Frontline TKI in Intermediate-Risk Renal Cell Carcinoma - Episode 2
Now we have to think about what the best treatment options are for these patients. And really it’s evolved quite a bit. Historically, 5, 6 years ago, this would have been a patient where you’d really be thinking sunitinib or pazopanib. Both are active VEGF tyrosine kinase inhibitors with activity in frontline renal cell carcinoma.
They’ve had studies trying to compare the 2. At the end of the day, 1 is really not superior to the other in terms of outcomes. But with the COMPARZ trial and the PISCES trial, 2 trials that try to look at these in more detail, while the outcomes were similar in the COMPARZ trial, toxicity profile was different with pazopanib, with potentially a better quality of life with pazopanib, although increased toxicities. And that was sort of seen as well in the PISCES trial, where patient-reported outcomes really showed that pazopanib was preferred. So for that, pazopanib had become a mainstay, as well as sunitinib in the frontline setting.
And then more recently we had the arrival of cabozantinib, which in the second-line setting has been the only drug showing improved response rate, PFS [progression-free survival], overall survival versus everolimus. And so given those impressive responses in the second-line setting, they were studied in the frontline setting, the logic being that cabozantinib in addition to inhibiting VEGF, also inhibits MET and AXL, which we know are important factors in driving sunitinib resistance. We had a randomized phase II trial, CABOSUN, that was done with a cooperative group led by Toni Choueiri, MD, that looked at cabozantinib versus sunitinib in those with intermediate- or poor-risk disease. This trial accrued close to 150 patients, randomizing between the 2 arms.
And what the trial did show was that cabozantinib was superior to sunitinib in terms of response rate, 20% versus less than 10%, and progression-free survival of just over 9 months versus around 5 months, so clearly an active agent. And while not statistically significant, with 34-month follow-up there’s actually improvement in overall survival in this by about 26 versus 21 months. So certainly, cabozantinib is a very active agent in the frontline setting, specifically for those patients with intermediate- or poor-risk disease. And as such, if you look at NCCN [National Comprehensive Cancer Network] guidelines, that is actually now one of the preferred options for those with intermediate- or poor-risk disease.
Notably, the label for the FDA indication does not limit to intermediate- or poor-risk disease, the thought being that there’s no reason to suggest that this should not work in good-risk patients, although the data really are for those with intermediate- and poor-risk disease. So obviously, those are great options. With the advent of immunotherapy, immunotherapy has now moved into the frontline as well, as everyone is well aware, with the combination of nivolumab/ipilimumab, as well as pembrolizumab with axitinib or avelumab with axitinib, all shown to improve outcome versus sunitinib in the frontline setting. As such, those are very intriguing options.
Transcript edited for clarity.
Case: A 70-Year-Old Man with Intermediate-Risk RCC
A 70-year-old Caucasian man presented to ER complaining of blood in his urine and abdominal pain.
H & P