The Rapidly Changing Landscape in RCC Therapy: What Future Research May Hold

Bradley Carthon, MD, PhD

Assistant Professor

Department of Hematology and Medical Oncology

Emory University School of Medicine

Approximately 43,000 cases of kidney cancer in men and 23,000 cases in women will occur in the United States in 2018.¹ Almost 90% of those cases will be renal cell carcinoma (RCC), generally affecting individuals between the ages of 50 and 70.^1,2 There are varying histologies that make up RCC, with clear cell histology being the most common, accounting for 70% of all cases.² No singular cause of kidney cancer, including RCC, is known.² However, certain risk factors have been identified, including obesity, smoking, environmental exposures and family history or genetics.²

RCC can mutate quickly, and one-third of diagnosed patients present with metastatic disease.^3,4 This is due to the fact that the majority of patients are identified incidentally while undergoing workup for another issue, as the “classic” triad of symptoms—including palpable flank mass, pain and hematuria—are often absent, especially in early kidney cancer.⁵ These and other signs and symptoms—such as loss of appetite, fatigue and unexplained weight loss—are often attributable to other benign causes and may not trigger an immediate checkup.²

Because presentation with metastatic disease is relatively common, long-term survival outcomes for patients with advanced RCC have been poor, with 5-year survival rates of 11.7% for patients with stage IV disease.^3,6 These poor outcomes have prompted intensive clinical research aimed at developing novel therapeutic options addressing unmet needs of these patients.

Current Research Focused on Advanced Disease

While there have been important advances in research around metastatic RCC, work still remains. Recent median overall survival for metastatic RCC is still less than approximately 3.5 years, even in the best prognostic groups, and survival in those patients with poor risk factors is worse, at about 7.8 months in a recent study.⁷ According to criteria established by the International Metastatic Renal Cell Carcinoma Database Consortium, the majority of patients fall into either the intermediate- or poor-risk category, highlighting the continued urgency to develop new approaches for this disease.⁸Given the unmet needs for patients with metastatic RCC, much of the research on treatment has been for this specific population. As such, molecularly targeted systemic therapies for advanced RCC have today often supplanted previously used therapies that are no longer supported by guidelines.^9,10 The current research landscape may be roughly divided into 3 broad categories based on therapeutic targets: antiangiogenic agents, related molecular pathways such as the mTOR pathway, and immunotherapies—including cytokine therapy.⁹

Antiangiogenic agents make up the majority of metastatic RCC treatment options. Early studies of these agents utilized monoclonal antibodies against the VEGF molecule and small molecule inhibitors of the VEGF receptor.^11,12 More recently, multiple oral receptor tyrosine kinase inhibitors (TKIs) with varying affinity for the VEGF receptor and other receptors have been developed.¹³

Another important therapeutic target, mTOR, forms complexes with other proteins that regulate various processes such as cellular growth, enhanced activity of the cell cycle, and deceased apoptosis.¹⁴ This pathway feeds back into the biologically important process of angiogenesis, inhibition of which may result in antitumor activity.¹⁴ While these agents have primarily been studied as monotherapies, there has also been recent investigation into the combination of mTOR-based agents and VEGFR inhibitors.^4,14

Immunotherapy in RCC has been a therapeutic option for decades, as RCC has been well-established as an immunogenic cancer.^15,16 Strategies include exploring how to activate the immune system directly and understand the processes by which cancer cells evade the immune system, which may in turn inform methods for inhibiting the suppression mechanisms of tumors.^17-21 It is important to note that immunotherapy may also result in the attack of healthy cells along with cancerous cells.²²

Future Directions

Modern research beyond cytokine therapy has elucidated the various immune cells—including T cells, dendritic cells and natural killer (NK) cells—within renal cell tumors.¹⁶ In patients with RCC, there is the potential for a specific antitumor immune response and susceptibility to immune attack.²³ The immune system modulates the activating and repressive signals that mediate surveillance of foreign antigens and a T-cell response to tumors.²⁴ Tumor antigen-specific T cells have been isolated in peripheral blood of patients with RCC.^25,26Over the last several years, immunotherapy research has focused on inhibition of common targets within the tumor microenvironment.²⁷ Researchers are also looking at additional activating and inhibiting signals that modulate T-cell responses. Further, investigators are exploring ways that tumor cells develop to avoid being recognized and killed by an immune response. This includes altering antigens, warding off natural killer (NK) cells through factors that suppress immunity, and alerting immune checkpoints that would otherwise recognize the tumor as a foreign body.^16,28-30

Addressing these mechanisms may allow immune responses to evolve and expand by continually recognizing and recalling tumor antigens, with the potential to improve over time.³¹ Building upon these findings, research is now examining additional roles for immunotherapies and potentially using them in earlier lines of therapy.^32,33 Combination approaches are also actively being studied in clinical trials, whether it is immunotherapy plus immunotherapy or immunotherapy combined with targeted agents.³⁴

The explosion of data from clinical research in RCC has been exciting, but also poses new questions and prompts different approaches to research. Providing long-term survival benefits for those with advanced RCC continues to be a key objective for research, especially as incidence rates continue to rise.³⁵ RCC research is advancing quickly, which may offer hope to patients.

However, in the face of this rapid evolution, several points should be noted. For example, what will the role of single therapeutic options be compared with combinations? How will emerging options apply in frontline and subsequent settings?

As the treatment landscape changes, so too will the design of clinical trials. Future studies should address novel single-agent and combination therapies, and determine whether reliable biomarkers or other measures exist to predict suitable patients prior to starting treatment.

Updated comparator arms should be considered in subsequent-line studies; moreover, appropriate endpoints should be a priority to guide meaningful studies.

Finally, understanding this emerging landscape is important. Informed and mutual decision-making will help ensure that patients and families have guidance on their various treatment options and the necessary support to navigate this exciting time in RCC research and therapeutic options.

This article was written by Dr. Carthon in collaboration with Bristol-Myers Squibb, which he has provided consulting and advisory services for.

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