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Simple Summary: The treatment of metastatic renal cell carcinoma continues to rapidly evolve, with various combinations of immune checkpoint inhibitors and targeted tyrosine kinase inhibitors improving outcomes in the first-line setting. However, a significant subset of patients fail to respond to these therapies, and many patients eventually progress, necessitating effective therapeutic options in the treatment-refractory setting. Here, we review the treatment of refractory renal cell carcinoma, including the current standard of care, ongoing trials with the potential to alter current paradigms, and considerations for non-clear cell histologies. First-line treatment for metastatic renal cell carcinoma (mRCC) rapidly shifted in recent years with the advent of combination therapies, including immune checkpoint inhibitor (ICI) doublets and combinations of an ICI with a vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitor (TKI). Despite improvements in overall survival and many durable responses, there exists a significant number of patients who fail to respond to these agents, and many patients eventually progress. Given the rapid changes in the front-line setting, it is essential to understand treatment options in refractory mRCC. Here, we review the evidence behind current options for later-line therapies, often involving additional VEGFR-TKIs alone or in combination with mammalian target of rapamycin (mTOR) targeted agents, as well as situations where consideration of immunotherapy rechallenge may be appropriate. Additionally, we describe ongoing clinical trials examining concurrent ICI and TKI in the refractory setting, as well as those studying novel agents, such as targeted drug–antibody conjugates and hypoxia inducible factor 2α (HIF-2α) inhibitors. Finally, we review considerations for non-clear cell histologies in the refractory setting and mechanisms of resistance in mRCC. [ABSTRACT FROM AUTHOR]

First-line pembrolizumab + axitinib significantly improved overall survival, progression-free survival, and objective response rate over sunitinib, while health-related quality of life outcomes were not different between groups. In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response rate over sunitinib monotherapy for advanced renal cell carcinoma (RCC). To evaluate health-related quality of life (HRQoL) in KEYNOTE-426. A total of 861 patients were randomly assigned to receive pembrolizumab + axitinib (n = 432) or sunitinib (n = 429). HRQoL data were available for 429 patients treated with pembrolizumab + axitinib and 423 patients treated with sunitinib. HRQoL end points were measured using the European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), EQ-5D visual analog rating scale (VAS), and Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index—Disease-Related Symptoms (FKSI-DRS) questionnaires. Better or not different overall improvement rates from baseline between pembrolizumab + axitinib and sunitinib were observed for the FKSI-DRS (–0.79% improvement vs sunitinib; 95% confidence interval [CI] –7.2 to 5.6), QLQ-C30 (7.5% improvement vs sunitinib; 95% CI 1.0–14), and EQ-5D VAS (9.9% improvement vs sunitinib; 95% CI 3.2–17). For time to confirmed deterioration (TTcD) and time to first deterioration (TTfD), no differences were observed between arms for the QLQ-C30 (TTcD hazard ratio [HR] 1.0; 95% CI 0.82–1.3; TTfD HR 0.82; 95% CI 0.69–0.97) and EQ-5D VAS (TTcD HR 1.1; 95% CI 0.87–1.3; TTfD HR 0.98; 95% CI 0.83–1.2). TTfD was not different between treatment arms (HR 1.1; 95% CI 0.95–1.3) for the FKSI-DRS, but TTcD favored sunitinib (HR 1.4; 95% CI 1.1–1.7). Patients were assessed during the off-treatment period for sunitinib, which may have underestimated the negative impact of sunitinib on HRQoL. Overall, patient-reported outcome scales showed that results between the pembrolizumab + axitinib and sunitinib arms were not different, with the exception of TTcD by the FKSI-DRS. Compared with sunitinib, pembrolizumab + axitinib delays disease progression and extends survival, while HRQoL outcomes were not different between groups. [ABSTRACT FROM AUTHOR]

Simple Summary: Immuno-Oncology (IO) based combinations are now the standard of care for frontline advanced clear cell renal cell carcinoma. Despite the unprecedented durable efficacy of such combinations, many patients do not respond to IO or will eventually develop resistance. This review summarizes the ongoing efforts in drug development in clear cell renal cell carcinoma focusing on novel targets. The dual immune checkpoint blockade targeting CTLA-4 and PD-1 (ipilimumab/nivolumab) or the IO combinations targeting PD-1 and anti-VEGF TKIs (pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib) have demonstrated an overall survival benefit in advanced clear cell renal cell carcinoma (ccRCC). Despite this significant improvement in clinical outcomes in the frontline setting from IO/IO or the IO/TKI combinations, there is a subset of patients of advanced ccRCC that do not respond to such combinations or will lose the initial efficacy and have disease progression. Therefore, a remarkable unmet need exists to develop new therapeutics to improve outcomes. With an enhanced understanding of ccRCC biology and its interaction with the tumor microenvironment, several new therapies are under development targeting ccRCC metabolism, cytokine-signaling, alternative immune checkpoint proteins, and novel biological pathways. In addition, microbiome products enhancing IO response, antibody–drug conjugates, and targeted radionuclides are also being investigated. This review summarizes selected emerging agents that are under development in ccRCC. [ABSTRACT FROM AUTHOR]

Overlapping toxicities are a concern with combined tyrosine kinase inhibitor (TKI)/immuno-oncology (IO) therapy for advanced renal cell carcinoma. We analyzed the resolution time of common adverse events (AEs). Resolution time for axitinib monotherapy was ≤3 days and shorter versus other single-agent TKIs. This can support identification of the etiology of AEs with combined TKI-IO therapy and faster management plan implementation. Introduction: Combined axitinib and immuno-oncology (IO) therapy is approved for first-line advanced renal cell carcinoma. Overlapping toxicities represent a clinical challenge. Calculating the time to resolution (TTR) of common axitinibrelated adverse events (AEs) after treatment interruption may help to identify AE etiology and determine appropriate management strategies. Materials and Methods: Data from 5 randomized or single-arm axitinib monotherapy or combination studies were analyzed. Patients with histologically confirmed clear cell advanced renal cell carcinoma were pooled into 3 cohorts based on treatment received: axitinib monotherapy, axitinib + IO, and other tyrosine kinase inhibitor (TKI). Any grade and grade =3 treatment-emergent diarrhea, fatigue, hypertension, nausea, and palmar-plantar erythrodysesthesia syndrome were assessed. TTR was defined as the time from treatment interruption/discontinuation to resolution. Results: The axitinib monotherapy cohort comprised 532 patients, the axitinib + IO cohort 541 patients, and the other TKI cohort 882 patients. Median TTR for all AEs (any grade) in the axitinib monotherapy cohort ranged from 1 to 3 days, except for fatigue (8 days). For diarrhea, hypertension, nausea, and palmar-plantar erythrodysesthesia syndrome, median TTRs were longer in the axitinib + IO (4-11 days) and other TKI (7-8 days) cohorts versus the monotherapy cohort. Results were similar when only AEs of grade =3 were considered. Conclusions: The TTR of monotherapeutic axitinib-related AEs is =3 days, except for fatigue, and generally shorter than for other single-agent TKIs and axitinib + IO. This has important implications for identifying AE etiology with combined axitinib-IO therapy and implementation of appropriate management strategies. ClinicalTrials.org identifiers: NCT00678392, NCT00920816, NCT02493751, NCT02684006, NCT02853331. [ABSTRACT FROM AUTHOR]

Patients with metastatic renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and have shown limited responsiveness to inhibition of the VEGF pathway. We conducted a prespecified analysis of the randomised, phase 3 IMmotion151 trial in previously untreated patients with advanced or metastatic RCC to assess the effectiveness of atezolizumab + bevacizumab versus sunitinib in a subgroup of patients with sarcomatoid features. Patients whose tumour had any component of sarcomatoid features were included and received atezolizumab + bevacizumab (n = 68) or sunitinib (n = 74). Baseline characteristics were similar between the groups. Median progression-free survival was significantly longer in the group receiving atezolizumab + bevacizumab overall (8.3 vs 5.3 mo; hazard ratio [HR] 0.52 95% confidence interval [CI] 0.34–0.79) and in the subset of patients with PD-L1–positive tumours (8.6 vs 5.6 mo; HR 0.45, 95% CI 0.26–0.77). More patients receiving atezolizumab + bevacizumab achieved an objective response (49% vs 14%), including complete responses (10% vs 3%), and reported greater symptom improvements versus sunitinib. Safety was consistent with the known profiles of each drug and with that reported in the overall safety-evaluable population of IMmotion151. This analysis supports enhanced activity of atezolizumab + bevacizumab in patients with sRCC. In this report, we looked at patients with a specific type of kidney cancer (tumours with sarcomatoid features) that has been hard to treat. A treatment with two drugs (atezolizumab and bevacizumab) appeared to help patients live longer without the disease getting worse than another drug (sunitinib) that is often used. Patients who took the two drugs also said they were better able to carry out their everyday activities than patients who took sunitinib. The combination of these two drugs may work better in patients with this type of advanced kidney cancer. Atezolizumab + bevacizumab provided greater progression-free survival and objective response and improved patient-reported outcomes versus sunitinib among patients whose tumours had sarcomatoid features. This prespecified analysis of IMmotion151 supports enhanced activity of atezolizumab + bevacizumab in patients with metastatic renal cell carcinoma with sarcomatoid features. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the most common type of kidney cancer and comprises several subtypes with unique characteristics. The most common subtype (~70% of cases) is clear-cell RCC. RCC is considered to be an immunogenic tumour but is known to mediate immune dysfunction in large part by eliciting the infiltration of immune-inhibitory cells, such as regulatory T cells and myeloid-derived suppressor cells, into the tumour microenvironment. Several possible mechanisms have been proposed to explain how these multiple tumour-infiltrating cell types block the development of an effective anti-tumour immune response, including inhibition of the activity of effector T cells and of antigen presenting cells via upregulation of suppressive factors such as checkpoint molecules. Targeting immune suppression using checkpoint inhibition has resulted in clinical responses in some patients with RCC and combinatorial approaches involving checkpoint blockade are now standard of care in patients with advanced RCC. However, a substantial proportion of patients do not benefit from checkpoint blockade. The identification of reliable biomarkers of response to checkpoint blockade is crucial to facilitate improvements in the clinical efficacy of these therapies. In addition, there is a need for the development of other immune-based strategies that address the shortcomings of checkpoint blockade, such as adoptive cell therapies. [ABSTRACT FROM AUTHOR]

Background: Treatment for renal cell carcinoma has been revolutionised by inhibitors of VEGF receptor. Previous studies have suggested that treatment with a VEGF receptor (VEGFR) tyrosine kinase inhibitor might be effective in patients who had previous checkpoint inhibitor therapy. Therefore, TIVO-3 was designed to compare the efficacy and safety of tivozanib (a potent and selective VEGFR inhibitor) with those of sorafenib as third-line or fourth-line therapy in patients with metastatic renal cell carcinoma.Methods: In this open-label, randomised, controlled trial done at 120 academic hospitals in 12 countries, we enrolled eligible patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments (including at least one previous treatment with a VEGFR inhibitor), measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received previous treatment with tivozanib or sorafenib. Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy and randomised (1:1) with a complete permuted block design (block size of four) to either tivozanib 1·5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Investigators and patients were not masked to treatment. The primary endpoint was progression-free survival by independent review in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02627963.Findings: Between May 24, 2016, and Aug 14, 2017, 350 patients were randomly assigned to receive tivozanib (175 patients) or sorafenib (175 patients). Median follow-up was 19·0 months (IQR 15·0-23·4). Median progression-free survival was significantly longer with tivozanib (5·6 months, 95% CI 5·29-7·33) than with sorafenib (3·9 months, 3·71-5·55; hazard ratio 0·73, 95% CI 0·56-0·94; p=0·016). The most common grade 3 or 4 treatment-related adverse event was hypertension (35 [20%] of 173 patients treated with tivozanib and 23 [14%] of 170 patients treated with sorafenib). Serious treatment-related adverse events occurred in 19 (11%) patients with tivozanib and in 17 (10%) patients with sorafenib. No treatment-related deaths were reported.Interpretation: Our study showed that tivozanib as third-line or fourth-line therapy improved progression-free survival and was better tolerated compared with sorafenib in patients with metastatic renal cell carcinoma.Funding: AVEO Oncology. [ABSTRACT FROM AUTHOR]

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease. [ABSTRACT FROM AUTHOR]

Background: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.Methods: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.Findings: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.Interpretation: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.Funding: Bristol-Myers Squibb and ONO Pharmaceutical. [ABSTRACT FROM AUTHOR]

Localized renal cell carcinoma (RCC) has an associated risk of recurrence after nephrectomy. Several clinical risk models attempt to predict oncologic outcomes based on clinical and pathologic features. In addition, novel gene signatures have been developed to refine risk prediction based on tumor biology. Systemic therapies targeting angiogenic pathways that are effective in metastatic RCC failed to show an improvement in overall survival in the adjuvant setting. Immune checkpoint inhibitors have shown significant antitumor activity with prolonged and durable responses in metastatic RCC, which led to an interest in evaluating these agents in the adjuvant setting. In this review, clinical risk-predictive models, novel gene signatures, major clinical trials completed in the adjuvant setting, ongoing immune checkpoint inhibitor trials, and the perspective of adjuvant treatment in RCC are discussed. [ABSTRACT FROM AUTHOR]

Background: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.Methods: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.Findings: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.Interpretation: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.Funding: F Hoffmann-La Roche Ltd and Genentech Inc. [ABSTRACT FROM AUTHOR]

Immunotherapy has recently catapulted to the forefront of treatments for patients with solid tumors. Given its inherent immunogenic properties, renal cell carcinoma (RCC) has historically responded to immunotherapy and remains primed for further development. Although immunotherapy with high-dose interleukin 2 was a primary treatment for advanced RCC (aRCC), recent discoveries of key molecular and immunological alterations have led to the FDA-approval of nivolumab, an antiprogrammed cell death inhibitor, which has demonstrated an overall survival in patients with previously treated aRCC. However, despite recent therapeutic advances, aRCC remains an incurable disease for most patients. In this review, we assess the current landscape and future developments of immunotherapy in aRCC. [ABSTRACT FROM AUTHOR]

Background: In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects.Methods: The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02-positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 μg), with one dose of cyclophosphamide (300 mg/m2) 3 days before the first vaccination, or to receive sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01265901.Findings: Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive sunitinib plus IMA901 (n=204) or sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92-35·64). Median overall survival did not differ significantly between the groups (33·17 months [95% CI 27·81-41·36] in the sunitinib plus IMA901 group vs not reached [33·67-not reached] in the sunitinib monotherapy group; hazard ratio 1·34 [0·96-1·86]; p=0·087). 116 (57%) of 202 patients in the sunitinib plus IMA901 group and 62 (47%) of 132 in the sunitinib group had grade 3 or worse adverse events, the most common of which were hypertension, neutropenia, and anaemia in both groups, and mild-to-moderate transient injection-site reactions (eg, erythema, pruritus) were the most frequent IMA901-related side-effect in the sunitinib plus IMA901 group. Serious adverse events leading to death occurred in four (2%) patients (one respiratory failure and circulatory collapse [possibly related to sunitinib], one oesophageal varices haemorrhage [possibly related to sunitinib], one cardiac arrest [possibly related to sunitinib], and one myocardial infarction) and eight (6%) patients in the sunitinib group (one case each of renal failure, oesophageal varices haemorrhage, circulatory collapse, wound infection, ileus, cerebrovascular accident [possibly treatment related], and sepsis).Interpretation: IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated.Funding: Immatics Biotechnologies. [ABSTRACT FROM AUTHOR]

Background: A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance.Methods: In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing.Findings: Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma.Interpretation: A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach.Funding: None. [ABSTRACT FROM AUTHOR]

Summary: Background: Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods: In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Findings: Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). Interpretation: The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Funding: Pfizer Inc. [ABSTRACT FROM AUTHOR]

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (Vc) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy. [ABSTRACT FROM AUTHOR]

Although the long natural history of prostate cancer presents challenges in the development of novel therapeutics, major contributions have been observed recently. A better understanding of the long-term complications of androgen deprivation has changed the initial approach to most patients with advanced disease. Specifically, recognition of the limitations of prostate-specific antigen has driven the pursuit of new tools capable of becoming true surrogates for disease outcome. Understanding the molecular biology of castration-resistant prostate cancer (CRPC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease where the androgen receptor becomes a central therapeutic target. Specific adrenal inhibitors and engineered super androgen receptor inhibitors have become the most promising agents in the disease. Novel immune therapies have been shown to improve survival in selected patients with castration-resistant disease despite the inability to impact traditional markers of response. Similarly, agents such as cabazitaxel and abiraterone acetate have demonstrated clinical benefit are now a standard of care in docetaxel-refractory metastatic CRPC patients. All these changes have occurred in a relatively short period and are likely to change the prostate cancer treatment paradigm. This review summarizes the current management of CRPC and discusses potential future directions. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

The article presents a randomized phase three trial on the effectiveness of sorafenib and axitinib in patients with metastatic renal cell carcinoma (AXIS). The clinical test used sorafenib and axitinib, and participants were assessed by masked, analysed by intention of treating, and independent radiology review. The study treatment was stopped due to toxic effects in 14 patients or four percent patients treated with axitinib and 29 or eight percent patients treated with sorafenib.

Background Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib. We evaluated the association of sunitinib-induced HTN with antitumor efficacy and HTN-associated adverse events in patients with metastatic renal cell carcinoma. Methods This retrospective analysis included pooled efficacy (n = 544) and safety (n = 4917) data from four studies of patients with metastatic renal cell carcinoma who were treated with sunitinib 50 mg/d administered on a 4-week-on 2-week-off schedule (schedule 4/2). Blood pressure (BP) was measured in the clinic on days 1 and 28 of each 6-week cycle. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods; hazard ratios (HRs) for survival were also estimated by a Cox proportional hazards models using HTN as a time-dependent covariate. Efficacy outcomes were compared between patients with and without HTN (maximum systolic BP [SBP] ≥140 mm Hg or diastolic BP [DBP] ≥90 mm Hg). Adverse events were also compared between patients with and without HTN (mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg). All P values were two-sided. Results Patients with metastatic renal cell carcinoma and sunitinib-induced HTN defined by maximum SBP had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all). Similar results were obtained when comparing patients with vs without sunitinib-induced HTN defined by maximum DBP. In a Cox proportional hazards model using HTN as a time-dependent covariate, PFS (HR of disease progression or death = .603, 95% CI = .451 to .805; P < .001) and OS (HR of death = .332, 95% CI = .252 to .436; P < .001) were improved in patients with treatment-induced HTN defined by maximum SBP; OS (HR of death = .585, 95% CI = .463 to .740; P < .001) was improved in patients with treatment-induced HTN defined by maximum DBP, but PFS was not. Few any-cause cardiovascular, cerebrovascular, ocular, and renal adverse events were observed. Rates of adverse events were similar between patients with and without HTN defined by mean SBP; however, hypertensive patients had somewhat more renal adverse events (5% vs 3%; P = .013). Conclusions In patients with metastatic renal cell carcinoma, sunitinib-associated HTN is associated with improved clinical outcomes without clinically significant increases in HTN-associated adverse events, supporting its viability as an efficacy biomarker. [ABSTRACT FROM PUBLISHER]

BACKGROUND: On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte--associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had received ≤1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. Cancer 2011;117:758-67. [ABSTRACT FROM AUTHOR]

The article presents information on the treatment and management of refractory renal cell carcinoma in the U.S. Topics include therapy to inhibit vascular endothelial growth factor (VEGF) in people with renal cell carcinoma (RCC), the effectiveness of a multikinase inhibitor called cabozantinib, and the testing of several drugs such as everolimus, axitinib, and nivolumab.

Systematic studies evaluating clinical benefit of tumor genomic profiling are lacking. We conducted a prospective study in 250 patients with select solid tumors at the Cleveland Clinic. Eligibility required histopathologic diagnosis, age of 18 years or older, Eastern Cooperative Oncology Group performance status 0-2, and written informed consent. Tumors were sequenced using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board. Outcomes included feasibility and clinical impact. Colorectal (25%), breast (18%), lung (13%), and pancreatobiliary (13%) cancers were the most common diagnoses. Median time from consent to result was 25 days (range = 3-140). Of 223 evaluable samples, 49% (n = 109) of patients were recommended a specific therapy, but only 11% (n = 24) received such therapy: 12 on clinical trials, nine off-label, three on-label. Lack of clinical trial access (n = 49) and clinical deterioration (n = 29) were the most common reasons for nonrecommendation/nonreceipt of genomics-driven therapy. [ABSTRACT FROM AUTHOR]

Summary: Therapeutic targeting of integral biological pathways, including those involving vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), has produced robust clinical effects and revolutionised the treatment of metastatic renal-cell carcinoma (RCC). However, some patients are inherently resistant to these approaches and most, if not all, patients acquire resistance over time. As such, the biological basis for resistance to these targeted therapies and the clinical approach in this setting is of heightened interest. Emerging preclinical evidence suggests resistance is mediated via tumour and environmental changes, which allow for continued perfusion and tumour growth that is less reliant on VEGF. Furthermore, elements upstream of receptor blockade, such as hypoxia-inducible factor (HIF) and protein kinase B (AKT), in addition to pathways independent of VEGF or mTOR, could drive tumour growth despite adequate target blockade. These considerations provide a rational basis for combination or sequential therapy targeting these elements. Clinical data support activity of several agents in resistant patient populations, with large-scale clinical trials ongoing to more thoroughly test several postulations regarding the optimum clinical approach. [Copyright &y& Elsevier]

The article offers information on the effectiveness of vascular endothelial growth factor (VEGF)-targeted therapy in treating renal cell carcinoma (RCC). Result of a study shows that patients with metastatic RCC who are treated with VEGF-targeted therapy has long overall survival rate. However, it suggests that further investigation is needed to examine its elucidation of mechanisms of response and resistance and to explore the effects of sunitinib, sorafenib, axitinib and pazopanib.

The article discusses developments in the treatment of renal cell carcinoma. Innovative surgical techniques have revolutionized strategies for the management of the disease, particularly through emerging approaches that reduce invasiveness and preserve renal function for both partial nephrectomy and radical nephrectomy. The effectiveness of immunotherapy is addressed. The development of treatments using drugs that target specific biological pathways, such as inhibitors of vascular endothelial growth factor and rapamycin pathways, have shown promise as an alternative therapy for patients with metastatic renal cell carcinoma.

The article addresses the progress in the management of renal cell carcinoma (RCC) at both ends of the spectrum from small renal masses (SRMs) to advanced disease. An overriding aspect in the management of SRMs is to preserve renal function when possible. A major innovation in the field has been the demonstration that integration of surgery and systemic therapies may enhance survival of patients with metastatic RCC.

Background: Sunitinib and sorafenib are small molecules that inhibit the vascular endothelial growth factor and related receptors with substantial clinical activity reported in metastatic renal cell carcinoma (RCC). Cytopenia and macrocytosis have been described in patients treated with these agents.Methods: A retrospective review of all patients with metastatic RCC who were treated with sunitinib or sorafenib for at least 3 months at the Cleveland Clinic Taussig Cancer Institute was undertaken. Complete blood count (CBC) data including red blood cell indices were recorded at baseline, after 3 months of therapy, and at the end of treatment.Results: A total of 61 patients were treated with sunitinib and 37 patients were treated with sorafenib with available CBC data. In patients treated with sunitinib, the median corpuscular volume (MCV) increased significantly at 3 months compared with baseline (median increase of 5.1 femtoliters [fL]; P < .001) and continued to increase throughout treatment. Patients who developed hypothyroidism had a larger MCV increase at 3 months than patients who remained euthyroid (P = .06), although macrocytosis was observed in patients without hypothyroidism. Ten patients discontinued sunitinib therapy, and the MCV decreased in all patients within 2 to 4 months, without further intervention. Bone marrow analysis of 4 patients revealed a hypocellular bone marrow with trilineage hematopoiesis and no evidence of metastasis. There was no evidence of folate or vitamin B12 deficiency. In contrast to sunitinib, there was no change in the MCV for patients treated with sorafenib.Conclusions: Macrocytosis was a common occurrence after treatment with sunitinib but not sorafenib in patients with metastatic RCC. Sunitinib-induced macrocytosis is reversible with drug discontinuation. [ABSTRACT FROM AUTHOR]

Abstract: Vascular endothelial growth factor (VEGF) pathway activation leads to the angiogenic phenotype of renal cell carcinoma (RCC). Several different strategies targeting various aspects of this pathway have emerged as standard therapy in metastatic RCC. Bevacizumab, a VEGF ligand-binding antibody, sunitinib and sorafenib, small molecule inhibitors of the VEGF receptor, as well as temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) have all shown substantial clinical activity in metastatic RCC. Several relevant clinical aspects have also emerged with use of these agents such as defining resistance, measurement of response, and combination therapy. [Copyright &y& Elsevier]

The article presents medical research into immunotherapy for metastatic renal cell carcinoma. Treatments with cytokines interleukin-2 and interferon-alpha show consistent clinical results in antineoplastic activity. Interferon-alpha is a glycoprotein produced by the body in response to foreign antigens and viral infections.

OBJECTIVE To describe the relationship among patient characteristics, Von Hippel-Lindau (VHL) gene status and clinical outcome in metastatic renal cell carcinoma (RCC) in patients receiving vascular endothelial growth factor (VEGF)-targeted therapy. PATIENTS AND METHODS All patients with metastatic RCC who received therapy with interferon-α plus bevacizumab, SU11248 or AG013736 at the authors’ institution were considered. Clinical features were collected and activation status of the VHL gene ( VHL) was determined from baseline paraffin-embedded tumour samples. Tumour response, time to tumour progression (TTP) and overall survival were recorded. RESULTS Forty-three patients were evaluable for determination of VHL status and clinical response. There was an objective response in 18 patients (43%; 95% confidence interval 28–59%). The median TTP for the entire cohort was 8.1 months. There was an improved clinical outcome in patients with the following clinical features: male gender, lack of hepatic metastases, no previous radiation therapy and higher baseline haemoglobin level. Twenty-six patients (60%) had evidence of VHL mutation or promoter methylation; such patients had an objective response rate of 48%, vs 35% in patients with no VHL mutation or methylation. Patients with VHL methylation or a mutation predicted to truncate or shift the VHL reading frame had a median TTP of 13.3 months, vs 7.4 months in patients with none of these features ( P = 0.06). CONCLUSION VEGF-targeted therapy is active in metastatic RCC and the response can be associated with certain clinical features. The TTP with VEGF-targeted therapy might be prolonged in patients with VHL methylation or mutations that truncate or shift the VHL reading frame. Further investigation of VHL pathway components is needed to understand the biology of the response to VEGF-targeted agents in metastatic RCC. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine the biological effects of imatinib mesylate (STI-571, Gleevec®; Novartis Pharmaceuticals, Inc., East Hanover, NJ, USA), as measured by prostate-specific antigen (PSA) kinetics in men with biochemical relapse of prostate cancer after definitive local therapy. PATIENTS AND METHODS Men with prostate cancer, who had had definitive local therapy, with nonmetastatic recurrent disease as manifested by a rising PSA level, were enrolled on this phase II trial. Men received 400 mg of imatinib mesylate orally twice daily and continuously until disease progression or unacceptable toxicity. The PSA level was measured monthly. RESULTS In all, 20 men with biochemically relapsed prostate cancer were treated. The median pretreatment PSA level was 5.4 ng/mL. Of the 19 evaluable men, one achieved a ≥ 50% reduction in PSA level and two had decreases of <50%. For the 16 men in whom the on-treatment PSA doubling time (PSADT) could be calculated (those with increasing PSA level) the median PSADT did not increase significantly (5.8 vs 7.2 months, P = 0.64). Eleven of 20 men discontinued therapy due to toxicity and the trial was stopped early due to toxicity. CONCLUSIONS Based on the lack of PSA modulation and pronounced toxicities leading to early closure of this trial, further study of single-agent imatinib mesylate at this dose (400 mg twice daily) cannot be recommended in this patient population. [ABSTRACT FROM AUTHOR]

Abstract: A graft-versus-tumor effect through nonmyeloablative allogeneic stem cell transplantation (N-SCT) in metastatic renal cell carcinoma (RCC) has been reported. An Intergroup phase II trial was undertaken to define further the feasibility, toxicity and efficacy of this approach in a multi-institutional setting, Patients with cytokine-refractory, metastatic RCC were treated with N-SCT. The conditioning regimen was fludarabine 30 mg·m−2 ·d−1 on day (d) −7 through d −3 and cyclophosphamide 60 mg·kg−1 ·d−1 on d −4 and d −3. Patients received 2-8 × 106 CD34+ cells/kg of granulocyte colony-stimulating factor mobilized stem cells from a 6/6 HLA-matched sibling donor. Immunosuppression after transplantation included tacrolimus and methotrexate. Twenty-two patients were enrolled at 14 institutions. Greater than 90% donor T-cell chimerism was observed in 17 of 19 evaluable patients (89%) by d +120. No objective response was observed. Acute graft-versus-host disease (GVHD) was observed in 11 patients (50%). Chronic GVHD was reported in 5 patients (23%). There was 1 patient death from liver failure secondary to chronic GVHD. Regimen-related mortality was 2 of 22 (9%; liver failure, sepsis). Median survival time was 5.5 months (95% confidence interval, 3.9-12.0 months) and the median time to progression was 3.0 months (95% confidence interval, 2.3-4.2 months). N-SCT for metastatic RCC is feasible in a multi-institutional setting. Adequate donor T-cell engraftment was achieved in most patients before disease progression. A graft-versus-tumor effect was not observed in this study despite acute and chronic GVHD, thus highlighting the need for further understanding of this approach. Allogeneic SCT remains investigational in RCC. [Copyright &y& Elsevier]

This article presents a study focusing on the usefulness of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, as an additional aid in the standard treatment of patients with metastatic clear-cell renal cell carcinoma (RCC). The study incorporated a clinical trial which examined patients treated with sunitinib malate during the progression of their disease. Researchers examined the development of tumors and monitored the survival rate of the controlled group. The study found that sunitinib malate was almost uniformly successful in RCC and resulted in only minor side-effects for a small percentage of these patients.

In this section there is a wide diversity of mini-reviews, covering several areas of interest for readers. Authors from the USA write about clinical trials in patients with biochemically relapsed prostate cancer, again bridging the divide between medical oncologists and urologists who specialise in urological oncological surgery. The second paper is a joint one from Germany and the USA, bringing the reader up to date with advances in the treatment of stress urinary incontinence. Finally there are two papers from Australia describing the use of positron emission tomography in renal cancer and in prostate cancer. [ABSTRACT FROM AUTHOR]

The article focuses on the therapy targeted at vascular endothelial growth factor (VEGF) in metastatic renal cell carcinoma (RCC). VEGF is a glycoprotein that is critically important in both normal and tumour-associated angiogenesis through several mechanisms. Pertinent to RCC, VEGF expression results from the inactivation of the von Hippel-Lindau tumour-suppressor gene observed in most RCC, thus identifying VEGF as a particularly relevant therapeutic target in RCC. A recombinant human monoclonal antibody against VEGF binds and neutralises all biologically active isoforms of VEGF.

The components of an effective immune response have been elucidated in recent years. An understanding of the dysfunctional immune response in cancer in one or more of these components has lead to a variety of immunotherapeutic approaches. These therapeutic strategies are designed to stimulate dendritic cell (DC) proliferation, promote antigen uptake and processing, stimulate an effector cell response via direct antigen presentation or target tumor cells via antibody therapy. Many approaches in prostate cancer have demonstrated successful induction of the desired immune response. Limited clinical success has also been seen. [Copyright &y& Elsevier]

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy-based treatment options have become standard of care in metastatic renal cell carcinoma. Despite significant improvement in overall survival with these therapies, the tumors of many patients will eventually progress. This review highlights the ongoing efforts to develop biomarkers to help predict which patients are most likely to benefit from treatment with immunotherapy. Immunotherapy-based combinations, driven by PD-1, PD-L1, and CTLA-4 inhibitors, has altered the treatment landscape for metastatic renal cell carcinoma (RCC). Despite significant improvements in clinical outcomes, many patients do not experience deep or lasting benefits. Recent efforts to determine which patients are most likely to benefit from immunotherapy and immunotherapy-based combinations have shown promise but have not yet affected clinical practice. PD-L1 expression via immunohistochemistry (IHC) has shown promise in a few clinical trials, although variations in the IHC assays as well as the use of different values for positivity presents unique challenges for this potential biomarker. Several other candidate biomarkers were investigated including tumor mutational burden, gene expression signatures, single gene mutations, human endogenous retroviruses, the gastrointestinal microbiome, and peripheral blood laboratory markers. While individually these biomarkers have yet to explain the heterogeneity of treatment response to immunotherapy, using aggregate information from these biomarkers may inform clinically useful predictive biomarkers. [ABSTRACT FROM AUTHOR]

The authors comment on two clinical trials with sunitinib in patients with metastatic renal cell carcinoma (mRCC) and disease progression while receiving first-line cytokine therapy. They believe that the pharmacokinetic analyses and outcome of the studies have highlighted the advantages of 50-milligram (mg) dose using the 4/2 schedule. They also agree with the findings that treating patients at a low dose intensity may result in reduced efficacy.

The article discusses the management of clinical stage 1 (T1) renal mass which was presented at the American Urological Association meeting in Chicago, Illinois in 2009. Consensus statements about management options include Partial nephrectomy (PN) being a reference standard for clinical T1 renal masses, thermal ablation (TA) as a good option for high surgical risk patients, and active surveillance (AS) as a reasonable strategy for localized renal masses. Integration of surgery and systemic therapies have also been shown to improve survival rates.

The article presents information on several approaches to vascular endothelial growth factor (VEGF) pathway targets in renal cell carcinoma (RCC). It is stated that Bevacizumab is a recombinant human monoclonal antibody against VEGF that binds and neutralizes all biologically active isoforms of VEGF. Two phase II trials of the oral small molecule tyrosine kinase inhibitor called Sunitinib revealed objective response rates of approximately 40 percent.

Sunitinib is an inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors, and it has antitumor activity in metastatic renal cell carcinoma and gastrointestinal stromal tumors. To further investigate the fatigue associated with sunitinib therapy, thyroid function tests were performed on patients with metastatic renal cell carcinoma who were receiving sunitinib. Seventy-three patients with metastatic renal cell carcinoma were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and 66 of them had thyroid function test results available. Fifty-six (85%) of the 66 patients had one or more abnormality in their thyroid function test results, consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement was undertaken in 17 patients, and symptoms improved in nine of them. Thyroid function test abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, and routine monitoring is warranted. [ABSTRACT FROM AUTHOR]

Objective: To report the results of PADRES (Prior Axitinib as a Determinant of Outcome of Renal Surgery, NCT03438708), a study investigating neoadjuvant axitinib for tumours of high complexity with imperative indication for partial nephrectomy (PN). Methods: We conducted a single‐arm phase II clinical trial of localized (cT1b‐cT3M0) clear‐cell renal cell carcinoma (RCC) patients with imperative indications for nephron preservation, where PN is a high‐risk procedure due to complexity (RENAL score 10–12). Axitinib 5 mg was administered twice daily for 8 weeks with repeat imaging at completion, followed by surgery. The primary outcome was successful completion of planned PN following axitinib treatment. Secondary objectives included changes in tumour diameter, RENAL nephrometry score, renal function and Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and surgical complications. Results: Twenty‐seven patients were enrolled (median age 69 years). Prior to therapy, twenty patients (74.0%) had ≥ clinical T3a staged tumours. Axitinib resulted in reductions in tumour diameter (7.5 vs 6.2 cm; P < 0.001) and RENAL score (11 vs 10; P < 0.001). Nine patients (33.3%) had partial response based on RECIST and nine (33.3%) were clinically downstaged. PN was performed in twenty patients (74.0%); twenty‐five patients (96.2%) had negative margins. Six patients (22.2%) had Clavien III–IV complications. The median change in estimated glomerular filtration rate (preoperative to last follow‐up) was 8.5 mL/min/1.73 m2. Conclusion: Neoadjuvant axitnib resulted in reductions in tumour size and complexity, enabling safe and feasible PN and functional preservation in patients with complex renal masses and imperative indication. [ABSTRACT FROM AUTHOR]

In TIVO-3, tivozanib increased progression-free survival relative to sorafenib in patients with metastatic renal cell carcinoma. In the current analysis, tivozanib also increased quality-adjusted time without symptoms of disease and toxicity (Q-TWiST). As an outcome that integrates the quantity and quality of survival, Q-TWiST may be considered an alternative patient-centered measure of tivozanib benefit in renal cell carcinoma. Background: In TIVO-3, tivozanib increased progression-free survival with no difference in overall survival relative to sorafenib as third- or fourth-line therapy in patients with metastatic renal cell carcinoma. We applied quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) methods to quantify the net health benefits of tivozanib, in the presence of similar survival, when compared with sorafenib. Methods: The mean Q-TWiST was calculated by applying utility coefficients of 0.5, 1.0, and 0.5 to the 36-month restricted mean health states of time with toxicity (TOX), TWiST, and time after progression/relapse, respectively. The relative Q-TWiST gain was defined as the mean absolute Q-TWiST difference divided by the sorafenib mean overall survival. Results: The mean TWiST was longer for tivozanib than for sorafenib, mean time after progression/relapse was shorter for tivozanib, with no difference in mean TOX. Mean Q-TWiST was 15.04 months and 12.78 months for tivozanib and sorafenib, respectively (P = .0493). The tivozanib relative gain was 11.2%. Discussion: Tivozanib increased Q-TWiST relative to sorafenib, pr imar ily through an increase in TWiST, which is generally considered to be the highest utility state. Conclusion: Q-TWiST may be considered an alternative patient-centered measure of benefit of tivozanib in as a third- or fourth-line therapy in patients with renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Urethral adenocarcinoma of males is a rare disease with limited prospective data to define optimal treatment. Surgical excision remains the primary treatment for early-stage disease. Multimodality therapy with a combination of chemotherapy, radiation, or surgery has been explored in patients with locally advanced disease. We present the case of a 45-year-old-man with a locally recurrent urethral adenocarcinoma after initial surgical resection managed successfully with combined weekly cisplatinum and radiation therapy. [ABSTRACT FROM AUTHOR]