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

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

Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR)

Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer

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

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

Funder: Bristol Myers Squibb Pharmaceuticals Ltd.Abstract: 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

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

Abstract: 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

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

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

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

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