDMS-2 was 11.03% (pâ=â0.002) and 5.09% (pâ=â0.001) respectively. CONCLUSION: The immediate effects on fine motor skills in children with CP after the NHR board application were positive and encouraging. Hence, the NHR board can be recommended as an intervention to improve the fine motor abilities of children with CP.
Asunto(s)
Parálisis Cerebral , Niño , Humanos , Proyectos Piloto , Parálisis Cerebral/rehabilitación , Destreza Motora , Extremidad Superior , Mano , Espasticidad Muscular/tratamiento farmacológicoRESUMEN
BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments. OBJECTIVE: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients. METHODS: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation). Patients were stratified into high- and low-risk groups (overall survival [OS] and progression-free survival [PFS] outcomes) based on serum tumor biomarker levels. RESULTS: The CYFRA 21-1 and CA 125 biomarker combination predicted OS and PFS in patients with SD. Risk of death was ~4-fold higher for the biomarker-stratified high-risk versus low-risk SD patients (hazard ratio [HR] 3.80; 95% confidence interval [CI] 3.02-4.78; pâ<â0.0001). OS in patients with the low- and high-risk SD was comparable to that in patients with the CT-defined partial response (PR; HR 1.10; 95% CI 0.898-1.34) and progressive disease (PD) (HR 1.05; 95% CI 0.621-1.77), respectively. The findings were similar with PFS, and consistent across treatment arms. CONCLUSIONS: Biomarker testing shows potential for providing prognostic information to help direct treatment in NSCLC patients with SD. Prospective clinical studies are warranted.ClinicalTrials.gov: NCT02366143.
Asunto(s)
Antígenos de Neoplasias , Carcinoma de Pulmón de Células no Pequeñas , Queratina-19 , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Estudios Prospectivos , Biomarcadores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE: The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses. METHODS: Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety. RESULTS: Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; P = .3504; median, 5.4 months tiragolumab v 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; P = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively. CONCLUSION: Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Etopósido , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.
Asunto(s)
Evasión Inmune , Leucemia Mieloide Aguda , Animales , Humanos , Ratones , Médula Ósea , Inmunidad Celular , Inmunoterapia , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
BACKGROUND: Those experiencing houselessness rely on obtaining food from community organizers and donations. Simultaneously, the houseless face disproportionally high rates of medical conditions that may be affected by diet including diabetes, hypertension, and hyperlipidemia. There is limited literature on the resources and barriers of the houseless community regarding optimal nutrition from an actionable perspective. Further, less data is available on how street medicine organizations may best impact the nutrition of the unhoused they serve. Elucidating this information will inform how organizational efforts may best support the nutrition of the houseless community. METHODS: In partnership with the medical student-run organization, Chicago Street Medicine, at Northwestern University Feinberg School of Medicine, twenty adults experiencing houselessness in Chicago, Illinois participated in the cross-sectional study. A 10-item survey was verbally administered to characterize the participants' daily food intake, food sources, barriers, resources, and nutritional preferences and needs. All data was directly transcribed into REDCap. Descriptive statistics were generated. RESULTS: Individuals consumed a median of 2 snacks and meals per day (IQR: 1-3). No participant consumed adequate servings of every food group, with only one participant meeting the dietary intake requirements for one food group. Participants most often received their food from donations (n = 15), purchasing themselves (n = 11), food pantries (n = 4), and shelters (n = 3). Eleven of nineteen participants endorsed dental concerns as a major barrier to consuming certain foods. Twelve participants had access to a can opener and twelve could heat their meals on a stove or microwave. Seven had access to kitchen facilities where they may prepare a meal. Approximately half of participants had been counseled by a physician to maintain a particular diet, with most related to reducing sugar intake. CONCLUSION: Most houseless participants were unable to acquire a balanced diet and often relied on organizational efforts to eat. Organizations should consider the chronic health conditions, dentition needs, and physical resources and barriers to optimal nutrition when obtaining food to distribute to the unhoused.
Asunto(s)
Dieta , Comidas , Adulto , Humanos , Chicago , Estudios Transversales , Illinois , Personas con Mala ViviendaRESUMEN
The administration of therapeutic drugs through dermal routes, such as creams and ointments, has emerged as an increasingly popular alternative to traditional delivery methods, such as tablets and injections. In the context of drug development, it is crucial to identify the optimal doses and delivery routes that ensure successful outcomes. Physiologically based pharmacokinetic (PBPK) models have been proposed to simulate drug delivery and optimize drug formulations, but the calibration of these models is challenging due to the multitude of variables involved and limited experimental data. One significant research gap that this article addresses is the need for more efficient and accurate methods for calibrating PBPK models for dermal drug delivery. This manuscript presents a novel approach and an integrated dermal drug delivery model to address this gap that leverages virtual in vitro release (IVRT) and permeation (IVPT) testing data to optimize mechanistic models. The proposed approach was demonstrated through a study involving Desoximetasone cream and ointment formulations, where the release kinetics and permeation profiles of Desoximetasone were determined experimentally, and a computational model was created to simulate the results. The experimental studies showed that, even though the cumulative permeation of Desoximetasone at the end of the permeation study was comparable, there was a significant difference seen in the lag time in the permeation of Desoximetasone between the cream and ointment. Additionally, there was a significant difference seen in the amount of Desoximetasone permeated through human cadaver skin at early time points when the cream and ointment were compared. The computational model was optimized and validated, suggesting that this approach has the potential to bridge the existing research gap by improving the accuracy and efficiency of drug development processes. The model results show a good fit between the experimental data and model predictions. During the model optimization process, it became evident that there was variability in both the permeability and the partition coefficient within the stratum corneum. This variability had a significant and noteworthy influence on the overall performance of the model, especially when it came to its capacity to differentiate between cream and ointment formulations. Leveraging virtual models significantly aids the comprehension of drug release and permeation, mitigating the demanding data requirements. The use of virtual IVRT and IVPT data can accelerate the calibration of PBPK models, streamline the selection of the appropriate doses, and optimize drug delivery. Moreover, this novel approach could potentially reduce the time and resources involved in drug development, thus making it more cost-effective and efficient.
Asunto(s)
Desoximetasona , Piel , Humanos , Pomadas/farmacología , Piel/metabolismo , Absorción Cutánea , Simulación por Computador , Administración CutáneaRESUMEN
BACKGROUND: Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. METHODS: In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. RESULTS: We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 µg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. CONCLUSION: ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.
Asunto(s)
Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Infecciones Fúngicas Invasoras , Humanos , Masculino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Estudios Retrospectivos , Antifúngicos/uso terapéutico , Infecciones Fúngicas Invasoras/epidemiología , Infecciones Fúngicas Invasoras/prevención & control , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
Importance: Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors. Objective: To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors. Design, Setting, and Participants: The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022. Interventions: Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity. Main Outcomes and Measures: The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables. Results: Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months). Conclusions and Relevance: In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC. Trial Registration: ClinicalTrials.gov Identifier: NCT02794571.
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Esofágicas , Neoplasias Pulmonares , Humanos , Femenino , Persona de Mediana Edad , Masculino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Receptores Inmunológicos/uso terapéuticoRESUMEN
One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of treatment enabled risk stratification of patients with stable disease (hazard ratio (HR) = 3.2 (2.0-5.3), P < 0.001; median 7.1 versus 22.3 months for high- versus low-intermediate risk) and with partial response (HR = 3.3 (1.7-6.4), P < 0.001; median 8.8 versus 28.6 months). The model also identified high-risk patients in an external validation cohort from the randomized phase 3 OAK study of ICI versus chemo in NSCLC (OS HR = 3.73 (1.83-7.60), P = 0.00012). Simulations of clinical trial scenarios employing our ctDNA model suggested that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient risk stratification and may allow early differentiation between competing therapies during clinical trials.