New Therapy Options in Newly Diagnosed mRCC

Daniel George, MD:One other really important factor, when I’m deciding that first line of therapy for patients, is the treatment mechanism. Now, for the first time in kidney cancer in a long time, we have a choice. We have a choice between vascular endothelial growth factor-tyrosine kinase inhibitors, and there are several, but we also have a choice of immunotherapy. Historically, that might have been high-dose IL-2, for a small subset of patients. But now, with the advent of checkpoint inhibitors—in particular, with opportunities with nivolumab, and ipilimumab, and maybe even combinations of VEGF and checkpoints in the future—we’re going to have to decide how to start patients off. We are going to have to decide which arm of these different modalities we want to start with. I think this is going to be an evolution in progress.

I have a lot of experience in treating patients with VEGF-TKIs. I know how to do that. I know what doses patients can tolerate, and what the signs and symptoms to look for are. I know when to say that we need to take a break or lower the dose. What I like about those therapies is, for the most part, those toxicities are quickly reversible. If we run into trouble with diarrhea, nausea, hand-foot syndrome, or hypertension, I know that I can hold those medicines and, within days to a week or 2, they’re going to resolve.

The tricky thing with immune-oncology therapy, even though I think it’s extremely exciting and promising in some of our fields, particularly in lung cancer, where we haven’t had a lot of effective therapy, is that when we do run into side effects, they can last for a long period of time and be difficult to resolve. We probably see a little bit higher percentage of patients that don’t respond to immune-oncology therapies, that do respond to TKI therapies.

When I’m looking at this mix, the TKI therapies are still attractive for the patient in whom I feel like I really need this therapy to work for. I can’t afford to have this disease go unchecked, for a long period of time. The TKIs give me the opportunity to start there and see how they respond. If needed, I can hold it and restart it.

The immune-oncology therapies are great, particularly for our patients that have a little bit more of that lower burden of disease. If we do have to hold therapy for a longer period of time, that disease burden can grow without necessarily causing a lot of symptoms, or for people in whom I can radiate some symptoms or do some other things, in the context of that. So, I kind of look at those factors, as well.

I think that there’s going to be an attractiveness to starting with intravenous immune-oncology therapy for a lot of folks, long term, because of long-term tolerance. The beginning is really key to understanding who can tolerate that and do well with that, versus who we may need to hold that, in reserve, for a little bit, and start with a TKI. We recognize that for most of our kidney cancer patients, we’re going to use both of these modalities, either in sequence or in combination, eventually.

One of the things that I think we’ve learned in kidney cancer, over the last few years, is that sequence may matter in this disease. So, let me give you an example. Over the last 2 years, we’ve had a single checkpoint, nivolumab, as well as a number of TKIs, such as cabozantinib and axitinib, approved for renal cell carcinoma in the second-line space. That’s allowed us to kind of shuffle, a little bit, in sequence.

We’ve still, for the most part, started with VEGF-TKIs like sunitinib and pazopanib. But, when those patients progress, we’ve been able to use a drug like nivolumab. The advantage of that has been to change mechanisms. We can change side effect profiles to allow patients to recover from some of the side effects that they may have chronically experienced with TKIs. We can try a different modality, and really hit the tumor with a different strategy.

Many times, that has worked great. We’ve seen responses. But, there are also many patients who progress relatively rapidly when coming off of VEGF-TKI therapy while on a checkpoint inhibitor like nivolumab. But, it’s been interesting. Patients are going back on TKIs like cabozantinib or axitinib, and we are seeing responses in that setting. I think that suggests that there is some benefit to changing these mechanisms. We may be able to treat some patients concomitantly, with these strategies. For other patients, it may be just as effective, or even better tolerated, to give them in sequence. I think that’s something that we’re going to continue to learn about. I’m not sure that we really know what the best sequence is going to be, for every patient, in kidney cancer.

Transcript edited for clarity.

Case Scenario: A 52-year old male with mRCC

February 2018

• A 52-year old Caucasian man presented to his physician complaining of severe left-sided back pain
• Laboratory findings: mild anemia, otherwise WNL
• CT scan of the abdomen and pelvis showed a large left renal mass, several small lytic lesions in the lumbar and thoracic vertebrae, and a small pulmonary nodule
• The patient underwent cytoreductive nephrectomy
• Diagnosis; stage IV clear-cell renal cell carcinoma; good-risk
• He received radiation therapy to his spinal lesions and was then started on cabozantinib 60 mg daily
• The patient reported moderate nausea and vomiting and diarrhea after 6 weeks on therapy; he continues to do well with improved tolerance after dose adjustment to 40 mg
• Imaging at 3 months showed a significant decrease in size of the pulmonary nodule