Considerations When Choosing a First-Line Option for Patients with Advanced Kidney Cancer

When I finished training and joined the faculty at City of Hope a decade ago, there was a great deal of excitement over recent approvals of sunitinib and sorafenib for metastatic renal cell carcinoma (mRCC).  Throughout my training, I had seen many patients succumb to toxicities from interleukin-2 – despite the handful of victories, there were overwhelming losses.  With sunitinib and sorafenib, a broader spectrum of patients could benefit from therapy and I saw outcomes starting to shift in a favorable direction. 

Fast forward to 2018.  Now, with a dozen agents in our armamentarium, the game has changed.  Rather than being able to pick from one or two salient options, there are many.  Over the years, I have become firmly convinced that the sequence of therapies we apply is critical.  We know there is attrition across each line of treatment – amongst patients who receive front-line therapy, it has been estimated that 50% receive second-line treatment, and only 20% make it to third-line.  Thus, making the most appropriate selection up-front is critical. 

How do I pick my initial approach?  First, it’s important to consider the options at hand.  The two most recent approvals are for (1) cabozantinib and (2) the combination of nivolumab with ipilimumab.  Cabozantinib is a multikinase inhibitor with affinity for VEGF, MET, and AXL.  The agent was approved for first-line use on the basis of the randomized, phase II CABOSUN clinical trial comparing cabozantinib to sunitinib in patients with intermediate and poor risk disease by International mRCC Database Consortium (IMDC) criteria.  This NCI-funded study, performed by the Alliance cooperative group, demonstrated a significant improvement in progression-free survival (PFS) with cabozantinib over sunitinib.  The response rate was also double that observed with sunitinib.  Although the study was criticized initially for leaning on investigator-assessed response and PFS, to the credit of the Alliance, they were able to secure imaging for the majority of patients and perform an independent review.  This confirmed initial findings from the study and was used towards FDA approval. Toxicities seen with cabozantinib are not dissimilar from those with other tyrosine kinase inhibitors, including fatigue, diarrhea and hand-foot syndrome – many of these are manageable for the seasoned clinician with dose reductions and supportive care approaches. 

The other option, of course, is nivolumab with ipilimumab.  I was involved with the phase I assessment of nivolumab/ipilimumab in mRCC, and then subsequently participated in the phase III CheckMate214 trial, comparing nivolumab/ipilimumab to sunitinib in treatment-naïve patients with mRCC.  CheckMate214 demonstrated interesting results – there was a significant improvement in overall survival (OS) and a non-statistically significant trend towards increased PFS – but specifically in those patients with IMDC intermediate- and poor-risk disease.  In patients with good-risk disease, both PFS and response rate were higher with sunitinib.  My suspicion is that this is secondary to the risk assessment tool used – the IMDC criteria were built around patients with good risk disease.   Nivolumab/ipilimumab also produced some concerning toxicities – 24% of patients stopped therapy on account of toxicity, compared to only 12% of those patients receiving sunitinib.  Furthermore, an initial presentation of the data, it was reported that 60% of patients required steroids.  Thus, although we often think of immunotherapy as the “kinder, gentler” approach, perhaps this is not so.  Unless the treating oncologist has substantial experience, nivolumab/ipilimumab can be quite risky. 

So back to the question at hand – how do I treat patients front-line? For those individuals with good-risk disease, I favor cabozantinib.  Now, you may say that those patients were not included in CABOSUN – true, but I cannot think of any reason why good-risk patients would not have a better response to cabozantinib as compared to sunitinib. It’s a different story in CheckMate214 – again, good-risk patients didn’t realize the same benefit because the IMDC criteria were devised in the context of VEGF-treated patients.  In patients with intermediate and poor risk disease, nivolumab/ipilimumab is certainly on the table.  However, if I feel that patients may not have immediate access to medical attention, or may have issues with compliance, I tend to favor cabozantinib – patients on nivolumab/Ipilimumab can really get themselves into trouble without close medical oversight. I also favor cabozantinib in patients with bony metastatic disease and other aggressive features (e.g., brain metastases) – cabozantinib appears to have substantial benefit in this setting.  My colleagues have pointed to the 9% complete response rate observed in the nivolumab/ipilimumab experience.  Compelling, but bear in mind that in certain populations, a complete response simply can’t be achieved in the vast majority of cases (e.g., bony metastases).  

In summary, both cabozantinib and nivolumab/ipilimumab warrant discussion in the first-line setting, with the nuances noted above.  Keep in mind too that there are multiple other treatments looming on the horizon – the recent press release for the JAVELIN 101 trial – the combination of axitinib/avelumab may make a splash soon, and there is already compelling data for bevacizumab with atezolizumab.  My verdict? Keep enrolling patients in clinical studies.  We are running a study for cabozantinib with atezolizumab. This approach melds what I feel is the most potent tyrosine kinase inhibitor with an immunotherapeutic agent.  Until we are getting durable responses for the majority of all patients with this disease, our job is not done.

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