RESUMO
BACKGROUND: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC. METHODS: ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%). CONCLUSIONS: Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Sulfonamidas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Método Duplo-Cego , Pessoa de Meia-Idade , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Adulto , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , OximasRESUMO
WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan. WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).
RESUMO
BACKGROUND: Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry. METHODS: Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa). RESULTS: HGPCa are highly infiltrated by exhausted CD8+ T cells, myeloid cells, and regulatory T cells (TRegs). These HGPCa-infiltrating CD8+ T cells expressed high levels of exhaustion markers including TIM3, TOX, TCF7, PD-1, CTLA4, TIGIT, and CXCL13. By contrast, a high ratio of activated CD8+ effector T cells relative to TRegs and myeloid cells infiltrate the TME of LGPCa. HGPCa CD8+ tumor-infiltrating lymphocytes (TILs) expressed more androgen receptor and prostate-specific membran antigen yet less prostate-specific antigen than the LGPCa CD8+ TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers. CONCLUSIONS: Our study reveals a suppressive TME with high levels of CD8+ T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias da Próstata , Masculino , Humanos , Gradação de Tumores , Linfócitos T CD8-Positivos/patologia , Neoplasias da Próstata/patologia , Próstata/patologia , Antígeno Prostático Específico , Linfócitos do Interstício Tumoral , Imunossupressores , Análise de Célula Única , Microambiente TumoralRESUMO
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).
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Axitinibe/efeitos adversos , Neoplasias Renais/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. INTERPRETATION: Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. FUNDING: Merck Sharp & Dohme.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Carcinoma in Situ/tratamento farmacológico , Carcinoma Papilar/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma in Situ/imunologia , Carcinoma in Situ/patologia , Carcinoma Papilar/imunologia , Carcinoma Papilar/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. METHODS: EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. FINDINGS: Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. INTERPRETATION: Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. FUNDING: Astellas Pharma Global Development and Seagen.
Assuntos
Antígeno B7-H1/genética , Carcinoma/tratamento farmacológico , Moléculas de Adesão Celular/genética , Receptor de Morte Celular Programada 1/genética , Neoplasias Urológicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Carcinoma/genética , Carcinoma/patologia , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Urotélio/efeitos dos fármacos , Urotélio/patologiaRESUMO
The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Projetos de Pesquisa , Neoplasias Urológicas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Cisplatino/administração & dosagem , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/análogos & derivados , Terapia de Alvo Molecular , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prognóstico , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/etiologia , Neoplasias Urológicas/mortalidadeRESUMO
PURPOSE: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC-oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab. RESULTS: All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8-76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5' fusion partner ZC3H4. CONCLUSIONS: We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC-oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care.
Assuntos
Genômica , Perda de Heterozigosidade/genética , Neoplasias de Células Epitelioides Perivasculares/genética , Adolescente , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Criança , DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neoplasias de Células Epitelioides Perivasculares/patologia , Proteínas Proto-Oncogênicas , RNA/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor , Adulto JovemRESUMO
Neoadjuvant cisplatin-based chemotherapy (NAC; 70 mg/m2) is standard of care for muscle-invasive bladder carcinoma (MIBC). Many patients (pts) cannot receive cisplatin because of renal impairment, and administration of cisplatin 35 mg/m2 on day 1 + 8 or 1 + 2 (i.e., split schedule) is a commonly used alternative. In this retrospective analysis, we compared complete (pT0) and partial (Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
, Carcinoma de Células de Transição/terapia
, Cisplatino/administração & dosagem
, Terapia Neoadjuvante/métodos
, Neoplasias da Bexiga Urinária/terapia
, Idoso
, Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
, Carcinoma de Células de Transição/patologia
, Cisplatino/efeitos adversos
, Cistectomia
, Feminino
, Humanos
, Rim/efeitos dos fármacos
, Masculino
, Terapia Neoadjuvante/efeitos adversos
, Invasividade Neoplásica/patologia
, Estadiamento de Neoplasias
, Insuficiência Renal/induzido quimicamente
, Insuficiência Renal/epidemiologia
, Insuficiência Renal/prevenção & controle
, Estudos Retrospectivos
, Resultado do Tratamento
, Neoplasias da Bexiga Urinária/patologia
RESUMO
BACKGROUND: Clinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies. METHODS: In this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher's Exact test). The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox's regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC. RESULTS: Of 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p = 0.03), earlier stage at diagnosis (p = 0.04), had no prior nephrectomy (p = 0.04) and no immune-related adverse events (irAE) (p = 0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p = 0.02) and lower neutrophil:lymphocyte ratio (p = 0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p = 0.007) and irAE occurrence (p = 0.02) while improved OS was significantly correlated with overweight BMI (BMI 25-30; p = 0.03) and no brain metastasis (p = 0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS. CONCLUSIONS: Clinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.
Assuntos
Índice de Massa Corporal , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Imunoterapia/efeitos adversos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/imunologia , Bases de Dados Genéticas , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/imunologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Linfócitos T/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE OF REVIEW: Since 2016, five new programmed cell death protein 1/ligand 1 (PD-1/L1) checkpoint inhibitors have been approved for metastatic urothelial carcinoma. This review will summarize the data supporting the widespread use of these agents and highlight areas of ongoing clinical development. RECENT FINDINGS: PD-1/L1 axis inhibition has demonstrated clear superiority to chemotherapy for the treatment of metastatic urothelial cancer in the second-line setting. A multitude of ongoing studies are investigating the feasibility and efficacy of incorporating established and novel immunotherapies into earlier lines of therapy, including non-metastatic muscle-invasive bladder cancer and even non-muscle-invasive disease. Early-phase clinical trials have begun to explore the safety and activity of novel immune-oncology combinations across a range of clinical settings. Immunotherapy has a clearly defined role in the treatment of metastatic urothelial cancer both in the platinum-refractory setting and in the first-line cisplatin-ineligible setting. Ongoing clinical trials will dictate how to best incorporate immunotherapy into earlier lines of therapy and define the safety and activity of novel immunotherapy agents and combinations.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Animais , Humanos , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/secundário , Neoplasias Urológicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células de Transição/sangue , Cisplatino , Contraindicações , Feminino , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Urológicas/sangueRESUMO
BACKGROUND: More than half of all patients with advanced urothelial cancer cannot receive standard, first-line cisplatin-based chemotherapy because of renal dysfunction, poor performance status, or other comorbidities. We assessed the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer. METHODS: In this multicentre, single-arm, phase 2 study (KEYNOTE-052), cisplatin-ineligible patients with advanced urothelial cancer who had not been previously treated with systemic chemotherapy were recruited from 91 academic medical centres in 20 countries. Enrolled patients received intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response (the proportion of patients who achieved complete or partial response) in all patients and by PD-L1 expression status according to the Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by independent central review. PD-L1 expression was assessed in tumour and inflammatory cells from tumour biopsies provided at study entry. Activity and safety were analysed in all patients who received at least one dose of pembrolizumab (all-patients-treated population). This study is registered with ClinicalTrials.gov, number NCT02335424, and follow-up is ongoing. FINDINGS: Between Feb 24, 2015, and Aug 8, 2016, 374 patients were enrolled and 370 patients received at least one dose of pembrolizumab. 89 (24%, 95% CI 20-29) of 370 patients had a centrally assessed objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89 responses were ongoing. Median follow-up was 5 months (IQR 3·0-8·6). A PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab; 42 (38%, 95% CI 29-48) of 110 patients with a combined positive score of 10% or more had a centrally assessed objective response. The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis). INTERPRETATION: First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy. Pembrolizumab in the first-line setting is being further assessed in the phase 3 KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424). FUNDING: Merck & Co.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/mortalidade , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma de Células de Transição/patologia , Cisplatino , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Infusões Intravenosas , Internacionalidade , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Segurança do Paciente , Prognóstico , Estudos Prospectivos , Método Simples-Cego , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Urológicas/patologiaRESUMO
BACKGROUND: Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. METHODS: For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study. INTERPRETATION: Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. FUNDING: F Hoffmann-La Roche Ltd.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mutação/genética , Metástase Neoplásica , Critérios de Avaliação de Resposta em Tumores Sólidos , Resultado do Tratamento , Neoplasias Urológicas/genéticaRESUMO
Urothelial cancer has long been known as a chemotherapy-sensitive disease. However, clinical trial data to date suggest a plateau to the magnitude of benefit from cytotoxic therapy alone. In spite of level 1 evidence supporting cisplatin-based chemotherapy for patients with muscle-invasive and metastatic urothelial cancer, underuse prevails among patients with localized disease and only a modest survival benefit exists in the metastatic setting, although trials have consistently demonstrated that there is a subset of patients who clearly benefit. Recent comprehensive genomic profiling has identified a high prevalence of actionable genomic alterations as well as other potential targets yet to be fully understood. Modern clinical trials must now focus on identifying predictive biomarkers to select those patients who will benefit most from cytotoxic chemotherapy, molecularly targeted therapy, or potentially both.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , DNA de Neoplasias/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Urotélio/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/genética , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Esquema de Medicação , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metotrexato/administração & dosagem , Mutação/efeitos dos fármacos , Terapia Neoadjuvante/métodos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vimblastina/administração & dosagemRESUMO
PURPOSE: To explore associations of whole-lesion histogram diffusion metrics with pathologic findings and subsequent metastatic disease in bladder cancer patients undergoing radical cystectomy. METHODS: Twenty-three bladder cancer patients (21M, 2F; mean 70 ± 11 years) underwent MRI before cystectomy. A volume-of-interest was placed on all slices on the ADC map encompassing each lesion. Whole-lesion mean, kurtosis, and skewness of ADC were calculated and compared with T stage and pelvic nodal status at cystectomy and with subsequent metastasis in 20/25 patients with available follow-up. RESULTS: At cystectomy, 39 % (9/23) were stage T2, 61 % (14/23) ≥T3, and 28 % (5/23) exhibited positive nodes; 35 % (7/20) developed later metastases. Mean ADC was significantly lower in stage ≥T3 than in lower stage tumors (1.20 ± 0.36 × 10(-3) vs. 1.55 ± 0.36 × 10(-3) mm(2)/s; p = 0.044), but showed no association with nodal or metastatic disease (p = 0.362-0.709). Kurtosis was significantly lower in tumors with, compared to without, nodal disease (-0.05 ± 0.29 vs. 0.91 ± 1.16; p = 0.037), and showed a non-significant decrease in tumors with, compared to without, later metastases (0.23 ± 0.63 vs. 0.83 ± 0.89; p = 0.088). Kurtosis was not associated with T stage (p = 0.811), and skew was not associated with any outcome (p = 0.516-0.643). Mean ADC achieved highest AUC for identification of stage ≥T3 (AUC = 0.754 vs. 0.516-0.643 for other metrics). Kurtosis achieved highest AUC for nodal disease (AUC = 0.811 vs. 0.522-0.556 for other metrics) and metastases (AUC = 0.736 vs. 0.516-0.626 for other metrics). Only difference in AUC between skewness and kurtosis for nodal disease was significant (p = 0.031). CONCLUSION: While requiring larger studies, kurtosis has potential to complement mean ADC in bladder cancer prognosis using whole-lesion histogram analysis.
Assuntos
Imagem de Difusão por Ressonância Magnética , Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Taxanes have had a profound impact on the management of genitourinary tumors. In the perioperative and metastatic setting in bladder cancer, taxanes such as paclitaxel have an established role in combination chemotherapy strategies to improve survival. In metastatic prostate cancer, docetaxel was the only treatment, until recently, shown to improve survival after the development of castration resistance. More recently, cabazitaxel, a synthetic taxane derivative, is an effective option after docetaxel failure. In advanced testicular cancer, taxanes play an important role in the management of relapsed disease with the ability to still achieve cure. This chapter will focus on the development and current role of taxanes in the treatment of genitourinary cancers including bladder, prostate, and testis cancers as well as the status of novel agents currently under investigation.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/uso terapêutico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Humanos , MasculinoAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Cistectomia/métodos , Quimioterapia Combinada/métodos , Humanos , Imunoterapia , Interleucina-2/análogos & derivados , Interleucina-2/uso terapêutico , Invasividade Neoplásica , Estadiamento de Neoplasias , Nivolumabe/uso terapêutico , Polietilenoglicóis/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.