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The diagnosis, evaluation and management of patients with renal cell carcinoma has transformed in the 21(st) century. Utilizing biological discoveries and technological advances, the field has moved from blunt surgical and largely ineffective medical treatments, to nuanced and fine-tuned approaches based on biology, extent of disease and patient preferences. In this review we will summarize the last 25 years of progress in kidney cancer.

The standard of care (SOC) for muscle-invasive bladder cancer (MIBC) includes cisplatin-based combination chemotherapy in the neoadjuvant setting followed by radical cystectomy. Older patients often do not receive SOC due to perceived toxicity concerns despite guideline-directed recommendations.To characterize the safety and efficacy of neoadjuvant accelerated methotrexate, vinblastine, adriamycin, and cisplatin (aMVAC) in MIBC patients as a function of age.A retrospective analysis was conducted in 186 MIBC patients treated at Fox Chase Cancer Center between January 1, 2002 and December 31, 2018. Adults with histologically proven muscle-invasive urothelial cancer were eligible. The exclusion criteria included nonurothelial histology, lack of muscularis propria invasion, and primary upper tract or metastatic disease.Neoadjuvant chemotherapy with aMVAC.Patients were stratified by age (65, 65-74, and75 yr old). Renal function was assessed at baseline and at time points after treatment. Clinicopathologic variables were compared between age groups to determine efficacy.There were no statistically significant differences in dose reductions, treatment interruptions, time to surgery, or adverse events when patients were stratified by age in univariate and multivariate analyses. Full safety data were not available due to the retrospective nature of the study. Baseline renal function was significantly worse among older patients, and the percent decline in creatinine clearance was greater with older age. We found comparable efficacy of aMVAC regardless of age.Accelerated MVAC was safe and demonstrated efficacy in MIBC irrespective of age in this single-center, retrospective study. Careful selection based on clinical variables, and not age, should identify patients able to receive neoadjuvant chemotherapy.We examined the feasibility of the standard cisplatin-based chemotherapy regimen given prior to surgery in patients with muscle-invasive bladder cancer. Elderly patients experienced a greater decline in kidney function with treatment but not more complications than younger patients and tolerated therapy with minimal dose changes, resulting in benefit regardless of age.

Purpose Prostate cancer is the second leading cause of cancer death in men in the US. Since 2015, landmark studies have demonstrated improved survival outcomes with the use of docetaxel (DCT) or abiraterone (AA) in addition to androgen deprivation therapy (ADT) in the metastatic hormone-naive setting. These treatment strategies have not been prospectively compared but have similar overall survival benefits despite differing mechanisms of action, toxicity, and cost. We performed a cost-effectiveness analysis to provide insight into the value of AA vs. DCT in the first-line treatment of metastatic prostate cancer. Materials and Methods We developed Markov models by using a US-payer perspective and a 3-year time horizon to estimate costs (2018 US$) and progression-free quality-adjusted life years (PF-QALYs) for ADT alone, DCT, and AA. Health states were defined as initial state, treatment states according to experience of an adverse event, and progressed disease/death. State transition probabilities were derived from rates for drug discontinuation, frequency of adverse events, disease progression, and death from the randomized phase III trials ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) and LATITUDE. Univariate and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results DCT resulted in an increase of 0.32 PF-QALYs and $16,100 in cost and AA resulted in an increase of 0.52 PF-QALYs and $215,800 in cost compared to ADT alone. The incremental cost-effectiveness ratio for DCT vs. ADT was $50,500/PF-QALY and for AA vs. DCT was $1,010,000/PF-QALY. Probabilistic sensitivity analysis demonstrated that at a willingness-to-pay threshold of $150,000/PF-QALY AA was highly unlikely to be cost-effective. Conclusion DCT is substantially more cost-effective than AA in the treatment of metastatic hormone naive prostate cancer.

Summary Background Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. Methods We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Findings Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. Interpretation While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. Funding None.

The therapeutic landscape for advanced urothelial carcinoma (mUC) has changed significantly since studies establishing superiority of cisplatin as first-line therapy were conducted. Most patients who are eligible now receive either maintenance or second-line immune checkpoint inhibitors (ICI) and data comparing first-line platinum chemotherapy agents in this setting is limited.The objective of this study was to determine the impact of first-line platinum chemotherapy agent on survival for patients who receive second-line ICI. This is a retrospective cohort study of real-world data, performed from January 1, 2015, to March 21, 2021, included patients with a diagnosis of metastatic or locally advanced urothelial carcinoma. Exposure of interest was first-line platinum-doublet chemotherapy (gemcitabine and/or cisplatin or gemcitabine and/or carboplatin) followed by single-agent second-line ICI. The primary endpoint was overall survival from start of second-line therapy.2,042 patients received either gemcitabine and cisplatin (gem/cis) or gemcitabine and carboplatin (gem/carbo) as first-line therapy. The primary analysis of 890 patients who received second-line single-agent ICI had a median follow-up was 24.2 months from initiation of second-line therapy. Important differences in baseline demographics and/or clinical factors between groups were age, performance status, incidence of upper tract disease, and cisplatin eligibility. Unadjusted overall survival (OS) calculated from start of second-line therapy was longer in patients who received gem/cis compared to gem/carbo followed by ICI (median 9.3 vs. 8.8 months, P = 0.0009). However, OS adjusted for covariates was not significantly different with a hazard ratio (HR) of 0.94 (95% CI, 0.79-1.13; P = 0.50). A separate time-varying covariate model also showed no association between OS and first-line gem/cis (HR 1.00 [95% CI, 0.84-1.19]) while receiving second-line ICI.Survival time on ICI in the second-line setting is the same regardless of choice of prior platinum agent (cisplatin vs. carboplatin) suggesting against specific synergy for one of these agents with ICI. However, a significantly greater proportion of patients in a landmark analysis had long-term benefit with cisplatin strongly supporting it is as the preferred first-line platinum agent.

This large-scale, US-based study characterized real-world treatment patterns and clinical outcomes in patients with advanced or metastatic urothelial carcinoma (aUC).This retrospective cohort analysis included patients with stage IV or node-positive aUC between January 1, 2011, and August 31, 2020, from an electronic health record-derived, de-identified database (Flatiron Health). Baseline characteristics and treatment patterns were assessed by first-line (1L) systemic treatment received and cisplatin eligibility status. Overall survival (OS) and progression-free survival (PFS) were evaluated.Of 8,183 patients included, 5,855 (71.6%) received systemic 1L therapy and 2,328 (28.4%) did not. Median (range) follow-up from aUC diagnosis was 9.7 (0.2-116.6) months. Of patients who received 1L systemic therapy, 30.1% were cisplatin-eligible, 39.2% were cisplatin-ineligible, 10.5% did not receive cisplatin despite qualifying ECOG PS and renal function, and cisplatin eligibility was unknown in 20.2%. Of those treated, 74.8% received 1L chemotherapy and 23.0% received 1L immuno-oncology-based monotherapy. Median OS (95% CI) was 14.5 (14.0-15.2) months in patients who received 1L systemic therapy and 6.8 (6.2-7.3) months in those who did not. Of those treated, cisplatin-ineligible patients had worse OS and PFS outcomes vs. other subgroups. Among cisplatin-ineligible patients, 1L immuno-oncology monotherapy (n = 865) was associated with worse OS and PFS outcomes than 1L chemotherapy (n = 1,369).More than 25% of aUC patients did not receive 1L systemic therapy; of patients who were treated, most received chemotherapy, with less than 25% receiving immuno-oncology-based monotherapy. Overall, these results highlight the substantial unmet need in this population, specifically among cisplatin-ineligible patients.

Update on first-line immunotherapy in metastatic urothelial carcinoma.

To evaluate the evolution of treatment patterns and associated costs for metastatic renal cell carcinoma (mRCC) in the United States.The LifeLink Health Plan Claims Database was used to create a cohort of mRCC patients with at least 12 months of continuous enrollment from 2004 to 2011. We summarized treatment patterns over time; we used a nonparametric bootstrapping method to compare costs and logistic regression to examine the association between the likelihood of advancing to third-line therapy and beyond and the number of targeted therapy agents available.A total of 1527 mRCC patients were analyzed. In 2010, nine unique treatment regimens were used for first-line treatment, 8 for second-line treatment, and 8 for third-line treatment. A significant association (odds ratio 1.26; P = .001) between the odds of advancing to third-line therapy or beyond and the number of targeted agents available was noted. For 767 patients receiving modern therapy who were65 years old, and stratifying by whether the first-line treatment was oral or intravenous, drug cost per patient with ancillary services was $59,664 versus $86,518, respectively (P = .001). Total costs and drug out-of-pocket costs per patient during the first year increased by the number of switches: $111,680 to $2355 for no switches, $149,994 to $2538 for 1 switch, and $196,706 to $3524 for 2 or more switches. In 2004, the median drug cost was $11,458, while by 2010 it rose to $68,660.A marked shift in the management of mRCC has occurred, with wide heterogeneity in treatment patterns. More patients are able to receive more lines of therapy, but treatment costs are high.

We report on a 34-yr-old man with no medical history who presented in September 2014 with night sweats, fevers, bilateral pulmonary masses, extensive bony disease, and a left renal mass of 4.3 cm 4.1 cm. A lung biopsy showed poorly differentiated carcinoma with rhabdoid features consistent with high-grade renal cell carcinoma (RCC). Therapy with carboplatin and gemcitabine was initiated for palliative reasons, but a subsequent biopsy of the renal mass revealed papillary RCC with sarcomatoid and rhabdoid features. Genomic profiling revealed alterations in FAT1, as well as a number of variants of unknown significance (VUS) including DICER1, FANCL, SPTA1 and WISP3; most interestingly, a PBRM1 VUS was noted. After a brief clinical improvement on cytotoxic chemotherapy, the patient’s disease progressed and sunitinib was initiated at first alone and then with gemcitabine. Unfortunately, rapid progression once again occurred. ByMarch 2015 the patient was on 30 mg of long-acting morphine twice daily, as well as a short-acting narcotic for breakthrough pain. His performance statuswas rapidly declining and subcutaneous lesions were appearing. At that point we decided to treat the patient with the anti-programmed cell death protein 1 (PD-1) antibody nivolumab, as it was felt that no other standard therapy targeting vascular endothelial growth factor (VEGF) or mammalian target of rapamycin would be helpful given the rapidly progressive nature of his disease. At 3 wk after a single dose of nivolumab at 0.3 mg/kg, the patient felt dramatically better, with dissipation of all pain and discontinuation of all narcotics, improvement in laboratory values and energy, and disappearance of all subcutaneous lesions. After three doses of nivolumab, the patient’s hemoglobin increased from 10.5 to 14.3 g/dl, thrombocytosis resolved from 489 to 190 k/ml, and C-reactive protein decreased from 67.8 mg/dl in October 2014 to 0.7 mg/dl. Radiographic studies with magnetic resonance imaging and computed tomography before and after nivolumab demonstrated significant improvement in pulmonary, subcutaneous, and bony lesions (Fig. 1). No adverse reactions to nivolumab have occurred so far and the patient is working full time. Immunotherapy is rapidly being integrated into oncology practice and is poised to alter the therapeutic landscape for a variety of malignancies [1]. In RCC, single-agent and combination checkpoint inhibitor trials are either completed or under way, with promising results already published or presented [2]. Importantly, thus far all checkpoint inhibitor trials in RCC have required at least some clear cell component for enrollment [3], and patients with pure non–clear cell (NCC) histology have been excluded. In the patient described here, a PBRM1 variantwas noted. PBRM1 is a tumor suppressor gene that is mutated in approximately 40–50% of clear cell RCCs [4], but was only noted in 3% of papillary RCC patients in one analysis [5]. Thus, although no VHL alteration was reported and no response to a VEGF inhibitor was observed, it is possible that the patient has an aggressive form of clear cell RCC and not papillary RCC as histologically determined. Nevertheless, he would not have been eligible for any current clinical trial and the papillary histology was confirmed by two separate institutions. Previous analysis of tumor samples from 50 patients with papillary RCC demonstrated PD-1 ligand (PD-L1) positivity ranging from 10% to 60% depending on whether tumor cells or immune infiltrating cells were evaluated [6]. Other NCC subtypes such as chromophobe and translocation Xp11.2 type also express PD-L1. In clear cell RCC and other tumor types, although PD-L1 positivity is not required for a response, it appears to lead to a higher likelihood of benefit from anti-PD-1 therapy. Given the PDL1 expression in NCC RCC and clinical observations such as EU RO P E AN URO L OG Y 6 8 ( 2 0 1 5 ) 9 1 2 – 9 1 5

Bone complications are a frequent co-occurrence with prostate cancer (PCa). Androgen deprivation therapy, the mainstay of treatment in both castration-sensitive (CSPC) and castration-resistant PCa (CRPC), leads to a loss of bone mineral density and subsequent possible osteoporotic fractures. In men with metastatic CRPC (mCRPC), skeletalrelated events (SREs), commonly defined as pathologic fractures, spinal cord compressions, or a need for palliative local bone therapy, are common ( 50% without treatment [1]) because of the osteotropism of PCa. SREs are associated with increased pain and cost, as well as decreased quality of life and survival [2]. Over the last two decades a number of bone-targeted therapies (BTTs) have been developed, tested, and approved for use in men with PCa. These generally fall into three categories: radiopharmaceuticals, bisphosphonates, and a monoclonal antibody against receptor activator of nuclear factor kB ligand (RANKL), the latter two of which are osteoclast inhibitors [2]. The radiopharmaceuticals strontium-89 and samarium-153 are sometimes used to palliate pain, but do not improve survival; however, the recently approved alpha-emitting agent radium-223 both improves overall survival (OS) and increases time to first SRE. Bisphosphonates such as zoledronic acid have been extensively studied in PCa and work by attaching to the bony surface and preventing osteoclast-mediated bone resorption and arresting osteoclast development. InmCRPC, zoledronic acid decreases SRE incidence, prolongs time to first SRE, and decreases pain [1]. Denosumab, a RANKL inhibitor, was approved because of its superiority to zoledronic acid in preventing SREs in a phase 3 trial of

Randomized clinical trials are the benchmark for definitive phase 3 trials and are becoming increasingly critical in earlier phase, proof-of-concept trials in oncology, especially urologic oncology. Unfortunately, many of these trials are never completed or accrue extremely slowly, leading to tremendous waste of scientific, patient, and financial resources. The potential reasons for these failures are multiple, but are often difficult to discern in an individual trial and rarely analyzed objectively. A recent experience with a multicenter, randomized, phase 2 trial for which there was a compelling biologic premise, review and support from the US Food and Administration (FDA), good advertising, and acceptance from co-investigators but that still failed to successfully accrue provides an opportunity to examine potential causes for trial failure more

Corticosteroids have been a mainstay of treatment of men with metastatic prostate cancer (PCa) for decades. They are used for palliation of symptoms, to prevent adverse reactions or toxicity from other therapies, and for their antitumor effects mediated by way of the decrease of adrenal androgen production, transcription factors, and cytokines. Recently, two rationally designed oral drugs targeting the androgen receptor (AR) axis have become an important part of the armamentarium in treating men with castration-resistant PCa (CRPC). Abiraterone acetate, a CYP17A1 inhibitor, decreases androgen production in testicular, adrenal, and prostatic tissues; enzalutamide is a highly selective and effective AR antagonist that limits AR nuclear localization and downstream gene regulation. Both drugs improve survival in men with CRPC; however, unlike enzalutamide, abiraterone requires concurrent corticosteroid administration to mitigate its effect of increased mineralocorticoid production. Understanding the mechanisms of the inevitably acquired resistance to these drugs is vital, so the role of corticosteroids and the glucocorticoid receptor (GR) in CRPC is now being explored. CRPC progression can result from a number of ARmediated factors, including amplification of the AR, alternative splicing, and mutations of the AR that can lead to constitutive stimulation of the receptor, ligand-independent AR activation, and paradoxical stimulation of the receptor by other steroidal hormones and antiandrogens. As shown by the eventual clinical progression of CRPC despite highly effective AR-targeted therapies such as enzalutamide and abiraterone, there are undoubtedly other, non–ARmediated mechanisms of CRPC progression. One such posited mediator of AR-independent CRPC progression is the GR. The GR, which is activated by corticosteroids, is a nuclear hormone receptor in the same protein family as the AR, with structural homology and shared DNA response elements. Thus, the questions of how the GR and AR interact with corticosteroids and what their relationship to each other is in CRPC have been raised. GR protein levels in PCa tissue increase subsequent to AR blockade [1]. In addition, in preclinical models, corticosteroid activation of the GR can promote CRPC progression and resistance to effective second-generation AR antagonists such as enzalutamide [2,3]. A potential functional role for GR signaling in clinical CRPC progression is thus of great clinical interest. To address the role of theGR in CRPC, in thismonth’s issue of EuropeanUrology, a post hoc analysis byMontgomery et al. [4] examined whether baseline corticosteroid use in the phase 3 trial of abiraterone versus prednisone in men with metastatic CRPC after chemotherapy (COU-AA-301) was predictive of overall survival (OS) [5]. The study showed that the 33% of men who were receiving corticosteroids at baseline had universally worse disease characteristics at study entry than their counterparts, with inferior OS (16.1 vs 11.2mo; hazard ratio [HR]: 0.68; p < 0.0001) and an increased risk of death (HR: 1.48; p < 0.0001) on univariate analysis. However, in a multivariate model, baseline corticosteroid status did not predict OS when other clinical factors were included. These results suggest that baseline corticosteroid usewas an indicator of poor prognosis butwas not predictive of response to abiraterone. Several points should be highlighted. First, the use of abiraterone led to improvement in OS, prostate-specific antigen (PSA) progression, and progression-free survival regardless of baseline corticosteroid use. Second, all patients received prednisone once the trial commenced. Third, the duration of, and indications for, baseline EU RO P E AN URO L OG Y 6 7 ( 2 0 1 5 ) 8 7 4 – 8 7 5

Target-based therapeutic development has significantly changed cancer treatment and has generated new sense of optimism. Cancers that contain multiple genetic and epigenetic abnormalities remain addicted to one or few genes for their malignant phenotype and cell survival. Inhibition of these abnormalities via monoclonal antibodies (mAbs) and small-molecule inhibitors (SMIs) have brought about new hope in NSCLC. MET gene was initially discovered in the laboratory of George Vande Woude as part of a transforming fusion gene between transforming promoter region (TPR) and MET which was derived from a chromosomal translocation after treatment with N-methyl-N-nitro-N-nitrosoguanidine. 1 MET is located on chromosome 7, encodes for a single precursor which is post-transcriptionally digested, forming an extracellular -chain and a transmembrane s-chain linked by disulfide bonds. The ligand for MET is hepatocyte growth factor (HGF)/Scatter Factor (SF), which is synthesized as a single inactive polypeptide chain (pro-HGF/SF) and cleaved to an active, disulfide-linked dimer by serine proteases including uPA, tPA, and then binds to the MET Sema domain. 2 Ligation of the MET receptor by HGF leads to receptor dimerization and activation of its intrinsic tyrosine kinase and further autophosphorylation or phosphorylation of downstream intermediates and activation of signaling pathways. MET can be activated by mutations, autocrine/paracrine growth, overexpression by gene amplification, or decreased degradation. Germline and somatic MET gene mutations have been reported in hereditary and sporadic papillary renal cell cancers. 3‐5 Both MET gene mutations and amplifications have now been reported in other cancers, although at low frequencies but as genetic predictors of therapeutic sensitivity. 6 Expression of MET and phosphoMET has been studied in lung cancer, and recently it was shown that 40% of lung cancer tissues overexpressed MET. 7 Summary of Presentations MET as a therapeutic target in NSCLC Dr. Robert C. Doebele discussed some of the key background points surrounding MET inhibition in NSCLC. He noted that survival in NSCLC patients with 5 copies/cell is worse than those with less than 5 copies/cell and that MET gene amplification leads to EGFR tyrosine kinase resistance in EGFR mutant patients.8 Anti-HGF Abs, anti-MET Abs, and small-molecule MET TKI inhibitors are all in various stages of development, and predictive biomarkers for MET inhibitors will be important to elucidate for future trials and treatment decisions.