Nizar Tannir, MD: Let’s go through the first case. This is a patient with favorable-risk advanced clear cell RCC [renal cell carcinoma]. This is a 68-year-old woman who’s a nonsmoker. She presented with a 20-lb weight loss and right upper quadrant discomfort. Imaging showed a 7-cm mass in the right kidney with no enlarged adenopathy and no evidence of metastatic disease. Her review of systems was noncontributory except that she had a history of asthma and hyperlipidemia. She underwent a right radical nephrectomy, and the pathology revealed clear cell RCC grade 3 with renal vein invasion and no tumor necrosis. She was staged as having stage III disease based on pT3a, NX, and M0. We can discuss the staging later, and whether there are any data in how we approach patients post-nephrectomy if they have high risk for recurrence, like this patient.

The patient was followed with serial imaging for surveillance. Four years later, a CT scan of the chest, abdomen, and pelvis revealed bilateral pulmonary metastases, with some of these measuring 2.3 and 1.8 cm in size. A CT-guided biopsy was performed on one of these lung nodules and confirmed metastatic clear cell RCC. The work-up was then initiated with routine laboratory tests, including CBC [complete blood count] and comprehensive chemistries. Her hemoglobin, absolute neutrophil count, and platelet count were normal, as well as corrected serum calcium level and serum LDH [lactate dehydrogenase]. Her Karnofsky Performance Status was 90%. She was initiated on lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks.

I’d like to take the opportunity here to pause and ask my colleagues, starting with Scott, about the selection of therapy and about what you saw from this patient who had stage IV disease 4 years after initial nephrectomy, with lung metastasis and favorable risk by IMDC [International Metastatic RCC Database Consortium]. The choice here was lenvatinib and pembrolizumab. Do you agree with this? Would you have selected this treatment regimen for this patient? What factors do you consider when selecting the treatment for a patient with advanced clear cell RCC in the first-line setting? These are patients who are treatment naïve. What do you look at to select one regimen over another?

Scott Tykodi, MD, PhD: Thank you, Dr Tannir. Really nice overview. We have multiple frontline regimens, 4 that are commonly used, and there are no formal head-to-head comparison data. When you walk into the room to see your patient, you have to select one and try to have some sense or algorithm about how you wound up with what you are selecting. The risk category is probably the most clear-cut decision point between the regimens. The ipilimumab-nivolumab data were positive in the intermediate/poor-risk cohorts for benefit of the immunotherapy regimen vs sunitinib, but not for good risk. We generally exclude that for good-risk patients, as not being a choice that guides you toward the doublet. And from a practical standpoint, the FDA approval also is technically for intermediate and poor risk.

I generally think about an IO/TKI [immunotherapy/tyrosine kinase inhibitor] doublet for my good-risk patients, but that still leaves us with 3 combinations. How do you select between those? That’s where it gets a little more nuanced. There’s certainly no right or wrong answer. Familiarity of the treating doctor in the community [is probably a factor]. I’m sure many providers don’t have a lot of patients with kidney cancer in their panel and may not have used all the different regimens, so feeling confident on what you’re looking for and what you’re watching for [is important].

A point you made in the overview is something I think about in the clinic: the low rate of primary refractory disease with both nivolumab-cabozantinib and pembrolizumab-lenvatinib. If I’m worried about a patient with bulky or symptomatic disease, I generally opt for 1 of those 2 regimens because of their favorable profile. The other feature I often think about is the TKI dose intensity. It’s the standard full dose for lenvatinib and axitinib, but it’s an intermediate 40-mg starting dose for cabozantinib. Does that run with a little better patient tolerance and perhaps better quality-of-life scores for the nivolumab-cabozantinib regimen?

With older patients and patients for whom I’m worried about their tolerance, I often opt for nivolumab-cabozantinib. But for patients without a lot of comorbidities, I’m fond of the pembrolizumab-lenvatinib combination. It has the highest overall response rate. It has the best PFS [progression-free survival] data in the frontline setting. Those are certainly attractive features. That choice is very sensible for this patient, and I very well may have come to that conclusion and proposed that for my own patient if they had the same clinical features.

Nizar Tannir, MD: Thanks, Scott, for your insightful comment on this case, as well as your approach to selecting first-line therapy for your patients.

Transcript edited for clarity.