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BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Factor A de Crecimiento Endotelial Vascular/genética , Estudios Retrospectivos , Hibridación Fluorescente in SituRESUMEN
OBJECTIVE: To evaluate the prognostic value of programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) expression in patients with upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: A retrospective multicentre study was conducted in 283 patients with UTUC treated with radical nephroureterectomy (RNU) between 2000 and 2015 at 10 French hospitals. Immunohistochemistry analyses were performed using 2 mm-core tissue microarrays with NAT105® and 28.8® antibodies at a 5% cut-off for positivity on tumour cells and tumour-infiltrating lymphocytes to evaluate PD-L1 and PD-1 expression, respectively. Multivariable Cox regression models were used to determine the independent predictors of recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). RESULTS: Overall, 63 (22.3%) and 220 (77.7%) patients with UTUC had PD-L1-positive and -negative disease, respectively, while 91 (32.2%) and 192 (67.8%) had PD-1-positive and -negative disease, respectively. Patients who expressed PD-L1 or PD-1 were more likely to have pathological tumour stage ≥pT2 (68.3% vs 49.5%, P = 0.009; and 69.2% vs 46.4%, P < 0.001, respectively) and high-grade (90.5% vs 70.0%, P = 0.001; and 91.2% vs 66.7%, P < 0.001, respectively) disease with lymphovascular invasion (52.4% vs 17.3%, P < 0.001; and 39.6% vs 18.2%, P < 0.001, respectively) as compared to those who did not. In multivariable Cox regression analysis adjusting for each other, PD-L1 and PD-1 expression were significantly associated with decreased RFS (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.09-3.08, P = 0.023; and HR 1.59, 95% CI 1.01-2.54, P = 0.049; respectively), CSS (HR 2.73, 95% CI 1.48-5.04, P = 0.001; and HR 1.96, 95% CI 1.12-3.45, P = 0.019; respectively) and OS (HR 2.08, 95% CI 1.23-3.53, P = 0.006; and HR 1.71, 95% CI 1.05-2.78, P = 0.031; respectively). In addition, multivariable Cox regression analyses evaluating the four-tier combination of PD-L1 and PD-1 expression showed that only PD-L1/PD-1-positive patients (n = 38 [13.4%]) had significantly decreased RFS (HR 3.07, 95% CI 1.70-5.52; P < 0.001), CSS (HR 5.23, 95% CI 2.62-10.43; P < 0.001) and OS (HR 3.82, 95% CI 2.13-6.85; P < 0.001) as compared to those with PD-L1/PD-1-negative disease (n = 167 [59.0%]). CONCLUSIONS: We observed that PD-L1 and PD-1 expression were both associated with adverse pathological features that translated into an independent and cumulative adverse prognostic value in UTUC patients treated with RNU.
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BACKGROUND: Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer and is associated with poor prognosis. In platinum-refractory or -resistant SCLC patients, few treatment options are available. Topotecan is one of the standards of care for these patients, however, due to its high toxicity, several different approaches are employed. FOLFIRI (folinate, 5-fluorouracil and irinotecan) is a chemotherapy regimen used in digestive neuroendocrine carcinoma, which shares pathological similarities with SCLC. In this retrospective study, we evaluated the efficacy and safety of FOLFIRI in patients with platinum-resistant/refractory SCLC. METHODS: Medical records from all consecutive SCLC patients treated with FOLFIRI in a French University Hospital from 2013 to 2021 were analyzed retrospectively. The primary endpoint was the objective response rate according to RECIST v1.1 or EORTC criteria (ORR); secondary endpoints included duration of response, disease control rate, progression-free survival (PFS), overall survival (OS) and safety profile. RESULTS: Thirty-four patients with metastatic platinum-resistant (n = 14) or -refractory (n = 20) SCLC were included. Twenty-eight were evaluable for response, with a partial response observed in 5 patients for an overall ORR in the evaluable population of 17.9% (5/28) and 14.7% (5/34) in the overall population. The disease control rate was 50% (14/28) in the evaluable population. The median PFS and OS were 2.8 months (95%CI, 2.0-5.2 months) and 5.3 months (95%CI, 3.5-8.9 months), respectively. All patients were included in the safety analysis. Grade 3 or 4 adverse events occurred in 13 (38.2%) patients. The most common grade 3 or 4 adverse events were asthenia, neutropenia, thrombopenia and diarrhea. There was no adverse event leading to discontinuation or death. CONCLUSION: FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response and had an acceptable safety profile. However, caution is needed in interpreting this result. FOLFIRI could represent a potential new treatment for platinum-resistant/refractory SCLC patients. Further prospective studies are needed to assess the benefits of this chemotherapy regimen.HIGHLIGHTSFOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response.FOLFIRI was well-tolerated in platinum resistant/refractory SLCL patients.FOLFIRI could represent a potential new treatment for SCLC, prospective studies are needed.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Estudios Retrospectivos , Platino (Metal)/uso terapéutico , Camptotecina/efectos adversos , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
INTRODUCTION: Renal events are common in cancer patients and malignancy is a prevalent complication in both patients transplanted and under kidney replacement therapy (KRT). In recent years, onco-nephrology has been developed as a subspecialty whose scope has not been well established yet. The aim of our study was to assess resident and senior physicians' knowledge and expectations about onco-nephrology. METHODS AND MATERIALS: Two anonymous self-administered online questionnaires were developed by a multidisciplinary team and distributed to French residents and senior physicians. RESULTS: Two hundred twenty-eight physicians answered the survey, including 128 (56%) nephrologists, of which 98 (43%) were senior physicians and 130 (57%) were residents. Nephrologists rated their confidence in their ability to face onco-nephrological situation at 6/10 (interquartile range (IQR) 4.0-7.0) and oncologists at 6.0/10 (5.0-7.0). Managing cancer drugs in patients on KRT or in transplanted patients and discussion about introducing dialysis in cancer patients were designated as the most challenging topics. Asking if they had received appropriate learning, residents' median agreement was ranked at 3.0/10 (2.0-4.0). Forty-six percent of the respondents considered available resources as not appropriate. Specialized onco-nephrology consultations were accessible for 21% of the respondents. Finally, respondents thought there is a strong need for a national working group (8.3/10) with 87% of them expecting new reliable guidelines. CONCLUSION: The present survey revealed physicians' expectations about onco-nephrology implementation in France. An appropriate answer could be the creation of a national working group. Therefore, GRIFON (Groupe de Recherche Interdisciplinaire en OncoNéphrologie) has recently been created.
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Neoplasias , Nefrología , Médicos , Humanos , Nefrología/educación , Nefrología/métodos , Motivación , Neoplasias/terapia , Neoplasias/complicaciones , Diálisis Renal , Encuestas y CuestionariosRESUMEN
BACKGROUND: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear. METHODS: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-two patients with metastatic TRCC treated in the participating centers and evaluable for response were included. Median age at metastatic diagnosis was 40 years (IQR 28.5-53). Patients' IMDC risk groups at diagnosis were favorable (9/52), intermediate (35/52), and poor (8/52). Eleven (21.2%) patients received cabozantinib as frontline therapy, 15 (28.8%) at second line, and 26 (50%) at third line and beyond. The proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response. With a median follow-up of 25.1 months (IQR 12.6-39), median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6). No difference of response was identified according to fusion transcript features. CONCLUSION: This real-world study provides evidence of the activity of cabozantinib in TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs.
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Carcinoma de Células Renales , Neoplasias Renales , Adulto , Humanos , Persona de Mediana Edad , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Estudios de Cohortes , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Estudios RetrospectivosRESUMEN
INTRODUCTION: Controversy regarding the prognostic and/or predictive role of PD-1 and PD-L1 expression for upper tract urothelial carcinoma (UTUC) could partly be explained by inconsistencies in the immunohistochemistry (IHC) methodology. Objective is to standardize the methodology for routine evaluation of PD-1 and PD-L1 expression in UTUC patients. MATERIALS AND METHODS: Twenty-two cases treated with radical nephroureterectomy between 1996 and 2015 at 11 French hospitals were randomly selected to compare different methodologies for evaluation of PD-1 and PD-L1 expression. IHC was carried out on whole tissue sections and 0.6 mm- or 2 mm-core tissue micro-arrays (TMAs) using PD-1 NAT105 and PD-L1 28.8 or E1L3N on both tumor cells and tumor-infiltrating immune cells (TILs). Results obtained with whole tissue sections (WTS) were compared to those obtained with 0.6 mm- and 2 mm-core TMAs. Concordance was evaluated using Kappa coefficient. RESULTS: For evaluation of PD-1 and PD-L1 expression, the best concordance with WTS was observed using the PD-1 NAT105 and PD-L1 28.8 antibody on 2 mm-core TMAs, with 5% cut off for positivity on TILs and tumor cells, respectively (Kappa = 0.8). CONCLUSIONS: The most accurate methodology for routine evaluation of PD-1 and PD-L1 expression in UTUC may be based on 2 mm-core TMAs using NAT105 and 28.8 antibodies with a 5% cut off for positivity on TILs and tumor cells, respectively.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Biomarcadores de Tumor , Humanos , Inmunohistoquímica , Nefroureterectomía , Pronóstico , Receptor de Muerte Celular Programada 1RESUMEN
INTRODUCTION: The aim of the study was to extract anthropometric measures from CT by deep learning and to evaluate their prognostic value in patients with non-small-cell lung cancer (NSCLC). METHODS: A convolutional neural network was trained to perform automatic segmentation of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and muscular body mass (MBM) from low-dose CT images in 189 patients with NSCLC who underwent pretherapy PET/CT. After a fivefold cross-validation in a subset of 35 patients, anthropometric measures extracted by deep learning were normalized to the body surface area (BSA) to control the various patient morphologies. VAT/SAT ratio and clinical parameters were included in a Cox proportional-hazards model for progression-free survival (PFS) and overall survival (OS). RESULTS: Inference time for a whole volume was about 3 s. Mean Dice similarity coefficients in the validation set were 0.95, 0.93, and 0.91 for SAT, VAT, and MBM, respectively. For PFS prediction, T-stage, N-stage, chemotherapy, radiation therapy, and VAT/SAT ratio were associated with disease progression on univariate analysis. On multivariate analysis, only N-stage (HR = 1.7 [1.2-2.4]; p = 0.006), radiation therapy (HR = 2.4 [1.0-5.4]; p = 0.04), and VAT/SAT ratio (HR = 10.0 [2.7-37.9]; p < 0.001) remained significant prognosticators. For OS, male gender, smoking status, N-stage, a lower SAT/BSA ratio, and a higher VAT/SAT ratio were associated with mortality on univariate analysis. On multivariate analysis, male gender (HR = 2.8 [1.2-6.7]; p = 0.02), N-stage (HR = 2.1 [1.5-2.9]; p < 0.001), and the VAT/SAT ratio (HR = 7.9 [1.7-37.1]; p < 0.001) remained significant prognosticators. CONCLUSION: The BSA-normalized VAT/SAT ratio is an independent predictor of both PFS and OS in NSCLC patients. KEY POINTS: ⢠Deep learning will make CT-derived anthropometric measures clinically usable as they are currently too time-consuming to calculate in routine practice. ⢠Whole-body CT-derived anthropometrics in non-small-cell lung cancer are associated with progression-free survival and overall survival. ⢠A priori medical knowledge can be implemented in the neural network loss function calculation.
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Composición Corporal , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Aprendizaje Profundo , Grasa Intraabdominal/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Músculo Esquelético/diagnóstico por imagen , Grasa Subcutánea/diagnóstico por imagen , Imagen de Cuerpo Entero , Adulto , Anciano , Superficie Corporal , Carcinoma de Pulmón de Células no Pequeñas/terapia , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Tasa de SupervivenciaRESUMEN
BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).
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Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Androstenos/administración & dosificación , Androstenos/farmacocinética , Androstenos/uso terapéutico , Acetato de Abiraterona/administración & dosificación , Acetato de Abiraterona/farmacocinética , Acetato de Abiraterona/uso terapéutico , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/sangre , Metástasis de la NeoplasiaRESUMEN
The objective of this study was to determine the proportion of phase 3 clinical trials investigating a systemic therapy for patients with prostate, breast, lung, or colorectal cancer that excluded patients with Chronic Kidney Disease (CKD) and the exclusion criteria chosen, if any. A search was conducted using the ClinicalTrials.gov database to identify eligible studies. Of the 268 included trials, 185 (69%) had at least one renal exclusion criteria. Of these 185 trials, 116 (63%) had an undefined exclusion criterion. Only disease site was associated with exclusion of patients with CKD in the univariate analysis, but no factors in the multivariate analysis. There are several potential barriers to including patients with CKD in clinical trials. Nevertheless, solutions can be proposed to allow the inclusion of these patients. This would allow them to access to innovative therapeutic strategies, but also allow a better applicability of trial results to this patient population.
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Neoplasias Colorrectales , Insuficiencia Renal Crónica , Masculino , Humanos , Próstata , Riñón , PulmónRESUMEN
INTRODUCTION: The number of cancer patients receiving long-term hemodialysis (HD) is increasing, and HD could jeopardize treatments' safety and efficacy. Therefore, managing anticancer drugs is critical in this frail population. In addition, evidence of HD safety or risk is regularly released both for cytotoxic chemotherapy (CT) or hormone therapy (HT) as well as new therapies with molecularly targeted therapies (MTT), immune checkpoint inhibitors (ICI), and a summary of current knowledge is needed. METHODS: We aimed to synthesize available data on cancer treatments in HD patients using PubMed database, FDA labels, summary of product characteristics (SmPC), FDA and EMA approval documents, guidelines and finally case reports for which relevant pharmacokinetic (PK) data is available. RESULTS: For CT, recently proposed guidelines were balanced by the publication of particular toxic reports following them. SmPC was helpful in some cases, but no data was found for most CTs. MTT, both oral and monoclonal antibodies, were rarely modified by HD. However, HD patients have particular frailty that could require dose adaptation despite no substantial PK modification. Similarly, exposure to ICIs is unlikely to be modified by HD since immunoglobulins are not dialyzable. For HT, PK characteristics and HD impact were more heterogeneous and were reviewed molecule by molecule. CONCLUSIONS: We summarized current knowledge on HD and cancer treatments. Data remains scarce, and the latest guidelines rely on few clinical data. There is a need to collect both retrospective and prospective data to better characterize the safety and relevant dose and schedule adaptations whenever needed in this situation to reinforce future guidelines.
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BACKGROUND: Here, we aimed to assess the specific features of lung cancer in patients with long-term oxygen therapy (LTOT), and compare their outcomes with patients suffering from lung cancer without LTOT. METHODS: This retrospective, case-controlled study included patients with LTOT and an incident diagnosis of lung cancer treated at Rouen University Hospital. RESULTS: Out of 2201 patients with LTOT, 31 were diagnosed with lung cancer. Among 24 patients with proven lung cancer, the most frequent histological type was squamous cell carcinoma (n = 12/24, 50%). Active treatment of any type was given in 19/31 (61%) and 41/62 (66%) of patients in the LTOT and control groups, respectively (p = 0.83). In the LTOT group, median survival was 38 days with best supportive care and 462 days with active treatment (p = 0.003). However, when adjusting on performance status and disease stage, LTOT was not significantly associated with a worse outcome. Hazard ratio (HR): 1.56 (95% confidence interval [CI]: 0.87 to 2.81) (p = 0.137). Administration of any treatment was associated with a better prognostic: HR: 0.35 (95% CI: 0.19 to 0.66). Both groups had a similar treatment safety profile. CONCLUSION: Incidence of lung cancer in patients with LTOT was comparable to the general population. The proportion of LTOT patients who received active treatment was similar to controls, and overall survival did not differ from controls in a multivariate analysis. Although reaching a histological diagnosis may be challenging in LTOT patients, the efficacy and safety of the management strategies of lung cancer seem preserved.
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Neoplasias Pulmonares , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Incidencia , Estudios Retrospectivos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , OxígenoRESUMEN
ABSTRACT: Pituitary metastasis is a rare event, and the pituitary gland is an uncommonly involved location in patients with intracranial metastases as it accounts for only approximately 2% of malignant metastases. Here, the authors present the 18F-FDG PET study of a very rare case of relapsed non-small cell lung cancer, locally and with 1 pituitary metastasis, in a 75-year-old White woman with asthenia and diabetes insipidus. 18F-FDG PET and cerebral MRI were performed to guide the therapeutic strategy due to an atypical pituitary high FDG avidity.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Hipofisarias , Anciano , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/secundario , Tomografía Computarizada por Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
Immunotherapies and immune checkpoint inhibitors (ICI) represent the latest revolution in oncology. Several studies have reported an association between the use of corticosteroids and poorer outcomes for patients treated with ICIs. However, it has been never established whether corticoid-induced tumor progression under ICI treatment could be reversible. We report herein transient tumor progression induced by dexamethasone for a patient treated with pembrolizumab for metastatic bladder cancer. An 82-year-old man was treated with pembrolizumab as a second-line treatment for metastatic urothelial carcinoma with stable disease for 8 months as the best tumoral response. He experienced severe coronavirus disease 2019 (COVID-19) infection and was treated with high-dose dexamethasone for ten days according to the RECOVERY protocol. Following this episode, radiological CT-scan evaluation showed tumor progression. Pembrolizumab was maintained, and subsequent radiological evaluation showed tumor shrinkage. This case highlights that the antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Clinicians should be aware that tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients. Insights: The antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients.
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Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11−16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7−100 months and an objective response rate (ORR) of 39% (95% CI, 26−52%). Patients received a median of two (1−5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10−15% and disease control rates ranging 24−50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.
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INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for front-line therapy in metastatic renal cell carcinoma (mRCC). However, progressive disease often occurs and subsequent therapies are needed. ICI rechallenge may be an option, but there is a lack of data regarding efficacy and prognostic factors. We assessed efficacy of ICI rechallenge and factors associated with better outcomes. Patients and Methods. This ambispective multicenter study included 45 mRCC patients rechallenged with nivolumab ± ipilimumab between 2014 and 2020. Primary endpoint was investigator-assessed best objective response rate (ORR) for ICI rechallenge (ICI-2). Factors associated with ICI-2 progression-free survival (PFS) were evaluated with multivariate Cox models. RESULTS: ORR was 51% (n = 23) at first ICI therapy (ICI-1) and 16% (n = 7) for ICI-2. Median PFS was 11.4 months (95% CI, 9.8-23.5) and 3.5 months (95% CI, 2.8-9.7), and median overall survival was not reached (NR) (95% CI, 37.8-NR) and 24 months (95% CI, 9.9-NR) for ICI-1 and ICI-2, respectively. Factors associated with poorer ICI-2 PFS were a high number of metastatic sites, presence of liver metastases, use of an intervening treatment between ICI regimens, Eastern Cooperative Oncology Group performance status ≥2, and poor International Metastatic RCC Database Consortium score at ICI-2 start. Conversely, ICI-1 PFS >6 months was associated with better ICI-2 PFS. In multivariate analysis, there were only statistical trends toward better ICI-2 PFS in patients with ICI-1 PFS >6 months (p=0.07) and toward poorer ICI-2 PFS in patients who received a treatment between ICI regimens (p=0.07). CONCLUSION: Rechallenge with nivolumab-based ICI has some efficacy in mRCC. We identified various prognostic factors in univariate analysis but only statistical trends in multivariate analysis. Our findings bring new evidence on ICI rechallenge and preliminary but unique data that may help clinicians to select patients who will benefit from this strategy.
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Background: Patients with triple-negative breast cancers (TNBC) have a poor prognosis unless a pathological complete response (pCR) is achieved after neoadjuvant chemotherapy (NAC). Few studies have analyzed changes in TIL levels following dose-dense dose-intense (dd-di) NAC. Patients and methods: From 2009 to 2018, 117 patients with TNBC received dd-di NAC at our institution. We aimed to identify factors associated with pre- and post-NAC TIL levels, and oncological outcomes relapse-free survival (RFS), and overall survival (OS). Results: Median pre-NAC and post-NAC TIL levels were 15% and 3%, respectively. Change in TIL levels with treatment was significantly correlated with metabolic response (SUV) and pCR. High post-NAC TIL levels were associated with a weak metabolic response after two cycles of NAC, with the presence of residual disease and nodal involvement at NAC completion. In multivariate analyses, high post-NAC TIL levels independently predicted poor RFS and poor OS (HR = 1.4 per 10% increment, 95%CI (1.1; 1.9) p = 0.014 and HR = 1.8 per 10% increment 95%CI (1.3−2.3), p < 0.0001, respectively). Conclusion: Our results suggest that TNBC patients with TIL enrichment after NAC are at higher risk of relapse. These patients are potential candidates for adjuvant treatment, such as immunotherapy, in clinical trials.
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BACKGROUND: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. METHODS: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days). RESULTS: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). CONCLUSION: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.
Asunto(s)
Lesión Renal Aguda , Inhibidores de Puntos de Control Inmunológico , Lesión Renal Aguda/inducido químicamente , Corticoesteroides/farmacología , Corticoesteroides/uso terapéutico , Estudios de Cohortes , Creatinina , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversosRESUMEN
Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. SIGNIFICANCE: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli-specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Antígeno B7-H1 , Quimiocina CXCL13 , Escherichia coli , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoglobulina G , Músculos , Terapia Neoadyuvante , Receptor de Muerte Celular Programada 1 , Linfocitos T Colaboradores-Inductores , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Crizotinib is a tyrosine kinase inhibitor (TKI) indicated in first-line treatment of rearranged c-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) metastatic non-small-cell lung cancer (NSCLC). However, the common response reported after treatment is partial and few complete responses have been reported in PROFILE studies with computed tomography (CT) evaluation. To date, only one case report of complete metabolic response on 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography-computed tomography (18F-FDG-PET/CT) was published, reporting on a patient with ROS1 rearranged NSCLC. We highlighted the 18F-FDG-PET/CT useful approach for therapeutic assessment of TKI in metastatic mutated NSCLC reporting two complete metabolic responses in patients treated with crizotinib for a rearranged ROS1 and a metastatic ALK NSCLC.