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BACKGROUND: Progression-free survival was significantly longer in patients who received avelumab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma (aRCC) in a randomized phase III trial. We report long-term safety and efficacy of avelumab plus axitinib as first-line treatment for patients with aRCC from the JAVELIN Renal 100 phase Ib trial (NCT02493751). MATERIALS AND METHODS: In this open-label, multicenter, phase Ib study, patients with untreated aRCC received avelumab 10 mg/kg every 2 weeks plus axitinib 5 mg twice daily or with axitinib for 7 days followed by avelumab plus axitinib. Safety and efficacy were assessed in all patients receiving at least one dose of avelumab or axitinib. RESULTS: Overall, 55 patients were enrolled and treated. Median follow-up was 55.7 months (95% CI, 54.5-58.7). Treatment-related adverse events of any grade or grade ≥3 occurred in 54 (98.2%) and 34 (61.8%) patients, respectively. The confirmed objective response rate was 60.0% (95% CI, 45.9-73.0), including complete response in 10.9% of patients. Median duration of response was 35.9 months (95% CI, 12.7-52.9); the probability of response was 65.8% (95% CI, 46.7-79.4) at 2 years. Median progression-free survival was 8.3 months (95% CI, 5.3-32.0). Median overall survival was not reached (95% CI, 40.8-not estimable); the 5-year overall survival rate was 57.3% (95% CI, 41.2-70.5). CONCLUSION: Five-year follow-up for combination treatment with avelumab plus axitinib in previously untreated patients with aRCC showed long-term clinical activity with no new safety signals, supporting use of this regimen within its approved indication in clinical practice (Clinicaltrials.gov NCT02493751).
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Axitinib/efectos adversos , Neoplasias Renales/patología , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OPINION STATEMENT: Current treatment options for patients with metastatic renal cell carcinoma (mRCC) are limited to immunotherapy with checkpoint inhibitors and targeted therapies that inhibit the vascular endothelial growth factor receptors (VEFG-R) and the mammalian target of rapamycin (mTOR). Despite significantly improved outcomes over the last few decades, most patients with mRCC will ultimately develop resistance to these therapies, thus highlighting the critical need for novel treatment options. As part of the VHL-HIF-VEGF axis that rests at the foundation of RCC pathogenesis, hypoxia-inducible factor 2α (HIF-2α) has been identified as a rationale target for mRCC treatment. Indeed, one such agent (belzutifan) is already approved for VHL-associated RCC and other VHL-associated neoplasms. Early trials of belzutifan indicate encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan and other HIF-2α inhibitors into the mRCC treatment armamentarium either as a single agent or as combination therapy would be a welcome addition for patients with mRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/etiología , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/etiología , Neoplasias Renales/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
BACKGROUND: Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor. METHODS: We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811. FINDINGS: Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2). INTERPRETATION: Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting. FUNDING: Pfizer.
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Antineoplásicos/administración & dosificación , Axitinib/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Anciano , Algoritmos , Antineoplásicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Axitinib/efectos adversos , Carcinoma de Células Renales/secundario , Deshidratación/inducido químicamente , Diarrea/inducido químicamente , Fatiga/inducido químicamente , Femenino , Humanos , Hipertensión/inducido químicamente , Ipilimumab/uso terapéutico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Nivolumab/uso terapéutico , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , RetratamientoRESUMEN
Therapy-related acute myeloid leukemia (t-AML) is an increasingly recognized sequela in patients receiving chemotherapy or radiotherapy for a primary malignancy or autoimmune disease. This study assessed factors related to the latency period (LP) between the antecedent disorder (AD) and t-AML diagnosis and developed a comprehensive prognostic model to predict overall survival (OS). We evaluated a cohort of newly diagnosed t-AML patients treated with cytarabine-based induction therapy from 2001 to 2011. Multivariable linear and proportional hazards models were used to assess the impact of different classes of chemotherapy on the LP and to identify independent prognostic factors for OS. Of 730 treated AML patients, 58 (7.9%) had t-AML. Median LP to t-AML was 5.6 years (range, 0.5-38.4). 64% of patients achieved CR and median OS was 10.7 months. Independent prognostic factors of short LP were age at AD (P < 0.0001) and prior treatment with mitotic inhibitors (P = 0.05). Unfavorable cytogenetics (P = 0.004), antecedent hematologic or autoimmune disease (P = 0.01), age >60 (P = 0.03), and platelet count <30,000 µL (P = 0.04) at the time of t-AML diagnosis were prognostic for inferior OS. A prognostic model using these factors was developed that risk stratified t-AML patients into two groups: favorable and unfavorable. Patients in the favorable group had a median OS of 37.6 months compared with 6.4 months in patients comprising the unfavorable group (P < 0.0001). Multicomponent prognostic models integrating disease or treatment-related covariates can help better understand how t-AML evolves; and can be clinically useful in risk stratifying t-AML patients undergoing induction therapy.
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Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Modelos Estadísticos , Neoplasias Primarias Secundarias , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/administración & dosificación , Femenino , Humanos , Quimioterapia de Inducción/efectos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Evaluación del Resultado de la Atención al Paciente , Pronóstico , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Most patients with treatment-naïve metastatic renal cell carcinoma (mRCC) receive combination-based immunotherapy with either 2 immune-oncology checkpoint inhibitors (IO/IO) or an IO agent in combination with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (IO/TKI). The rates of thromboembolism (TE) in these cohorts are not clearly described and can potentially impact decision-making between IO/IO and IO/TKI. METHODS: We conducted a retrospective investigation of patients with treatment-naïve mRCC treated with IO-based combinations between January 2015 and April 2021 at the Cleveland Clinic. TE events, including venous and arterial, were identified in each group. Competing risk regression was done to identify factors associated with the development of TE following therapy, with all-cause mortality treated as a competing event. RESULTS: Of 180 patients identified, 77 (43%) received IO/TKI and 103 (57%) received IO/IO. Median age was 65 years, 75% were male, and 80% had clear cell histology. Baseline characteristics were similar between the 2 groups. At a median follow-up of 22.0 months, 10.0% of all patients had a TE. The one-year incidence of TE was 8.1% (95% CI: 3.3%-15.8%) with IO/TKI and 9.8% (95% CI: 5.0%-16.5%) with IO/IO and was not significantly different between the 2 groups (HR 0.89, 95% CI: 0.35%-2.28%). Occurrence of TE was associated with decreased overall survival regardless of IO/IO or IO/TKI therapy (HR 2.80, 95% CI: 1.57-5.02). There was no difference in incidence of TE based on patient age, gender, prior history of TE, International Metastatic Renal Cell Carcinoma (IMDC) risk group, or Khorana score. CONCLUSIONS: Incidence of TE is similar between IO/IO and IO/TKI regimens in treatment-naïve mRCC and is also associated with decreased overall survival. While risk of TE may not guide decision-making in choice of front-line mRCC therapy, careful attention should be given to the high risk of TE in this population.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Anciano , Femenino , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Factor A de Crecimiento Endotelial Vascular , Estudios Retrospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Inmunoterapia/efectos adversosRESUMEN
INTRODUCTION: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. MATERIALS AND METHODS: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. RESULTS: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. CONCLUSION: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.
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Antineoplásicos Inmunológicos , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Interrupción del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inducido químicamente , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.
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Carcinoma de Células Renales , Neoplasias Renales , Melanoma , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Nivolumab/farmacología , Nivolumab/uso terapéutico , Ipilimumab/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patologíaRESUMEN
BACKGROUND: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. METHODS: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. RESULTS: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death. CONCLUSIONS: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. TRIAL REGISTRATION NUMBER: NCT03117309.
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Carcinoma de Células Renales , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Ipilimumab/efectos adversos , Terapia RecuperativaRESUMEN
Renal cell carcinomas vary considerably in their tumor biology and disease course, which is reflected in the range of treatment paradigms in localized and metastatic renal cell carcinoma (mRCC). Active surveillance remains an important component of all renal cell carcinoma management. In mRCC, the rapid evolution from cytokine-based therapy to targeted therapy to immunotherapy with checkpoint blockade has revolutionized the field and drastically altered treatment outcomes. More recently, combination therapies have become a standard of care for most patients with mRCC. In this review, we highlight recent critical data that led to changes in treatment paradigms and provide a practical framework for the management of patients with mRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Inmunoterapia/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , MasculinoRESUMEN
BACKGROUND: Immunotherapy has become one of the mainstays for metastatic urothelial carcinoma treatment. Whether immune checkpoint inhibitor therapy increases thromboembolism (TE) risk is unknown. OBJECTIVE: We investigated the incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) events and its associated outcomes in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors. METHODS: Patients with urothelial cancer treated with immune checkpoint inhibitors at the Cleveland Clinic from 1/1/2015 to 12/31/2019 were identified. The Kaplan-Meier method estimated overall survival and Cox proportional hazards regression evaluated the impact of TE on overall survival. RESULTS: Of 279 patients, 72% were men with pure urothelial cancer (62%) who started atezolizumab (40%), nivolumab (3%), or pembrolizumab (57%). At a median follow-up of 5.6 months (range 0.3-51.6), 42 patients developed a TE (VTE n = 37, 13%, ATE n = 5, 2%). The cumulative incidence of TE after immune checkpoint inhibitor therapy was 9.1% (95% confidence interval 6.0-13.0) at 6 months and 13.6% (95% confidence interval 9.6-18.4) at 12 months. Most TE (VTE 62%, ATE 100%) occurred within 6 months of immune checkpoint inhibitor initiation (median doses 5, range 1-59), and the majority (VTE 81%, ATE 100%) resulted in hospitalization (median: 5 days, 4 days, respectively). Thromboembolism (hazard ratio 2.296, p = 0.0004), Bajorin score 1 or 2 (hazard ratio 1.490, p = 0.0315), and Bajorin score 2 (hazard ratio 3.50, p < 0.0001) were associated with worse overall survival. CONCLUSIONS: Immune checkpoint inhibitors are associated with a high TE risk. Thromboembolism is associated with worsened survival, among other poor outcomes. Further investigation into the mechanism behind immune checkpoint inhibitor-associated TE is needed.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Tromboembolia Venosa , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Nivolumab/efectos adversos , Estudios Retrospectivos , Tromboembolia Venosa/etiologíaRESUMEN
Active surveillance (AS) may be used in the management of metastatic renal cell carcinoma (mRCC), but consensus regarding its application is lacking. We report an exploratory analysis of prospectively collected specimens prespecified in the only modern clinical trial evaluating AS in mRCC. Whole-exome and RNA sequencing were performed for patients providing consent to identify putative biomarkers associated with time on AS (TAS), the primary endpoint. Log-rank tests and multivariable Cox proportional-hazards models were used for analyses. Patients with mutations in either TP53 or SMARCA4 tumor suppressor genes had shorter TAS (7.5 vs 14.2 mo; log-rank p = 0.004). While these patients exhibited features of aggressive disease clinically, the two-gene model was independently predictive in multivariable analyses (hazard ratio 3.30, 95% confidence interval 1.07-10.18; p = 0.038). In conclusion, insight into the underlying RCC biology improves patient selection for AS. If validated, this two-gene model could help in stratifying patients with mRCC and identifying those who are poor candidates for AS. PATIENT SUMMARY: In this study, we analyzed tumors from patients with metastatic kidney cancer enrolled in a clinical trial of imaging surveillance. We found that tumors with mutations in either the TP53 or SMARCA4 gene progressed faster than tumors without these mutations. Thus, patients harboring mutations in these genes may not be good candidates for AS.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , ADN Helicasas/genética , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/terapia , Biología Molecular , Proteínas Nucleares/genética , Estudios Prospectivos , Estudios Retrospectivos , Factores de Transcripción/genética , Espera VigilanteRESUMEN
BACKGROUND: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy. METHODS: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. RESULTS: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS. CONCLUSION: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Antígeno B7-H1/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Antígeno CTLA-4/uso terapéutico , Factores de Transcripción Forkhead , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/farmacología , Ipilimumab/uso terapéutico , Neoplasias Renales/patología , Nivolumab/farmacología , Nivolumab/uso terapéutico , Estudios Retrospectivos , Microambiente TumoralRESUMEN
While immune checkpoint inhibitors (ICI) can lead to sustained responses in metastatic renal cell carcinoma (mRCC), the optimal duration of therapy remains unknown. We aimed to examine treatment-free survival (TFS) in objective responders who discontinued ICI and to explore factors that may impact objective response rate (ORR) and TFS. MEDLINE/PubMed, Embase, and the Cochrane Library were searched for prospective studies reporting individual outcomes after ICI discontinuation in patients with mRCC. Pooled ORR and TFS were estimated using random-effects meta-analyses, and associations between ICI regimen type or treatment line and ORR or TFS were evaluated. Sixteen cohorts comprising 1833 patients treated with ICI were included. The pooled ORR was 43% (95% CI 33% to 53%), and significant differences in summary estimates existed among patients who received ICI monotherapy (22%, 95% CI 18% to 26%), ICI plus a vascular endothelial growth factor (VEGF) pathway inhibitor (57%, 95% CI 48% to 65%), and dual ICI (40%, 95% CI 36% to 44%). Of 572 responders who had available data, 327 stopped ICI, with 86 (26%) continuing to respond off-treatment. Pooled TFS rates at 6 and 12 months were 35% (95% CI 20% to 50%) and 20% (95% CI 8% to 35%), respectively, and were highest for responders treated with dual ICI and lowest for those treated with ICI plus a VEGF pathway inhibitor. Thus, a subset of patients with mRCC who are treated with ICI-based therapy can have durable TFS after therapy discontinuation. Prospective clinical trials and biomarkers are needed to identify patients who can discontinue ICI therapy without compromising clinical outcomes.
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Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
There have been significant advances in the treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy (IO)-based combinations as the standard-of-care treatment in the front-line setting. IO in this setting is paired with another IO agent or with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI). One IO/IO combination and four IO/TKI combinations are currently approved. However, the role of the salvage IO in patients with disease progression on TKI monotherapy is uncertain. Here, we present a case series of five patients who were on single-agent TKI therapy for treatment-refractory mRCC and upon disease progression had an IO agent added to their TKI. The median duration of TKI monotherapy was 11.2 months (range, 1.7-31.1 months), and the median duration of response after the addition of IO was 4 months (range, 2.8-10.5 months). Although IO salvage therapy has a plausible rationale, this case series did not show a clear benefit to this approach. Further clinical trials are needed to determine the clinical utility of IO salvage therapy in mRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Humanos , Inmunoterapia , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Terapia Recuperativa , Factor A de Crecimiento Endotelial Vascular/uso terapéuticoRESUMEN
The role and timing of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving immunotherapy-based regimens is unclear. However, the ability to achieve a complete response for metastatic renal cell carcinoma likely requires a nephrectomy at some point during treatment. Here we present a case series of three patients with metastatic clear-cell renal-cell carcinoma who received front-line immunotherapy-based treatment and subsequently underwent a cytoreductive nephrectomy. All three patients had a complete response to therapy and have subsequently remained off systemic therapy for a median of 531 days (range, 476-602). We also review the limited literature in this setting and highlight ongoing clinical trials. Although the role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving immunotherapy-based treatment is uncertain, a subset of patients will benefit from either an immediate or deferred cytoreductive nephrectomy. Ongoing trials are underway to further determine how to incorporate cytoreductive nephrectomy into the treatment paradigm for patients with metastatic renal cell carcinoma.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/terapia , Procedimientos Quirúrgicos de Citorreducción , Humanos , Inmunoterapia , Neoplasias Renales/cirugía , NefrectomíaRESUMEN
BACKGROUND: Bone metastases (BM) in renal cell carcinoma (RCC) patients are associated with poor outcomes. There are limited published data on outcomes in these patients with immunotherapy agents. We present a multi-institutional, retrospective analysis of metastatic RCC patients with BM treated with ipilimumab and nivolumab (I + N). OBJECTIVE: Patient, tumor, and treatment-related variables were retrospectively collected from electronic medical records of patients with a histologically confirmed diagnosis of RCC and at least one radiographically confirmed BM prior to initiation of I + N. Best objective response was assessed by clinical chart review, imaging reports, and treating physician evaluation; progression-free survival (PFS) and overall survival (OS) were recorded as of 31 December 2020. Descriptive statistics were used to summarize patient characteristics and BM-related variables. Kaplan-Meier method and Mantel-Haenszel log-rank test were used to compare survival among groups. Cox regression univariable and multivariable models were used to correlate patient- and treatment-related variables to outcomes. RESULTS: Eighty patients with RCC and BM treated with I + N were identified. Patients were predominantly male and Caucasian presenting primarily with IMDC intermediate or poor-risk clear-cell RCC. Best response to I + N was progressive disease (46%), stable disease (28%), partial response (21%), and not evaluable (5%). Median PFS was 6.1 months (95% CI 3.8-8.9 months) with the majority of patients (65%) discontinuing I + N due to disease progression. Median OS was 25.6 months (95% CI 14.9-NA) with median follow-up of 25.2 months. A multivariable regression model for PFS showed several variables to be significantly associated with worse PFS including female gender [p = 0.02; hazard ratio (HR) 2.16; 95% CI 1.14-4.12], metastases to other sites (p = 0.006; HR 2.12; 95% CI 1.24-3.62) and presence of BM to ribs (p = 0.0007; HR 2.61; 95% CI 1.50-4.52). A multivariable Cox model of OS showed no prior radiation therapy to BM (p = 0.02; HR 2.17; 95% CI 1.13-4.17) and presence of liver metastases (p = 0.0006; HR 3.19; 95% CI 1.65-6.19) to be significantly associated with worse OS. CONCLUSION: RCC patients with ≥ 1 BM who received I + N therapy had a relatively low response rate, PFS, and OS. Strategies to improve outcomes in this subset of patients are needed.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Ipilimumab/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Masculino , Nivolumab/farmacología , Nivolumab/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: Metastatic renal cell carcinoma (mRCC) is associated with a high risk of thromboembolism (TE). OBJECTIVE: We investigated whether immunotherapy (IO) increases the hypercoagulable state in this high-risk population. PATIENTS AND METHODS: Patients with mRCC treated with IO between 1 January 2015 and 31 December 2019 at the Cleveland Clinic were identified. Cumulative incidence analysis calculated TE rates over time and Gray's test determined differences in TE rates among groups. The Kaplan-Meier method estimated survival, while Cox proportional hazard regression evaluated the impact of TE on OS. RESULTS: Of 351 patients, 75% were men with clear cell mRCC (81%) and International Metastatic Renal Cell Carcinoma (IMDC) intermediate- to poor-risk disease (77%). Patients received single-agent IO (52%), doublet IO (31%), or IO with non-IO therapy (17%). The median number of IO doses was 8 (range 1-81). At a median follow-up of 12.8 months, 12% of patients (n = 43) had a TE event (venous n = 37 [11%], arterial n = 6 [2%]). The cumulative TE incidence at 6 months was 4.4% (95% confidence interval [CI] 2.6-6.9) and 9.8% (95% CI 6.8-13.4) at 12 months. No factors, including IMDC or Khorana score, were identified to predict TE development. Seventy-two percent of TE resulted in hospitalization (9% TE-related mortality and 21% TE-related dose delay). TE (p < 0.0001), poor IMDC score (p < 0.0001), and Khorana score ≥ 2 (p < 0.0001) were associated with worse OS. CONCLUSIONS: Patients with mRCC treated with IO had a high incidence of TE. TE was associated with risk of treatment delay, hospitalization, and mortality, while TE, IMDC poor risk, and Khorana score ≥ 2 were associated with worse survival. Further investigations into IO-associated TE are needed to identify benefit from primary thromboprophylaxis.
Patients with advanced renal cell carcinoma carry an increased risk of clotting, both in their arteries and veins. Historically, risk scores such as the Khorana score were used to assess which patients with solid tumors would benefit from preventative blood thinning medications as they undergo chemotherapy. Whether the Khorana score can be applied to use with immunotherapy is not known. Currently, limited knowledge exists of the impact of immunotherapy on additional clotting in patients with renal cell carcinoma. This study shows an increased incidence of clotting under immunotherapy treatment in patients with advanced renal cancer compared with rates seen in the literature. This study highlights an associated risk of hospitalization, need to stop cancer therapy, as well as risk of death from clotting. Additionally, we determine that clotting, poor disease pathology (as assessed by the International Metastatic Renal Cell Carcinoma Database Consortium), and a Khorana score of ≥2 are predictors of a worse overall survival. This information will be useful in future studies that will address the usefulness of preventative blood thinner medications in this high-risk population.
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Carcinoma de Células Renales , Neoplasias Renales , Tromboembolia Venosa , Anticoagulantes/uso terapéutico , Carcinoma de Células Renales/patología , Femenino , Humanos , Inmunoterapia , Neoplasias Renales/patología , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher's exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0-35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/secundario , Carcinoma de Células Renales/tratamiento farmacológico , Ipilimumab/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Nivolumab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Femenino , Humanos , Ipilimumab/farmacología , Masculino , Metástasis de la Neoplasia , Nivolumab/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND: Prostate-specific antigen screening is controversial. In 2008, the United States Preventive Services Task Force recommended against screening men aged ≥ 75 years, and in 2012, expanded this to include all men. The impact of these changes continues to unfold. We hypothesized that these screening changes could delay the diagnosis of advanced prostate cancer. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify men (age, 55-69 years) diagnosed with prostate cancer in 2004 to 2008 (group 1), 2009 to 2012 (group 2), and 2013 to 2015 (group 3). Groups reflect United States Preventive Services Task Force guideline changes. Descriptive statistics were used to present baseline statistics and the number of patients diagnosed in aforementioned groups. Data was adjusted for population growth. RESULTS: A total of 328,586 men were identified (group 1, 135,625; group 2, 117,979; group 3, 74,982). The average number of men diagnosed annually with N1M0 (group 1, 381; group 2, 477; group 3, 660) and M1 (group 1, 523; group 2, 761; group 3, 1037) disease increased. With group 1 as control, there was a decrease in the incidence of localized disease (group 2, 9.2%; group 3, 33.2%). However, the incidence of N1M0 (group 2, 5.3%; group 3, 30.1%) and M1 disease (group 2, 22.6%; group 3, 49.2%) increased. Separate analyses of patients (age 50-75 years) and African Americans showed similar trends. CONCLUSION: With each recommendation, there was increased incidence of de novo metastatic prostate cancer. The sequelae of advanced disease include financial, emotional, and physical burden. Future studies are needed to identify screening strategies that reduce the risk of developing metastatic disease without over-diagnosing indolent cancers.
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Detección Precoz del Cáncer , Neoplasias de la Próstata , Comités Consultivos , Negro o Afroamericano , Anciano , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by an expanding armamentarium of systemic therapies, which have resulted in improved patient outcomes. Multimodal approaches that include cytoreductive nephrectomy (CN), immunotherapy, and targeted therapy are necessary to optimize clinical care. Active surveillance (AS) and CN are two cornerstones of treatment in mRCC, which require reexamination in the context of new systemic therapies. Herein, we review the data and provide a practical approach for the incorporation of AS and CN in the management of mRCC.