RESUMEN
INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be spread by individuals unaware they are infected. Such dissemination has heightened ramifications in cancer patients, who may need to visit healthcare facilities frequently, be exposed to immune-compromising therapies, and face greater morbidity from coronavirus disease 2019 (COVID-19). We determined characteristics of (1) asymptomatic, clinically diagnosed, and (2) serologically documented but clinically undiagnosed SARS-CoV-2 infection among individuals with lung cancer. PATIENTS AND METHODS: In a multicenter registry, individuals with lung cancer (regardless of prior SARS-CoV-2 vaccination or documented infection) underwent collection of clinical data and serial blood samples, which were tested for antinucleocapsid protein antibody (anti-N Ab) or IgG (N) levels. We used multivariable logistic regression models to investigate clinical characteristics associated with the presence or absence of symptoms and the presence or absence of a clinical diagnosis among patients with their first SARS-CoV-2 infection. RESULTS: Among patients with serologic evidence or clinically documented SARS-CoV-2 infection, 80/142 (56%) had no reported symptoms at their first infection, and 61/149 (40%) were never diagnosed. Asymptomatic infection was more common among older individuals and earlier-stage lung cancer. In multivariable analysis, non-white individuals with SARS-CoV-2 serologic positivity were 70% less likely ever to be clinically diagnosed (P = .002). CONCLUSIONS: In a multicenter lung cancer population, a substantial proportion of SARS-CoV-2 infections had no associated symptoms or were never clinically diagnosed. Because such cases appear to occur more frequently in populations that may face greater COVID-19-associated morbidity, measures to limit disease spread and severity remain critical.
RESUMEN
INTRODUCTION: Consolidative durvalumab, an anti-programmed death ligand 1 (PDL1) immune checkpoint inhibitor, administered after concurrent chemoradiation improves outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) without substantially increasing toxicities. We studied a chemotherapy-free regimen of thoracic radiotherapy (RT) with concurrent and consolidative durvalumab. METHODS: This single-arm phase II trial enrolled patients with stage III NSCLC (regardless of tumor PDL1 expression), performance status ECOG 0-1, adequate pulmonary function, and RT fields meeting standard organ constraints. Participants received two cycles of durvalumab (1500 mg every 4 weeks) concurrently with thoracic RT (60 Gy in 30 fractions), followed by up to 13 cycles of consolidative durvalumab. RESULTS: After 10 patients were enrolled, the trial was closed due to poor clinical outcomes. With a median follow-up of 12 months, five patients had disease progression and eight patients died. Six patients experienced 15 treatment-related, grade ≥3 events, including one grade 4 acute kidney injury during consolidation and two fatal pulmonary events. One fatal pulmonary event occurred during the concurrent phase in an active smoker; the other occurred after the first cycle of consolidative durvalumab. The primary endpoint of progression-free survival (PFS) at 12 months was 20% (50% for PDL1≥1% versus 0% for PDL1 unavailable or <1%). Median overall survival (OS) was not reached, 10.5 months, and 7 months, for PDL1 ≥1%, <1%, and unavailable, respectively. CONCLUSIONS: In PDL1 unselected stage III NSCLC, thoracic RT plus concurrent and consolidative durvalumab is associated with high-grade toxicity and early disease progression.
RESUMEN
In patients with lung cancer (LC), understanding factors that impact the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike antibody (SAb) titers over time is critical, but challenging, due to evolving treatments, infections, vaccinations, and health status. The objective was to develop a time-dependent regression model elucidating individual contributions of factors influencing SAb levels in LC patients using a prospective, longitudinal, multi-institutional cohort study initiated in January 2021. The study evaluated 296 LC patients-median age 69; 55% female; 50% stage IV. Blood samples were collected every three months to measure SAb levels using FDA-approved ELISA. Asymptomatic and unreported infections were documented through measurement of anti-nucleocapsid Ab levels (Meso Scale Discovery). Associations between clinical characteristics and titers were evaluated using a time-dependent linear regression model with a generalized estimating equation (GEE), considering time-independent variables (age, sex, ethnicity, smoking history, histology, and stage) and time-dependent variables (booster vaccinations, SARS-CoV-2 infections, cancer treatment, steroid use, and influenza vaccination). Significant time-dependent effects increasing titer levels were observed for prior SARS-CoV-2 infection (p < 0.001) and vaccination/boosters (p < 0.001). Steroid use (p = 0.043) and chemotherapy (p = 0.033) reduced titer levels. Influenza vaccination was associated with increased SAb levels (p < 0.001), independent of SARS-CoV-2 vaccine boosters. Prior smoking significantly decreased titers in females (p = 0.001). Age showed no association with titers. This GEE-based linear regression model unveiled the nuanced impact of multiple variables on patient anti-spike Ab levels over time. After controlling for the major influences of vaccine and SARS-CoV-2 infections, chemotherapy and steroid use were found to have negatively affected titers. Smoking in females significantly decreased titers. Surprisingly, influenza vaccinations were also significantly associated, likely indirectly, with improved SARS-CoV-2 titers.
RESUMEN
Introduction: Racial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer. Methods: Patients scheduled to receive cancer immunotherapy were enrolled in a multi-institutional prospective biospecimen collection registry. Clinical and demographic information were obtained from electronic medical records. Pre-treatment peripheral blood samples were collected and analyzed for cytokines using a multiplex panel and for immune cell populations using mass cytometry. Differences between Black and White patients were determined and corrected for multiple comparisons. Results: A total of 187 patients with non-small cell lung cancer (Black, 19; White, 168) were included in the analysis. There were no significant differences in baseline characteristics between Black and White patients. Compared to White patients, Black patients had significantly lower levels of CCL23 and CCL27, and significantly higher levels of CCL8, CXCL1, CCL26, CCL25, CCL1, IL-1 b, CXCL16, and IFN-γ (all P <0.05, FDR<0.1). Black patients also exhibited greater populations of non-classical CD16+ monocytes, NKT-like cells, CD4+ cells, CD38+ monocytes, and CD57+ gamma delta T cells (all P <0.05). Conclusions: Black and White patients with lung cancer exhibit several differences in immune parameters, with Black patients exhibiting greater levels of numerous pro-inflammatory cytokines and cell populations. The etiology and clinical significance of these differences warrant further evaluation.
RESUMEN
BACKGROUND: Recent modifications to low-dose CT (LDCT)-based lung cancer screening guidelines increase the number of eligible individuals, particularly among racial and ethnic minorities. Because these populations disproportionately live in metropolitan areas, we analyzed the association between travel time and initial LDCT completion within an integrated, urban safety-net health care system. METHODS: Using Esri's StreetMap Premium, OpenStreetMap, and the r5r package in R, we determined projected private vehicle and public transportation travel times between patient residence and the screening facility for LDCT ordered in March 2017 through December 2022 at Parkland Memorial Hospital in Dallas, Texas. We characterized associations between travel time and LDCT completion in univariable and multivariable analyses. We tested these associations in a simulation of 10,000 permutations of private vehicle and public transportation distribution. RESULTS: A total of 2,287 patients were included in the analysis, of whom 1,553 (68%) completed the initial ordered LDCT. Mean age was 63 years, and 73% were underrepresented minorities. Median travel time from patient residence to the LDCT screening facility was 17 minutes by private vehicle and 67 minutes by public transportation. There was a small difference in travel time to the LDCT screening facility by public transportation for patients who completed LDCT versus those who did not (67 vs 66 min, respectively; P=.04) but no difference in travel time by private vehicle for these patients (17 min for both; P=.67). In multivariable analysis, LDCT completion was not associated with projected travel time to the LDCT facility by private vehicle (odds ratio, 1.01; 95% CI, 0.82-1.25) or public transportation (odds ratio, 1.14; 95% CI, 0.89-1.44). Similar results were noted across travel-type permutations. Black individuals were 29% less likely to complete LDCT screening compared with White individuals. CONCLUSIONS: In an urban population comprising predominantly underrepresented minorities, projected travel time is not associated with initial LDCT completion in an integrated health care system. Other reasons for differences in LDCT completion warrant investigation.
Asunto(s)
Detección Precoz del Cáncer , Accesibilidad a los Servicios de Salud , Neoplasias Pulmonares , Proveedores de Redes de Seguridad , Tomografía Computarizada por Rayos X , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Femenino , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Tomografía Computarizada por Rayos X/métodos , Anciano , Proveedores de Redes de Seguridad/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/normas , Texas/epidemiología , Población Urbana/estadística & datos numéricos , Viaje/estadística & datos numéricos , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Tamizaje Masivo/normas , Transportes/estadística & datos numéricos , Transportes/métodosRESUMEN
BACKGROUND: Although low-dose, CT-based lung cancer screening (LCS) can decrease lung cancer mortality in high-risk individuals, the process may be complex and pose challenges to patients, particularly those from minority underinsured and uninsured populations. We conducted a randomized controlled trial of telephone-based navigation for LCS within an integrated, urban, safety-net health care system. PATIENTS AND METHODS: Patients eligible for LCS were randomized (1:1) to usual care with or without navigation at Parkland Health in Dallas, Texas. The primary endpoint was completion of the first 3 consecutive steps in a patient's LCS process. We explored differences in completion of LCS steps between navigation and usual care groups, controlling for patient characteristics using the chi-square test. RESULTS: Patients (N=447) were randomized to either navigation (n=225) or usual care (n=222). Mean patient age was 62 years, 46% were female, and 69% were racial/ethnic minorities. There was no difference in completion of the first 3 steps of the LCS algorithm between arms (12% vs 9%, respectively; P=.30). For ordered LCS steps, completion rates were higher among patients who received navigation (86% vs 79%; P=.03). The primary reason for step noncompletion was lack of order placement. CONCLUSIONS: In this study, lack of order placement was a key reason for incomplete LCS steps. When orders were placed, patients who received navigation had higher rates of completion. Clinical team education and enhanced electronic health record processes to simplify order placement, coupled with patient navigation, may improve LCS in safety-net health care systems.
Asunto(s)
Neoplasias Pulmonares , Navegación de Pacientes , Humanos , Femenino , Persona de Mediana Edad , Masculino , Neoplasias Pulmonares/diagnóstico , Detección Precoz del Cáncer , Poblaciones Vulnerables , Grupos Minoritarios , Tamizaje MasivoRESUMEN
BACKGROUND: Although low dose computed tomography (LDCT)-based lung cancer screening (LCS) can decrease lung cancer-related mortality among high-risk individuals, it remains an imperfect and substantially underutilized process. LDCT-based LCS may result in false-positive findings, which can lead to invasive procedures and potential morbidity. Conversely, current guidelines may fail to capture at-risk individuals, particularly those from under-represented minority populations. To address these limitations, numerous biomarkers have emerged to complement LDCT and improve early lung cancer detection. CONTENT: This review focuses primarily on blood-based biomarkers, including protein, microRNAs, circulating DNA, and methylated DNA panels, in current clinical development for LCS. We also examine other emerging biomarkers-utilizing airway epithelia, exhaled breath, sputum, and urine-under investigation. We highlight challenges and limitations of biomarker testing, as well as recent strategies to integrate molecular strategies with imaging technologies. SUMMARY: Multiple biomarkers are under active investigation for LCS, either to improve risk-stratification after nodule detection or to optimize risk-based patient selection for LDCT-based screening. Results from ongoing and future clinical trials will elucidate the clinical utility of biomarkers in the LCS paradigm.
Asunto(s)
Líquidos Corporales , Neoplasias Pulmonares , MicroARNs , Humanos , Detección Precoz del Cáncer , Neoplasias Pulmonares/diagnóstico por imagen , BiomarcadoresRESUMEN
BACKGROUND: Mixed response (MR), a scenario featuring discordant tumor changes, has been reported primarily with targeted therapies or immunotherapy. We determined the incidence and prognostic significance of MR in advanced non-small cell lung cancer (NSCLC) treated with cytotoxic chemotherapy. PATIENTS AND METHODS: We analyzed patient-level data from ECOG-ACRIN E5508 (carboplatin-paclitaxelâ +â bevacizumab induction followed by randomization to maintenance therapy regimens). For patients with at least 2 target lesions and available measurements after cycle 2, we characterized response as homogeneous response (HR, similar behavior of all lesions), MR (similar behavior but >30% difference in magnitude of best and least responding lesions), or true mixed response (TMR, best and least responding lesions showing different behavior: ≥10% growth versus ≥10% shrinkage). We compared category characteristics using Mann-Whitney U and Chi-square tests, and overall survival (OS) using log-rank test and Cox models. RESULTS: Among 965 evaluable patients, HR occurred in 609 patients (63%), MR in 208 (22%), and TMR in 148 (15%). Median OS was 13.6 months for HR, 12.0 months for MR, and 7.6 months for TMR (Pâ <â .001). Compared to HR, TMR had inferior OS among stable disease cases (HR 1.62; 95% CI, 1.23-2.12; Pâ <â .001) and a trend toward inferior OS among progressive disease cases (HR 1.39; 95% CI, 0.83-2.33; Pâ =â .2). In multivariate analysis, TMR was associated with worse OS (HR 1.48; 95% CI, 1.22-1.79; Pâ <â .001). CONCLUSION: True mixed response occurs in a substantial minority of lung cancer cases treated with chemotherapy and independently confers poor prognosis.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Pronóstico , Incidencia , Modelos de Riesgos Proporcionales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Paclitaxel/uso terapéuticoRESUMEN
This cohort study among patients with cancer examines changes in the time from posting of test results in the electronic health record to patient viewing in the patient portal before and after implementation of the 21st Century Cures Act.
Asunto(s)
Neoplasias , Portales del Paciente , Humanos , Registros Electrónicos de Salud , Neoplasias/diagnóstico , Neoplasias/epidemiología , PacientesRESUMEN
OBJECTIVES: AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC. MATERIALS AND METHODS: Escalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured. RESULTS: 21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7-10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. CONCLUSION: Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Persona de Mediana Edad , Femenino , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel/uso terapéutico , Neoplasias Pulmonares/patología , Taxoides/uso terapéutico , Factor Estimulante de Colonias de Granulocitos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Resultado del TratamientoRESUMEN
Low-dose computed tomography-based lung cancer screening represents a complex clinical undertaking that could require multiple referrals, appointments, and time-intensive procedures. These steps may pose difficulties and raise concerns among patients, particularly minority, under-, and uninsured populations. The authors implemented patient navigation to identify and address these challenges. They conducted a pragmatic randomized controlled trial of telephone-based navigation for lung cancer screening in an integrated, urban safety-net health care system. Following standardized protocols, bilingual (Spanish and English) navigators educated, motivated, and empowered patients to traverse the health system. Navigators made systematic contact with patients, recording standardized call characteristics in a study-specific database. Call type, duration, and content were recorded. Univariable and multivariable multinomial logistic regression was performed to investigate associations between call characteristics and reported barriers. Among 225 patients (mean age 63 years, 46% female, 70% racial/ethnic minority) assigned navigation, a total of 559 barriers to screening were identified during 806 telephone calls. The most common barrier categories were personal (46%), provider (30%), and practical (17%). System (6%) and psychosocial (1%) barriers were described by English-speaking patients, but not by Spanish-speaking patients. Over the course of the lung cancer screening process, provider-related barriers decreased 80% (P = 0.008). The authors conclude that patients undergoing lung cancer screening frequently report personal and health care provider-related barriers to successful participation. Barrier types may differ among patient populations and over the course of the screening process. Further understanding of these concerns may increase screening uptake and adherence. Clinical Trial Registration number: (NCT02758054).
Asunto(s)
Neoplasias Pulmonares , Navegación de Pacientes , Humanos , Femenino , Persona de Mediana Edad , Masculino , Neoplasias Pulmonares/diagnóstico , Detección Precoz del Cáncer/métodos , Navegación de Pacientes/métodos , Etnicidad , Grupos MinoritariosRESUMEN
PURPOSE OF REVIEW: The AXL signaling pathway is associated with tumor growth as well as poor prognosis in cancer. Here, we highlight recent strategies for targeting AXL in the treatment of solid and hematological malignancies. RECENT FINDINGS: AXL is a key player in survival, metastasis, and therapeutic resistance in many cancers. A range of AXL-targeted therapies, including tyrosine kinase inhibitors, monoclonal antibodies, antibody-drug conjugates, and soluble receptors, have entered clinical development. Notably, AXL inhibitors in combination with immune checkpoint inhibitors demonstrate early promise; however, further understanding of predictive biomarkers and treatment sequencing is necessary. Based on its role in tumor growth and drug resistance, AXL represents a promising therapeutic target in oncology. Results from ongoing clinical trials will provide valuable insights into the role of AXL inhibitors, both as single agents and in combination with other therapies.
Asunto(s)
Tirosina Quinasa del Receptor Axl , Neoplasias , Humanos , Proteínas Tirosina Quinasas Receptoras , Proteínas Proto-Oncogénicas/uso terapéutico , Transducción de Señal , Neoplasias/tratamiento farmacológicoRESUMEN
INTRODUCTION: Patients with lung cancer (LC) are susceptible to severe outcomes from COVID-19. This study evaluated disruption to care of patients with LC during the COVID-19 pandemic. METHODS: The COVID-19 and Cancer Outcomes Study (CCOS) is a prospective cohort study comprised of patients with a current or past history of hematological or solid malignancies with outpatient visits between March 2 and March 6, 2020, at two academic cancer centers in the Northeastern United States (US). Data was collected for the three months prior to the index week (baseline period) and the following three months (pandemic period). RESULTS: 313 of 2365 patients had LC, 1578 had other solid tumors, and 474 had hematological malignancies. Patients with LC were not at increased risk of COVID-19 diagnosis compared to patients with other solid or hematological malignancies. When comparing data from the pandemic period to the baseline period, patients with LC were more likely to have a decrease in in-person visits compared to patients with other solid tumors (aOR 1.94; 95% CI, 1.46-2.58), but without an increase in telehealth visits (aOR 1.13; 95% CI 0.85-1.50). Patients with LC were more likely to experience pandemic-related treatment delays than patients with other solid tumors (aOR 1.80; 95% CI 1.13-2.80) and were more likely to experience imaging/diagnostic procedure delays than patients with other solid tumors (aOR 2.59; 95% CI, 1.46-4.47) and hematological malignancies (aOR 2.01; 95% CI, 1.02-3.93). Among patients on systemic therapy, patients with LC were also at increased risk for decreased in-person visits and increased treatment delays compared to those with other solid tumors. DISCUSSION: Patients with LC experienced increased cancer care disruption compared to patients with other malignancies during the early phase of the COVID-19 pandemic. Focused efforts to ensure continuity of care for this patient population are warranted.
Asunto(s)
COVID-19 , Neoplasias Pulmonares , Prueba de COVID-19 , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Pandemias , Estudios Prospectivos , SARS-CoV-2RESUMEN
BACKGROUND: Neoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC. AIM: To evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence-free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC. METHODS AND RESULTS: Medical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty-six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0-1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11-0.72) and OS (HR 0.13; 95% CI 0.2-0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2-3) after NAC, was not associated with improved RFS or OS. CONCLUSIONS: GIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/mortalidad , Neoplasias Gastrointestinales/patología , Terapia Neoadyuvante/mortalidad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20-40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1+ disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.
Asunto(s)
Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/tratamiento farmacológico , Biomarcadores Farmacológicos/análisis , Biopsia , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunohistoquímica , Neoplasias/patología , Manejo de Especímenes/métodos , Resultado del TratamientoRESUMEN
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for advanced non-small cell lung cancer (NSCLC). Although certain patients achieve significant, long-lasting responses from checkpoint blockade, the majority of patients with NSCLC do not and may be unnecessarily exposed to inadequate therapies and immune-related toxicities. Therefore, there is a critical need to identify biomarkers predictive of immunotherapy response. While tumor and immune cell expression of programmed death ligand-1 and, more recently, tumor mutational burden are used in clinical practice and may correlate with immunotherapy response in selected circumstances, neither consistently predicts an individual patient's likelihood of clinical benefit from ICI therapy. More recently, innovative approaches such as blood-based assays and combination biomarker strategies are under active investigation. This review will focus on the current role and challenges of programmed death ligand-1 and tumor mutational burden as predictive biomarkers for immunotherapy response in advanced NSCLC and explore promising novel biomarker strategies.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genéticaAsunto(s)
COVID-19/prevención & control , Disparidades en Atención de Salud/estadística & datos numéricos , Oncología Médica/organización & administración , Neoplasias/terapia , Telemedicina/organización & administración , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/transmisión , Control de Enfermedades Transmisibles/normas , Femenino , Estudios de Seguimiento , Humanos , Masculino , Oncología Médica/normas , Oncología Médica/estadística & datos numéricos , Persona de Mediana Edad , Pandemias/prevención & control , Estudios Prospectivos , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidad , Telemedicina/normas , Telemedicina/estadística & datos numéricos , Factores de Tiempo , Tiempo de Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Patients with malignancy are particularly vulnerable to infection with Severe Acute Respiratory Disease-Coronavirus-2 (SARS-CoV-2) given their immunodeficiency secondary to their underlying disease and cancer-directed therapy. We report a case series of patients with cancer who received convalescent plasma, an investigational therapy for severe Coronavirus Disease 2019 (COVID-19). METHODS: Patients with cancer were identified who received convalescent plasma. Enrolled patients had confirmed COVID-19 with severe or life-threatening disease and were transfused with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of ≥ 1:320 dilution. Oxygen requirements and clinical outcomes of interests were captured as well as laboratory parameters at baseline and 3 days after treatment. RESULTS: We identified 24 patients with cancer, 14 of whom had a hematological malignancy, who were treated with convalescent plasma. Fifteen patients (62.5%) were on cancer-directed treatment at the time of COVID-19 infection. After a median of hospital duration of 9 days, 13 patients (54.2%) had been discharged home, 1 patient (4.2%) was still hospitalized, and 10 patients had died (41.7%). Non-intubated patients, particularly those on nasal cannula alone, had favorable outcomes. Three mild febrile non-hemolytic transfusion reactions were observed. C-reactive protein significantly decreased after 3 days of treatment, while other laboratory parameters including ferritin and D-dimer remained unchanged. CONCLUSIONS: Convalescent plasma may be a promising therapy in cancer patients with COVID-19.
Asunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/complicaciones , Hospitalización/estadística & datos numéricos , Neoplasias/terapia , Neumonía Viral/complicaciones , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Femenino , Humanos , Inmunización Pasiva , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/virología , Pandemias , Neumonía Viral/terapia , Neumonía Viral/transmisión , Neumonía Viral/virología , Pronóstico , Factores de Riesgo , SARS-CoV-2 , Tasa de Supervivencia , Estados Unidos/epidemiología , Sueroterapia para COVID-19RESUMEN
Observational data suggest an acquired prothrombotic state may contribute to the pathophysiology of COVID-19. These data include elevated D-dimers observed among many COVID-19 patients. We present a retrospective analysis of admission D-dimer, and D-dimer trends, among 1065 adult hospitalized COVID-19 patients, across 6 New York Hospitals. The primary outcome was all-cause mortality. Secondary outcomes were intubation and venous thromboembolism (VTE). Three-hundred-thirteen patients (29.4%) died, 319 (30.0%) required intubation, and 30 (2.8%) had diagnosed VTE. Using Cox proportional-hazard modeling, each 1 µg/ml increase in admission D-dimer level was associated with a hazard ratio (HR) of 1.06 (95%CI 1.04-1.08, p < 0.0001) for death, 1.08 (95%CI 1.06-1.10, p < 0.0001) for intubation, and 1.08 (95%CI 1.03-1.13, p = 0.0087) for VTE. Time-dependent receiver-operator-curves for admission D-dimer as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.694, 0.621, and 0.565 respectively. Joint-latent-class-modeling identified distinct groups of patients with respect to D-dimer trend. Patients with stable D-dimer trajectories had HRs of 0.29 (95%CI 0.17-0.49, p < 0.0001) and 0.22 (95%CI 0.10-0.45, p = 0.0001) relative to those with increasing D-dimer trajectories, for the outcomes death and intubation respectively. Patients with low-increasing D-dimer trajectories had a multivariable HR for VTE of 0.18 (95%CI 0.05-0.68, p = 0.0117) relative to those with high-decreasing D-dimer trajectories. Time-dependent receiver-operator-curves for D-dimer trend as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.678, 0.699, and 0.722 respectively. Although admission D-dimer levels, and D-dimer trends, are associated with outcomes in COVID-19, they have limited performance characteristics as prognostic tests.