Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM).

PURPOSE: Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS: Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS: Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION: Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.

A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA).

BACKGROUND: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor. METHODS: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity. RESULTS: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype. CONCLUSIONS: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery. CLINICAL TRIAL REGISTRATION: NCT03494816.

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

OBJECTIVE: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial. PATIENTS AND METHODS: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (KTrans , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03). CONCLUSION: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.

Early Clinical Experience with Cabozantinib for Advanced Renal Cell Carcinoma in the UK: Real-World Treatment Pathways and Clinical Outcomes.

BACKGROUND: Cabozantinib monotherapy is approved in the UK for patients with treatment-naïve intermediate- or poor-risk advanced renal cell carcinoma (aRCC), or patients who received prior vascular endothelial growth factor-targeted therapy. Data are limited on the real-world use of cabozantinib for aRCC. PATIENTS AND METHODS: CERES (NCT03696407) was a retrospective study of patients with aRCC who received cabozantinib through the UK managed access programme (MAP; August 2016-July 2017), at which time cabozantinib had European regulatory approval for second- or later-line use only. The study objectives were to characterize aRCC treatment patterns and evaluate cabozantinib effectiveness. Outcomes were stratified by cabozantinib treatment line, MAP treatment date (months 0-7 vs. 8-12) and (post hoc) Charlson Comorbidity Index (CCI; ≥ 6 vs. < 6). RESULTS: Of 100 patients included, 99% had stage IV disease, 63% had a CCI ≥ 6 and 81% had an Eastern Cooperative Oncology Group Performance Status 0-1. Median (range) duration of follow-up was 10.8 (0.4-33.5) months. Cabozantinib was administered as second-line, third-line and fourth- or later-line in 41%, 31% and 28% of patients, respectively. Most patients (84%) initiated cabozantinib at 60 mg. Average (range) cabozantinib dose was 45.5 (19.6-59.8) mg/day; 66% of patients had ≥ 1 dose reduction. Disease progression was the most common reason for discontinuation (65.1%). Median (95% confidence interval) progression-free survival (PFS) and overall survival (OS) were 6.01 (5.16-7.85) and 10.84 (7.92-16.85) months, respectively. Overall response rate was 34.5%; disease control rate 70.1% and duration of response 6.9 (1.8-26.9) months. No significant differences in survival estimates were observed between treatment line or treatment date subgroups. Total CCI score ≤ 6 (vs. > 6) was associated with prolonged median PFS and OS. CONCLUSION: Cabozantinib demonstrated clinical activity in this UK real-world aRCC population. The results provide a benchmark for future real-world studies in aRCC.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

Case Report: Clinical Experience With Avelumab in Patients With Metastatic Merkel Cell Carcinoma and Brain Metastases Treated in Europe.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that can metastasize rapidly. In patients with metastatic MCC (mMCC), brain metastases are uncommon but are associated with poor prognosis; furthermore, there is limited published literature regarding treatment of these patients, and no specific regimens are currently recommended by guidelines. Avelumab, an anti-programmed death ligand 1 monoclonal antibody, was the first approved treatment for patients with mMCC. Here, we present 4 cases of patients with mMCC and brain metastases treated with avelumab. Patient age ranged from 48 to 70 years, and all patients received avelumab as second-line therapy following disease progression with platinum-based chemotherapy. Patient cases 1 and 2 received avelumab alone and experienced rapid disease progression according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In patient case 3, avelumab alone resulted in a prolonged complete response by RECIST 1.1 of 1 brain metastasis and partial response by RECIST 1.1 of a second brain metastasis. After 11 months of avelumab treatment, the patient received concurrent stereotactic radiosurgery that resulted in complete response of the second metastasis. Patient case 4 achieved a partial response by RECIST 1.1 with avelumab plus stereotactic radiosurgery. These results suggest that avelumab followed by radiotherapy or with concurrent radiotherapy may be an effective treatment option for patients with mMCC and brain metastases.

A Decision Analysis Evaluating Screening for Kidney Cancer Using Focused Renal Ultrasound.

BACKGROUND: Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value. OBJECTIVE: To determine (1) whether current evidence suggests that screening is potentially cost-effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps. DESIGN, SETTING, AND PARTICIPANTS: A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted. INTERVENTION: A single focused renal ultrasound scan compared with standard of care (no screening). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum. RESULTS AND LIMITATIONS: Given a prevalence of RCC of 0.34% (0.18-0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08-0.25%), screening 60-yr-old women resulted in an ICER of £37327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was <£30000/QALY as long as the prevalence of RCC was ≥0.25% for men and ≥0.2% for women at age 60yr. Given the willingness to pay a threshold of £30000/QALY (€37 878/QALY), the population-expected values of perfect information were £194 million (€244 million) and £97 million (€123 million) for 60-yr-old men and women, respectively. The expected value of perfect parameter information suggests that the prevalence of RCC and stage shift associated with screening are key research priorities. CONCLUSIONS: Current evidence suggests that one-off screening of 60-yr-old men is potentially cost-effective and that further research into this topic would be of value to society. PATIENT SUMMARY: Economic modelling suggests that screening 60-yr-old men for kidney cancer using ultrasound may be a good use of resources and that further research on this topic should be performed.

Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site.

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location. SIGNIFICANCE: Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.See related commentary by De Dominici and DeGregori, p. 227.This article is highlighted in the In This Issue feature, p. 211.

Treatment patterns and health outcomes in metastatic renal cell carcinoma patients treated with targeted systemic therapies in the UK.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) treated with targeted systemic therapies have demonstrated favourable outcomes in randomised controlled trials, however real-world evidence is limited. Thus, this study aimed to determine the effectiveness of targeted systemic therapies for patients with mRCC in routine clinical practice in the UK. METHODS: A retrospective, observational, longitudinal study based on chart review of newly diagnosed adult mRCC patients treated at two UK hospitals from 2008 to 2015 was conducted. Targeted systemic therapies recommended for use in mRCC patients were evaluated across first to third lines of therapy (1LOT-3LOT). Important exclusions were treatment with cytokine therapy and within non-standard of care clinical trials. Primary outcome measure was overall survival (OS); data were analysed descriptively and using Kaplan-Meyer analysis. RESULTS: 652 patients (65.3% male, 35.0% ≥70 years) were included. In 1LOT, 98.5% of patients received sunitinib or pazopanib. In 2LOT and 3LOT, 99.0 and 94.4% received axitinib or everolimus. Median OS was 12.9, 6.5 and 5.9 months at 1LOT, 2LOT and 3LOT respectively. Estimated OS at 1-year was 52.4% (95% CI: 48.6-56.4%) in 1LOT, 31.5% (25.2-39.5%) in 2LOT and 23.8% (10.1-55.9%) in 3LOT. Median OS from 1LOT in favourable, intermediate and poor MSKCC were 39.7, 15.8 and 6.1 months respectively. CONCLUSIONS: In this study, treatment was consistent with current National Institute for Health and Care Excellence (NICE) guidelines for mRCC patients. Although the study population favoured poorer prognosis patients, outcomes were more favourable than those for England at the same time. However, overall survival in this 'real-world' population remains poor and indicates significant unmet need for effective and safe treatment options to improve survival among mRCC patients.

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy.

BACKGROUND: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH). OBJECTIVE: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC). DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. INTERVENTION: The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria. RESULTS AND LIMITATIONS: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design. CONCLUSIONS: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required. PATIENT SUMMARY: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.

PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma.

BACKGROUND: The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. METHODS: The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. DISCUSSION: The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. TRIAL REGISTRATION: PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). TRIAL STATUS: At the time of submission, PRISM is open to recruitment and data collection is ongoing.

Augmenting the randomized controlled trial with real-world data to aid clinical decision making in metastatic renal cell carcinoma: a systematic review and meta-analysis.

Aim: To evaluate how efficacy outcomes from real-world data (RWD) can support those from randomized controlled trials (RCTs), in the context of first-line tyrosine kinase inhibitor treatment of metastatic renal cell carcinoma. Patients & methods: PubMed, Ovid, MEDLINE and EMBASE were searched for RCTs and RWD studies with ≥50 adult patients per arm published in 2000-2017. Outcome measures were median progression-free survival, median overall survival and objective response rate. Results: A total of 13 RCTs and 22 RWD studies met eligibility criteria; 31, 28 and 25 studies, respectively, reported median progression-free survival, median overall survival and objective response rate. Summary outcome measures were similar in RWD and RCTs. Conclusion: RWD validates efficacy-based outcomes from RCTs and may provide supportive evidence to inform clinical decisions.

The VENUSS prognostic model to predict disease recurrence following surgery for non-metastatic papillary renal cell carcinoma: development and evaluation using the ASSURE prospective clinical trial cohort.

BACKGROUND: The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply because they occur in the same organ. Specifically, there is a paucity of tools to risk-stratify patients with papillary RCC (PRCC). The purpose of this study was to develop and evaluate a tool to risk-stratify patients with clinically non-metastatic PRCC following curative surgery. METHODS: We studied clinicopathological variables and outcomes of 556 patients, who underwent full resection of sporadic, unilateral, non-metastatic (T1-4, N0-1, M0) PRCC at five institutions. Based on multivariable Fine-Gray competing risks regression models, we developed a prognostic scoring system to predict disease recurrence. This was further evaluated in the 150 PRCC patients recruited to the ASSURE trial. We compared the discrimination, calibration and decision-curve clinical net benefit against the Tumour, Node, Metastasis (TNM) stage group, University of California Integrated Staging System (UISS) and the 2018 Leibovich prognostic groups. RESULTS: We developed the VENUSS score from significant variables on multivariable analysis, which were the presence of VEnous tumour thrombus, NUclear grade, Size, T and N Stage. We created three risk groups based on the VENUSS score, with a 5-year cumulative incidence of recurrence equalling 2.9% in low-risk, 15.4% in intermediate-risk and 54.5% in high-risk patients. 91.7% of low-risk patients had oligometastatic recurrent disease, compared to 16.7% of intermediate-risk and 40.0% of high-risk patients. Discrimination, calibration and clinical net benefit from VENUSS appeared to be superior to UISS, TNM and Leibovich prognostic groups. CONCLUSIONS: We developed and tested a prognostic model for patients with clinically non-metastatic PRCC, which is based on routine pathological variables. This model may be superior to standard models and could be used for tailoring postoperative surveillance and defining inclusion for prospective adjuvant clinical trials.

Sunitinib for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World and Clinical Trials Data.

BACKGROUND: Randomized controlled trials (RCTs) have stringent inclusion criteria and may not fully represent patients seen in everyday clinical practice. Real-world data (RWD) can provide supportive evidence for the effectiveness of medical interventions in more heterogeneous populations than RCTs. Sunitinib is a widely used first-line treatment for patients with metastatic renal cell carcinoma (mRCC). OBJECTIVE: This is the first comprehensive meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and RWD. METHODS: RCTs and RWD studies published between 2000 and 2017 were identified from PubMed, Ovid, MEDLINE, and EMBASE. Eligible studies contained a cohort of ≥ 50 adult patients with mRCC receiving first-line sunitinib treatment. The meta-analysis combined RWD and RCT treatment groups, adjusting for data type (RCT or RWD). Recorded outcomes were median progression-free survival (mPFS), median overall survival (mOS), and objective response rate (ORR). Publication bias was assessed via review of funnel plots for each outcome measure. A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimates. RESULTS: Of the 3611 studies identified through medical database searches, 22 (15 RWD studies, 7 RCTs) met eligibility criteria and were analyzed. mPFS (18 studies), mOS (19 studies), and ORR (15 studies) were reported for aggregate measures based on 4815, 5321, and 4183 patients, respectively. Reported mPFS (RWD, 7.5-11.0 months; RCTs, 5.6-15.1 months) and ORR data (RWD, 14.0-34.6%; RCTs, 18.8-46.9%) were consistent with the overall confidence estimates (95% confidence interval [CI]) of 9.3 (8.6-10.2) months and 27.9% (24.2-32.0), respectively. Reported mOS showed greater variation in RWD (6.8-33.2 months) compared with RCTs (21.8-31.5 months), with an overall confidence estimate (95% CI) of 23.0 (19.2-27.6) months. Inspection of funnel plots and sensitivity analyses indicated that there was no publication bias for any efficacy endpoint. Sensitivity analyses showed no evidence of lack of robustness for mPFS, mOS, or ORR. Interpretation of these results is limited by differences in trial design, cohort characteristics, and missing data. CONCLUSIONS: This novel, comprehensive meta-analysis validates sunitinib as an effective first-line treatment for patients with mRCC in both RCTs and everyday clinical practice. The methodology provides a framework for future analyses combining data from RCTs and RWD.

Dose escalation of axitinib on disease progression as a strategy in the treatment of metastatic renal cell carcinoma.

INTRODUCTION: The AXIS trial established axitinib as a standard of care treatment for patients with metastatic renal cell carcinoma (mRCC) after failure of a prior tyrosine kinase inhibitor. Axitinib dosing begins at 5 mg twice daily, with escalation of doses to 7 and 10 mg after consecutive 2-week intervals if tolerated (as per the drug label). Given clinical concerns about drug-related toxicity, we have used a pragmatic strategy where dose escalations were made only after disease progression or where rapid responses were clinically required. METHODS: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for >2 weeks at Addenbrooke's Hospital, Cambridge, UK, over a 37 -month period to determine the clinical and radiological effects of dose escalations made according to the above strategy. RESULTS: 42 patients fitting these criteria were identified, 29 having ≥1 dose escalation event (DEE). 60 DEEs were identified (median of two per patient), and the objective radiological consequences of 53 DEEs could be evaluated. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% vs 70%). 56.6 % of all DEEs and 63.6 % of DEEs made as a result of disease progression resulted in disease control. The median OS from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 16.5 months for the entire cohort. The mean dose (for all patients) at 90 days after starting axitinib was 5.92 mg. CONCLUSION: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and this may be a preferred option in patients in whom there are particular concerns about drug-related toxicity, quality of life optimisation or healthcare-associated costs.

External validation of a predictive model of survival after cytoreductive nephrectomy for metastatic renal cell carcinoma.

INTRODUCTION: Recent trials have emphasized the importance of a precise patient selection for cytoreductive nephrectomy (CN). In 2013, a nomogram was developed for pre- and postoperative prediction of the probability of death (PoD) after CN in patients with metastatic renal cell carcinoma. To date, the single-institutional nomogram which included mostly patients from the cytokine era has not been externally validated. Our objective is to validate the predictive model in contemporary patients in the targeted therapy era. METHODS: Multi-institutional European and North American data from patients who underwent CN between 2006 and 2013 were used for external validation. Variables evaluated included preoperative serum albumin and lactate dehydrogenase levels, intraoperative blood transfusions (yes/no) and postoperative pathologic stage (primary tumour and nodes). In addition, patient characteristics and MSKCC risk factors were collected. Using the original calibration indices and quantiles of the distribution of predictions, Kaplan-Meier estimates and calibration plots of observed versus predicted PoD were calculated. For the preoperative model a decision curve analysis (DCA) was performed. RESULTS: Of 1108 patients [median OS of 27 months (95% CI 24.6-29.4)], 536 and 469 patients had full data for the validation of the pre- and postoperative models, respectively. The AUC for the pre- and postoperative model was 0.68 (95% CI 0.62-0.74) and 0.73 (95% CI 0.68-0.78), respectively. In the DCA the preoperative model performs well within threshold survival probabilities of 20-50%. Most important limitation was the retrospective collection of this external validation dataset. CONCLUSIONS: In this external validation, the pre- and postoperative nomograms predicting PoD following CN were well calibrated. Although performance of the preoperative nomogram was lower than in the internal validation, it retains the ability to predict early death after CN.

Prognostic effect of cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma: a comparative study using inverse probability of treatment weighting.

PURPOSE: To test the hypothesis that cytoreductive nephrectomy (CN) improves overall survival (OS) of patients with synchronous metastatic renal cell carcinoma (mRCC), who subsequently receive targeted therapies (TT). METHODS: We identified 261 patients who received TT for synchronous mRCC with or without prior CN. To achieve balance in baseline characteristics between groups, we used the inverse probability of treatment weighting (IPTW) method. We conducted OS analyses, including IPTW-adjusted Kaplan-Meier curves, Cox regression models, interaction term, and landmark and sensitivity analyses. RESULTS: Of the 261 patients, 97 (37.2%) received CN and 164 (62.8%) did not. IPTW-adjusted analyses showed a statistically significant OS benefit for patients treated with CN (HR 0.63, 95% CI 0.46-0.83, P = 0.0015). While there was no statistically significant difference in OS at 3 months (P = 0.97), 6 months (P = 0.67), and 12 months (P = 0.11) from diagnosis, a benefit for the CN group was noted at 18 months (P = 0.005) and 24 months (P = 0.004). On interaction term analyses, the beneficial effect of CN increased with better performance status (P = 0.06), in women (P = 0.03), and in patients with thrombocytosis (P = 0.01). CONCLUSIONS: IPTW-adjusted analysis of our patient cohort suggests that CN improves OS of patients with synchronous mRCC treated with TT. On the whole, the survival difference appears after 12 months. Specific subgroups may particularly benefit from CN, and these subgroups warrant further investigation in prospective trials.

Assessment of quality of life using Skindex-16 in patients with advanced basal cell carcinoma treated with vismodegib in the STEVIE study.

Health-related quality of life (HRQoL) data are limited in patients with advanced basal cell carcinoma. To report HRQoL outcomes based on STEVIE (NCT01367665), a phase 2 study of vismodegib safety in patients with metastatic BCC or locally advanced BCC that is unsuitable for surgery or radiotherapy. Skindex-16 and MD Anderson Symptom Inventory (MDASI) questionnaires were completed at baseline and at three subsequent visits. Clinically meaningful improvement was defined as a ≥10-point decrease from baseline (Skindex-16) or improvement of at least 3 points from baseline (MDASI). HRQoL-evaluable patients with locally advanced BCC (n = 730) had ≥10-point improvements in Skindex-16 emotion domain scores at all time points. Changes in symptom and function scores in these patients or in any domain scores at any time point in patients with metastatic BCC (n = 10) were not clinically meaningful. Of 10 patients with symptomatic metastatic BCC at baseline, six had ≥3-point improvements in MDASI symptom severity. Skindex-16 and MDASI showed improvement in HRQoL in vismodegib-treated patients with locally advanced or metastatic BCC or BCC.