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BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogeneous and biologically diverse RCC histologies, including but not limited to papillary, chromophobe, and unclassified subtypes. Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) that demonstrated activity in RCC with clear cell component. The objective of this analysis was to determine the efficacy of tivozanib in histologically unclassified/mixed RCC. METHODS: We identified patients with nccRCC enrolled in Study 201 (NCT00502307) between October 2007 and July 2008. This was a phase II randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGFR-targeted treatment. Clinical outcomes including investigator-assessed objective response rate (ORR), disease control rate (DCR, defined by complete response + partial response + stable disease), and progression-free survival (PFS) were examined. RESULTS: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC: 11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) mixed/unclassified. Of the 46 patients with nccRCC, 38 were continuously treated with tivozanib and the best ORR was 21.1% (confirmed) and 31.6% (confirmed and unconfirmed). The DCR was 73.7% and median PFS was 6.7 months (95% confidence interval, 125-366 days). There were no new safety signals compared to the ITT population. Limitations include the small number of individual nccRCC subtypes and the randomized discontinuation design. CONCLUSION: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. These data add to the body of evidence supporting the use of VEGFR-TKI in advanced nccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Compostos de Fenilureia/efeitos adversos , Receptores Proteína Tirosina Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Fator A de Crescimento do Endotélio VascularRESUMO
BACKGROUND: There are limited data regarding the impact of ethnicity among patients receiving immune checkpoint inhibitors. We evaluated real-world outcomes between Latinx and non-Latinx patients with metastatic renal-cell carcinoma (mRCC) treated with first-line nivolumab/ipilimumab within 2 different healthcare settings. METHODS: We performed a retrospective analysis of patients with mRCC who received nivolumab/ipilimumab within the Los Angeles County Department of Health Services (LAC-DHS), a safety-net healthcare system, and the City of Hope Comprehensive Cancer Center (COH), a tertiary oncology center, between January 1, 2015 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. RESULTS: Of 94 patients, 40 patients (43%) were Latinx while the remainder were non-Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (53%) and 44 (47%) patients received their care at COH and LAC-DHS, respectively. Most Latinx patients (95%) were treated at LAC-DHS, and most non-Latinx patients (89%) were treated at COH. Pooled analysis by ethnicity demonstrated significantly shorter PFS in Latinx versus non-Latinx patients (10.1 vs. 25.2 months, hazard ratios [HR] 3.61, 95% CI 1.96-6.66, P ≤ .01). Multivariate analysis revealed a HR of 3.41 (95% CI 1.31-8.84; P = .01). At a median follow-up of 11.0 months, the median OS was not reached in either arm at the time of data cutoff. CONCLUSION: Latinx patients with mRCC had a shorter PFS treated with frontline nivolumab/ipilimumab compared to their non-Latinx counterparts. No difference was observed in OS although these data were immature. Larger studies are needed to further interrogate the social and economic determinants of ethnicity on clinical outcomes in mRCC.
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Antineoplásicos Imunológicos , Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Humanos , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Hispânico ou Latino , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Nivolumabe/uso terapêutico , Estudos Retrospectivos , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Activating mutations in the mitogen-activated protein kinase (MAPK) pathway represent driver alterations governing tumorigenesis, metastasis, and therapy resistance. MAPK activation predominantly occurs through genomic alterations in RAS and BRAF. BRAF is an effector kinase that functions downstream of RAS and propagates this oncogenic activity through MEK and ERK. Across cancers, BRAF alterations include gain-of-function mutations, copy-number alterations, and structural rearrangements. In cancer patients, BRAF-targeting precision therapeutics are effective against Class I BRAF alterations (p.V600 hotspot mutations) in tumors such as melanomas, thyroid cancers, and colorectal cancers. However, numerous non-Class I BRAF inhibitors are also in development and have been explored in some cancers. Here we discuss the diverse forms of BRAF alterations found in human cancers and the strategies to inhibit them in patients harboring cancers of distinct origins.
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Terapia de Alvo Molecular , Neoplasias , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Animais , Sistema de Sinalização das MAP Quinases/genéticaRESUMO
INTRODUCTION: Patients with synchronous (de novo) metastatic castration-sensitive prostate cancer appear to have worse survival outcomes and shorter time to develop castration resistance than patients with metachronous disease. However, the impact of synchronous metastasis on outcomes in metastatic castration-resistant prostate cancer (mCRPC) setting is unknown in patients without prior exposure to androgen receptor pathway inhibitors (ARPIs). In this study, we assessed the impact of initial timing of metastasis (synchronous vs metachronous) on survival outcomes of patients with new-onset mCRPC in a real-world population treated with first-line abiraterone or enzalutamide. METHODS: Data were collected retrospectively from 323 patients with a confirmed diagnosis of mCRPC who received ARPIs as first-line therapy and had no prior exposure to ARPIs. The study endpoints were progression-free survival and overall survival. RESULTS: The results showed that median overall survival was significantly shorter in patients with synchronous disease than those with metachronous disease (26 vs 38.7 months, HR 1.42, 95% CI 1.09-1.86, P = .011). However, there was no difference in median progression-free survival. CONCLUSIONS: The initial presentation with synchronous metastasis remained an independent factor associated with shorter OS in the multivariable analysis. These hypothesis-generating data, after external validation, may have implications in patient counseling, prognostication, and design of future clinical trials in the new-onset mCRPC setting.
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Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Antagonistas de Receptores de Andrógenos/uso terapêutico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/metabolismo , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: The impact of time of metastasis onset with respect toprimary renal cell carcinoma (RCC) diagnosis on survival outcomes is not well characterized in the era of immune checkpoint inhibitor (ICI)-based combinations. Herein, we assessed differences in clinical outcomes between synchronous and metachronous metastatic RCC (mRCC). METHODS: Data for patients with mRCC treated with first-line ICI-based combination therapies between 2014 and 2023 were retrospectively collected. Patients were categorized as having synchronous metastasis if present within 3 mo of RCC diagnosis; metachronous metastasis was defined as metastasis >3 mo after primary diagnosis. Time to treatment failure (TTF), overall survival (OS), and the disease control rate (DCR) were assessed. KEY FINDINGS AND LIMITATIONS: Our analysis included 223 eligible patients (126 synchronous and 97 metachronous). Median TTF did not significantly differ between the synchronous and metachronous groups (9 vs 19.8 mo; p = 0.063). Median OS was significantly shorter in the synchronous group (28.0 vs 50.9 mo; p = 0.001). Similarly, patients with synchronous metachronous metastasis (58.7% vs. 78.4%; p = 0.002). On multivariable analyses, synchronous metastasis remained independently associated with worse OS and DCR. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this hypothesis-generating study, patients with mRCC with synchronous metastasis who were treated with first-line ICI-based combinations have a poorer OS and worse DCR than those with metachronous mRCC. If these results are externally validated, time to metastasis could be included in prognostic models for mRCC. PATIENT SUMMARY: Our study demonstrates that patients treated with current first-line immunotherapies, who present with metastasis at the initial diagnosis of kidney cancer have worse overall survival compared to those who develop metastasis later. These results can help physicians and patients understand life expectancy.
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Importance: While an overwhelming majority of patients diagnosed with cancer express willingness to participate in clinical trials, only a fraction will enroll onto a research protocol. Objective: To identify critical barriers to trial enrollment to translate findings into actionable practice changes that increase cancer clinical trial enrollment. Design, Setting, and Participants: This survey study included designated site contacts at oncology practices with teams who were highly involved with the Association of Community Cancer Centers (ACCC) Community Oncology Research Institute (ACORI) clinical trials activities, all American Society of Clinical Oncology (ASCO)-ACCC collaboration pilot sites, and/or sites providing care to at least 25% African American and Hispanic residents. To determine participation trends among health care practices in oncology-focused research, identify barriers to clinical trial implementation and operation, and establish unmet needs for cancer clinics interested in trial participation, a 34-question survey was designed. Survey questions were defined within 3 categories: cancer center demographic characteristics, clinical trial characteristics, and referral practices. The survey was distributed through email and was open from June 20 through October 5, 2022. Main Outcomes and Measures: Participation in and barriers to conducting oncology trials in different community oncology settings. Results: The survey was distributed to 100 cancer centers, with completion by 58 centers (58%) across 25 states. Fifty-two centers (88%) reported that they conduct therapeutic clinical trials, of which 33 (63%) were from urban settings, 11 (21%) were from suburban settings, and 8 (15%) were from rural settings. Only 25% of rural practices (2 of 8) offered phase 1 trials, compared with 67% of urban practices (22 of 33) (P = .01). Respondents noted challenges in conducting research, including patient recruitment (27 respondents [52%]), limited staffing (27 [52%]), and nonrelevant trials for their patient population (25 [48%]). Among sites not offering therapeutic trials, barriers to research conduct included limited infrastructure, funding, and staffing. Most centers (46 of 58 [79%]) referred patients to outside centers for clinical trial enrollment, particularly in the context of late-stage disease and/or disease progression. Only 17 of these sites (37%) had established protocols for patient follow-up subsequent to outside referral. Conclusions and Relevance: In this national survey study of barriers to clinical trial implementation, most sites offered therapeutic trials, but there were significant disparities in trial availability across care settings. Furthermore, fundamental deficiencies in trial support infrastructure limited research activity, including within programs currently conducting research as well as at sites interested in future clinical research opportunities. These results identify crucial unmet needs for oncology clinics to effectively offer clinical trials to patients seeking care.
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Ensaios Clínicos como Assunto , Humanos , Inquéritos e Questionários , Neoplasias/terapia , Seleção de Pacientes , Centros Comunitários de Saúde/estatística & dados numéricos , Estados Unidos , Institutos de Câncer/estatística & dados numéricos , FemininoRESUMO
Papillary renal cell carcinoma (pRCC) is the second-most common subtype of kidney cancer following clear cell renal cell carcinoma (ccRCC), representing 15% of kidney cancers. Despite advances in therapy, including combination strategies with targeted therapies and immune checkpoint inhibitors, progress has lagged behind that of ccRCC. This is in part due to the heterogenous nature of the various subtypes of pRCC. More recently, investigators have turned efforts towards histology and biology-based trials. In this review, we outline some of the distinct biological characteristics of pRCC and discuss the most impactful clinical trials to date. Finally, we look ahead to several highly anticipated ongoing trials in pRCC.
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BACKGROUND: Recently data suggest that telomerase reverse transcripatase (TERT) promoter mutations portend superior outcomes with immune checkpoint inhibitor (ICI) therapy in mUC. In our retrospective analysis from 2 tertiary cancer centers, we assessed the predictive role of TERT mutations along with other parameters. METHODS: Patient registries were queried for patients treated with ICI for mUC with available genomic and clinical data. Select clinical and laboratory parameters, in addition to primary tumor site, histology, treatment modality, and setting were recorded. Tumor mutational burden (TMB), and mutational status of TERT, CDKN2A, CDKN2B, TMB, TP53, RB1, KMT2D, ARID1A, ERBB2, KDM6A, PIK3CA, FGFR3, and ATM were noted. Univariate analysis of significance concerning overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) was conducted. RESULTS: In total, 113 patients were found to meet inclusion criteria. In our study, ORR was 55%, median PFS was 5.1 months (0.2-71.8), and median OS was 13.4 months (0.2-84.8). On univariate analysis, female sex, NLR>5, and ATM mutation were associated with inferior PFS and OS, whereas upper tract primary disease and ECOG score ≥ 2 were associated with worse OS. On multivariate analysis, NLR >5 was associated with worse PFS and OS whereas upper tract primary disease, albumin <3.4 g/dL, hemoglobin <10 g/dL and ATM mutation were significantly associated with worse OS on multivariate analysis. No significant differences were seen in ORR, PFS, or OS regarding TERT promoter mutations. CONCLUSION: TERT promoter mutations were not significantly associated with any difference in outcome in patients treated with ICI.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma de Células de Transição/patologia , Prognóstico , Estudos Retrospectivos , Biomarcadores Tumorais/genética , GenômicaRESUMO
Introduction: Immune checkpoint blockade (ICB) improved clinical outcomes in renal and bladder cancer patients, but the response rates remain limited especially in metastatic disease. While STAT3 transcription factor is well-known master regulator of tumor immune evasion, little is known about the role of STAT3 in the resistance of renal or bladder cancers to immunotherapy. Methods: To better understand immune alterations associated with ICB resistance, we assessed blood biomarkers in renal cancer patients classified as responders or non-responders to first line nivolumab/ipilimumab immunotherapy. Results: We observed that non-responders showed elevated levels of proinflammatory mediators, such as IL-1RA, IL-6, IL-8 and to lesser extent IL-10, which are associated with STAT3 activation and tumor immunosuppression. In addition, we found STAT3 activation primarily in circulating myeloid immune cells such as tolerogenic MDSCs. To assess whether STAT3 inhibition within these cell subsets can promote antitumor immune responses and/or enhance sensitivity to ICB in vivo, we used an original antisense oligonucleotide (ASO) strategy for myeloid-cell selective STAT3 knockdown (CpG-STAT3ASO). Our results in syngeneic models of renal and bladder cancers in mice demonstrated potent antitumor activity of CpG-STAT3ASO alone in contrast to PD1 blockade alone in both models. The CpG-STAT3ASO/anti-PD1 combination improved therapeutic efficacy especially against bladder tumors. Therapeutic efficacy correlated with activation of dendritic cells (DCs) and M1 macrophages in the tumor microenvironment, reduced percentages of regulatory T cells (Tregs) and the expansion of CD8 T cells in both tumor models. Discussion/Conclusion: Our study underscores the potential of using myeloid-cell targeted CpG-STAT3 inhibitors for genitourinary cancer therapy to disrupt tolerogenic signaling, restore immune cell activity and sensitivity to immune checkpoint inhibitors and/or T cell-based immunotherapies.
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Neoplasias Renais , Neoplasias da Bexiga Urinária , Humanos , Animais , Camundongos , Fator de Transcrição STAT3 , Neoplasias da Bexiga Urinária/terapia , Imunoterapia , Rim , Neoplasias Renais/terapia , Células Apresentadoras de Antígenos , Microambiente TumoralRESUMO
PURPOSE: Circulating tumor DNA (ctDNA) has been validated across multiple indications in the adjuvant and surveillance settings. We evaluated whether targeted digital sequencing (TARDIS) may distinguish a partial response (PR) from a complete response (CR) among patients with metastatic renal cell carcinoma (mRCC) receiving immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: Eligible patients had mRCC that yielded a PR or CR to ICI therapy. Peripheral blood was obtained at a single time point for ctDNA analysis. TARDIS was used for quantification of average variant allele fractions (VAFs). Our primary objective was to determine the association between VAFs and depth of response (PR v CR). A secondary objective was to determine whether VAFs were associated with disease progression. RESULTS: Twelve patients were analyzed, nine of whom achieved a PR (75%). Patients received either nivolumab monotherapy (50%) or nivolumab plus ipilimumab (50%). ctDNA analysis incorporated an average of 30 patient-specific mutations (range, 19-35); average coverage depth was 103,342 reads per target. TARDIS quantified a significant difference in VAFs between PR and CR (median, 0.181% [IQR, 0.077%-0.420%] v 0.007% [IQR, 0.0%-0.028%], respectively [P = .014]). Of the 12 patients in the series, six patients demonstrated radiographic progression subsequent to ctDNA assessment. Patients who progressed on subsequent scans had significantly higher ctDNA than those who maintained their response (median, 0.362% [IQR, 0.181%-2.71%] v 0.033% [IQR, 0.007%-0.077%], respectively [P = .026]). CONCLUSION: In this pilot study, TARDIS accurately differentiated PR from CR among patients with mRCC receiving immunotherapy, and also prospectively identified patients at risk for subsequent progression. Given these findings, we envision subsequent studies that validate these results and investigate the utility of this assay to discern appropriate candidates for discontinuation of immunotherapy.
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Carcinoma de Células Renais , DNA Tumoral Circulante , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , DNA Tumoral Circulante/genética , Nivolumabe/uso terapêutico , Projetos Piloto , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Imunoterapia/métodosRESUMO
PURPOSE: Eligibility criteria illustrate the characteristics of the study population and promote the safety of participants. However, overreliance on restrictive eligibility criteria may limit the generalizability of outcomes. As a result, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) issued statements to curtail these challenges. In this study, we aimed to assess restrictiveness in eligibility criteria across advanced prostate cancer clinical trials. MATERIALS AND METHODS: We identified all phase I, II, and III advanced prostate cancer clinical trials between June 30, 2012, and June 30, 2022, through Clinicaltrials.gov. We evaluated whether a clinical trial excluded, conditionally included, or did not report 4 common criteria: brain metastases, prior or concurrent malignancies, HIV infection, and hepatitis B virus (HBV)/hepatitis C virus (HCV) infection. Performance status (PS) criteria were recorded based on the Eastern Cooperative Oncology Group (ECOG) scale. RESULTS: Out of 699 clinical trials within our search strategy, 265 (37.9%) trials possessed all the required data and were included in our analysis. The most common excluded condition of our interest was brain metastases (60.8%), followed by HIV positivity (46.4%), HBV/HCV positivity (46.0%), and concurrent malignancies (15.5%). Additionally, 50.9% of clinical trials only included patients with ECOG PS 0 to 1. HIV and HBV/HCV infection were exclusion criteria of 22 (80.8%) and 19 (73.1%) immunotherapy trials, respectively. CONCLUSION: Patients with brain metastases, prior or concurrent malignancies, HIV infection, HBV/HCV infection, or low-functioning PS were overly restricted from participating in advanced prostate clinical trials. Advocating for broader criteria may ameliorate generalizability.
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Neoplasias Encefálicas , Infecções por HIV , Hepatite C , Neoplasias da Próstata , Masculino , Humanos , Infecções por HIV/tratamento farmacológico , Amigos , Neoplasias da Próstata/terapia , OncologiaRESUMO
Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for metastatic UCC. Even with these treatments the median overall survival is estimated to be about 15 months. Recently, immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment. However only a minority of patients (~20%) respond to ICIs, which highlights the need to better understand the mechanisms behind resistance. In this review, we (i) examine the pathophysiology of Wnt/ß-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/ß-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through clinical trials.
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BACKGROUND: Circulating cytokines and angiogenic factors have been associated with clinical outcomes in patients with metastatic renal cell carcinoma (RCC) receiving systemic therapy. However, none have yet examined cytokine concentrations in parallel cohorts receiving either immunotherapy or targeted therapy. METHODS: In this prospective correlative study, we enrolled 56 patients who were planned for treatment with either a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Eligibility requirements permitted any RCC histologic subtype, International Metastatic Renal Cell Carcinoma risk classification, and line of therapy. Immunologic profile was assessed at baseline and after 1 month on treatment using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit was defined as complete response, partial response, or stable disease ≥6 months per RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria. RESULTS: Clinical benefit was similar between VEGF-TKI and ICI arms (65% vs 54%). Patients with clinical benefit from VEGF-TKIs had lower pretreatment levels of interleukin-6 (IL-6) (p=0.02), IL-1RA (p=0.03), and granulocyte colony-stimulating factor (CSF) (p=0.02). At 1 month, patients with clinical benefit from ICIs had higher levels of interferon-γ (IFN-γ) (p=0.04) and IL-12 (p=0.03). Among patients on VEGF-TKIs, those with clinical benefit had lower 1 month IL-13 (p=0.02) and granulocyte macrophage CSF (p=0.01) as well as higher 1 month VEGF (p=0.04) compared with patients with no clinical benefit. CONCLUSION: For patients receiving VEGF-TKI or ICI therapy, distinct plasma cytokines were associated with clinical benefit. Our findings support additional investigation into plasma cytokines as biomarkers in metastatic RCC.
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Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Citocinas/sangue , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/secundário , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Renais/sangue , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Valor Preditivo dos Testes , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Tertiary cancer centers offer clinical expertise and multi-modal approaches to treatment alongside the integration of research protocols. Nevertheless, most patients receive their cancer care at community practices. A better understanding of the relationships between tertiary and community practice environments may enhance collaborations and advance patient care. METHODS: A 31-item survey was distributed to community and tertiary oncologists in Southern California using REDCap. Survey questions assessed the following attributes: demographics and features of clinical practice, referral patterns, availability and knowledge of clinical trials and precision medicine, strategies for knowledge acquisition, and integration of community and tertiary practices. RESULTS: The survey was distributed to 98 oncologists, 85 (87%) of whom completed it. In total, 52 (61%) respondents were community practitioners and 33 (38%) were tertiary oncologists. A majority (56%) of community oncologists defined themselves as general oncologists, whereas almost all (97%) tertiary oncologists reported a subspecialty. Clinical trial availability was the most common reason for patient referrals to tertiary centers (73%). The most frequent barrier to tertiary referral was financial considerations (59%). Clinical trials were offered by 97% of tertiary practitioners compared to 67% of community oncologists (p = 0.001). Most oncologists (82%) reported only a minimal-to-moderate understanding of clinical trials available at regional tertiary centers. CONCLUSIONS: Community oncologists refer patients to tertiary centers primarily with the intent of clinical trial enrollment; however, significant gaps exist in their knowledge of trial availability. Our results identify the need for enhanced communication and collaboration between community and tertiary providers to expand patients' access to clinical trials.
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Colaboração Intersetorial , Neoplasias/terapia , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude do Pessoal de Saúde , California , Institutos de Câncer/organização & administração , Institutos de Câncer/estatística & dados numéricos , Ensaios Clínicos como Assunto , Comunicação , Feminino , Hospitais Comunitários/organização & administração , Hospitais Comunitários/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Oncologistas/estatística & dados numéricos , Encaminhamento e Consulta/organização & administração , Inquéritos e Questionários/estatística & dados numéricos , Centros de Atenção Terciária/organização & administração , Centros de Atenção Terciária/estatística & dados numéricosRESUMO
PURPOSE: The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC. EXPERIMENTAL DESIGN: Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed. RESULTS: ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays. CONCLUSIONS: This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.
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Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/genética , DNA Tumoral Circulante/sangue , Neoplasias Renais/sangue , Neoplasias Renais/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/secundário , Feminino , Genoma , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Recent therapeutic advancements have incorporated immune checkpoint inhibitors (ICIs) into the management of metastatic renal cell carcinoma. Pivotal phase III trials have resulted in Food and Drug Administration approval for anti-programmed death 1/programmed death ligand 1 ICIs, either in combination with anti-cytotoxic T-lymphocyte antigen 4 ICIs or with vascular endothelial growth factor-directed targeted therapies, as standard-of-care frontline regimens. Immune checkpoint inhibitors offer improved clinical outcomes when compared to previous treatment options. However, these agents also present unique toxicity profiles collectively referred to as immune-related adverse events. Common immune-related adverse events include colitis, hepatitis, dermatitis, and thyroiditis. Rare toxicities, such as myocarditis and pneumonitis, have the potential for causing severe harm. Herein, we provide a case-based discussion of how to identify, grade, and manage irAEs in metastatic renal cell carcinoma.
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Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
There is growing interest in identifying predictive biomarkers for inhibitors of programmed cell death protein 1 receptor (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Given the links between the stool microbiota, anticancer immunosurveillance, and general health, the composition of the gut microbiome has recently undergone investigation as a biomarker for immunotherapy. In this review, we highlight published results from preclinical and clinical studies to date supporting a relationship between the gut microbiome and antitumor efficacy of immune checkpoint inhibitors. Despite the promising and hypothesis-generating findings that have been produced in this arena to date, there remain some inconsistencies amongst present data that may need to be resolved to contribute to further development. Among these, a better understanding of the immunomodulatory function of the microbiome, standardization in sampling, sequencing techniques, and data analysis, and ensuring uniformity across various aspects of study design are warranted in conducting future prospective studies seeking to validate the gut microbiome as a potential biomarker of response to checkpoint blockade.
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Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy.