Recent Advances in the Management of Advanced Renal Cell Carcinoma (RCC)

One-third of all patients with renal cell carcinoma present with advanced disease. In this Precision Medicine Perspectives series “Recent Advances in the Management of Advanced Renal Cell Carcinoma (RCC)”, Moshe Ornstein, MD, a genitourinary medical oncologist who specializes in the treatment and research of renal cell carcinoma at the Cleveland Clinic, discusses the classification, risk stratification, and treatment armamentarium for advanced renal cell carcinoma.

Targeted Oncology™:Could you please provide a brief overview of renal cell carcinoma (RCC), including its prevalence, the typical patient profile, and prognosis?

Dr Ornstein: Renal cell carcinoma is the most common cancer of the kidney. There are approximately 80,000 new cases per year in the U.S., and unfortunately, approximately 14,000 people pass away every year as a result of renal cell carcinoma within the United States. Typically, the patient profile is someone in their early to mid-60s. Risk factors include a history of hypertension, obesity, and smoking. Generally, we see more men with this disease than women.

The prognosis of renal cell carcinoma depends on the stage of presentation. Patients who present with localized disease—cancer limited to the kidney—or even cancer that has spread to the local lymph nodes are going to fare much better in the long run and have a more favorable prognosis than patients who present with or develop metastatic RCC over time, where the cancer has spread beyond the kidney or even beyond the locoregional lymph nodes.

Targeted Oncology™:What percentage of patients progress to advanced disease? How would advanced disease be diagnosed?

Dr Ornstein: The simplest way to break down the presentation of renal cell carcinoma is into 2 categories. There’s the category of RCC that presents localized to the kidney or the kidney area, and then there’s the class of patients in the other group who present with metastatic disease, in which their cancer has already spread beyond the kidney or even beyond the locoregional lymph nodes. The classic teaching in kidney cancer is that approximately two-thirds of patients will present with locoregional disease, and their cancer at presentation is generally treated with definitive curative intent. In other words, their cancer is limited to the kidney and maybe some local lymph nodes, and treated with surgery to render them disease-free. That’s two-thirds of patients. The other third of patients present with metastatic disease. At the time of presentation, they already have cancer in other sites outside the kidney, including their lungs, liver, or bones.

Many people ask how we detect renal cell carcinoma. For the two-thirds of patients who initially present with localized disease, that cancer is picked up in 1 of 2 main ways. Either they have presented with flank pain, stomach pain, or blood in their urine and had imaging done to assess for that underlying presentation—and during that imaging, the RCC is found—or they presented with other vague complaints for which they had imaging and the kidney cancer is picked up incidentally.

Patients with metastatic RCC at presentation—that third of patients who present with their cancer already having spread—can present in a host of different ways. It can be picked up incidentally. It can also be picked up when there’s an evaluation being done for blood in the urine, abdominal pain, flank pain, shortness of breath due to metastatic disease in the lungs, or abnormal liver tests. It can be picked up in a variety of ways.

Although we mentioned that two-thirds of patients are treated with curative intent, depending on their surgical pathology results, some of those patients will ultimately progress and then develop metastatic disease over time. For patients who do have surgery, they still need to be monitored with CT imaging to assess for recurrence of disease. Depending on the stage of their initial diagnosis, they may be at higher risk of disease recurrence.

Targeted Oncology™:How do you classify RCC, whether that’s through histology, IMDC [International Metastatic RCC Database Consortium], or Memorial Sloan-Kettering Cancer Center [MSKCC] criteria risk groups? Are there other factors that you consider when choosing an appropriate treatment?

Dr Ornstein: There are multiple ways to classify RCC. The primary way we classify the differences between RCC subtypes is dividing them into clear cell vs non–clear cell. Seventy-five percent to 80% of patients with RCC have clear cell renal cell carcinoma. The other 20% will have non–clear cell renal cell carcinoma. Defining patients as non–clear cell does not do their cancer justice because non–clear cell comprises a variety of different histologies: papillary, chromophobe, and translocation, to name a few. But the general characterization of RCC is classifying them as clear cell vs non–clear cell. In general, when we’re talking about RCC, we’re referring to the overwhelming majority of patients who have clear cell RCC.

Once a patient presents with renal cell carcinoma, specifically patients with metastatic disease, we further classify them based on their risk groups. There are 2 primary risk groups used: the MSKCC risk group and the IMDC risk group, which is more commonly used. That takes into consideration neutrophil count, hemoglobin, platelets, calcium, performance status, and time from diagnosis to treatment. Based on the score that patients get with those 6 factors, they’re classified into 3 categories: favorable-, intermediate-, and poor-risk RCC. Their clinical outcomes can be divided along those groups. Patients with favorable-risk RCC by IMDC criteria tend to do far better than patients with poor-risk [RCC], and the intermediate-risk patients do somewhere in between. It’s important to note that this tells us about the population as a whole, but it doesn’t tell us about an individual patient. We use these data to guide decision-making in the clinic, but for an individual patient, an individual decision needs to be made.

Lastly, in addition to clear cell vs non–clear cell in IMDC risk stratification, we also use sites of disease to give us a sense of how extensive and aggressive a patient’s metastatic RCC is. Patients who have liver or brain metastases tend to fare poorer than patients whose metastases are limited to the lungs and lymph nodes. Overall, there are 3 main ways to categorize patients with advanced RCC: clear cell vs non–clear cell; IMDC risk categorization of favorable, intermediate, and poor; and by sites of disease.

Targeted Oncology™:What is the treatment arsenal of available frontline agents for patients with advanced renal cell carcinoma?

Dr Ornstein: Over the last 5-plus years, there has been a revolution in the treatment of treatment-naïve advanced RCC. Historically, patients with metastatic RCC were treated either with agents that targeted the VEGF pathway or with agents that targeted the mTOR pathway. With the advent of immunotherapy in the form of checkpoint inhibitors, the standard of care in early 2023 for almost all patients with advanced frontline RCC is an immunotherapy-based combination. There are 2 main categories of immunotherapy-based combinations in frontline advanced RCC. One is the I/O–I/O [immuno-oncology] approach, where patients are treated with the combination of ipilimumab and nivolumab. The other is the I/O plus TKI [tyrosine kinase inhibitor] approach, where patients are treated with a checkpoint inhibitor plus a VEGFR tyrosine kinase inhibitor. That category includes multiple regimens, including axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab as the most common of the I/O–TKIs used to treat patients with metastatic RCC in the frontline setting.

Targeted Oncology™: How does the treatment strategy change for patients who have progressed beyond those early lines of therapy?

Dr Ornstein: We’ve seen tremendous progress in the treatment arsenal for patients with metastatic RCC in the frontline setting. But using these immunotherapy-based combinations in the frontline setting has led to a real challenge in terms of what to do with patients whose cancer has progressed on one of these immunotherapy-based combinations. The standard of care is to give these patients VEGFR TKIs. For example, if a patient was treated with ipilimumab and nivolumab in the frontline setting, they could get cabozantinib or axitinib, to name a few of the TKIs available in the refractory setting. Similarly, a patient who got cabozantinib and nivolumab in the frontline setting could then get axitinib or lenvatinib and everolimus in the second-line setting.

The point is that the standard of care after immunotherapy-based treatment in the frontline setting is to be treated with a TKI in the second line and beyond. There are ongoing trials that are investigating the role of immunotherapy in the refractory setting. If you have a patient who progresses on an immunotherapy-based regimen, is there a role to continue treating them with another immunotherapy agent? Although the standard is for patients to be on a TKI in the refractory setting, there are ongoing trials investigating the role of immunotherapy in patients whose advanced RCC has progressed despite treatment with an I/O–based regimen in the front line.

Targeted Oncology™:What are some unmet needs in the diagnosis and treatment for patients with advanced RCC?

Dr Ornstein: Despite the amazing progress that has been made in the treatment options and long-term survival outcomes for patients with advanced RCC, a number of critical unmet needs remain. The first is the treatment management of patients with non–clear cell RCC. We’ve seen and discussed a lot of data of these advancements in renal cell carcinoma treatment, but it has predominantly been limited to the clear cell population. Although the clear cell population comprises approximately 80% of patients with advanced RCC, that still leaves 20% of patients who need further drug development and more clinical trial options to lead to more standard-of-care options.

The second unmet need is biomarkers. With multiple options available for patients in the frontline setting, how do we know which patient is appropriate for immunotherapy plus immunotherapy? And how do we know which patients should be treated with an immunotherapy and a tyrosine kinase inhibitor? Is there a biomarker that can tell us which patient needs I/O–I/O and which patient needs an I/O–TKI? Is there a biomarker that can tell us which patient might need just an I/O or a TKI in the frontline setting? Unmet need No. 2 is biomarkers to help guide treatment decision-making in the frontline and subsequent settings.

Lastly, another unmet need is novel therapeutics. We’ve spent a good amount of time talking about immunotherapy-based combinations—I/O–I/O, I/O–TKI, using TKIs after I/O—but we need to move beyond VEGFR TKIs and beyond thinking of immunotherapy within the context of I/O checkpoint inhibitors.