RCC Treatment Decision-Making Requires a Balance of Efficacy and Individual Patient Considerations

Marc R. Matrana, MD

The frontline treatment landscape for renal cell carcinoma (RCC) has progressed substantially with the introduction of combination therapies that have driven an increase in disease control in the up-front setting, according to Marc R. Matrana, MD, who added that the abundance of options in the first line requires individualized approaches to determine an optimal therapy.

“At the end of the day, [the best therapy] is what you [and the patient] feel more comfortable with, and what you have access to at your institution,” Matrana said, who noted that the development of a clinically relevant biomarker could help inform treatment selection in the frontline setting in the future.

In an interview with OncLive® following a State of the Science discussion on RCC treatment advances, Matrana underscored the urgent need for predictive biomarkers to guide therapeutic selection, his process for selecting frontline combination therapies for patients with RCC, and why these combinations have been important for patients with this malignancy.

Matrana is a medical oncologist at Ochsner Health and director of Genitourinary Medical Oncology Research in New Orleans, Louisiana.

OncLive: How has the frontline treatment of RCC evolved in recent years?

Matrana: It wasn't that many years ago when we had treatments like high-dose interleukin 2 and interferon alpha, which were extremely toxic and not terribly effective. Fast forward to 2025, we have some great combinations [that can drive] disease control for approximately 95% to 98% of patients.

However, selecting which combination is right for which patient [remains a challenge]. Trying to decide whether every patient needs combination therapy, or if some [patients may] respond [to a single-agent treatment] has been a challenge and muddied the waters in some ways. We're almost at a spot where we have too many great therapies in RCC, [where] you're left with the challenge of selecting the best treatment for each patient.

As I always tell my patients, the best therapy is the one that works for you, and at this point in time, the only way we know which one that is to give it a try. What we lack in RCC—and hopefully this will be changing soon—is a really good biomarker, [such as] prostate-specific antigen [in prostate cancer]. Those biomarkers will allow us to [better] personalize treatment based on which therapy will work for which patient [based on the biomarker]. [Finding a actionable biomarker] is the Holy Grail of RCC treatment, in my opinion. It's still ta void that we need to fill, and I know people are excited about some up-and-coming biomarkers, but we've been there before. Hopefully one will materialize soon that'll change things.

What factors influence your decision to select one therapeutic agent over another when initiating treatment for RCC?

[First], I look at patient characteristics. For example, does the patient have liver disease [or] an autoimmune disease? Have they been a transplant recipient in the past? All of those [answers] will guide me a little bit. If they have had a solid organ transplant, I'm going to be less likely to give an immunotherapy.

Similarly, if patients have uncontrolled autoimmune disease, I might be a little more hesitant about immunotherapy. Likewise, if the patient has severe liver disease, you might be more hesitant with some of the VEGF-targeting TKIs, or [if patients have] severely uncontrolled hypertension, you'd want to deal with that first before jumping right into therapies that might increase blood pressure.

[Secondly], I would look at disease characteristics. Do they have bone metastases? Certain TKIs like cabozantinib [Cabometyx] are very efficacious for bone metastases. I [also] look [whether] the disease crossed the blood-brain barrier and [led to] central nervous system metastases. Do patients have clear cell or non–clear cell disease? Some TKIs have more data in non–clear cell [RCC] than others.

[Considering both] patient characteristics and the disease characteristics [is valuable], and then you try to personalize [treatment decisions] based on those [factors].

What has the use of these frontline combinations meant for the management of advanced RCC?

[For example, in the] phase 3 KEYNOTE-426 trial [NCT02853331], pembrolizumab [Keytruda] was paired with axitinib [Inlyta] in the first-line setting for patients with metastatic clear cell RCC, and it was compared against sunitinib [Sutent] monotherapy, which was a standard of care at the time this trial was designed. Most of the big combination studies of TKIs and immunotherapies [in RCC] have used sunitinib as a comparator, but if they were designed today, sunitinib would not be an appropriate comparator. [Other] combinations would be an appropriate comparator.

[KEYNOTE-426] looked at overall survival and progression-free survival for these patients, and we saw statistically significant improvements in both settings [with pembrolizumab plus axitinib]. We also saw was a phenomenal overall response rate and a disease control rate, as well.

At the end of the day, the disease control rate is important [for my patients]. For the first time in history with these combinations, I have the advantage of being able to tell a patient, ‘Yes, we have a combination therapy option for you that has a [very good] chance of at least stabilizing your disease.’ That's a good feeling, and that's what combinations like pembrolizumab plus axitinib allow us to do. They allow us to give the most efficacious therapy head-on in the first line for these patients in order to control this disease.