Switching Therapies in Advanced Clear Cell RCC without Dose Reduction


Dr Scott Tykodi explains the scenarios in which he would switch a patient to another regimen without dose reduction first.

Nizar Tannir, MD: Scott, are there any instances in which you would consider switching from an IO [immunotherapy]-TKI [tyrosine kinase inhibitor] or an IO combination to another regimen? Is there a particular situation in which the patient doesn’t tolerate pembrolizumab-lenvatinib and you go, “Instead of reducing the lenvatinib dose, I’m going to switch to cabozantinib-nivolumab,” or you stick with the same regimen and dose adjust to tolerance?

Scott Tykodi, MD, PhD: [There are] a couple of scenarios. If you have given ipilimumab-nivolumab, gone through the combination dosing phase, and you’re on nivolumab monotherapy and progressing, it isn’t evidence-based, but it’s tempting to add cabozantinib to nivolumab and do nivolumab-cabozantinib as your second-line regimen. I’ve certainly done that for many patients. In a sense, it’s a transition from IO-IO to IO-TKI.

We referred to the desire to have a study that will guide us as to whether there’s true synergy in that setting. There’s also a cooperative group study looking at risk-adapted use of cabozantinib in that fashion. It would be lovely to have those data. But it’s such a natural transition to make, particularly in a patient who has had success, an early response, and then lost it a year after starting therapy. It feels right to try to extend the use of the IO compound.

Conversely, I did pembrolizumab-axitinib when it was the only IO-TKI, and now we’ve gone to some of the competitors. Often, with the patient who had early success, a partial response, and didn’t have a lot of toxicity but is beginning to progress through it, I have certainly used ipilimumab-nivolumab in the salvage setting many times. There’s a decent response rate for ipilimumab as a salvage drug, in the 15% to 20% range for most data sets. You don’t see depth of response. You don’t see CRs [complete responses] emerge in that context, but the response rate and the disease control rate rival giving a targeted drug in that setting. You’d like to feel that the personal track record of the patient who had good IO tolerance and some success maybe enriches for the likelihood of success. I certainly have done that as well. I’ve gone both ways with changing a doublet, one vs the other, depending on where we started.

Nizar Tannir, MD: Moshe, [what are] your thoughts on that?

Moshe Ornstein, MD, MA: Interestingly, although I give more IO-TKI in the frontline setting than IO-IO, an argument to give IO-IO up front is the benefit of giving ipilimumab in the frontline setting, which appears to be far superior than giving ipilimumab in the salvage setting. In some ways, when you give an IO-TKI up front, you lose out on the true benefit of ipilimumab, which is probably that it contributes to that tail of the curve in the combination of ipilimumab and nivolumab in the treatment-naïve setting.

I generally shy away from giving salvage ipilimumab. I might give it to a patient who had a nice initial response to an IO agent, but I’d give it in a subsequent setting and not immediately following the frontline setting. I’d reserve it for a later line of treatment. I have also done the addition of cabozantinib to nivolumab. With a patient who got ipilimumab-nivolumab per the CheckMate 214 study, has been on nivolumab monotherapy for 12 to 18 months, and has a slow PD [progression of disease], there’s the potential for synergy there. By adding the TKI to the IO, there might be more of a benefit than giving the TKI as a monotherapy, although we don’t know. We have ongoing trials to determine that.

We have clinical trial data, although they aren’t randomized, for giving lenvatinib and pembrolizumab in patients who have received prior IO-based combination therapy. The response rates look very impressive, but it isn’t randomized. I have given IO-TKI combinations in refractory settings. As a general rule, I don’t give a doublet followed by a doublet. I generally give an IO-based combination followed by a monotherapy. Recently, as many patients are fortunately doing well in the long run, I almost feel like it’s a reset in their tumor biology. If they can tolerate it, I’ll give them a combination therapy in the third, fourth, or even fifth line. But as a standard, I don’t switch. I start with a combination and then switch to a monotherapy.

Transcript edited for clarity.

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