Patient and Disease Characteristics Serve as Key Factors Behind Treatment Considerations in Advanced RCC

Vitaly Margulis, MD

When treating patients with advanced renal cell carcinoma (RCC), patient factors such as comorbidities and socio-economic disparities, as well as disease characteristics such as symptoms and tumor burden, need to be weighed together to arrive at the optimal strategy for each individual patient, according to Vitaly Margulis, MD.

“[Although there are many] discussions that we must have with our patients, it's not always a simple solution. It's always good to have options as far as addressing the primary tumor immediately,” Margulis said following a presentation on advanced RCC at an OncLive® State of the Science Summit™ (SOSS) on genitourinary cancers.

In the interview, Margulis expanded on the factors to consider when treating patients with advanced RCC and how these could help inform the selection of immunotherapy-based combinations in the frontline setting. Margulis is a urologic oncologist at the Harold C. Simmons Comprehensive Cancer Center and a professor of urology, as well as the Paul C. Peters, MD Chair of Urology, at the UT Southwestern Medical Center, in Dallas, Texas.

OncLive: What are some of the most important factors to consider when treating a patient with advanced RCC?

Margulis: There are 2 general factors that I always consider. [First], what are the some of the patient characteristics? For example, what is the overall performance status? How healthy is the patient? What is their life expectancy from other comorbidities? What are their goals of care? Do they have symptoms? What is their socio-economic support structure? This [question covers] a broad category of issues.

The second [factor] pertains more to the cancer situation. What is the extent of cancer? Are there metastases? How symptomatic [is the patient] and what is their risk? What category does a patient fall into if they have metastatic disease? There are other factors, but broadly, I [consider the] cancer-driven factors and overall patient factors.

Could you elaborate more on how socio-economic status influences treatment decisions?

A good example would be in patients who are considered for systemic therapies and would potentially require infusions that require driving for long distances into a specialized cancer center. Some of these patients don't have the support to do so, which will eventually translate into lack of compliance with care, and most likely, suboptimal outcomes.

Diving into the case presentations from the SOSS, what would you say are some of the most important discussion points that arose?

Of the cases illustrated, there were some important questions that both doctors and patients must address when deciding how to treat their specific cancer. We are in an era where we have options, which are good to have; however, in some cases, there are multiple options available. Therefore, the key consideration, especially when we talk about patients with metastatic disease, is [whether to start] with the immune checkpoint inhibitor combination vs immune checkpoint inhibitor plus targeted therapy combination. These are 2 broad treatment categories. The era of single-agent treatment, especially in the frontline [setting], is no longer here. We've moved on [to using combinations as the standard of care], and that's important to remember.

The second question, especially from a surgical standpoint and in cases where patients still have their primary tumors in place: what do we do with the primary tumor? We need to address that immediately. Can we treat the patient with systemic therapy first, reevaluate, and address later? These are, as a surgeon, some of the thoughts that go through my mind.

As far as which therapy to select, there are multiple factors that may sway the practitioner one way or the other. For example, if the patient has bulky, symptomatic disease, then a very appealing option is to lead in with is an immune-oncology [IO]/TKI combination. This is because that provides rapid control of the disease and palliation of symptoms. Certainly, at a later date, a second immune checkpoint inhibitor can be added. Patients who have relatively stable disease and are not overtly symptomatic, to me, [are the] patients who [are candidates for dual] immune checkpoint inhibitor combinations.

I [compare these treatment decisions] to investing into a 401k or winning a lottery off the bat. With an IO/IO combination, we know that these combinations provide the highest probability of long, deep responses and [potential] cures to our patients. Leading in with an IO/TKI combination [likely] provides the highest immediate responses, but the long-term cure rates may not be there at the same level as we see with IO/IO combinations.

How could the ongoing phase 3 PROBE trial (NCT04510597) evaluating IO-based combinations with or without cytoreductive nephrectomy potentially affect treatment decisions in the frontline setting for patients with metastatic RCC?

[PROBE] is very well designed, and it's poised to answer these questions. It's a little bit ambitious, but it will give us some of the much-needed answers. A lot of times when trials like this read out, the paradigm of treatment has already changed. Now we must see how to implement the data in the current environment. I'm optimistic. These are the types of trials that we should be doing, and I look forward to the results.

With the approval of pembrolizumab (Keytruda) in the adjuvant setting for select patients with RCC, how has that affected your interactions with medical oncology colleagues?

We finally have an approved agent in an adjuvant space that I believe does have some efficacy. [There is an ongoing] debate because there are no overall survival data [yet], and we continue to debate the merits and utility of single-agent immunotherapy in the adjuvant setting. There are high enough risk populations where I believe this strategy is viable. Certainly, for all patients who qualify for adjuvant treatment, I urge them to have discussions with medical oncologists about the pros and cons.

We should remember that immunotherapy does have significant adverse effects, and we should remember that, especially in an adjuvant setting, approximately half of these patients are already cured and don't need any treatment at all, and [this presented the risk of] significantly over treating patients with drugs that have significant toxicity.

Finally, one of the biggest detractors from the adjuvant immunotherapy is the simple fact that we are aiming to treat micro-metastatic disease in this setting. We know that single-agent therapies are probably not as effective as combinations. There is some controversy about single-agent immunotherapy in an adjuvant setting. There is probably patient population where it makes sense, but we await the maturation of the survival data.