RESUMEN
OBJECTIVES: ALK inhibitors (ALKi) are the standard-of-care treatment for metastatic ALK-rearranged non-small cell lung cancer (NSCLC) in the first- and second-line setting. We conducted a real-world multi-institutional analysis, aiming to compare the efficacy of third-line ALKi versus chemotherapy in these patients. METHODS: Consecutive ALK-positive metastatic NSCLC patients treated with at least one ALKi were identified in the working databases of 7 Israeli oncology centers (the full cohort). Demographic and clinical data were collected. Patients receiving any systemic treatment beyond 2 ALKi comprised the third-line cohort, whether a third ALKi (group A) or chemotherapy (group B). Groups A and B were compared in terms of overall survival (OS) and time-to-next-treatment line (TNT). RESULTS: At a median follow-up of 41 months (95% confidence interval [CI]: 32-55), 80 (47.1%) have died. Median OS (mOS) in the full cohort (n = 170) was 52 months (95% CI: 32-65). Number of ALKi (hazard ratio [HR] 0.765; 95% CI: 0.61-0.95; P = .024) and age (HR 1.02, 95% CI: 1.01-1.04, P = .009) significantly associated with OS in the full cohort. The third-line cohort included 40 patients, of which 27 were treated with third ALKi (group A) and 13 treated with chemotherapy (group B). mOS from third-line initiation was 27 months in group A (95% CI: 13-NR) and 13 months for group B (95% CI: 3-NR); the difference was not significant (NS; P = .12). Chemotherapy as first line (HR 0.17, 95% CI: 0.05-0.52, P = .002) and a higher number of ALKi (HR 0.38, 95% CI: 0.20-0.86, P = .011) associated significantly with longer OS of the third-line cohort. TNT was 10 months for group A (95% CI: 5-19) and 3 months for group B (95% CI: 0-NR); the difference was NS (P = .079). CONCLUSION: We report mature real-world data of more than 4-year mOS in ALK-positive patients. The number of ALKi given was associated with a better outcome. OS and TNT demonstrated a statistically nonsignificant trend for a better outcome in patients receiving a third-line ALKi.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Trinitrotolueno , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
In advanced nonsmall cell lung cancer (aNSCLC), stopping nivolumab after 12 months negatively affects outcomes. We performed a world data-based analysis assessing the value of nivolumab continuation and optimal dosing beyond 24 months. Out of 697 consecutive patients with aNSCLC in whom nivolumab was initiated between 2015 and 2018, 45 patients receiving nivolumab for ≥24 months were selected. These were divided into Groups A: nivolumab administered at a dose 3 mg/kg q2 weeks/240 mg q2 weeks/480 mg q4 weeks, n = 25; B: nivolumab re-scheduled to a nonstandard dose 3 mg/kg q3 weeks-q8 weeks, n = 13; C: nivolumab stopped after 24 months, n = 7; (in Groups B and C-for reasons other than progressive disease or intolerable toxicity). Progression-free survival (PFS) (Revised Response Evaluation Criteria in Solid Tumors, version 1.1) and safety (Common Terminology Criteria for Adverse Events, version 4.03) were assessed. With median follow-up of 35.6 months (interquartile range 28.4-41.8), 4%, 31%, 29% and 30% of patients progressed in Groups A, B, C and B+C, respectively. PFS at 36 months since nivolumab initiation comprised 100%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. PFS at 40 months since nivolumab initiation comprised 83%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. Allocation to Group A vs Group B, C and B+C was associated with hazard ratio for PFS-0.20 (95% confidence interval [CI], 0.02-1.77, P-.15), 0.20 (95% CI, 0.02-2.25, P-.19) and 0.20 (95% CI, 0.02-1.66, P-.14), respectively. No differences in newly occurring or worsening adverse events between the groups were observed. A trend for worse PFS was observed with alternative nivolumab scheduling or quitting 24 months after initiation. Continuing nivolumab at a standard dose until disease progression or intolerable toxicity remains the standard treatment option.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Nivolumab/administración & dosificación , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Esquema de Medicación , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Supervivencia sin Progresión , Factores de TiempoRESUMEN
One of the major hurdles for the advancement of cancer immunotherapy is lack of robust, accessible experimental models. We aimed to produce an ex-vivo organ culture (EVOC) model of immunotherapy for non-small cell lung cancer (NSCLC). Freshly resected early stage tumors were collected from the operating room, fragmented to clusters < 450 µm and cultured with fetal calf serum and human autologous serum. The resulting EVOC includes cancer epithelial cells within tumor tissue clusters and immune cells. Original tissue features are reflected in the EVOCs. The response to immune checkpoint inhibitors (ICI) was assessed by IFNγ gene induction. Interestingly, IFNγ EVOC induction was numerically higher when anti-CTLA4 was added to anti-PD-L1 treatment, supporting the notion that anti-CTLA4 impacts cancer partly through tumor-resident immune cells. In parallel, immunohistochemistry (IHC) for key immune-related proteins was performed on the formalin-fixed paraffin embedded (FFPE) corresponding tumors. EVOC IFNγ induction by ICI correlated with basal non-induced IFNγ, CD8, CD4 and FOXP3 mRNA levels within EVOCs and with tumor-FFPE-IHC for CD8 and granzyme B. A weaker correlation was seen with tumor-FFPE-IHC for CD3, CD4, CD68, FOXP3 and tumor-PD-L1. Tertiary lymphoid structure density was also correlated with the ICI response. Our study provides novel data about biomarkers that correlate with ICI-induced response of early stage NSCLC. Retention of the microenvironment and minimal addition of exogenous factors suggest this model to reliably represent the original tumor. The cluster-based EVOC model we describe can provide a valuable, yet simple and widely applicable tool for the study of immunotherapy in NSCLC.
Asunto(s)
Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Antígeno B7-H1/inmunología , Biomarcadores de Tumor/inmunología , Antígenos CD4/inmunología , Antígenos CD8/inmunología , Antígeno CTLA-4/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Factores de Transcripción Forkhead/inmunología , Humanos , Inmunohistoquímica/métodos , Factores Inmunológicos/inmunología , Inmunoterapia/métodos , Interferón gamma/inmunología , Técnicas de Cultivo de Órganos/métodos , Microambiente Tumoral/inmunologíaRESUMEN
PURPOSE: We aimed to assess the incidence, clinical and biochemical course of immunotherapy-induced thyroiditis and its implication on patients' survival, based on an extensive clinical experience from a tertiary cancer center. METHODS: Analyses were based on data from the electronic medical records of cancer patients treated with CPIs. Data included demographic characteristics, cancer type, Thyroid function tests (TFT), and survival. RESULTS: Thyroid function tests were available for 934 patients. After excluding patients with impaired baseline TFT or levothyroxine treatment, 754 euthyroid patients were included in the core analyses. Of those, 301 (39.9%) patients developed thyroid dysfunction ('thyroiditis'). Thyroiditis was more prevalent in patients with renal cell carcinoma than other types of cancer. Survival rates were comparable in patients who developed thyroiditis and in those who did not. during the 5 years follow-up period, there was a non-significant trend toward improved survival in patients who developed TD in four predefined groups: melanoma, lung cancer, renal cell carcinoma, and transitional cell carcinoma. Nevertheless, we observed a highly significant survival benefit for patients with renal cell carcinoma who developed TD (HR = 0.19, 95% CI 0.06-0.60; p = 0.005). CONCLUSIONS: Thyroiditis is common, often asymptomatic, and is more prevalent in patients treated with combinations of nivolumab and PD-L1 inhibitors, and in patients with renal cell carcinoma. Thyroiditis was associated with a trend for a survival benefit, particularly in patients with renal cell carcinoma.
Asunto(s)
Neoplasias Renales , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/epidemiología , Neoplasias Pulmonares/tratamiento farmacológico , Nivolumab/efectos adversos , Glándula TiroidesRESUMEN
BACKGROUND: Guidelines recommend testing for multiple biomarkers in non-small cell lung cancer (NSCLC) tumors. Blood-based liquid biopsy analyzing cell-free DNA (cfDNA) could be used in addition to tumor biopsy genotyping, especially if tissue/time are limiting. OBJECTIVES: To investigate the clinical utility of early cfDNA analysis (Guardant360® CDx) in treatment-naïve NSCLC patients. METHODS: A prospective cohort of treatment-naïve patients with metastatic NSCLC who underwent tumor and cfDNA analysis between 12/2018 and 2/2019 were included. RESULTS: Ten patients were included: 6 males, median age 70.5 years (range 48-87), 8 prior smokers. Liquid biopsy was sent when cancer cells were detected in the biopsy specimen. Median time from diagnosis to receiving the report on the last biomarker from the tumor biopsy was 20 days (range 9-34); median time from blood draw to receiving the cfDNA findings was 9 days (range 7-12). The median difference between the cfDNA and the tumor analysis reports was 20 days (range 9-28). Actionable biomarkers were identified in four patients by both the biopsy analysis and the cfDNA analysis (2cases with EGFR mutations, one with ROS1 fusion, and one with EML4-ALK fusion for whom the biopsy analysis also identified an EGFR mutation not detected in the cfDNA analysis). Overall, eight patients received treatment (2 died before treatment initiation). Three patients received biomarker-based treatment (1 osimertinib, 1 alectinib, and 1 crizotinib). CONCLUSIONS: These findings suggest that cfDNA analysis should be ordered by the pulmonologists early in the evaluation of patients with NSCLC, which might complement the tumor biopsy.
Asunto(s)
Adenocarcinoma del Pulmón/diagnóstico , Neoplasias Pulmonares/diagnóstico , Acrilamidas/uso terapéutico , Adenocarcinoma del Pulmón/sangre , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carbazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Crizotinib/uso terapéutico , ADN de Neoplasias/sangre , Femenino , Técnicas de Genotipaje , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Piperidinas/uso terapéutico , Estudios ProspectivosRESUMEN
BACKGROUND: Lung cancer is the most common cause of cancer-related death. OBJECTIVES: To identify changing patterns of lung cancer and its histologic subtypes among different population groups in Israel over a 25 year period. METHODS: Primary lung cancers, all types and all stages, diagnosed during 1990-2014 were recorded in the Israel National Cancer Registry database. Demographic information was retrieved from the National Population Register. Age-standardized rates for the different subgroups were calculated for each year. Joinpoint software was used to analyze trends in incidence. RESULTS: We identified 42,672 lung cancer cases. The most common histology was adenocarcinoma (34%), followed by squamous cell carcinoma (19%), large cell/not-otherwise-specified (19%), other histologies (15%), and small cell lung cancer (11%). The adenocarcinoma incidence rose from 25.7% to 48.2% during the examined period. Large cell/not-otherwise-specified incidence peaked around 2005-2006 and declined after. Lung cancer incidence increased significantly for the population overall and specifically in Arab females, followed by Jewish females and by Arab males. Adenocarcinoma and small cell lung cancer increased in Jewish females and in Arab males. A younger age of diagnosis was seen in Arab compared to Jewish patients. CONCLUSIONS: Jewish females and Arab males and females living in Israel demonstrated a constant increase in lung cancer incidence, mostly in adenocarcinoma and small cell lung cancer incidence. In addition, a younger age of diagnosis in Arabs was noted. Smoking reduction interventions and screening should be implemented in those populations.
Asunto(s)
Árabes/estadística & datos numéricos , Judíos/estadística & datos numéricos , Neoplasias Pulmonares/epidemiología , Adenocarcinoma/epidemiología , Adenocarcinoma/etnología , Factores de Edad , Anciano , Carcinoma de Células Grandes/epidemiología , Carcinoma de Células Grandes/etnología , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/etnología , Femenino , Humanos , Incidencia , Israel/epidemiología , Neoplasias Pulmonares/etnología , Masculino , Persona de Mediana Edad , Sistema de Registros , Factores Sexuales , Carcinoma Pulmonar de Células Pequeñas/epidemiología , Carcinoma Pulmonar de Células Pequeñas/etnologíaRESUMEN
BACKGROUND: Neoadjuvant chemo-radiation therapy (CRT) dosages in locally advanced non-small cell lung cancer (NSCLC) were traditionally limited to 45 Gray (Gy). OBJECTIVES: To retrospectively analyze outcomes of patients treated with 60 Gy CRT followed by surgery. METHODS: A retrospective chart review identified patients selected for CRT to 60 Gy followed by surgery between August 2012 and April 2016. Selection for surgery was based on the extent of disease, cardiopulmonary function, and response to treatment. Pathological response after neoadjuvant CRT was scored using the modified tumor regression grading. Local control (LC), disease free survival (DFS), and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: Our cohort included 52 patients: 75% (39/52) were stage IIIA. A radiation dose of 60 Gy (range 50-62Gy) was delivered in 82.7%. Surgeries performed included: lobectomy, chest-wall resection, and pneumonectomy in 67.3%, 13.4%, and 19.2%, respectively. At median follow-up of 22.4 months, the 3 year OS was 74% (95% confidence interval [CI] 52-87%), LC was 84% (95%CI 65-93), and DFS 35% (95%CI 14-59). Grade 4-5 postoperative complications were observed in 17.3% of cases and included chest wall necrosis (5.7%), bronco-pleural fistula (7.7%), and death (3.8%). A major pathologic regression with < 10% residual tumor occurred in 68.7% of patients (36/52) and showed a trend to improved OS (P = 0.1). Pneumonectomy cases had statistically worse OS (P = 0.01). CONCLUSIONS: Major pathologic regression was observed 68.7% with 60 Gy neoadjuvant CRT with a trend to improved survival. Pneumonectomy correlated with worse survival.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Quimioradioterapia , Neoplasias Pulmonares , Terapia Neoadyuvante , Neumonectomía , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Supervivencia sin Enfermedad , Prueba de Esfuerzo/métodos , Femenino , Humanos , Israel/epidemiología , Pulmón/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/métodos , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neumonectomía/efectos adversos , Neumonectomía/métodos , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Stereotactic ablative radiation therapy (SABR) is the application of a very high radiation dose to a small treatment volume. It is the new standard of care in medically inoperable early-stage lung cancer. OBJECTIVES: To report the outcomes of SABR in stage I lung cancer at Sheba Medical Center since its introduction in 2009. METHODS: We conducted a retrospective chart review of patients with stage I lung cancer treated during the period 2009-2015. Survival status was retrieved from the electronic medical records and confirmed with the national registry. Local failure was defined as increased FDG uptake on PETCT scan within a 2 cm radius of the treated region. Toxicity was estimated from medical records and graded according to common toxicity criteria for adverse events (CTCAE) version 4.03. Overall survival and local control were estimated by the Kaplan-Meier method. RESULTS: During the study period 114 patients were treated for 122 stage I lung cancer lesions. Median follow-up time was 27 months (range 8.2-69.5 months), median age was 76 years. Eighty-two percent of the tumors were stage IA (size ≤ 3 cm). Median survival was 46 months; estimated 3 year overall survival was 59% (95%CI 47-69%) and local control was 88% (95%CI 78-94%). Toxicity included chest wall pain in 8.4% of patients, rib fracture in 0.9%, grade 1-2 pneumonitis in 12%, grade 3 in 12% and grade 5 (death) in 0.9%. CONCLUSIONS: SABR has been successfully implemented at Sheba Medical Center for the treatment of stage I lung cancer in inoperable patients. It is associated with excellent local control, minor toxicity and an acceptable overall survival.
Asunto(s)
Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Radiocirugia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/mortalidad , Carcinoma/patología , Carcinoma/cirugía , Femenino , Tomografía Computarizada Cuatridimensional , Humanos , Israel/epidemiología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Radiografía Intervencional , Radiocirugia/efectos adversos , Dosificación Radioterapéutica , Estudios RetrospectivosRESUMEN
BACKGROUND: Progastrin-releasing peptide (ProGRP) is a potential marker for small-cell lung cancer (SCLC) in serum; however, it may be more stable in plasma. We investigated a new plasma assay (ProGRPp) and its usefulness in diagnosing and monitoring SCLC. METHODS: The marker concentrations were determined on the ARCHITECT i system. RESULTS: The assay could distinguish SCLC from non-small-cell lung cancer (NSCLC: area under the curve 0.931, 95% CI 0.893-0.969; cross-validated accuracy 0.813; sensitivity 84.0%, specificity 96.3%; at 140 pg ml(-1) cutoff). The probability of SCLC when ProGRPp was >140 pg ml(-1) was 91.8%, after adjusting for age, gender, and renal dysfunction. The NSCLC patients with ProGRPp >140 pg ml(-1) were at high risk (odds ratio=37.0, P<0.001) for tumours with neuroendocrine features. False negatives in SCLC were associated with a lack of thyroid transcription factor-1 (P<0.001). A decrease of ProGRPp to <140 pg ml(-1) during chemotherapy was significantly associated with the image-based response (P<0.001), and independently affected progression-free survival (PFS, relative risk=2.51, P=0.04) and overall survival (OS, relative risk=4.38, P=0.003), after adjustment for imaging response, performance status, and stage. CONCLUSIONS: The ProGRPp assay is specific and sensitive for diagnosing SCLC. Changes in ProGRPp during chemotherapy are significantly associated with image-based response, PFS, and OS.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Pulmonares/sangre , Fragmentos de Péptidos/sangre , Carcinoma Pulmonar de Células Pequeñas/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Casos y Controles , Diagnóstico Diferencial , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Proteínas Recombinantes , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
PURPOSE: To compare the postoperative recovery of patients with superior sulcus tumors (Pancoast tumors) following conventional open surgery vs. a hybrid video-assisted and limited open approach (VALO). METHODS: The subjects of this retrospective study were 20 patients we operated on to resect a Pancoast tumor. All patients received induction chemo-radiation followed by surgery, performed via either a conventional thoracotomy approach (n = 10) or the hybrid VALO approach (n = 10). In the hybrid VALO group, lobectomy and internal chest wall preparation were performed using a video technique, with rib resection and specimen removal through a limited incision. RESULTS: There was no mortality in either group. Two patients from the thoracotomy group required mechanical ventilation, but there was no major morbidity in the hybrid VALO group. The operative times were similar for the two procedures. The average length of hospital stay was shorter and the average pain scores were significantly lower in the hybrid VALO group. The incidence of chronic pain was 10 % in the hybrid VALO group vs. 50 % in the thoracotomy group. CONCLUSIONS: Hybrid VALO resection of Pancoast tumors is feasible and safe, resulting in faster patient recovery and a significantly lower incidence of severe chronic pain than open thoracotomy. We conclude that centers experienced with video-assisted lobectomy should consider hybrid VALO surgery as the procedure of choice for Pancoast tumors.
Asunto(s)
Síndrome de Pancoast/cirugía , Neumonectomía/métodos , Cirugía Torácica Asistida por Video/métodos , Anciano , Estudios de Factibilidad , Femenino , Humanos , Incidencia , Tiempo de Internación , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/epidemiología , Toracotomía/métodos , Resultado del Tratamiento , Cirugía Asistida por VideoAsunto(s)
Infecciones por Coronavirus/epidemiología , Control de Infecciones , Neoplasias , Pandemias , Neumonía Viral/epidemiología , Oncología por Radiación , Gestión de Riesgos , Betacoronavirus/aislamiento & purificación , COVID-19 , Comorbilidad , Humanos , Control de Infecciones/métodos , Control de Infecciones/organización & administración , Israel/epidemiología , Neoplasias/epidemiología , Neoplasias/radioterapia , Innovación Organizacional , Oncología por Radiación/métodos , Oncología por Radiación/organización & administración , Oncología por Radiación/tendencias , Radioterapia/métodos , Ajuste de Riesgo/métodos , Factores de Riesgo , Gestión de Riesgos/métodos , Gestión de Riesgos/organización & administración , SARS-CoV-2RESUMEN
PURPOSE: Testing tumor samples for the presence of a mutation in the epithelial growth factor receptor (EGFR) gene is recommended for advanced non-squamous non-small cell lung cancer (NSCLC) patients. We aimed to collect data about common practice among Medical Oncologists treating lung cancer patients, regarding EGFR mutation testing in advanced NSCLC patients. METHODS: An internet-based survey was conducted among members of the Israeli Society for Clinical Oncology and Radiotherapy involved in the treatment of lung cancer patients. RESULTS: 24 Oncologists participated in the survey. The participants encompass the Oncologists treating most of the lung cancer patients in Israel. 79% of them use EGFR testing routinely for all advanced NSCLC patients. Opinions were split regarding the preferable biopsy site for EGFR testing material. 60% of participants recommend waiting for EGFR test results prior to initiation of first-line therapy. CONCLUSIONS: EGFR testing is requested in Israel routinely by most treating Oncologists for all advanced NSCLC patients, regardless of histology. In most cases, systemic treatment is deferred until the results of this test are received.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Análisis Mutacional de ADN/tendencias , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutación , Pautas de la Práctica en Medicina/tendencias , Antineoplásicos/uso terapéutico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Análisis Mutacional de ADN/estadística & datos numéricos , Predisposición Genética a la Enfermedad , Encuestas de Atención de la Salud , Humanos , Internet , Israel , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , Fenotipo , Medicina de Precisión , Valor Predictivo de las Pruebas , Encuestas y CuestionariosRESUMEN
Cancer exploits different mechanisms to escape T-cell immunosurveillance, including overexpression of checkpoint ligands, secretion of immunosuppressive molecules, and aberrant glycosylation. Herein, we report that IFNγ, a potent immunomodulator secreted in the tumor microenvironment, can induce α2,6 hypersialylation in cancer cell lines derived from various histologies. We then focused on Siglec-9, a receptor for sialic acid moieties, and demonstrated that the Siglec-9+ T-cell population displayed reduced effector function. We speculated that Siglec-9 in primary human T cells can act as a checkpoint molecule and demonstrated that knocking out Siglec-9 using a CRISPR/Cas9 system enhanced the functionality of primary human T cells. Finally, we aimed to augment cancer-specific T-cell activity by taking advantage of tumor hypersialylation. Thus, we designed several Siglec-9-based chimeric switch receptors (CSRs), which included an intracellular moiety derived from costimulatory molecules (CD28/41BB) and different hinge regions. In an antigen specific context, T cells transduced with Siglec-9 CSRs demonstrated increased cytokine secretions and upregulation of activation markers. Moreover, T cells equipped with specific Siglec-9 CSRs mediated robust antitumor activity in a xenograft model of human tumors. Overall, this work sheds light on tumor evasion mechanisms mediated by sialylated residues and exemplifies an approach to improve engineered T cell-based cancer treatment.
RESUMEN
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Although the CNS activity of selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC) has been previously described, the ability of potent RET inhibition to prevent new CNS metastases from developing has been challenging to measure without randomized data. Serial CNS scans were studied from LIBRETTO-431, a randomized phase III trial of selpercatinib versus platinum/pemetrexed ± pembrolizumab whose primary results have been previously disclosed. Intracranial outcomes were assessed by neuroradiologic blinded independent central review in patients with baseline and ≥1 postbaseline CNS scans. Of the 192 patients within the intention-to-treat pembrolizumab population with baseline CNS scans, 150 patients were without baseline CNS metastases. The cumulative incidence of CNS progression in these patients was reduced with selpercatinib versus chemotherapy + pembrolizumab (cause-specific hazard ratio [HR], 0.17 [95% CI, 0.04 to 0.69]). The HR for intracranial progression-free survival (PFS) was 0.46 (95% CI, 0.18 to 1.18). Among the 42 patients with baseline CNS metastases, similar trends were observed in the cumulative incidence of CNS progression (cause-specific HR, 0.61 [95% CI, 0.19 to 1.92]) and intracranial PFS (HR, 0.74 [95% CI, 0.28 to 1.97]). These data demonstrate that selpercatinib effectively treats existing CNS disease and prevents or delays the formation of new CNS metastases. These results reinforce the importance of identifying RET fusions in first-line patients with NSCLC and treating with selpercatinib.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-ret , Pirazoles , Piridinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Pemetrexed/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias del Sistema Nervioso Central/secundario , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Adulto , Supervivencia sin ProgresiónRESUMEN
Despite the remarkable success of anti-cancer immunotherapy, its effectiveness remains confined to a subset of patients-emphasizing the importance of predictive biomarkers in clinical decision-making and further mechanistic understanding of treatment response. Current biomarkers, however, lack the power required to accurately stratify patients. Here, we identify interferon-stimulated, Ly6Ehi neutrophils as a blood-borne biomarker of anti-PD1 response in mice at baseline. Ly6Ehi neutrophils are induced by tumor-intrinsic activation of the STING (stimulator of interferon genes) signaling pathway and possess the ability to directly sensitize otherwise non-responsive tumors to anti-PD1 therapy, in part through IL12b-dependent activation of cytotoxic T cells. By translating our pre-clinical findings to a cohort of patients with non-small cell lung cancer and melanoma (n = 109), and to public data (n = 1440), we demonstrate the ability of Ly6Ehi neutrophils to predict immunotherapy response in humans with high accuracy (average AUC ≈ 0.9). Overall, our study identifies a functionally active biomarker for use in both mice and humans.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Ratones , Animales , Interferones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neutrófilos/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Biomarcadores , InmunoterapiaRESUMEN
BACKGROUND: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC. METHODS: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB. RESULTS: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively). CONCLUSIONS: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy.
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/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Pemetrexed/uso terapéutico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. Methods: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. Results: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. Conclusions: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1 , Proteómica , Neoplasias Pulmonares/tratamiento farmacológico , Inmunoterapia , Inhibidores de Puntos de Control Inmunológico , PlasmaRESUMEN
PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptor de Muerte Celular Programada 1/uso terapéutico , Proteoma , ProteómicaRESUMEN
PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.
RESUMEN
INTRODUCTION: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown. METHODS: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used. RESULTS: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3). CONCLUSIONS: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.