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Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma

BACKGROUNDnCabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.nnnMETHODSnWe randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.nnnRESULTSnMedian progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.nnnCONCLUSIONSnProgression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

Molecular Biomarkers in Advanced Renal Cell Carcinoma

The availability of agents directly targeting tumorigenic and angiogenic pathways has significantly improved the outcomes of patients with advanced renal cell carcinoma (RCC) in recent years. However, all patients eventually become resistant and a substantial percentage experience immediate disease progression with first-line targeted therapy. In addition, patients have variable clinical benefit and/or tolerance to different agents, including drugs within the same class. Thus, the choice of therapy for an individual patient remains empiric at present. Upon this landscape, several molecular biomarkers have been investigated with the purpose of guiding therapy. This review discusses prognostic biomarkers correlating with the outcome of patients independent of therapy, and predictive biomarkers of treatment response, including circulating biomarkers (such as VEGF and VEGF-related proteins, cytokine and angiogenic factors, and lactate dehydrogenase), and tissue-based biomarkers (such as single-nucleotide polymorphisms). Many potential prognostic and predictive molecular biomarkers have now been identified in RCC, although none has yet entered into clinical practice, and all require prospective validation in appropriately designed randomized studies. In the near future, however, validated biomarkers may become integral to management strategies in RCC, enabling tailored treatment for individual patients to improve clinical outcomes. Clin Cancer Res; 20(8); 2060–71. ©2014 AACR.

Predictive Factors for Impaired Renal Function following Nephroureterectomy in Upper Urinary Tract Urothelial Cell Carcinoma

Objectives: Despite the uncertain value of adjuvant chemotherapy after radical nephroureterectomy (RNU) it is clear that impaired renal function represents a contraindication to its administration. The objective of this study was to identify possible predictive clinical factors for impaired renal function following RNU in patients with upper urinary tract urothelial cell carcinoma (UUT-UCC). Patients and Methods: A retrospective analysis was conducted of 546 patients who underwent RNU between 1992 and 2008 at our institution. Data of interest for this study included estimated glomerular filtration rate (eGFR), age, pathological stage and preoperative hydronephrosis (HN). The predictive value of HN, age and pathological stage for impaired renal function after RNU was calculated by multivariate linear regression analysis. Results: In total, 138 patients met the criteria for inclusion, including 108 men (78%). Mean age at surgery was 67 ± 10 years. There was a significant correlation (p < 0.001) between pre- and postoperative eGFR (decrease of 21% after NU). Preoperative HN was present in 51 patients (37%). On linear regression analysis, preoperative eGFR ≤60 ml/min (p = 0.012; OR = 4.60) and HN (p = 0.027; OR = 10.34) were confirmed to be predictive factors for a postoperative eGFR ≤60 ml/min. When postoperative eGFR ≤45 ml/min was used as the criterion for impaired renal function, predictive factors proved to be preoperative eGFR ≤45 ml/min (p < 0.0001; OR = 18.53), HN (p = 0.038; OR = 0.380) and age ≥70 years (p < 0.0001; OR = 0.169). Conclusions: Preoperative HN, older age and preoperative eGFR <60 ml/min were proven to be predictive factors for impaired renal function after RNU. In these settings, neoadjuvant chemotherapy may be considered.

Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis

BACKGROUNDnPapillary histology accounts for 10-15% of renal cell carcinoma (RCC), and treatment options for patients with this subtype are limited. The RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) study evaluated first-line everolimus in patients with papillary metastatic RCC (mRCC).nnnMETHODSnThis phase 2 trial enrolled previously untreated patients with type 1 or type 2 papillary mRCC. Papillary histology was confirmed by central review and was performed for every patient. Patients received oral everolimus 10xa0mg once daily until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS) rate at 6 months among the first 44 patients of the per protocol (PP) population. Secondary end-points included PFS, tumour response, overall survival (OS), and safety.nnnFINDINGSnAnalysis sets included safety (Nxa0=xa092; 100%), intent-to-treat (ITT) (nxa0=xa088), and PP populations (nxa0=xa046). In the safety population, most patients were men (78%) and the mean age was 60 years (range 23-84). Papillary histology was confirmed in 78% of patients (type 1, 32%; type 2, 64%; missing information, 4%). PFS rate at 6 months was 34% (80% confidence interval [CI] 25-45). In the ITT population, median PFS was 4.1 months (95% CI 3.6-5.5), 65% of patients achieved stable disease, and median OS was 21.4 months (95% CI 15.4-28.4). Among patients with type 1 or type 2 histology, median PFS was 7.9 months (95% CI 2.1-11.0) and 5.1 months (95% CI 3.3-5.5), respectively, and median OS was 28.0 months (95% CI 7.6-not estimable) and 24.2 months (95% CI 15.8-32.8), respectively. Common grade >2 adverse events were asthenia (13%), anaemia (7%), and fatigue (5%).nnnINTERPRETATIONnResults of this large prospective study in papillary mRCC demonstrated that everolimus provides some clinical benefit to this patient population and highlight the need for central pathological review of this rare tumour.

Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812-21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.

Current management of muscle-invasive bladder cancer

Management of muscle-invasive bladder cancer (MIBC) has changed little in the last twenty years. The gold standard treatment is still cystectomy, but it has a significant negative impact on quality of life. Bladder-preservation strategies can be used in some cases but patient selection for this approach remains unclear. New chemotherapy and biologic agents in combination with surgery or radiotherapy could improve results and these possibilities are currently under investigation.

402 FDG PET-CT vs CT scan in the staging of urothelial neoplasms

INTRODUCTION AND OBJECTIVES: Thoracic and abdominal CT scan remains the gold standard for staging of urothelial carcinoma. No prospective trials have adequately assessed the role of FDG PET-CT. METHODS: From May 2011 to April 2015, we prospectively collected data of 47 patients referred to the hospital for treatment of either bladder or upper urinary tract tumors and staged by CT as surgical candidates with localized or locally advanced disease. PET-CT was performed either before neoajuvant or adjuvant chemotherapy for final clinical staging. RESULTS: Median age was 68 years (47-87), 87% (41) were men. 41 patients (87%) had bladder cancer, 5 an upper urinary tract tumor (10%) and 1 patient had a cancer of the urethra (2%). Histology was urothelial in 45 cases (96%) and squamous in 2 (4%).Median time fromCT to PET-CTwas1.7months (0.33-5.87). PET-CTwasdonebefore taking final therapeutic decision in 27 cases (57.4%), and after surgery in 20 (42.6%). Overall, discrepancies between CT and PET were seen in 26/47 cases (55%), implicating a change in the recommended treatment of 19 patients (40%). PET-CT identified unknown visceral metastases in 16 patients (34%); of them 5 patients had thoracic metastases (31%), 6 extrathoracic (38%), and 5 had both (31%). For patients referred for neoadjuvant chemotherapy, 11/27 patients (40%) were restaged as M1 by PET-CT. For patients referred for adjuvant chemotherapy, 8/20 (40%) patients had metastatic disease detected by PET-CT (3 nodal, 5 visceral). Final Staging by CT vs PET was as follows: II on 36% vs 28%, III on 15% vs 10%, IV on 49% vs 62%. From the 32 patients (66%) who had finally surgery, pathological stage was II on 7 (23%), III on 8 (26%) and IV on 16 (52%). CONCLUSIONS: In our experience, FDG PET-CT in urothelial cancer not only provided additional prognostic information compared to CT, but also changed management of patients.

836PTREATMENT AND OUTCOME(S) OF A LARGE COHORT OF POOR RISK METASTATIC RENAL CELL CARCINOMA (PRRCC) PATIENTS (PTS)

ABSTRACT Aim: With the exception of the Temsirolimus (Tem) registration trial, prRCC is grossly underrepresented in clinical trials. Methods: We collected information on a large cohort of prRCC (239 pts) from 20 Italian and 2 Spanish centers. Results: Three prognostic models (MSKCC, modified MSKCC - mMSKCC, International Metastatic RCC Database Consortium - DC) and 8 individual risk factors (RF) were considered: multiple metastatic sites (89%), time from diagnosis to treatment (82%), and anaemia (77%) were the most frequent individual RF. Eighty-nine percent, 63%, and 61% of pts had at least 3 RF according to mMSKCC, MSKCC, and DC, respectively; mMSKCC had the best discriminating power between intermediate and prRCC (median OS: 28 vs 8 mos, respectively; p 6 mos) was 44% and was significantly higher for pts receiving first-line TKI versus Tem (50% vs 26%, p = 0.002). Age, nephrectomy status, mMSKCC, and total number of RF, but not the type of treatment received (Tem vs VEGFR-TKI), were independently associated with OS at multivariate analysis. Thirty seven percent of prRCC pts survived >12 mos (29% and 40% in pts receiving Tem and VEGFR-TKI, respectively). Basal Hb and calcium levels within normal limits were significantly associated with higher chances of achieving long-term survival upon VEGFR-TKI treatment, while a non-significant trend towards a higher proportion of long-term survivors upon Tem treatment was observed for longer time from diagnosis to treatment and normal LDH levels, in an exploratory analysis of predictive factors. Conclusions: Despite heterogeneity, prRCC may benefit from systemic treatment across multiple lines of therapy. Further prognostic/predictive stratification within the prRCC group is clearly necessary (see also the abstract by Guida et al. at this Meeting). Disclosure: All authors have declared no conflicts of interest.

Tomografía de emisión de positrones como método diagnóstico y guía para la cirugía de resección en la recidiva de cáncer de colon

Resumen La elevada frecuencia de recidivas tumorales en el cancer colorrectal hace que, al evaluar sus posibilidades terapeuticas quirurgicas, se efectuen estudios (eco/TAC/RMN) capaces de determinar el grado de diseminacion de la enfermedad. La tomografia de emision de positrones (PET) permite una mejor estadificacion de la extension de la recidiva metastasica, tal como se demuestra en los dos casos que presentamos (uno con una segunda recidiva ganglionar mesenterica y otro con recidiva exclusivamente hepatica), lo que permitio en ambos casos una exeresis de dicha recidiva con caracter radical. Queda por definir el impacto de la PET sobre los resultados de esta cirugia de rescate en el cancer colorrectal.