#GU15 - Renal cell cancer keynote: Management of RCC: Future needs and opportunities - Session Highlights

ORLANDO, FL, USA (UroToday.com) - Dr. Daniel George commenced his talk by discussing current and emerging clinical trials.

In the adjuvant setting, there are currently 6 studies including (ASSURE, S-TRAC, SORCE, PROTECT, EVEREST, ATLAS). While we have a negative ASSURE study, there are still results of 5 other trials pending. However, Dr. George highlights the concern that the other trials may also suffer from problems with assumptions that are universal across all these trials. We use stage and grade to select the patients, and although using stage and grade makes selection easier, and they are good about prognostics, they do not tell us about tumor biology, which we target via immunotherapy or targeted therapy. Biology becomes more and more heterogeneous with higher grade and stage and these host effects can have irreparable effects on the outcomes of the studies.

Within untreated or treated metastatic RCC, NCCN guidelines have not changed within the last 6 years. However, we have multiple phase III trials ongoing (CheckMate 214, CarboSun, WO29074, ADAPT, METEOR) that may shed light here. However, he again highlights that we are not selecting by biology. He questioned whether the risk group stratification is enough. Again, if there is a positive study, does improvement in progression-free survival offset increased toxicities? Additionally, does immunotherapy, as being investigated in ADAPT and CheckMate 214, represent a paradigm shift from targeted therapy. Or is combination of targeted and immunotherapy better? These questions still need to be answered.

Currently, with ongoing studies, there are tremendous opportunities for defining care. However, the question is not wheter we develop an immunotherapy/targeted therapy cocktail but how do we incorporate these within our patients? How do we tell who benefits from these? How do we tell who will tolerate therapy or suffer from toxicities? Dr. George than focused on predictive biomarkers that are currently being investigated that may shed some light on these questions. These predictive factors are disease or host characteristics that estimate the chance of improvement in outcome with a particular treatment. The examples of these are treatment-induced HTN for VEGF inhibition, baseline IL-6 and hepatic-growth factor for VEGF inhibition, and baseline LDH levels for mTOR inhibition. Dr. George then presented literature behind all of these examples.

With respect to HTN, Dr. George shared results of multiple meta-analyses that showed development of systolic hypertension or diastolic hypertension with the use of axotinib or sunitinib and how can effect the overall survival negatively. Monitoring of HTN may be important and prospective trials are needed to test whether the continuation of VEGFR TKI is beneficial in the absence of HTN and monitoring of such a biomarker is possible. He highlighted a Duke-based feasibility pilot study that aims to monitor patients’ physical activity, weight, and blood pressure using an Apple HealthKit interface app that will automatically wirelessly pass the data on to the patient’s medical record.

Plasma markers were then discussed. High plasma IL-6 predicts OS benefit for pazopanib and bevacizumab in 2 independent data sets. Serum LDH is predictive of OS for temsorilimus for RCC. All of these biomarkers need to be incorporated in prospective clinical trials.

Current clinical outcomes that we measure fail to assess cardiovascular toxicity, serially. Additionally, we do not measure patient fatigue using qualitative assessments. Roughly half of all metastatic RCC never receive a second-line therapy. We need to identify why some patients drop out of treatment using patient-specific assessment tools. Novel assessments of patient toxicity are needed to determine who will not tolerate long-term targeted therapy, to mitigate patient decline in quality of life, and to develop predictors of toxicity. Additionally, we need to ensure that what is being studied in academic centers is translated in a community setting. He showed data from the ACORN retrospective registry, which showed tripling of OS of patients who were seen and treated at DUKE vs in a community center—about 12 months in community and 36 in academic setting. There was no randomization in this registry to control for confounding variables, and selection bias can be present. However, we cannot exclude the possibility of management disparity and this needs to be prospectively evaluated. It is currently being evaluated in the “More prospective evaluation of practice patterns in mRCC is needed—mRCC Registry.”

Dr. George highlighted 6 important, unmet needs in metastatic RCC. First, we need to identify mechanisms resulting in immune-escape specific to RCC. Second, we need to develop and validate tumor predictors of response to therapy. Third, we need an international registry of metastatic RCC to determine variations of care. Fourth, we need to develop genetically engineered mouse models that more closely approximate clear cell RCC. Fifth, we need molecular characterization of non-clear cell RCC and to test targeted therapies in these. Sixth, we need to identify therapeutic targets downstream of chromosome 3p21 tumor suppression mutations such as SETD2, BAP1.

Dr. George concluded by stating that ongoing trials signify we are in a promising era, and we are in an active field. We need to address the use of emerging markers within the clinical research. We need to mitigate patient-related toxicities. Finally, we need to understand outcome disparities in care from community to academic settings to universally optimize patient outcomes.

Presented by Daniel J. George, MD at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA

Duke University School of Medicine, Durham, NC USA

Reported by Mohammed Haseebuddin, MD, medical writer for UroToday.com