The biggest change that we have seen over the last maybe three years has been that we have two agents that have shown survival improvement in the second line space. So most patients who develop advanced kidney cancer have now over six, seven, eight lines of therapy and the bigger question for us clinically has been which is the frontline treatment and how do you sequence the patients with the treatments that we have. We know that probably around 60% of patients who go from frontline therapy develop disease progression, move on to second line therapy. But we also know then when you go from second to third line therapy you drop a lot of patients because of mortality. So around 20-25% of patients, maybe up to 30% of patients, can actually go to third line therapy. So the question for us historically has been which is the best first line treatment. Historically it has been the utilisation of agents that are able to disrupt vascular supply, what we call the tyrosine kinase inhibitors that basically block what we call KDR which is the receptor 2 for the vascular endothelial growth factor which is an agent, basically a factor, that promotes angiogenesis. So sunitinib and pazopanib historically since 2005 and 2009 have become sort of the standard frontline agents of choice.
When people progress then the bigger question was what to do for those patients. Only two agents in the second line space have demonstrated a survival benefit. One is called cabozantinib which is a c-MET dual with KDR inhibition - in the METEOR data survival improvement, delay in progression free survival and response rate, what we call the trifecta effect. Then an agent called nivolumab, which is a PD-1 inhibitor, also with survival benefit. Not a PFS improvement because immune oncology agents don’t really lead to PFS improvement but also a response rate that is quite robust. Those two trials, one is called CHECKMATE-025 for nivolumab and the second one is called the METEOR data for cabozantinib, reshaped the second line space for advanced disease. We didn’t know which is the agent to use in the second line but those were the two agents that had shown survival improvement in the second line space. Most of us, at least in the United States, were actually using adopting nivolumab just by virtue of the side effect profile of this agent compared with cabozantinib but both agents were actually agents that were approved in that space.
What had changed for us drastically over the last eighteen months or so is the utilisation of immune oncology agents in the frontline space for patients with untreated metastatic RCC, specifically we’re talking now patients with the most common histology which is called clear cell carcinoma or clear cell RCC. So ipilimumab nivolumab, ipilimumab is a CTLA-4 inhibitors, nivolumab is a PD-1 inhibitor, the combination of ipilimumab and nivolumab followed by maintenance nivolumab has become the standard of care for men with untreated clear cell metastatic renal cell carcinoma, but specifically for a big subset of patients looking at patients with intermediate or poor risk features which are features of your disease that would predict how likely you’re going to do well over time. So that is the standard of care right now in the United States for patients with metastatic disease.
Recently Tom Powell from the UK along with Brian Rini co-led a trial looking at pembrolizumab, which is a PD-1 inhibitor, in combination with a VEGF inhibitor called axitinib and they compared that regimen against sunitinib in the frontline space, similar to CHECKMATE-214 comparing ipilimumab nivolumab against sunitinib. This data also demonstrated a significant improvement in survival for those patients who received the pembrolizumab and axitinib combination over sunitinib. So now, although pembrolizumab axitinib is not approved and I don’t have a vested interest in whether or not it’s going to get approved or not, one would predict that the new standard of care for advanced untreated disease is going to be either ipilimumab nivolumab or pembrolizumab axitinib. So the bigger question that we’re going to face in the field is which out of those two regimens one will use. Since the ipilimumab nivolumab approval, at least in the United States, was for intermediate and poor risk patients, I would argue that that remains the standard of care but the pembrolizumab axitinib data challenged that data because the pembrolizumab axitinib was for all comers. If, indeed, it’s approved my prediction again will be that it will be approved for all comers with untreated disease. So it’s going to be between ipilimumab nivolumab or pembrolizumab axitinib. We have never compared them head to head so it’s going to be a clinical decision based upon the patient that you have in front of you and also based upon what is the perception of the clinician as to which is the regimen that will provide the best benefit with the least side effect profile.
One of the challenges in renal cell carcinoma right now for us is that we continue to rely on very obsolete clinical features because we haven’t been able to pin down a biomarker, a molecular biomarker that we can use to predict response. So at this point in the absence of that biomarker driven approach we continue to actually utilise our clinical features. That is a big change in renal cell carcinoma, that we challenge not only how you see the patients, how you treat them up front but, more important than that, it will leave a big vacuum as to which is the best second agent of choice to use if you’ve got those two regimens as a frontline treatment.