Clinical and Genomic Features of Patients with Renal Cell Carcinoma and Advanced Chronic Kidney Disease: Analysis of a Multi-Institutional Database.

BACKGROUND: Patients with advanced chronic kidney disease (ACKD) are at an increased risk of developing renal cell carcinoma (RCC), but molecular alterations in RCC specimens arising from ACKD and overall survival (OS) in affected patients are not well defined. PATIENTS AND METHODS: Using the Oncology Research Information Exchange Network (ORIEN) Total Cancer Care® protocol, 296 consented adult patients with RCC and somatic tumor whole exome sequencing were included. Patients with ACKD were defined as those with serum creatinine ≥1.5 mg/dL prior to RCC diagnosis. RESULTS: Of 296 patients with RCC, 61 met the criteria for ACKD. The most common somatic mutations in the overall cohort were in VHL (126, 42.6%), PBRM1 (102, 34.5%), and SETD2 (54, 18.2%). BAP1 had a decreased mutational frequency in RCC specimens from patients without ACKD as compared to those with ACKD (10.6% versus 1.6%), but this was not statistically significant in univariable (OR 0.14, p = 0.056) or multivariable (OR 0.15, p = 0.067) analysis. Median OS was not reached in either cohort. CONCLUSIONS: Using the clinicogenomic ORIEN database, our study found lower rates of BAP1 mutations in RCC specimens from patients with ACKD, which may reflect a BAP1-independent mutational driver of RCC in patients with ACKD.

Neoadjuvant Cisplatin-based Chemotherapy in Nonmetastatic Muscle-invasive Bladder Cancer: A Systematic Review and Pooled Meta-analysis to Determine the Preferred Regimen.

OBJECTIVE: To determine whether neoadjuvant gemcitabine and cisplatin (GC) vs dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) before radical cystectomy improves overall survival (OS), progression-free survival (PFS), and pathologic complete response (pCR) for patients with muscle-invasive bladder cancer with secondary analyses of pathological downstaging and toxicity. MATERIALS AND METHODS: This systematic review and meta-analysis identified studies of patients with muscle-invasive bladder cancer treated with neoadjuvant GC compared to ddMVAC from PubMed, Web of Science, and EMBASE. Random-effect models for pooled log-transformed hazard ratios (HR) for OS and PFS and pooled odds ratios for pCR and downstaging were developed using the generic inverse variance method and Mantel-Haenszel method, respectively. RESULTS: Ten studies were identified (4 OS, 2 PFS, and 6 pCR clinical endpoints). Neoadjuvant ddMVAC improved OS (HR 0.71 [95% confidence intervals 0.56; 0.90]), PFS (HR 0.76 [95% confidence intervals 0.60; 0.97]), and pathological downstaging (odds ratio 1.34 [95% confidence interval 1.01; 1.78]) as compared to GC. There was no significant difference between regimens for pCR rates (odds ratio 1.38 [95% confidence interval 0.90; 2.12]). Treatment toxicity was greater with ddMVAC. Limitations result from differences in number of ddMVAC cycles and patient selection between studies. CONCLUSION: Neoadjuvant ddMVAC is associated with improved OS and PFS vs gemcitabine/cisplatin for patients with muscle-invasive bladder cancer before radical cystectomy. Although rates of pathological complete response were not significantly different, pathological downstaging correlated with OS. ddMVAC should be preferred over gemcitabine/cisplatin for patients with muscle-invasive bladder cancer who can tolerate its greater toxicity.

A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma.

Purpose: Immune checkpoint inhibitor and VEGFR inhibitor combinations are effective treatments for patients with metastatic renal cell carcinoma (mRCC). This phase I/II clinical trial evaluated the safety and efficacy of pembrolizumab and cabozantinib in patients with mRCC. Experimental Design: Eligible patients had mRCC with clear-cell or non-clear cell histology, adequate organ function, Eastern Cooperative Oncology Group 0-1 performance status, and no prior exposure to pembrolizumab or cabozantinib. The primary endpoint was objective response rate (ORR) at the recommended phase II dose (RP2D). Secondary endpoints included safety, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Forty-five patients were enrolled. A total of 40 patients were treated at the RP2D of pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily, 38 of which were evaluable for response. The ORR was 65.8% [95% confidence interval (CI), 49.9-78.8] for all evaluable patients [78.6% as first-line therapy, 58.3% as second-line therapy]. The DCR was 97.4% (95% CI, 86.5-99.9). Median DoR was 8.3 months (interquartile range, 4.6-15.1). At a median follow-up of 23.54 months, the median PFS was 10.45 months (95% CI, 6.25-14.63) and median OS was 30.81 months (95% CI, 24.2-not reached). The most common grade 1 and/or 2 treatment-related adverse events (TRAE) were diarrhea, anorexia, dysgeusia, weight loss, and nausea. The most common grade 3 and/or 4 TRAEs were hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. There was one grade 5 TRAE of reversible posterior encephalopathy syndrome related to cabozantinib. Conclusions: Pembrolizumab and cabozantinib treatment in patients with mRCC demonstrated encouraging preliminary efficacy and a manageable toxicity profile comparable with other available checkpoint inhibitor-tyrosine kinase inhibitor combinations. Trial Registration: ClinicalTrials.gov Identifier: NCT03149822 https://clinicaltrials.gov/ct2/show/NCT03149822. Significance: This study evaluated the safety and effectiveness of the combination of pembrolizumab and cabozantinib in patients with mRCC. The safety profile was manageable. The combination showed promising activity with an objective response rate of 65.8%, median PFS of 10.45 months, and median OS of 30.81 months.

Outcomes of Second-Line Therapies in Patients With Metastatic de Novo and Treatment-Emergent Neuroendocrine Prostate Cancer: A Multi-Institutional Study.

BACKGROUND: De novo neuroendocrine prostate cancer (NEPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) are rare diseases with a poor prognosis. After first-line platinum chemotherapy, there is no consensus on second-line treatments. PATIENTS AND METHODS: Patients with a pathologic diagnosis of de novo NEPC or T-NEPC between 2000 and 2020 who received first-line platinum and any second-line systemic therapy were selected and standardized clinical data was collected via the electronic health record at each institution. The primary endpoint was overall survival (OS) based on second-line therapy. Secondary endpoints included objective response rate (ORR) to second-line therapy, PSA response, and time on treatment. RESULTS: Fifty-eight patients (32 de novo NEPC, 26 T-NEPC) from 8 institutions were included. At de novo NEPC or T-NEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 59.2-70.3) and median PSA of 3.0 ng/dL (IQR 0.6-17.9). Following first-line platinum chemotherapy, 21 patients (36.2%) received platinum chemotherapy, 10 (17.2%) taxane monotherapy, 11 (19.0%) immunotherapy, 10 (17.2%) other chemotherapy, and 6 (16.2%) other systemic therapy. Among 41 evaluable patients, the ORR was 23.5%. The mOS after start of second-line therapy was 7.4 months (95% CI 6.1-11.9). CONCLUSIONS: In this retrospective study, patients with de novo NEPC or T-NEPC who received second-line therapy were treated with wide variety of treatment regimens, reflecting the lack of consensus in this setting. Most patients received chemotherapy-based treatments. Overall prognosis was poor and ORR was low in the second line regardless of treatment choice.

Effectiveness and durability of benefit of mTOR inhibitors in a real-world cohort of patients with metastatic prostate cancer and PI3K pathway alterations.

BACKGROUND: Alterations in the PTEN/PI3K/AKT/mTOR pathway are prevalent in prostate cancer. In this retrospective study, we evaluated the clinical effectiveness of mTOR inhibitors (mTORi) in patients with metastatic prostate cancer (mPCA) and tissue assessed phosphatidyl-3-inositol kinase (PI3K) pathway alterations. METHODS: This study used a nationwide (US-based) de-identified PCA clinico-genomic database, originating from approximately 280 US cancer clinics (~800 sites of care). We evaluated treatment data for patients with PCA from October 2014 to February 2020. In a cohort of 2301 PCA patients with 7208 evaluable treatment lines, we selected 17 mPCA patients (2 hormone-sensitive, 15 castrate-resistant) with tissue assessed PI3K pathway alterations by comprehensive genomic profiling who received mTORi treatment. RESULTS: Patients had a median age of 72 years (IQR 68.0, 76.0) and were heavily pretreated with a median 3 lines of therapy prior to mTORi use (range 0-6). The PI3K pathway alterations included PTENdel (10 patients, 58.8%), AKT1mut (4 patients, 23.5%), PTENmut (2 patients, 11.8%), and dual PTENmut and PIK3CAmut (1 patient, 5.9%). Most (15 patients, 88.2%) were treated with everolimus monotherapy. Among 10 patients with on treatment PSA available, 2 patients had a PSA decrease ≥10% at week 12 and 5 patients overall had a subsequent PSA decrease. For those on mTORi, the median time to next treatment was 3.62 months (range 0, 8.52). CONCLUSIONS: In this small cohort of mPCA patients with tissue assessed PI3K pathway alterations, mTORi therapy was not effective with few PSA responses and short duration of therapy.

Characteristics and impact of the most-cited palliative oncology studies from 1995 to 2016.

BACKGROUND: Palliative care, as a relatively young field within medicine, has increasingly used original research to validate and standardize its practice. In particular, palliative care has been incorporated into oncology to better address end-of-life decisions and care. The goal of this study is to identify seminal studies in the field of palliative oncology while more broadly characterizing the trends across the literature. METHODS: The publication databases Scopus and Web of Science were queried using predefined search terms to identify palliative oncology studies published between 1995 and 2016. The 100 most-cited articles from the time periods 1995-2005 and 2006-2016 were selected and analysed for publication data and study content. RESULTS: Palliative oncology studies were found to primarily examine patients with multiple rather than single cancer types and rarely were randomized controlled trials. Early research topics of pain, symptoms, and survival studies have been replaced by the issues of access to care, healthcare utilization, and religion and spirituality. CONCLUSIONS: By identifying and analyzing notable studies in palliative oncology, we found areas of research that are commonly investigated or overlooked and identified model studies that highlight the need for additional disease-specific randomized control trials to provide high quality clinical evidence in the field.