Strategies for Managing VEGF-TKI Toxicities

Daniel George, MD:Toxicity management, in kidney cancer, is probably one of the most important aspects to a successful outcome for our patients. Yes, the drugs do the work. They make a difference. They can shrink the cancer. They can prolong the survival and change the natural history. It’s a wonderful advancement, that we’ve seen, mechanistically—with several agents, in the field, that have been approved for kidney cancer.

But, if we can’t manage the toxicity in these patients, it’s a hollow victory. I’ve had patients where we’ve seen the tumor regress, but the patients have been so damaged by the therapy that the quality of life is almost not worth the disease control that we achieved. So, to me, recognizing upfront the importance of this tolerance is critical. We also have to help the patients realize that, you know, this is going to probably be a factor, in terms of their satisfaction with the therapy over the next 2 to 5 years, or however long they have to live. So, that’s a really important aspect.

And then, with each agent, it’s different. It’s even different within the different TKIs. We may say that one TKI has a comparable side effect profile to another, and that’s true. But, on an individual basis, I’m going to see different profiles with these agents.

Let’s take cabozantinib, for example. One of the things that we see with that agent is a lot of elevations of blood pressure. Some of them can be pretty significant. So, that’s important to recognize. It’s an on-target effect. It’s something we see. It’s a class effect. It’s important to recognize that it’s going to take a proactive approach, at a different pace from what primary care might do. In primary care, blood pressure may be managed with a change. Then, they see you back at 2 months later. We’re going to make a change and see you back in 1 or 2 weeks, because this blood pressure issue is likely to get worse, rather than better. If this isn’t making an impact, we’ll need to be more aggressive. With cabozantinib, I can do that because it’s constant dosing. When I use a drug like sunitinib, it’s a little trickier because we have these built-in 1- or 2-week breaks. And so, we kind of go up. But, we don’t want to overshoot and end up with issues while on the off-period. I’m more aggressive with my hypertension management when I have a drug like cabozantinib, especially early-on. I know that drug’s going to continue to build up in their system because of the long half-life.

Diarrhea is another one. Thankfully, with diarrhea, it’s a slow onset. With some of our drugs, like axitinib, the half-life is so short. They get up to steady state within a matter of days, and diarrhea can really get ahead of patients quickly. But, we can hold the drug and wash it out pretty quickly.

With cabozantinib, it’s going to be a little slower onset. But, when I hold the drug, it’s not going to wash out as quickly. So, I’m more likely, again, to use Imodium and other drugs to control it a little more aggressively. Even if it ends up stopping them up a little bit, I know I can back off on those medicines and that things will come back, again. So, it’s important to help patients recognize, and even think, in our mind, that not all of these drugs are alike. You’ve got to think about the half-life, the pace, and the tolerance of these drugs.

One of the things that I like to do with dose modifications is interruptions. I like interruptions because they allow me to maintain that full dose, when I restart, and I can do interruptions for any length of time. I can do them for 2 weeks, or I can do them for 2 days. And if I do them early, I can do them for 2 days and be back on the drug. Again, it’s not going to pile up, too quickly.

When I’m managing a toxicity, if it’s starting to build up quickly in the first 2 to 4 weeks, I’m going to use dose interruptions during that period of time. Even with a drug like sunitinib, where I know I’m going to use a dose interruption at 4 weeks, I’m still going to interrupt earlier, for shorter periods, if I’m running into significant toxicity in the first 4 weeks. I’d rather do that, and then, if I have to when I restart, if I still have toxicity, I’m going to lower dose. But, for the most part, I’m going to use my interruptions early, and I’m going to use my dose reductions slower. Once I dose reduce, I’m probably not going to go back up again. So, to me, it’s really important to recognize that there’s no downside to some dose interruptions during those first 6-week periods. But, once I commit down to a lower dose, it’s really hard to get back up, again. To me, those are some of the key takeaways that I can give other people—from the experience of treating hundreds of patients with these drugs, versus folks that may have only have treated a handful of folks.

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