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.

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 .

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.

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.

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.

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.

Managing adverse events associated with vismodegib in the treatment of basal cell carcinoma.

Basal cell carcinomas are the most common form of skin cancer. Some develop into advanced cases not suitable for standard therapy. Vismodegib is the first-in-class oral hedgehog pathway inhibitor (which is dysregulated in 90% of basal cell carcinomas), and has demonstrated efficacy for advanced disease in clinical trials. An UK expert panel met to discuss management strategies for adverse events associated with vismodegib (most commonly taste disturbances, muscle cramps and alopecia). Managing patient expectations and implementing treatment breaks were considered important strategies. Quinine was useful to alleviate muscle cramps. For taste disturbances, food swaps alongside dietician referral were suggested. The experts concluded that these common adverse events can be successfully managed to allow optimum treatment duration of vismodegib.

Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma.

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.

Pazopanib versus sunitinib in metastatic renal-cell carcinoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (P<0.05 for all 11 comparisons). CONCLUSIONS: 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.).

Evolving treatment options for melanoma brain metastases.

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.

Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.

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.

Pazopanib for the treatment of renal cell carcinoma.

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.

Management of melanoma.

BACKGROUND: Melanoma is a potentially curable cancer, but around 20% of patients will develop disease which is beyond surgical clearance. Rising incidence alongside breakthroughs in understanding the molecular biology of this disease identifying systemic therapies offering survival gains now demand a more proactive, integrated approach to melanoma management. SOURCES OF DATA: PubMed references relating to aspects of melanoma research and treatment. AREAS OF AGREEMENT: Rapidly rising incidence throughout the world. Effective surgery as well as new molecular targeted systemic biological agents and immunotherapies necessitating early diagnosis and multidisciplinary therapeutic interventions. AREAS OF CONTROVERSY: Role of screening and prevention. Benefit of interventions for locoregional melanoma, including role of sentinel lymph node biopsy. Integration and sequencing of treatments for unresectable melanoma. GROWING POINTS: Molecular determinants of melanoma influencing disease outcome and treatment decisions. AREAS TIMELY FOR DEVELOPING RESEARCH: Education and training of patient and healthcare professionals. Role of screening, surveillance and follow-up strategies. Biology of melanoma guiding treatment decisions.

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.

Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial.

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.