Current Clinical Pharmacology - Volume 6, Issue 3, 2011

Renal Cancer: Is Targeted Therapy Really Empiric? It is a routine clinic day for me. I am being pulled in ten different directions between unstable patients, infusion reactions and phone calls and messages needing attention. Amidst this chaos I walk into the room to meet my new consult. He is a very young 20+ year old man sitting with quiet resignation to his fate. However what is most striking is that his mother is looking at me with beseeching eyes. Those eyes are fiercely challenging me, and simultaneously begging me, to help her precious son and make this black shadow on his existence, a thing of the past. This patient has kidney cancer with roaring metastases in the bones, lungs and lymph nodes. This case serves as a repeated reminder to me that nothing about kidney cancer is routine and all the recent advances that we are all applauding, are just not enough. The biggest failures of targeted therapy have been no clearly identified target to attack, and individualize therapy, and a lack of complete remissions. Novel therapeutic development unfortunately continues along the same path with more vascular pathway inhibitors being evaluated in clinical trials. So the field has only moved laterally despite the FDA approval and subsequent clinical availability of six agents in the last six years. Research efforts exploring the scientific methodology for detecting targets, and identifying and selecting the patients for specific therapies have been fewer. There are some commendable steps being taken in that direction with HLA subtype based immunotherapy and antibody based therapies. But tumor tissue screening for predicting response or resistance to specific targeted therapies needs to be one of the priorities for future investigations in kidney cancer. In addition, within kidney cancer, non clear cell histologies to this date have no proven standard therapy and are still orphan indications. Most clinical investigations are limited to small single arm prospective trials or case series reports. This is also gradually changing and some concerted efforts to conduct larger studies in this patient population are ongoing. Meanwhile the incidence of this lethal disease of kidney cancer continues to increase and we face more and more young patients afflicted with it. Renal cancer is a flagship for multidisciplinary care and input. The incorporation of surgery or non invasive image guided local therapies is likely to contribute a new dimension to the care of this disease, especially when systemic response has been obtained. With appropriate targeted systemic therapies and the use of local therapies as adjuncts, it maybe possible to work towards the lofty goal of rendering every metastatic kidney cancer patient in remission. I assure you that the patients are with us in this fight, and we have their support to generate better clinical trials that they would enroll on. The rapid advances made in the last decade, with the enrollment of thousands of patients to clinical trials, are testament to the fact that patients are eager to join the fray and do their part. The kidney cancer patients rarely get the credit they deserve for being on the front line giving their life and extremely valuable time (which they have precious little of) for the strife against this deadly disease. They are the unsung heroes and I would like to dedicate this issue on “Current State of Kidney Cancer and Future Targets and Directions” to them and honor them with a salute and solemn promise to continue the struggle.

Nephrectomy continues to be the cornerstone of treatment for localized renal cell carcinoma (RCC). Despite undergoing nephrectomy, recurrence of disease remains a concern in many patients, and different medical therapies are being investigated as means to decrease this risk. The use of the traditional immunotherapy options has not provided benefit as adjuvant treatment in this disease state. Recently, the treatment of metastatic RCC has experienced key advances with the introduction of targeted agents against the vascular endothelial growth factor (VEGF) molecule and related pathways as well as inhibitors of the mammalian target of rapamycin (mTOR), in addition to improvements in surgical technique. Additionally, there are questions about the optimal timing of systemic therapy in the context of high risk non-metastatic disease. There is optimism that locally advanced RCC might benefit from adjuvant or neoadjuvant treatment with these therapies. Ongoing clinical trials are addressing the role of targeted agents in this disease state.

Renal cell carcinoma (RCC) accounts for 4% of all new cancer cases in males and 3% in females in the US. Compared to other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiation therapy. However, it appears to be an immune-responsive tumor and several immunotherapeutic strategies have been investigated in the management of RCC with variable degrees of success. Active immunotherapy refers mainly to the use of vaccines, while adoptive (passive) immunotherapy includes the use of autologous immune cells, allogeneic immune cells (stem cell transplantation, donor lymphocyte infusion), as well as antibody delivery. Cytokine delivery with IL-2 has resulted in long-term disease-free survival in a small proportion of patients with metastatic disease. The continuous understanding of the mechanisms that underlie the immune complex networks has led to the identification of key molecules that play a major role in the immune response process. A panel of immuno-modulatory compounds that target such molecules has been tested in the preclinical and clinical setting. At the post-genomic era, the development of novel biomarkers can contribute to more accurate patient selection, resulting in higher responses and less toxicity of immunotherapeutic approaches.

Metastatic renal cell carcinoma (RCC) is predominantly refractory to treatment with traditional cytotoxic chemotherapies, and until recently management options were limited to immunotherapy, palliative care, or phase I trials. The past five years have witnessed a major change in the treatment of advanced RCC with the introduction of targeted therapies that derive their efficacy through affecting angiogenesis. The main class of agents involves drugs that target the vascular endothelial growth factor (VEGF). Several VEGF inhibitors are now approved for the treatment of metastatic RCC. The field is expanding rapidly with goals including 1) developing novel more potent and better tolerated agents and 2) defining the role of combination and sequential anti-VEGF regimens.

The advent of targeted systemic therapies has significantly improved treatment options for patients with metastatic renal cell carcinoma (RCC). Multiple agents that inhibit angiogenesis, cell growth, and proliferation via the VEGF and mTOR (TORC1) pathways have been USFDA-approved for locally advanced or metastatic renal cell carcinoma in recent years, although the majority of clinical trials have focused only on clear cell RCC. While clear cell RCC is the most common histologic subtype, nearly 25% of RCC cases are histologic variants representing a diverse group of diseases with different prognoses underlying biology and molecular targets and therapies. This review will focus on the incidence, clinical and pathologic features, pathogenesis, and treatment strategies of non-clear cell RCC in both the adjuvant and metastatic setting. These non-clear, cell subtypes include papillary type 1 and type 2, chromophobe, translocation carcinoma, and collecting duct RCC. Controlled studies in these relatively rare subgroups are needed to inform upon clinical practice, which is currently based on small series of uncontrolled studies. Ongoing clinical trials and areas of future research will be discussed.

The targeted therapies available to treat metastatic kidney cancer include vascular endothelial growth factor (VEGF) inhibitors, bevacizumab, sorafenib, sunitinib, pazopanib, and the mTor inhibitors temsirolimus and everolimus. These agents have significantly improved patient outcomes but are associated with toxicities. The most common toxicities seen with the VEGF inhibitors are hypertension, fatigue, and hand- foot syndrome. The mTor inhibitors exhibit a different toxicity profile which includes hyperglycemia and hypertriglyceridemia. Recognition and understanding the mechanism of the toxicities is crucial for optimal patient management.

Insights into renal cell carcinoma (RCC) biology have greatly expanded the treatment armamentarium for metastatic RCC (mRCC). Since 2005, six targeted agents have been approved by the US Food and Drug Administration (FDA) for the management of mRCC, and many new targeted therapies are in development. A number of novel VEGF Inhibitors/Multi-Tyrosine Kinase Inhibitors are currently in various stages of development. New targeted agents with novel mechanisms of action are also being studied, including Histone Deacetylase Inhibitors, Angiopoietin/TIE-2 Inhibitors, Carbonic Anhydrase IX Inhibitors, vaccines, and others. In addition to combining currently available immunologic therapies with emerging agents, researchers are also developing novel immunologic therapies to treat mRCC, including those that block Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). Several trials evaluating combinations and sequential therapy of targeted agents have been published, and several others are underway. Trials of special mRCC populations, including poor-risk disease, Non-Clear Cell RCC (NCC-RCC), and papillary type RCC are further refining the use of targeted treatments. As new targeted agents emerge and therapies with novel mechanisms of action are developed, the treatments options available for metastatic RCC are expected to increase. New therapies will likely have fewer detrimental side effects and better efficacy, leading to better quality of life for patients.

The incidence rates of renal cell carcinoma (RCC) have continued to rise with 58,000 new cases in the United States. RCC has notoriously been refractory to traditional chemotherapeutic including radiation and cytokine therapies. The advent of the use of molecularly targeted therapies for RCC has significantly improved the standard of care. Yet, there still remains room for improvement as many of the current therapies are limited by acquired resistance and dosing restrictions due to toxicity. In this review we discuss many potential therapeutic targets that have been suggested for development as advancements are made in discovering the underlying molecular biology of RCC. Among the targets that discussed are additional targets within the well-established VHL/HIF axis, the PI3K/AKT/mTOR pathway, independent targets, and those identified by synthetic lethality screens.

In recent years an improved understanding of renal cell carcinoma (RCC) tumor biology has translated into major advancements in the treatment of patients with metastatic RCC. These novel therapies include inhibitors of the vascular endothelial growth factor (VEGF) pathway, and inhibitors of the mammalian target of rapamycin (mTor) pathway. In contrast to the results seen with molecularly targeted therapies, the administration of high-dose bolus IL-2 (HD IL-2) can produce durable responses in a small percentage of patients. While the substantial toxicity and limited efficacy that is associated with HD IL-2 limits its application, novel immunotherapies may be able to produce durable benefit with less toxicity. Once the standard of care, the role of low-dose single-agent cytokines is now limited in patients with RCC. However, combinations of cytokines with targeted therapy may have merit. The advent of targeted therapy in RCC does not eliminate the potential utility of immunotherapy but rather requires a rational refinement of this approach through improvements in patient selection and combination therapy that may increase the cure rate for patients with this disease.

Inhibitors of the mammalian target of rapamycin (mTOR) have entered the landscape of treatment for advanced RCC. Their development has been based on their unique biology and their potential to simultaneously inhibit both tumor cell proliferation and angiogenesis. Despite the solid biologic rationale for their development, existing clinical data is somewhat mixed. Although Temsirolimus is capable of improving overall survival it does so only in a minority of selected mRCC patients and its effects on tumor burden reduction and PFS are minimal. Similarly the activity and clinical utility of Everolimus in the refractory setting is questionable. First, because it is unknown if mTOR becomes the major driver or cancer growth after developing progressive disease on a VEGF inhibitor and secondly because existing sequential VEGF data in same setting appears to be the same if not a bit more robust to that reported with Everolimus. Combination of mTOR and VEGF inhibitors has been disappointing due to the excessive toxicities encountered in early trials without a noticeable difference in efficacy. Efforts are now placed in a series of novel compounds capable of inhibiting both mTOR and the upstream signaling pathway of PI3K/AKT.