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TPS684 Background: The anti-PD-1 antibody nivo improves overall survival in metastatic RCC and is well tolerated. There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Priming the immune system prior to surgery with anti-PD-1 has shown an OS benefit compared to a pure adjuvant approach in mouse solid tumor models. The PROSPER RCC trial aims to improve clinical outcomes by priming the immune system prior to nephrectomy with neoadjuvant nivo and continued engagement with adjuvant blockade in patients with high risk M0 RCC compared to surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is currently accruing patients with clinical stage ≥T2 or node positive M0 RCC of any histology. Tumor biopsy prior to randomization is mandatory to ensure RCC and permits in depth correlative science. The investigational arm will receive two doses of nivo 240mg prior to surgery followed by adjuvant nivo for 9 months (q2 wks x 3 mo followed by 480mg q4 wks x 6 mo). The control arm will undergo standard nephrectomy followed by observation. Randomized patients are stratified by clinical T stage, node positivity, and histology. To enhance accrual and patient quality of life, key upcoming amendments are being instituted. These include biopsy only in the nivo arm, allowance of oligometastatic disease and bilateral renal masses that can be fully resected/ablated, and change of nivo dosing to q4 wks (1 neoadj; 9 adj). With accrual of 766 patients, there is 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival (RFS) at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is also powered to evaluate a significant increase in overall survival (HR 0.67). Safety, feasibility, and quality of life endpoints critical to adjuvant therapy considerations are incorporated. PROSPER RCC embeds a wealth of translational work aimed at investigating the impact of the baseline immune milieu, the changes induced by neoadjuvant anti-PD-1 priming, and how both correlate with clinical outcomes. Clinical trial information: NCT03055013.

AbstractBoth cancer and therapies used in the treatment of cancer can have significant deleterious effects on the skeleton, increasing the risks for both bone loss and fracture development. While advancements in cancer therapies have resulted in enhanced cancer survivorship for patients with many types of malignancies, it is increasingly recognized that efforts to reduce bone loss and limit fractures must be considered for nearly all patients undergoing cancer therapy in order to diminish the anticipated future skeletal consequences. To date, most studies examining the impact of cancer therapies on skeletal outcomes have focused on endocrine‐associated cancers of the breast and prostate, with more recent advances in our understanding of bone loss and fracture risk in other malignancies. Pharmacologic efforts to limit the adverse effects of cancer therapies on bone have nearly universally employed anti‐resorptive approaches, although studies have frequently relied on surrogate outcomes such as changes in bone mineral density or bone turnover markers, rather than on fractures or other skeletal‐related events, as primary study endpoints. Compounding current deficiencies for the provision of optimal care is the recognition that despite clearly written and straightforward society‐based guidelines, vulnerable eligible patients are very often neither identified nor provided with appropriate treatments to limit the skeletal impact of their cancer therapies.

The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from “bench to bedside and back again”. Several of the leading BPs achieved “blockbuster” status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.

Eosinophils increase airway sensory nerve density in humans with asthma and in mice, which promotes airway hyperresponsiveness.