Marc R. Matrana, MD, is a medical oncologist and director of Genitourinary Medical Oncology Research at Ochsner MD Anderson Cancer Center, as well as a professor of internal medicine at The University of Queensland Medical School – Ochsner Health.

Marc R. Matrana, MD, discusses the ongoing need for validated biomarkers to guide treatment selection in renal cell carcinoma.

Dr Matrana on the Persisting Need For Validated Biomarkers to Guide Treatment Selection in RCC

"Selecting which combination is right for which patient, and trying to decide if every patient needs combination therapy or will respond just one therapy or another, has really been a challenge for clinicians. What we really lack in RCC—and hopefully that will be changing soon—is a really good biomarker."

Marc R. Matrana, MD, professor of internal medicine at The University of Queensland Medical School – Ochsner Health and medical oncologist at Ochsner MD Anderson Cancer Center, underscored the ongoing need for validated biomarkers to guide treatment selection in renal cell carcinoma (RCC), particularly in the context of increasingly complex therapeutic options.

Although several immuno-oncology–based combination regimens featuring dual immune checkpoint inhibitors or an immune checkpoint inhibitor with a TKI are now available for first-line treatment of advanced RCC—including pembrolizumab (Keytruda) plus axitinib (Inlyta) from the phase 3 KEYNOTE-426 trial (NCT02853331), and nivolumab (Opdivo) plus ipilimumab (Yervoy) from the phase 3 CheckMate 214 trial (NCT02231749)—Matrana noted that treatment selection remains largely empirical. Clinicians currently lack a predictive biomarker analogous to prostate-specific antigen (PSA) in prostate cancer, which limits the ability to personalize therapy based on individual patient biology.

Matrana explained that in the absence of such a biomarker, treatment decisions are guided by clinical risk stratification models such as the International Metastatic RCC Database Consortium (IMDC) criteria and a trial-and-error approach. He emphasized that although having multiple effective combinations represents significant therapeutic progress, it also complicates clinical decision-making, especially when attempting to determine whether combination therapy is required or if select patients may respond well to monotherapy.

The development of a robust, predictive biomarker remains a major unmet need and is viewed by many in the field—including Matrana—as the “Holy Grail” of RCC research. A reliable biomarker could help stratify patients by likelihood of benefit from IO-based regimens vs TKI monotherapy or other strategies, thereby optimizing treatment efficacy while potentially reducing unnecessary toxicity.

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Dr Matrana on Advantages and Challenges of the Expanding First-Line RCC Treatment Paradigm

“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 [and are] left with the challenge of selecting the best treatment for each patient.”

Marc Matrana, MD, director of the Precision Cancer Therapies (Phase I) Research Program at the Louisiana Cancer Research Center, part of the Ochsner Health System, discussed the evolution of first-line treatment strategies for patients with renal cell carcinoma (RCC).

Historically, the therapeutic paradigm for previously untreated RCC was limited to agents like high-dose IL-2 and interferon alfa, which are associated with substantial toxicity and modest efficacy, Matrana began. However, in 2025, there are now several highly effective combination regimens capable of achieving disease control in approximately 95% to 98% of patients, he stated.

Despite these advances, the optimal selection of therapy remains a complex issue, according to Matrana. Determining whether all patients require combination therapy or whether a subset may derive sufficient benefit from single-agent treatment continues to be a subject of clinical uncertainty, he noted. In many respects, the abundance of highly active therapeutic options for RCC presents a new challenge: identifying the most appropriate regimen for individual patients, he reported.

Matrana often explains to patients that the most effective therapy is ultimately the one that works for them; however, currently, the only method to determine the optimal therapy for each patient is through empirical treatment. An urgent need that is lacking in RCC is a reliable, actionable predictive biomarker akin to prostate-specific antigen in prostate cancer, he explained. Such a biomarker would enable a more personalized approach to therapy selection by predicting treatment response, he said. Although there is growing enthusiasm around several emerging biomarker candidates, prior efforts have not produced a clinically validated tool for predicting therapeutic benefit in RCC, he emphasized. However, Matrana concluded that he remains hopeful that a transformative biomarker will emerge in the near future.

Marc Matrana, MD, discusses how the expansion of the frontline RCC treatment paradigm opens the door to further questions regarding personalized treatment.

Marc R. Matrana, MD, emphasizes the need for combination therapies for the treatment of patients with advanced or metastatic renal cell carcinoma.

Dr Matrana on the Importance of Combination Therapies in Metastatic RCC

“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—an option for you that has a 90% to 95% chance of at least stabilizing your disease and essentially working for you.’ That's a really good feeling to have.”

Marc R. Matrana, MD, professor of internal medicine at The University of Queensland Medical School – Ochsner Health and a medical oncologist at Ochsner MD Anderson Cancer Center, emphasized the importance of having combination therapy options for the first-line treatment of advanced or metastatic renal cell carcinoma (RCC).

Results from the phase 3 KEYNOTE-426 trial (NCT02853331), which evaluated pembrolizumab (Keytruda) plus axitinib (Inlyta) as first-line therapy for patients with advanced clear cell RCC (ccRCC), demonstrated that 60-month overall survival (OS) rates were 41.9% for those given the combination compared with 37.1% in patients treated with sunitinib (Sutent). Of note, the 60-month progression-free survival (PFS) rates were 18.3% vs 7.3% in the pembrolizumab/axitinib vs sunitinib arms, respectively.

Discussions about first-line therapy options and disease control rates are essential for patients with newly diagnosed metastatic RCC, Matrana began. Historically, there were not many combination therapies for kidney cancer, particularly in the first-line setting for advanced or metastatic disease, he noted. However, based on data from the KEYNOTE-426 study, he underscored the importance of having this option and others for respective patients, especially one that could help with disease control.

Having access to combination therapies in the first-line setting, such as pembrolizumab/axitinib, has paved the way for additional modalities to control disease, which is a good feeling to have, Matrana said.

The study included patients with confirmed locally advanced or metastatic ccRCC with or without sarcomatoid features, who did not previously receive systemic therapy for their metastatic disease. Patients were also required to have a Karnofsky performance status of 70% or greater and 1 or more measurable lesions per RECIST 1.1 criteria. Among the 861 patients enrolled on the study, 432 were randomly assigned to the pembrolizumab/axitinib arm and 429 were randomly assigned to the sunitinib arm. Those treated with pembrolizumab/axitinib received 200 mg of intravenous pembrolizumab every 3 weeks for 35 doses with oral axitinib at 5 mg twice daily. Patients in the sunitinib arm received 50 mg of oral sunitinib once daily on a 4-week on, 2-week off schedule. Data from this study 

 of pembrolizumab plus axitinib for the first-line treatment of patients with advanced RCC.

Dr Matrana on Factors Influencing Upfront Treatment Approaches for RCC

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

Marc R. Matrana, MD, a medical oncologist and director of Genitourinary Medical Oncology Research at Ochsner MD Anderson Cancer Center, as well as a professor of internal medicine at The University of Queensland Medical School – Ochsner Health, outlined factors informing treatment decision-making in the frontline setting for patients with renal cell carcinoma (RCC).

Treatment selection in advanced RCC requires careful consideration of both patient-specific and disease-related characteristics to optimize efficacy and simultaneously minimize the potential for developing adverse effects, Matrana began. The initial step involves assessment of comorbid conditions that may affect the safety or feasibility of certain systemic therapies, he shared. For example, the presence of liver dysfunction or pre-existing autoimmune disease may necessitate a more cautious RCC treatment approach, Matrana explained. Patients with a history of solid organ transplantation or uncontrolled autoimmune disorders may not be ideal candidates for immune checkpoint inhibitors due to the risk of allograft rejection or immune-mediated toxicity, he added. Similarly, in patients with significant hepatic impairment or uncontrolled hypertension, VEGF-targeted TKIs may pose additional risks, such as hepatotoxicity or increased blood pressure, Matrana noted.

The second component of treatment decision-making includes an evaluation of tumor characteristics, he continued. The presence of bone metastases may favor the use of cabozantinib (Cabometyx), a TKI with demonstrated efficacy in skeletal disease, Matrana stated. Central nervous system (CNS) involvement is another critical factor; although data in this setting remain limited, treatment selection may need to prioritize agents with CNS activity or accessibility, he said, adding that histologic RCC subtype is also relevant, as most clinical trial data are derived from patients with clear cell RCC. However, some TKIs have shown activity in non–clear cell subtypes, which may guide off-label use in these populations, Matrana noted.

By integrating both patient and tumor features, oncologists can tailor treatment strategies to individual patient profiles, Matrana reiterates. Ultimately, the goal is to maximize clinical benefit and minimize harm through a personalized treatment framework grounded in a nuanced understanding of comorbidities and tumor biology, he concluded.

Marc R. Matrana, MD, shares his approach to navigating treatment selection when initiating therapy for patients with RCC.
 

Marc R. Matrana, MD

Articles

Dr Matrana on the Persisting Need For Validated Biomarkers to Guide Treatment Selection in RCC

Dr Matrana on Advantages and Challenges of the Expanding First-Line RCC Treatment Paradigm

Dr Matrana on the Importance of Combination Therapies in Metastatic RCC

Dr Matrana on Factors Influencing Upfront Treatment Approaches for RCC