Robert Motzer, MD: For patients in clinical trials who receive first-line therapy, there are defined criteria. They are called RECIST. If a person meets progression by RECIST, in the past those patients would come off that therapy and would get second or subsequent therapy. One of the things that we are realizing is that although there may be small growths in the tumor meeting RECIST criteria, sometimes there can be fluctuations in terms of the size or measurements of the tumor. Sometimes patients, even though there is a degree of progression, are still clinically benefitting from the medication. They may be feeling well on the medication and they may make slow progression.

The choice of stopping a first-line treatment and going to second-line treatment is dependent on the relative rate of progression, whether the patient is symptomatic, how they were doing in terms of feeling on the first study, and if there are good options for second- or third-line therapy. For patients who have been treated with sequential therapies in the past, if there really is not another good option for those patients, we generally continue the program for as long as we can, as long as they’re feeling well. When going from a first-line therapy to subsequent therapy in RCC [renal cell carcinoma], for the most part, the paradigm has been defined for people who are treated with tyrosine kinase inhibitors [TKIs], like sunitinib and pazopanib, in first-line therapy, because that’s where the evidence lies. Nivolumab, cabozantinib, axitinib, lenvatinib/everolimus all show benefits in that setting and are approved in second- or third-line therapy. Now, the situation has changed.

Now, monotherapy with TKIs is not used for the majority of patients in first-line therapy. Now it’s IO [immunotherapy] combinations. It has left us with the question of what to do when people progress on an IO combination as a second- or third-line therapy. Studies need to be done to define what the optimal therapy is there. It is clear that, for patients who have progressed on ipilimumab/nivolumab who haven’t been treated with a VEGF-targeted therapy, there is good activity for most of the VEGF-targeted therapies in that setting. Certainly cabozantinib, axitinib, and lenvatinib/everolimus are good candidates for a patient who progressed on ipilimumab/nivolumab. We do not know what the best strategy is for the patients who have had a TKI in the first-line setting, the patients who have progressed on axitinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab. We really do not have good data about the best way to treat those patients. In clinical practice, for the most part, the practice has been dominated by switching to a different TKI.

If a patient has progressed on axitinib/pembrolizumab, we might use lenvatinib/everolimus or cabozantinib. But the question is, is there a role for IO therapy for those patients? Why are we choosing a second-line TKI and not another IO therapy? That needs to be addressed with clinical trials. There has been one large, single-arm experience where over 100 patients were treated with lenvatinib/pembrolizumab in that setting. People had progressed on an earlier IO, and in that series, the response rate was over 50%. There was long progression-free survival. It looks like there may be a benefit for IO/TKI therapy in the subsequent rounds of treatment for people who have progressed on first-line IO therapy.

There is a randomized clinical trial, the CONTACT study, that is addressing that issue. It compares cabozantinib/atezolizumab versus cabozantinib. We need to further tease out which patients seem to benefit from an IO/TKI therapy based on their prior response and their prior agents. It is also an area where we need to look for novel drugs. There is a new novel drug, a HIF [hypoxia-inducible factor] inhibitor, that is from Merck & Co, Inc. That is a drug that showed activity in heavily pretreated patients. Looking for a drug that uses a novel mechanism of action is important also.

Robert Alter, MD: When choosing second-line therapy, we have to always think about what the patient received as first-line therapy. Historically, looking at sequencing when we only had options of TKI therapy, it was relatively simple. In 2007 to 2009, we had the introduction of mTOR inhibitors. It was an easy sequence of a TKI, to an mTOR, back to a TKI. There were questions of a TKI, followed by TKI, followed by an mTOR.

In 2015, we had the introduction of using immunotherapy, that being nivolumab, as a second-line therapy. It became easier to use nivolumab as a second-line therapy now that we are using immunotherapy. So the first-line agent, it is important to recognize that the second-line therapy and subsequent therapies will be based upon the patient’s response to what they received as first-line therapy. Tolerance is quite important as well.

It does get a little confusing if your patient has toxicity to a combination therapy, especially if you are trying to eliminate one and continuing the second. Then you start going on disease progression as a guide to how to think. Going back to data gives some insight. There are still not much data in regard to sequencing therapies, and that is where the art of practicing oncology for the patient with renal cell carcinoma is quite important.

Transcript edited for clarity.