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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

BACKGROUND: Little has been published regarding how doctors think and talk about prognosis and the potential benefits of adjuvant therapy. OBJECTIVE: We sought predictions of survival rates and survival times, for patients with and without adjuvant therapy, from the clinicians of patients participating in a randomised trial of adjuvant sorafenib after nephrectomy for renal cell carcinoma. METHODS: A subset of medical oncologists and urologists in the SORCE trial completed questionnaires eliciting their predictions of survival rates and survival times, with and without adjuvant sorafenib, for each of their participating patients. To compare predictions elicited as survival times versus survival rates, we transformed survival times to survival rates. To compare predicted benefits elicited as absolute improvements in rates and times, we transformed them into hazard ratios (HR), a measure of relative benefit.We postulated that a plausible benefit in overall survival (OS) should be smaller than that hypothesized for disease–free survival (DFS) in the trials original sample size justification (i.e. HR for OS should be ≥ 0.75). RESULTS: Sixty–one medical oncologists and 17 urologists completed questionnaires on 216 patients between 2007 and 2013. Predictions of survival without adjuvant sorafenib were similar whether elicited as survival rates or survival times (median 5–year survival rate of 61% vs 60%, p = 0.6). Predicted benefits of sorafenib were larger when elicited as improvements in survival rates than survival times (median HR 0.76 vs 0.83, p < 0.0001). The proportion of HR for predicted OS with sorafenib that reflected a plausible benefit (smaller effect of sorafenib on OS than hypothesized on DFS, i.e. HR ≥ 0.75) was 51% for survival rates, and 65% for survival times. CONCLUSIONS: The predicted benefits of adjuvant sorafenib were larger when elicited as improvements in survival rates than as survival times, and were often larger than the sample size justification for the trial. These potential biases should be considered when thinking and talking about individual patients in clinical practice, and when designing clinical trials.

Funder: AstraZeneca (GB), 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.

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.

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. Electronic supplementary material The online version of this article (10.1007/s11523-019-00653-5) contains supplementary material, which is available to authorized users.

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.

Funder: Bristol Myers Squibb Pharmaceuticals Ltd., 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.

Background Cabozantinib monotherapy is approved in the UK for patients with treatment-naive 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 versus 8–12) and (post hoc) Charlson Comorbidity Index (CCI; ≥6 versus 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 (versus >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. MicroAbstract This retrospective study, CERES (NCT03696407), describes early clinical experience with cabozantinib in patients with advanced renal cell carcinoma (aRCC) enrolled in the UK managed access programme. Cabozantinib demonstrated clinically meaningful activity in all patients across multiple lines of therapy. Charlson comorbidity score warrants further investigation as a prognostic/predictive marker. Our results provide a benchmark for future real-world studies in aRCC.

Background: The use of conventionally fractionated intensity modulated radiotherapy (IMRT) in the management of oligometastatic renal cell carcinoma (RCC) is currently poorly characterised in the literature. Objective: To evaluate the safety and effectiveness of IMRT for intraabdominal and retroperitoneal RCC oligometastases. Methods: Retrospective analysis of 14 patients with oligometastatic RCC treated with IMRT with the aim of inducing long-term control. Indications for radiotherapy included bleeding abdominal mass (5 patients), solitary renal bed recurrence (5 patients) and isolated, asymptomatic pancreatic mass (4 patients). The prescribed radiotherapy dose was 50 Gray in 20 to 25 fractions. Patients were followed up long-term using regular cross-sectional imaging and clinical review to assess local and distant disease control and treatment related toxicity. Results: At median follow up of 33.5 (6–68) months, 12 patients remain alive (86%), of whom 11 (92%) have no evidence of local recurrence. Six patients (43%) developed further metastatic disease, of whom 4 (67%) received systemic treatment. Median duration of local control was 33.5 months, and 1- and 3-year overall survival (OS) was 92.9% and 85.7% respectively. No treatment-related toxicities ≥ grade 3 and no long-term sequelae were observed. Conclusions: IMRT to intra-abdominal and retroperitoneal metastasis in oligo-metastatic RCC can be delivered safely, provide durable responses and excellent longer-term survival if given to a sufficiently high dose over a conventionally fractionated course. Our study is the first to date with long-term follow up to evaluate the role of IMRT in such cases and has important implications for treatment of oligometastatic RCC.

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.

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.

Background:\ud \ud 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).\ud Objective:\ud \ud To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC).\ud Design, setting, and participants:\ud \ud 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.\ud Intervention:\ud \ud The phase II trial assessed vascular endothelial growth factor-targeted therapy ± Src inhibition.\ud Outcome measurements and statistical analysis:\ud \ud 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.\ud Results and limitations:\ud \ud 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.\ud Conclusions:\ud \ud RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required.\ud Patient summary:\ud \ud 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.

e16561 Background: CheckMate 025 demonstrated favorable efficacy and safety results for nivolumab monotherapy in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, real-world evidence on treatment patterns and clinical outcomes is limited. Methods: This multi-centre, retrospective cohort study examined treatment patterns and overall survival (OS) in aRCC patients treated with nivolumab monotherapy. Eligible patients who initiated nivolumab at second-line (2L) or beyond (index) between 01 March 2016 and 30 June 2018 were sampled from four UK centers. Data were extracted using an electronic case report form from index to earliest of: most recent visit; death; end of follow up (31 May 2019). Results: Overall , 151 patients were included in analyses (mean age at index 66.9 years, 72.2% male, median follow-up from index 15.2 months), with 109 (72.2%) and 42 (27.8%) receiving nivolumab at 2L and ≥ third-line (3L+), respectively. Key clinical characteristics are outlined in Table 1. All 2L nivolumab patients had received first-line (1L) tyrosine kinase inhibitors (TKI), pazopanib (57.8%), sunitinib (30.3%), or both in sequence (10.1%). After 2L nivolumab, 3L cabozantinib (36/52, 69.2%) was most common. Most 3L nivolumab patients received 2L TKI (31/36, 86.1%) - commonly axitinib (70.9%). After 3L nivolumab, most patients received fourth-line cabozantinib (8/12, 66.7%). Median time on line of therapy (LOT) decreased with LOT progression: from 7.8 months at 1L to 4.6 months at fifth-line (5L). The proportion of patients who discontinued treatment due to adverse events decreased by LOT, (28.6%, 22.7%, 16.0% and 0%, and 34.7%, 28.1%, 0% and 0% from 2L to 5L, overall and for nivolumab treatment, respectively). Overall, median OS from nivolumab initiation was 19.2 months [95% CI, 16.9-27.0]. Patients who received 2L nivolumab had longest median OS (23.0 months [95% CI, 17.2, not reached]), comparable to CheckMate 025 (25.8 months [95% CI, 22.2-29.8]). Median OS for 3L+ nivolumab patients was 12.4 months [95% CI, 8.8, 23.2]. Among 2L nivolumab patients, 73.9%, 46.2%, and 33.6% survived 12, 24, and 36 months, respectively. For the same respective timeframes, 52.4%, 24.7%, and 18.6% of 3L+ nivolumab patients survived. Conclusions: This study provides real-world evidence on the characteristics, treatment patterns and effectiveness of 2L or ≥ 3L nivolumab monotherapy in previously treated aRCC patients. OS results from UK routine clinical care were comparable to those found in CheckMate 025.[Table: see text]

e17089 Background: Cabozantinib is approved in the UK in treatment-naïve adults with intermediate or poor risk aRCC or following prior VEGF-targeted therapy. Here we describe treatment pathways and clinical outcomes of patients with aRCC who received cabozantinib early and later in the UK managed access program (MAP) as disease severity may differ in these patient populations. Methods: A non-interventional retrospective chart review study was carried out in six specialist centres in the UK to describe early clinical experience with cabozantinib in patients with aRCC (CERES, NCT03696407). Progression-free survival (PFS) and overall survival (OS) were calculated from cabozantinib initiation using the Kaplan-Meier method. Patients were grouped into those who initiated cabozantinib early (Aug 2016-Feb 2017) or late (Mar-Aug 2017) in the MAP. Results: Overall 100 patients were eligible; median (95%CI) PFS was 6.01 (5.16; 7.85) months and median OS was 10.84 (7.92; 16.85) months. Patients in the early MAP group received a mean (SD) of 2.2 (1.4) lines of prior therapy, most commonly sunitinib (n = 32, 56.1%) and pazopanib (n = 30, 52.6%). Patients in the late MAP group received a mean of 1.9 (SD 1.2) lines of prior therapy, most commonly pazopanib (n = 23, 53.5%) and sunitinib (n = 19, 44.2%). At least one post-cabozantinib therapy was prescribed in 44.6% (25/57) and 27.9% (12/43) of patients in the early and late groups, respectively, most commonly nivolumab (both groups). See table for characteristics and outcomes by MAP group. Conclusions: Cabozantinib was effective in this small, real-world study of patients receiving treatment as part of a MAP. The results are supportive of the data seen in the registrational study, METEOR. Patients enrolled early in the MAP were possibly more heavily pre-treated but overall outcomes were similar to those who enrolled later. [Table: see text]

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.

Melanoma is a leading cause of lost productivity due to premature cancer mortality. Melanoma frequently spreads to the brain and is associated with rapid deterioration in quality and quantity of life. Until now, treatment options have been restricted to surgery and radiotherapy, although neither modality has been well studied in clinical trials. However, the new immune checkpoint inhibitors and molecularly targeted agents that have been introduced for treatment of metastatic melanoma are active against brain metastases and offer new opportunities to improve disease outcomes. New challenges arise, including how to integrate or sequence multiple treatment modalities, and current practice varies widely. In this Review, we summarise evidence for the treatment of melanoma brain metastases, and discuss the rationale and evidence for combination modalities, highlighting areas for future research.

ABSTRACT The incidence and mortality from renal cell cancer (RCC) is increasing. RCC tumors are particularly vascular in nature as a result of disruption of the VHL gene and/or its upstream pathway leading to upregulation of the hypoxia-inducible factor transcription factor. The hypoxia-inducible factor pathway drives angiogenesis by upregulating VEGF and bFGF, amongst other proangiogenic downstream target genes. Therapies which target angiogenesis have been successful in treating metastatic RCC (mRCC) and the receptor tyrosine kinase inhibitor, pazopanib, is licensed for first line treatment of mRCC. This review details the past, current and future roles of pazopanib in the treatment of mRCC.

650 Background: Randomized controlled trials (RCTs) are the basis of approval for medical interventions, but may not fully reflect populations seen in clinical practice. Sunitinib is a widely used 1st-line treatment for patients (pts) with metastatic renal cell carcinoma (mRCC). This is the first large-scale meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and real-world data (RWD). Methods: PubMed, Ovid, MEDLINE and EMBASE were searched from 2000-2017 for RCTs and RWD studies of sunitinib as 1st-line treatment in pts with mRCC. Eligible studies contained a cohort of ≥50 adult pts per study arm. The meta-analysis combined RWD and RCT study arms, adjusting for data type (RCT or RWD). Recorded outcomes were: median progression-free survival (mPFS), median overall survival (mOS) and objective response rate (ORR). A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimate. Results: Of the studies that met eligibility criteria, mPFS, mOS and ORR were reported by 18, 19 and 15 studies, respectively. Combined RWD and RCT analyses are presented in the Table. Reported mPFS (RWD, 7.5–11.0; RCTs, 5.6–15.1 months) and ORR data (RWD, 14.0–34.6%; RCTs, 18.8–46.9%) were consistent with the overall estimates. Reported mOS showed greater variation in RWD (6.8–33.2 months) compared with RCTs (21.8–31.5 months). 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 and cohort characteristics. Conclusions: This novel, large-scale meta-analysis validates sunitinib as an effective 1st-line treatment for pts with mRCC in both RCTs and everyday clinical practice. [Table: see text]

Background The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665 ), assessed safety and efficacy of vismodegib—a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)—in a patient population representative of clinical practice. Primary analysis data are presented. Patients and methods Patients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points. Results Evaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0–44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7–71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6–48.1) in patients with metastatic BCC. Conclusions The primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control. ClinicalTrials.gov NCT01367665 .

Background Treatment of non–clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vascular Endothelial growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC. Methods We performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan–Meier method. Results 91 mChRCC patients from 26 centres were included. Median follow-up from the date of first metastasis was 6.1 years (range: 0–13.9). Median OS was 37.9 months (95% confidence interval [CI]: 21.4–46.8) from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months (95% CI: 5.2–10.9) and 22.9 months (95% CI: 17.8–49.2) versus 1.9 months (95% CI: 1.0–6.0) and 3.2 months (95% CI: 2.3–not evaluable) with mTOR inhibitors, respectively. A stratified log-rank test was used to compare AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (p = 0.26) or for OS (p = 0.55). Conclusion We report the largest retrospective cohort of patients with mChRCC treated with TT and no significant difference between AA and mTOR inhibitors was observed for TTF and OS.

Purpose Fatigue is a distressing symptom occurring in more than 60% of patients with cancer. The CNS stimulants modafinil and methylphenidate are recommended for the treatment of cancer-related fatigue, despite a limited evidence base. We aimed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non–small-cell lung cancer (NSCLC). Patients and Methods Adults with advanced NSCLC and performance status of 0 to 2, who were not treated with chemotherapy or radiotherapy within the last 4 weeks, were randomly assigned to daily modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or matched placebo. The primary outcome was change in Functional Assessment of Chronic Illness Therapy (FACIT) –Fatigue score from baseline to 28 days, adjusted for baseline fatigue and performance status. Secondary outcomes included safety and patient-reported measures of depression, daytime sleepiness, and quality of life. Results A total of 208 patients were randomly assigned, and 160 patients (modafinil, n = 75; placebo, n = 85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. FACIT-Fatigue scores improved from baseline to day 28 (mean score change: modafinil, 5.29; 95% CI, 2.57 to 8.02; placebo, 5.09; 95% CI, 2.54 to 7.65), but there was no difference between treatments (0.20; 95% CI, −3.56 to 3.97). There was also no difference between treatments for the secondary outcomes; 47% of the modafinil group and 23% of the placebo group stated that the intervention was not helpful. Conclusion Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect.

Vismodegib and sonidegib are Hedgehog pathway inhibitors (HPIs) approved for treatment of patients with advanced basal cell carcinoma. The adverse events (AEs) associated with these therapies can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described in this article., Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1–2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy. Implications for Practice: The hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib represent a therapeutic breakthrough for patients with advanced basal cell carcinoma. However, the nature of the low-grade adverse events (AEs) commonly observed in HPI-treated patients, including muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and fatigue, can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described, with the goal of enabling health care professionals to provide appropriate counseling and supportive care interventions to their patients.

Summary Background Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. Methods Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. Findings The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7–34·4, IQR 2·5–18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7–52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. Interpretation Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring. Funding Bayer HealthCare Pharmaceuticals.

e16578Background: The randomised phase III METEOR trial showed survival benefit of cabozantinib over everolimus in patients with mRCC who progressed after VEGF targeted therapy. We report real worl...

SRC inhibition may help overcome resistance to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cancer. This hypothesis was tested in a randomized phase II study. Results showed saracatinib (SRC inhibitor) did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers.Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. Patients with disease progression after a parts per thousand yen1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2 alpha : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. NCT00942877.

International audience; BACKGROUND:The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up.METHODS:In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing.FINDINGS:Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7-62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1-71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7-57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses).INTERPRETATION:This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially.FUNDING:F Hoffmann-La Roche.

e16061 Background: Markers of the systemic inflammatory response have prognostic value in ccRCC prior to starting treatment. Dynamic changes during therapy and their role in predicting prognosis are not well characterised. Methods: A retrospective analysis was conducted of a randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic ccRCC (COSAK). Haemoglobin (Hb), neutrophil count (N0) platelet count (Plt), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were recorded at randomisation, 8-weeks and progression (PD). Change in mean values at each time point were compared. Baseline prognostic values for overall survival (OS) were assessed using Cox regression. Absolute changes in parameters were calculated at 8 weeks and PD, patients were grouped around the upper or lower quartile. Prognostic value of dynamic changes was assessed at 8 weeks and PD using the Kaplan-Meier method. Results: 138 patients were assessed; median OS was 12.0 months (IQR 8.1-15.6 months). Outcomes in the combination arm were similar to single agent arm (HR 1.28 (1.00–1.63)). On multivariate analysis at baseline, MSKCC score (0/1-2/≥3) (HR 2.52 (1.60 -3.96)), CRP ( < 10/≥10mg/L) (HR 1.72 (1.04 – 2.86)) and N0 ( < 7.5/≥7.5x109) (HR 2.38 (1.43 – 3.96)) were independent predictors of OS. Mean CRP was significantly different at baseline, 8 weeks and PD (64.9, 42.3 and 85.7 mg/L respectively, p < 0.001). Mean N0 count at baseline was 5.3 x109/L and was significantly higher 6.3x 109/L at PD (p < 0.001). Mean Hb at baseline, 8 weeks and PD was 11.5, 13.0 and 12.9g/L respectively (P < 0.001). A rise in CRP or N0 at 8 weeks was predictive of poor outcome ((HR 1.62 (1.10-2.56) and (HR 1.77 (1.19-2.61) respectively). A fall in Hb was predictive of poor outcome at 8 weeks (HR 1.75 (1.18-2.60)) and PD (HR 1.80 (1.20-2.76)). Conclusions: Dynamic changes occur in prognostic markers in patients receiving VEGF-targeted therapy in ccRCC and may predict OS.

e16087 Background: Sunitinib improves clinical outcomes in patients (pts) with mRCC. The single arm phase II NeoSun trial was designed to investigate its added value to nephrectomy, and to explore translational biological and imaging biomarkers. Methods: Pts with mRCC, scheduled for nephrectomy, no prior systemic therapy were recruited to receive 50mg OD sunitinib for 12 days, then post-surgery on a 4 week-on, 2 week-off, repeating 6 week cycle until disease progression. Diffusion-weighted, BOLD and dynamic contrast enhanced MR imaging (DW-MRI, DCE-MRI) and research blood sample collection were performed at baseline and end of 12 days. CT Imaging was performed at baseline, pre- and post-surgery, and then every 2 cycles. The primary endpoint was objective response rate (RECIST). Secondary endpoints included changes in diffusion DW-MRI, DCE- MRI of the tumour following 12 days suntinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Results: 14 pts received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All 14 underwent total nephrectomy, and 13 recommenced sunitinib post-operatively. The mean number of post-surgery cycles was 11 (range 2 – 22). 58.3% (7/12) of pts achieved confirmed response (95% CI: 27.7 - 84.8%).91.7% (11/12) achieved objective clinical benefit (95% CI: 61.5 - 99.8%). Median OS is 33.7m and median PFS is 15.7m. Amongst those achieving PR/CR, median response duration is 8.7m. No unexpected surgical or sunitinib-related toxicities or complications were observed and the mean number of days from surgery to hospital discharge was 5.9 (range 3.0 – 17.0).There was a trend forOS to be better in pts with high baseline plasma VEGF-A (p = 0.06) or VEGF-C (p = 0.02) expression. A larger % tumour volume reduction after 12 days treatment is correlated with a smaller baseline % necrosis (coefficient = -0.51, p = 0.03). Conclusions: Sunitinib is effective and safe when given before and after nephrectomy to previously untreated pts with mRCC. Neoadjuvant studies such as NeoSun can safely explore translational biological and imaging endpoints. Clinical trial information: 2005-004502-82.

464 Background: The AXIS trial established axitinib as an effective second line treatment for patients with metastatic renal cell carcinoma (mRCC). The dosing schedule of axitinib in this trial begins at 5mg twice daily, with escalation of individual doses to 7mg and 10mg after consecutive 2 week intervals if tolerated. We observed significant drug-related toxicity using this dosing strategy, particularly after dose escalations, while clinical responses were often observed at the starting dose. We therefore switched to a pragmatic strategy where dose escalations were made only after disease progression or where a rapid response was deemed clinically pertinent. Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for greater than 2 weeks at Addenbrooke’s Hospital, Cambridge, UK (a tertiary referral center), over a 40 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; of these, 29 had at least one dose escalation event (DEE). A total of 58 DEEs were identified, with a median of 2 per patient, and the objective radiological consequences of 50 of these could be determined. 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% versus 70%). 56% of all DEEs, and 62.5% of DEEs made as a result of disease progression, resulted in disease control. The median overall survival from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 6.7 months for non-dose-escalated patients. The median survival for dose-escalated patients with a higher than median time on a prior tyrosine kinase inhibitor has not been reached at the time of data cut-off. The mean dose (for all patients) at 90 days after starting axitinib was 5.92 mg. Conclusions: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and may reduce toxicity through lower drug exposure. Our survival data compares favourably to the AXIS trial in a real practice population.

Summary Lymph-node metastasis is an indicator of poor prognosis for patients with melanoma. The management of regional nodes is controversial, with continuing debate about whether surgery or radiotherapy of positive lymph nodes improves longterm survival or whether nodal involvement is merely a marker of aggressive disease. However, there is general agreement that systemic chemotherapy is rarely an effective form of management. This review therefore considers surgical and radiotherapeutic aspects of lymph-node management in patients with melanoma. We discuss regional control and survival after lymphnode surgery in retrospective series, randomised trials of elective lymph-node dissection, the role of ‘sentinel' lymph-node biopsy, radiobiology and radiotherapy fractionation issues in melanoma treatment, retrospective studies of adjuvant nodal radiotherapy, and finally, randomised trials of adjuvant radiotherapy after lymph-node dissection.

Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval,1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P0.05 for all 11 comparisons).Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

9532Background: VISMO, a first-in-class HPI, is approved (US and EU) for use in adults with aBCC. STEVIE is an open-label study focusing on safety of VISMO in pts with aBCC in a real-world setting....

4561 Background: Metastatic Chromophobe renal cell carcinoma (mChRCC) is a rare entity with no specific targeted therapy recommended. We aim to assess the outcome of targeted therapy (TT) in a larg...

Aim: Metastatic clear cell renal cancer (RCC) patients who are resistant to VEGF targeted therapy have a poor outcome. Further VEGF targeted therapy is a standard treatment option for these patients. It is speculated that SRC may play a role in this VEGF resistance. In the study cediranib (a VEGF tyrosine kinase inhibitor), was given with saracatinib (a SRC TKI) or placebo in VEGF resistant disease to test this hypothesis. Methods: This investigator led double bind randomised (1:1) phase II study recruited patients between 2010 and 2012 (n = 138). The primary endpoint was progression free survival (PFS) by RECIST v1.1. Toxicity was assessed using CTC V4. Patients received cediranib and saracatinib (CS) (n = 69) or cediranib and placebo (C) (n= 69). All patients had metastatic measurable RCC and had progression of disease on VEGF targeted therapy. Stratification factors included MSKCC prognostic score. Results: 15%,70%, 15% had MSKCC good, intermediate or poor risk disease respectively. Overall the characteristics of the 2 groups were well balanced. Partial responses were seen in 13% for C and 14.5% for CS respectively (p = NS). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS [HR 1.18 (0.94-1.48)], or overall survival [HR 1.28 (1.00-1.63)] for the 2 groups. The median overall survival for the whole cohort was 12.0 months (8.5-15.6 months. There was no significant difference in the frequency key adverse events. Discontinuation and dose reductions due to adverse events with C and CS occurred in 13%/8% and 19%/18% respectively. Biomarker analysis will be presented at the meeting. Conclusions: The addition of saracatinib to VEGF targeted therapy did not result in clinical benefit in VEGF resistant metastatic RCC. Cediranib appears to have modest activity in VEGF resistant disease. Disclosure: T. Powles: Research Funding from: AZ GSK Novartis. Honoraria from Pfizer GSK Novartis; R.J. Jones: Research funding from AZ; S. Chowdhury: GSK and Pfizer for speaking. All other authors have declared no conflicts of interest.

7595 Background: Most SCLC patients initially respond to chemotherapy but then relapse and die so new therapies are urgently required. Pre-clinical data shows statins induce growth arrest and apoptosis in SCLC and several other tumour cell types and are additive with chemotherapy. This may in part be due to impaired Ras superfamily function as statins deplete mevalonate, reducing geranylgeranylation and farnesylation of these proteins. We therefore undertook this large pragmatic phase III trial in order to determine if overall survival (OS) was affected by the addition of pravastatin in SCLC. Methods: Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity. Results: Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed > 4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Updated results showing OS, PFS, local PFS and toxicity will be presented. Conclusions: This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients. Clinical trial information: ISRCTN56306957.