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Fifteen years ago, the average patient who walked into an oncology clinic with metastatic renal cell carcinoma (RCC) would be told that they had a median survival of 12 to 18 months.

"This was an era where clinicians were using primarily interferon or interleukin-2," said Moshe Ornstein, MD, MA, of the Cleveland Clinic. "The drastic shift since that time is that now we expect most patients to live for years."

Approved frontline treatment options include single-agent vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs), such as sunitinib (Sutent), pazopanib (Votrient), and cabozantinib (Cabometyx); combination immunotherapy with ipilimumab (Yervoy)/nivolumab (Opdivo); and combination immunotherapy/TKI regimens, such as axitinib (Inlyta)/pembrolizumab (Keytruda), cabozantinib/nivolumab, and lenvatinib (Lenvima)/pembrolizumab.

Some studies of these modern treatment regimens, such as , have showed a median overall survival (OS) of 4 years or more, representing improvements in outcomes for certain patients with metastatic disease, Ornstein said.

"Today there is a much broader field and significantly more options that can definitely be confusing for practitioners when choosing first-line therapy for this group of patients," said Victor R. Adorno Febles, MD, of NYU Langone Perlmutter Cancer Center in New York City.

Risk and Surveillance

Most patients diagnosed with RCC will present with localized disease; however, .

"One of the first things to look at when selecting treatment for a patient is the IMDC [International Metastatic RCC Database Consortium] criteria that stratify patients into either good, intermediate, or poor risk," Adorno said.

The incorporates two clinical values (Karnofsky Performance Status and time from diagnosis to treatment of less than 1 year) and four laboratory values (hemoglobin less than the lower limit of normal, calcium greater than the upper limit of normal [ULN], neutrophil count greater than the ULN, and platelet count greater than the ULN) that have been shown to be associated with adverse outcomes. Identifying a patient's risk category can help to determine best options for first-line treatment, as well as which patients may qualify for active surveillance.

"When I walk into a patient's room, my first question to myself is, 'Does this patient require treatment now or can the patient be put on surveillance?'" Ornstein said.

published in 2016 examined the use of initial active surveillance in 52 patients with asymptomatic metastatic RCC. Patients could continue on surveillance at the discretion of the treating physician. Of the 48 patients included in the analysis, median time on surveillance was 14.9 months. Twenty patients who developed progressive disease continued on surveillance, with a median duration of additional surveillance of 15.8 months. Patients with a higher number of IMDC risk factors (two or more) or those with three or more metastatic organ systems involved had shorter surveillance periods, providing a framework for whether or not to defer systemic therapy.

If the patient does not meet the criteria for active surveillance, the clinician must consider other first-line options.

Need for Response

TKI monotherapies were among the first advances made in the treatment of metastatic RCC, but today they are used only in a minority of patients as first-line treatment, Ornstein said.

In some studies testing immunotherapy/TKI combinations compared with sunitinib, the benefit of combination therapy was smaller among patients with favorable-risk disease. For example, study, the 2-year OS rate was 85.3% in patients with favorable risk treated with the combination of pembrolizumab plus axitinib compared with 87.7% in patients treated with sunitinib. A subgroup analysis of the study showed that the OS benefit was only seen among intermediate- and poor-risk patients.

"As a general rule, all patients with metastatic disease who are going to undergo treatment should be treated with an immunotherapy-based combination," Ornstein noted. "The only patients that I treat with TKI monotherapy are patients with an absolute contraindication to immunotherapy, and that is a very select group."

Clinicians are left then to choose between the use of an immunotherapy combination (ipilimumab/nivolumab) or one of the available immunotherapy/TKI combinations.

First-line treatment recommendations made by international guidelines are independent of patients' prognostic risk, except in the case of ipilimumab/nivolumab. In the CheckMate-214 trial, the primary efficacy population was limited to only those patients with poor- or intermediate-risk disease. Therefore, if a patient has favorable risk, ipilimumab/nivolumab would not be an option.

For intermediate- and poor-risk patients, several things should be considered when choosing between ipilimumab/nivolumab and immunotherapy/TKI combinations. For example, tolerability of side effects may come into play when selecting ipilimumab/nivolumab, according to Adorno.

"The immunotherapy-alone combination has a finite time of therapy," he said. "It is primarily given as four cycles with the combination followed by maintenance nivolumab. The toxicity is front-loaded, and after 4 to 6 months, if the disease is stable without significant immune-related adverse events, the patient will likely continue to do well."

Additionally, ipilimumab/nivolumab is just one monthly infusion and patients do not have to worry about side effects frequently seen with TKIs, such as hand-foot syndrome, mucositis, diarrhea, or fatigue, Ornstein said.

This may be the best option in situations where the goal of therapy is to reduce toxicity and the patient does not need response right away.

In contrast, if a patient is symptomatic, has back pain, fevers, chills, and weight loss, that patient needs a more immediate response to therapy, Ornstein explained.

"It is hard then to give drugs with a response rate around 40% like ipilimumab/nivolumab, when you can give a therapy with a response rate around 70%," he added.

Choosing an Immunotherapy/TKI

Although ipilimumab/nivolumab has the longest follow-up data available, the combination has a lower overall response rate and a shorter progression-free survival (PFS) than the immunotherapy/TKI combinations.

"If you have a patient that is intermediate or poor risk and feel they are symptomatic and need a response, then I strongly favor the immunotherapy/TKI combination based on the higher likelihood of response in those studies," Adorno said.

However, with the immunotherapy/TKI combinations, it is hard to say that there is one regimen that is better than the others, Adorno and Ornstein pointed out.

Acknowledging that cross-trial comparisons are never exact, CheckMate-214 showed an overall response rate of 42%, with an 11.6-month PFS and a , with ipilimumab/nivolumab in patients with intermediate or poor risk. showed that axitinib/pembrolizumab led to an objective response rate of 59.3%, with a 15.1-month PFS and a median OS of 45.7 months. The of lenvatinib/pembrolizumab showed an objective response rate of 71%, with a median PFS of 23.9 months. The of cabozantinib/nivolumab found an objective response rate of 55.7%, with a PFS of 16.6 months and a median OS not yet reached. Finally, the of axitinib/avelumab (Bavencio) showed an objective response rate of 55.2%, with a median PFS of 13.8 months.

"If you line up the data side by side and look at response rates, complete response rates, and progression-free survival, the best data appear to be with lenvatinib and pembrolizumab," Ornstein said. "That is difficult to do because it is a cross-trial comparison, but assuming the trials are somewhat similar, many would pick that [regimen]. But, in reality, any of the approved immunotherapy/TKI regimens are appropriate, as each has nuances that may favor its use. Perhaps more important than which combination one chooses is to feel comfortable managing the toxicities."

Lenvatinib probably has more toxicities than axitinib, so in patients with concerns about toxicities, lenvatinib may not be his first choice, he noted, adding that all of these combinations have toxicities that need to be expertly managed.

"As a general rule, we really only see complete responses and deep durable partial responses in frontline therapy. Therefore, my opinion is to pick what you feel is the best option for your patient in the frontline setting in the hope that the patient will be one with either deep and durable partial response or complete response," he said.

Even with all of these options, there are research questions that could further guide treatment selection.

"One would be to have some form of biomarker to help guide that initial therapy selection and determine which patients would benefit most from immunotherapy combinations rather than VEGF TKI/immunotherapy or vice versa," Adorno said.

Adorno and Ornstein are both also interested to see the results of trials testing triplet therapy with newer PD-L1/CTLA-4/VEGF TKI combinations.

"We need to see if any improvement of outcomes or overall survival would warrant the likely increase in toxicity we would see with more agents added to treatment," Adorno noted.

Another important area of research is looking more closely at these regimens and others in histologies of RCC outside of clear cell. Multiple trials are just getting up and running, so additional guidance is likely still a few years into the future.

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