Robert Motzer, MD: So, the other important study that was presented at ASCO was the Phase 3 trial that compared atezolizumab plus cabozantinib, to cabozantinib alone following progression of prior immune checkpoint inhibitor therapy, the Phase 3 contact trial that was presented by Dr Choueiri. Dr Ornstein, could you review that study and your take on it from the ASCO presentation?

Moshe Ornstein, MD: Absolutely. So, this was a real highlight in the RCC field at ASCO of 2023. It's presented by Dr Toni Choueiri of Dana-Farber; “The Efficacy and Safety of Atezolizumab plus Cabozantinib Versus Cabozantinib Alone in Patients With Metastatic RCC who had Disease Progression Following Treatment With a Prior IO-based Therapy.” And really the background here is that we know that most patients with clear cell RCC are going to receive an IO-based therapy as their initial regimen or even in a refractory setting. And the question the field has is whether there is a role for immunotherapy-based treatment in patients whose cancer progressed on a checkpoint inhibitor? So, if you look at the inclusion criteria for this study, these were patients with advanced or metastatic clear cell or non-clear cell RCC, with or without a sarcomatoid component, patients had to have had radiographic progression on or immediately after the ICI, the IO-based therapy. In other words, the immediately preceding therapy to this trial had to be the IO-based regimen. It could have been given as adjuvant therapy, first-line therapy, second-line therapy, either as a single agent or in combination with one of the other approved agents. Patients were stratified by IMDC risk group, by histology, and by the most recent line of ICI. Patients were randomized one-to-one to receive atezolizumab 1200 milligrams IV every three weeks, plus cabozantinib at a 60-milligram dose daily as per the standard dosing of the refractory setting. So cabozantinib plus atezolizumab versus cabozantinib at 60 milligrams daily with primary endpoints being independent centrally assessed PFS and overall survival. The primary analysis of centrally reviewed PFS, again, this was one of the primary endpoints, showed that the median PFS for the combination arm of atezolizumab plus cabozantinib was 10.6 months. And the median PFS for cabozantinib alone as monotherapy was 10.8 months. You see the hazard ratio over there of 1.03. And really the curves themselves tell the story nearly overlapping for PFS, no benefit seen for the addition of atezolizumab to cabozantinib in patients with RCC who've progressed on prior immunotherapy. In terms of the other primary endpoint, this was an interim analysis of the overall survival. Again, you see something similar to what we saw in the PFS curve, very similar looking curves, median OS of 25.7 months in the atezolizumab-cabozantinib arm. Not a valuable yet in the cabozantinib arm, but you can see the stratified hazard ratio of 0.94 with a confidence interval that is wide and crossing one and a P value of nearly 0.7. Again, you're seeing no noticeable benefit in terms of overall survival for patients who got atezolizumab plus cabozantinib versus cabozantinib alone. I thought one of the interesting findings in this study, obviously was really important to see no benefit for the combination in terms of PFS or at the interim look at overall survival, but the objective response rates for both arms were very similar with response rates of 40.5% for atezolizumab plus cabozantinib versus 40.9% for cabozantinib alone. And again, this is RECIST per central review. To me, that was an impressive number, seeing cabozantinib perform that well in a refractory setting with response rates of approximately 40 to 41%. The other finding I found interesting, in terms of looking at their responses, was looking at the primary PD rate, in other words, progressive disease as their best response. Really whether patients got cabozantinib or cabozantinib plus atezolizumab, there seemed to be pretty good control overall with a progressive disease as best response rate of only 4% or 5% in both the cabozantinib-atezolizumab and the cabozantinib as monotherapy arm. So, in summary, when I look at this trial, it confirms my clinical practice, which is not to use an IO-based therapy in patients whose cancer has just progressed on an IO-based combination. For me, when I see a patient who has disease progression after receiving IPI nivo or axitinib-pembrolizumab, or even if they have gotten a TKI followed by nivolumab as monotherapy, I would not follow that up immediately with another IO-based regimen. I think the standard of care would be to give that patient a TKI monotherapy certainly appears based on these data that cabozantinib would be a reasonable approach seeing the response rate of 40% in the setting and seeing the PFS from a little over 10 months in the setting as well.

Robert Motzer, MD: Well, I think that's a really good overview of the trial and your take on its impact and on standard of care.