mRCC management: past, present and future

Aims and scope Over the last six years, the use of targeted agents has revolutionised the treatment of metastatic renal cell carcinoma (mRCC) and dramatically improved outcomes for patients. Multiple effective first-and second-line agents are now available or are in development, raising key questions and new challenges around the long-term management of mRCC. These topics were the focus of a Pfizer meeting held at the 7 th European International Kidney Cancer Symposium (EIKCS) in Vienna (4–5 May 2012), where leading European oncology experts discussed recent advances and ongoing issues in mRCC clinical practice. 'It is important for clinicians who see large numbers of patients with this rare disease to get together and share their experience and observations, for the benefit of those who only see few patients in their practice', said Professor Manuela Schmidinger, Chair of the meeting. This report offers an overview of the critical evidence and the issues of long-term mRCC management debated at the meeting. It also presents key conclusions from the recently launched report 'Europe 2012: is kidney cancer management at a crossroad?', written by a selected panel of European kidney cancer experts to highlight current barriers to the optimal treatment of mRCC patients and the development of solutions to address these

Development and Validation of a Bedside Score to Predict Early Death in Cancer of Unknown Primary Patients

BACKGROUND: We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients. METHODS: Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4). RESULTS: The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5 x the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0-1], 2 and [3]-[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values. CONCLUSIONS: We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy

Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

BACKGROUND: In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib. METHODS: We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety. RESULTS: A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups. CONCLUSIONS: Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.)

Axitinib for the Treatment of Metastatic Renal Cell Carcinoma

Axitinib is a novel, oral, multitargeted tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptors 1, 2, and 3 at subnanomolar concentrations in vitro. In the phase III clinical trial in patients with metastatic renal cell carcinoma, axitinib showed a high objective response rate, and significantly prolonged progression-free survival compared with sorafenib. Thus, it is the first drug that has proven the concept of sequencing tyrosine kinase inhibitors in second-line treatment in a phase III prospective randomized trial. Although generally well tolerated and associated with a low incidence of grade 3 or 4 toxicities, axitinib shows a distinct pattern of adverse events that require monitoring and management. The most common adverse events observed with axitinib include diarrhea, hypertension, fatigue, nausea, and vomiting. This article summarizes the most important adverse events observed and proposes recommendations for their monitoring, prevention, and treatment. The recommendations are based on the existing literature and discussion by an expert group of international physicians and nurses specialized in oncologic treatment of metastatic renal cell carcinoma, which gathered in July 2011 in London, UK. Proactive assessment and management of adverse events during axitinib therapy can minimize treatment interruptions and ensure optimal effect of treatment

Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer

Aim: The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC). Methods: We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m 2 . The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity. Results: All patients had received irinotecan and 5-fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group (P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction. Conclusion: There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan

Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer

Aim: The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC). Methods: We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m 2 . The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity. Results: All patients had received irinotecan and 5-fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group (P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction. Conclusion: There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan

Axitinib, cabozantinib, or everolimus in the treatment of prior sunitinib-treated patients with metastatic renal cell carcinoma: results of matching-adjusted indirect comparison analyses

Abstract Background In the absence of head-to-head trials comparing axitinib with cabozantinib or everolimus, the aim of this study was to conduct an indirect comparison of their relative efficacy in patients with metastatic renal cell carcinoma (mRCC), using data from the AXIS and METEOR trials. Methods Progression-free survival (PFS) and overall survival (OS) in prior sunitinib-treated patients with mRCC were compared by conducting matching-adjusted indirect comparison (MAIC) analyses, including base-case and sensitivity analyses. Individual patient-level data from prior sunitinib-treated patients who received axitinib in AXIS were weighted to match published baseline characteristics of prior sunitinib-treated patients who received either cabozantinib or everolimus in METEOR. Results There was no statistically significant difference in PFS (aHR [adjusted hazard ratio] = 1.15 [CI: 0.82–1.63]) and OS (aHR = 1.00 [CI: 0.69–1.46]) between axitinib versus cabozantinib in the base-case analysis. In the sensitivity analysis, PFS (aHR = 1.39 [CI: 1.00–1.92]) and OS (aHR = 1.35 [CI: 0.95–1.92]) were shorter for axitinib compared with cabozantinib; however, the OS difference was not statistically significant. Axitinib was associated with significantly longer PFS compared with everolimus in the base-case (aHR = 0.53 [CI: 0.36–0.80]) and sensitivity analyses (aHR = 0.63 [CI: 0.45–0.88]), respectively. Results suggested an OS benefit for axitinib versus everolimus in base-case analyses (aHR = 0.63 [CI: 0.42–0.96]); however, the difference in OS in the sensitivity analysis was not statistically significant (aHR = 0.84 [CI: 0.59–1.18]). Conclusions MAIC analyses suggest PFS and OS for axitinib and cabozantinib are dependent on the Memorial Sloan Kettering Cancer Center definition used; in the base-case analysis, there was no significant difference in PFS and OS between axitinib and cabozantinib. In the sensitivity analysis, PFS in favour of cabozantinib was significant; however, the trend for prolonged OS with cabozantinib was not significant. For axitinib and everolimus, MAIC analyses indicate patients treated with axitinib may have an improved PFS and OS benefit when compared to everolimus. Disparities between the base-case and sensitivity analyses in this study underscore the importance of adjusting for the differences in baseline characteristics and that naïve indirect comparisons are not appropriate