Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma and End-stage Renal Disease at 2 Centers

IntroductionThere is scarce information regarding nivolumab treatment for metastatic renal cell carcinoma (mRCC) in patients with end-stage renal disease (ESRD). This study investigated the safety and efficacy of nivolumab in patients with mRCC and ESRD.Materials and MethodsThis 2-center retrospective study evaluated 62 patients who were administered nivolumab for mRCC between June 2013 and August 2018. The ESRD group (n = 7) and non-ESRD group (n = 55) were compared in terms of their immune-related adverse events (irAEs), objective response rate, progression-free survival, and overall survival.ResultsAll 7 patients with ESRD were male (median age, 67 years; range, 52-73 years), and their median duration of nivolumab use was 6.0 months (range, 1.8-8.2 months). One patient experienced a partial response, and 4 patients had stable disease. The objective response rate was lower in the ESRD group than in the non-ESRD group (16.7% vs. 37.5%; P = .25). Relative to the non-ESRD group, the ESRD group had slightly lower rates of all irAEs (42.9% vs. 58.7%) and grade 3 or higher irAEs (14.3% vs. 21.7%). The irAEs in the ESRD group were skin rash (grade 1), diarrhea (grade 1), and severe fatigue (grade 3) after the first nivolumab infusion, which required treatment discontinuation. The Kapan-Meier curves revealed no significant differences between the ESRD and non-ESRD groups in terms of progression-free (P = .63) and overall survival (P = .62).ConclusionIt may be possible to safely and effectively use nivolumab for select patients with mRCC and ESRD.     

The Necessity of Cytoreductive Nephrectomy in Patients With Metastatic Renal Cell Carcinoma Using Antiangiogenic Targeted Therapy After Interferon Alfa-2b

BackgroundTargeted therapy has improved the survival of patients with metastatic RCC. In the present study, we evaluated whether there was an effect of cytoreductive surgery on prognosis of patients with metastatic RCC using antiangiogenic tyrosine kinase inhibitor (TKI) agents.Patients and MethodsA total of 52 patients with metastatic RCC from Akdeniz University, Afyon Kocatepe University, and Medipol University participated in the study. All the patients had received targeted antiangiogenic therapy after interferon alfa-2b. According to previous CRN, the patients were divided into 2 groups as CRN (+) and CRN (−).ResultsThe CRN (+) group was younger than the CRN (−) group (P < .001) and the hemoglobin levels were significantly higher in the CRN (+) group (P = .023). The median progression-free survival time from the date of starting TKIs were 8.5 and 3.0 months for the CRN (+) and CRN (−) groups, respectively (P = .104). The median overall survival was 15.1 and 5.4 months for the CRN (+) and CRN (−) groups, respectively (P = .034).ConclusionWe speculate that CRN is still an important part of treatment modalities in patients with metastatic RCC in modern era targeted therapy, which is currently the best systemic therapy. However, the indications of CRN might be limited to good-risk patients with metastatic RCC. Further randomized studies are warranted to clarify the necessity of CRN in patients with metastatic RCC.     

Temozolomide as a Single Agent Maintenance Therapy in Elderly Patients With Primary CNS Lymphoma

IntroductionOptimal management of elderly patients with primary central nervous system lymphoma (PCNSL) after induction therapy is unclear. Whole-brain radiotherapy and autologous stem cell transplantation carry increased toxicity in patients older than 60 years of age, which might outweigh the benefits in this group. Temozolomide (TMZ) has established antineoplastic activity in the central nervous system in other disease states, with a favorable toxicity profile.Patients and MethodsWe report efficacy and tolerability in a series of 10 patients treated off-label with TMZ maintenance after completion of R-MPV (rituximab, methotrexate, procarbazine and vincristine) treatment for or primary diagnosed PCNSL.ResultsMedian progression-free survival (PFS) was 57 months, 2-year PFS was 67%, and 5-year PFS was 33%. Median overall survival (OS) was 63 months, 2-year OS was 88%, and 5-year OS was 57%. TMZ was generally well tolerated, with the most common toxicity of Grade 3 or higher being thrombocytopenia in 3 patients (30%).ConclusionThese outcomes suggest that TMZ might have activity for maintenance in elderly patients with PCNSL, when more aggressive treatments are contraindicated.     

Novel Predictive Models of Early Death Less Than 1 Year in Patients With Metastatic Renal Cell Carcinoma After Treatment With First-line Tyrosine Kinase Inhibitors

BackgroundWe aimed to develop a modified International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model that can predict early death less than 1 year in patients with metastatic renal cell carcinoma (mRCC) after receiving first-line tyrosine kinase inhibitors (TKIs).Patients and MethodsWe retrospectively reviewed records of patients with mRCC treated with first-line TKIs at our institution between 2007 and 2012. The primary endpoint was the rate of early death within 1 year after first-line TKI administration. We determined statistically significant factors predicting early death by performing multiple logistic regression. The modified IMDC model 1 was developed using new variables in addition to the risk criteria of the IMDC model, and model 2 was developed using new variables irrespective of the risk classification of IMDC model.ResultsEarly mortality within 1 year of first-line TKI treatment was 19.7% (n = 98) in 462 patients. Although the C-index of the IMDC model for early death was 0.655, the C-index of model 1, which includes 5 variables (previous nephrectomy, body mass index, multiple metastases, previous metastasectomy, and serum albumin level) in addition to the Heng criteria, was 0.823. The C-index of model 2, which includes 7 variables (hemoglobin, neutrophil level, and the 5 variables of model 1) was 0.822. Of note, there was no significant difference in net reclassification index between the 2 models.ConclusionThis is the first study suggesting novel prediction models for early death less than 1 year in patients with mRCC treated with first-line TKI.     

Determinants of Guideline-Based Treatment in Patients With cT1 Bladder Cancer

IntroductionClinical T1 (cT1) bladder cancer is associated with high rates of recurrence, upstaging, and progression. Guidelines recommend that these patients be treated with adjuvant intravesical Bacillus Calmette-Guérin immunotherapy (BCG) or upfront radical cystectomy (RC). We analyzed the National Cancer Database (NCDB) to identify demographic and clinical determinants of guideline-based treatment (GBT) and RC.Patients and MethodsWe identified 47,694 patients in the NCDB with cT1 bladder cancer diagnosed in 2004-2013. Those who did not receive any treatment or underwent primary chemotherapy were excluded. Mixed effects logistic regression adjusted for facility-level variation was used to identify factors associated with receipt of GBT.ResultsThe median age of the cohort was 72 years (interquartile range, 63-79). Of the patients, 22.4% were female, 5.1% were African American, and 2.7% had variant histology. Nearly one-third of patients received GBT: 11,453 (24%) were initially treated with BCG and 3320 (7%) were initially treated with RC. Recent year of diagnosis (odds ratio [OR], 1.67; 95% confidence interval [CI], 1.52-1.85; P < .001), treatment at an academic center (OR, 2.42; 95% CI, 2.27-2.59; P < .001), and private insurance status (OR, 1.41; 95% CI, 1.19-1.66; P < .001) were associated with increased odds of GBT. Of patients who received GBT, variant histology (OR, 5.89; 95% CI, 4.65-7.47; P < .001), and recent year of diagnosis (OR, 1.89; 95% CI, 1.50-2.39; P < .001) were associated with greater odds of RC.ConclusionThere is low treatment-guideline compliance for patients with cT1 disease. However, there appears to be a temporal trend toward increased use of GBT. Efforts should be made to understand why many cT1 bladder cancer patients do not receive GBT.     

Sarcomatoid Renal Cell Carcinoma: Population-Based Study of 879 Patients

BackgroundSarcomatoid renal cell carcinoma (sRCC) constitutes a rare and aggressive subtype of renal cell carcinoma. We aimed to investigate its clinicopathologic characteristics and outcomes at a national level.Patients and MethodsWe accessed the National Cancer Institute's Surveillance, Epidemiology, and End Results database (2010-2015) and extracted data on patients with sRCC. We estimated median, 1-, 3-, and 5-year disease-specific survival (DSS) probabilities after generation of Kaplan-Meier curves and used multivariable regression to evaluate variables associated with nephrectomy and DSS.ResultsA total of 879 patients with sRCC were identified; 60.9% patients had stage IV disease at diagnosis, and the median tumor size was 8.3 cm (interquartile range, 5.5-12 cm). The 5-year DSS were 77.7%, 67.8%, 35.4%, and 3.5% for patients with stage I, II, III, and IV disease at diagnosis, respectively; median DSS was 9 months (interquartile range, 4-42 months) for the entire cohort. Older age (hazard ratio [HR] = 1.01; 95% confidence interval [CI], 1.00-1.02), higher tumor stage (stage III vs. I: HR = 3.81; 95% CI, 2.18-6.67; stage IV vs. I: HR = 9.89; 95% CI, 5.80-16.98), and performance of nephrectomy (HR = 0.53; 95% CI, 0.43-0.66) were found to independently affect DSS.ConclusionIn the largest sRCC cohort to date, we found that most patients present with metastatic disease, and the prognosis for this disease remains extremely poor. Nephrectomy should be considered in all patients with acceptable surgical risk, including cytoreductive nephrectomy in carefully selected patients with metastatic disease.     

Disease Characteristics and Completion of Treatment in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Radium-223 in an International Early Access Program

BackgroundRadium-223 is approved by the US Food and Drug Administration and European Medicines Agency for the treatment of metastatic castration-resistant prostate cancer (mCRPC). There are currently no markers for selecting patients most likely to complete radium-223 treatment.Patients and MethodsIn this phase IIIb, international, single-arm study, patients received radium-223, 55 kBq/kg, every 4 weeks for ≤6 cycles. Primary end points were safety and overall survival. In post hoc analyses patients were grouped according to number of radium-223 injections received (1-4 or 5-6). Associations between baseline covariates and number of injections were investigated.ResultsOf 696 eligible patients, 473 (68%) had received 5 to 6 radium-223 injections and 223 (32%) 1 to 4 injections. Patients with less pain (moderate-severe vs. none-mild, odds ratio [OR], 0.41; P < .0001), lower Eastern Cooperative Oncology Group performance status (≥2 vs. 0-1, OR, 0.51; P = .0074), lower prostate-specific antigen level (>141 μg/L vs. ≤141 μg/L, OR, 0.40; P < .0001), and higher hemoglobin level (<10 g/dL vs. ≥10 g/dL, OR, 0.50; P = .0206) were more likely to receive 5 to 6 than 1 to 4 injections. Median overall survival was not reached and was 6.3 months (95% confidence interval, 5.4-7.4) in patients who had received 5 to 6 and 1 to 4 radium-223 injections, respectively. Adverse events were less common in patients who received 5 to 6 than 1 to 4 injections; anemia was reported in 87 (18%) and 64 (29%) patients, respectively.ConclusionPatients with less advanced mCRPC are more likely to receive 5 to 6 radium-223 injections and to achieve better overall survival. Consideration of baseline and disease characteristics is recommended before initiation of radium-223 treatment.     

Validation of the IMDC Prognostic Model in Patients With Metastatic Renal-Cell Carcinoma Treated With First-Line Axitinib: A Multicenter Retrospective Study

BackgroundThe objective of the study was to validate the characteristics of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model in patients treated with first-line axitinib in clinical practice.Patients and MethodsWe retrospectively evaluated 143 patients with metastatic renal-cell carcinoma who were treated with axitinib as the first-line therapy between October 2008 and February 2019. Overall survival (OS) was evaluated according to the IMDC prognostic model. We investigated the intragroup heterogeneity in the intermediate-risk group and divided these patients according to abnormal C-reactive protein (CRP) levels. An inverse probability of treatment-weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate the effects of the CRP-risk model of OS in the patients in the IMDC intermediate-risk group.ResultsA significant difference in OS was observed in patients in the IMDC intermediate- and poor-risk group, although no significant difference was observed between the IMDC favorable- and intermediate-risk group. Significantly shorter prognosis was observed in patients in the IMDC intermediate-risk group who had 2 risk factors and CRP ≥0.3 mg/dL (inter-high group) than in those with 1 risk factor or 2 risk factors with CRP <0.3 mg/dL (inter-low group). IPTW-adjusted Cox regression analysis revealed significant differences in the OS between the inter-low and inter-high groups.ConclusionThe IMDC prognostic model was active in patients who received first-line axitinib treatment. The combination of CRP value with the number of positive risk factors in the IMDC model might predict prognosis in patients with IMDC intermediate-risk treated with first-line axitinib.     

Immunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma

The incidence of renal-cell carcinoma has been increasing each year, with nearly one third of new cases diagnosed at advanced or metastatic stage. The advent of targeted therapies for metastatic renal-cell carcinoma (mRCC) has underscored the need to subtype tumors according to tumor-immune expression profiles that may more reliably predict treatment outcomes. Over the past 2 decades, several vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors have been the mainstay for first- and second-line treatment of mRCC. Very recently, immunotherapy checkpoint inhibitors have significantly changed the treatment landscape for patients with mRCC, particularly for first-line treatment of intermediate to poor risk mRCC patients. Now, combination immunotherapy as well as combinations of immunotherapy with targeted agents can significantly alter disease outcomes. The field of immuno-oncology for mRCC has unveiled a deeper understanding of the immunoreactivity inherent to these tumors, and as a result combination therapy is evolving as a first-line modality. This review provides a timeline of advances and controversies in first-line treatment of mRCC, describes recent advances in understanding the immunoreactivity of these tumors, and addresses the future of combination anti-VEGF and immunotherapeutic platforms.     

Assessing Outcomes and Prognostic Factors for First-Line Therapy in Elderly Patients With Metastatic Renal Cell Carcinoma: Real-Life Data From a Single United Kingdom Institution

BackgroundElderly metastatic renal cell carcinoma (mRCC) patients are under-represented in clinical trials, whose results are therefore difficult to translate into routine management of older patients. We aimed at exploring treatment outcomes and prognostic factors in our real-life elderly mRCC cohort receiving first-line tyrosine kinase inhibitor (TKI) monotherapy.Patients and MethodsWe retrospectively analyzed demographic and clinicopathological characteristics, and treatment data of elderly (≥ 70 years old at first-line start) mRCC patients starting either pazopanib or sunitinib as first-line treatment in our institution between March 2012 and April 2018. Baseline characteristics included age-adjusted Charlson comorbidity index (CCI).ResultsIn total, the records of 35 elderly mRCC patients were identified and retrospectively analyzed. Overall response rate, median progression-free survival, and median overall survival were 20%, 9.7 months, and 21.6 months, respectively. Karnofsky performance status ≤ 70%, sarcomatoid features, absolute neutrophil count greater than upper limit of normal, and treatment-related Grade 3 arterial hypertension were independently associated with survival after multivariate analysis. Age-adjusted CCI was significantly associated with survival in univariate analysis only. The overall incidence of Grade 3 to 5 toxicities was 74%. Seven patients (20%) received early crossover to either sunitinib or pazopanib because of toxicity. Dose reduction was applied in 24 (73%) of the 33 patients who completed at least 1 cycle.ConclusionFirst-line TKI monotherapy provided clinical benefit in our elderly mRCC cohort. Relatively frequent dose reductions helped to maintain an acceptable tolerability profile. Further research is warranted to explore the significance of prognostic factors in elderly mRCC patients.     

Afatinib With Pembrolizumab for Treatment of Patients With Locally Advanced/Metastatic Squamous Cell Carcinoma of the Lung: The LUX-Lung IO/KEYNOTE 497 Study Protocol

BackgroundAfatinib is a selective, irreversible ErbB family blocker that has shown survival benefit in lung squamous-cell carcinoma (SCC) patients. Pembrolizumab, a humanized immunoglobulin G4 monoclonal antibody to the programmed cell death 1 (PD-1) receptor, has also shown survival benefit in lung SCC. Concurrent inhibition of the PD-1 and epidermal growth factor receptor (EGFR) pathways represents a rational approach to improve responses and delay the onset of treatment resistance in lung SCC.Trial DesignThis phase II, open-label, single-arm study (NCT03157089) is designed to assess the efficacy and safety of afatinib in combination with pembrolizumab in patients with stage IIIB/IV lung SCC that has progressed during/after first-line platinum-based chemotherapy. Eligible patients must have ≥1 target lesion (as per Response Evaluation Criteria in Solid Tumors version 1.1) and must have not received previous immune checkpoint inhibitor/EGFR-targeted therapy. The recommended phase II dose (RP2D) and safety profile will be determined during a safety run-in with oral afatinib (starting dose, 40 mg/d) with intravenous pembrolizumab (200 mg every 3 weeks). In the main study, all patients will receive afatinib at the RP2D with pembrolizumab until disease progression, unacceptable toxicity, or for up to 35 cycles. The primary end point is objective response (complete + partial response). Other end points include disease control, duration of objective response, progression-free survival, overall survival, tumor shrinkage, RP2D, and pharmacokinetics. Exploratory biomarker analysis will be performed. This study is being conducted in the United States, Spain, France, South Korea, and Turkey. Enrollment commenced in September 2017, with a target of 50 to 62 patients.     

Genetic Polymorphism in Sex Hormone-binding Globulin With a Prognosis of Androgen Deprivation Therapy in Metastatic Prostate Cancer Among Japanese Men

IntroductionTestosterone suppression in serum during androgen deprivation therapy (ADT) can affect the oncologic outcome of ADT. Although genetic variants in sex hormone-binding globulin (SHBG) were reported to be correlated with serum testosterone level, the association with serum testosterone during ADT remains unclear. Therefore, this study investigated the impact of a missense polymorphism in the SHBG gene among men treated with primary ADT for metastatic prostate cancer.Patients and MethodsThis study included 104 Japanese men with metastatic prostate cancer. The association of SHBG gene polymorphism (rs6259, D356N) with clinicopathologic parameters including serum testosterone levels during ADT, as well as prognosis, including progression-free survival and overall survival, was examined.ResultsThe serum testosterone levels during ADT were comparable between men carrying the homozygous wild-type (GG) and heterozygous/homozygous variant (GA/AA) in the SHBG gene. When adjusted for age, Gleason score, initial prostate-specific antigen, and clinical T-stage, the heterozygous/homozygous variant (GA/AA) in the SHBG gene was associated with a higher risk of progression (hazard ratio, 2.20; 95% confidence interval, 1.10-4.18; P = .027) and any-cause death (hazard ratio, 3.21; 95% confidence interval, 1.31-7.35; P = .012).ConclusionsThis study suggested genetic variation in SHBG (rs6259) might be an independent prognostic biomarker among men treated with primary ADT for metastatic prostate cancer.     

The Prevalence of DPYD*9A (c.85T&gt;C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines: Updated Analysis

IntroductionThe dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation.Patients and MethodsBetween 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis.ResultsHeterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275).ConclusionIn our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.