Tolerability of IO/TKI Combination Therapy for Advanced Clear Cell RCC


An expert explains how he assesses a patient’s tolerability of the IO-TKI combination regimens and at what point he discontinues treatment.

Nizar Tannir, MD: Looking at the slides as I was listening to both of you, one item that might also be important to bring up is the discontinuation rate. Obviously, these IO [immuno-oncology]-TKI [tyrosine kinase inhibitor] combinations have similar adverse events [AEs]: hypertension, diarrhea, fatigue, etc. But the discontinuation rate may be important, and it’s worth mentioning it. If I recall, the discontinuation rate with the cabozantinib [Cabometyx]/nivolumab [Opdivo] combination in the CheckMate 9ER study was less than 10% for both agents. It’s a little higher in the other regimens with IO-TKI, pembrolizumab [Keytruda]/lenvatinib [Lenvima] and pembrolizumab/axitinib [Inlyta].

Moshe, would you like to comment on this? Does that factor into your approach to treating patients with first-line therapy? Obviously, efficacy and tolerability are very important, along with the percentage of patients who require interruption, dose reduction, or discontinuation of a TKI. Is that a factor that you take into consideration?

Moshe Ornstein, MD, MA: Absolutely. This goes back to the tolerability. There’s the tolerability that we see when the toxicity profiles are listed in the clinical trials, and there’s a separate toxicity that we see in terms of treatment discontinuation and what we see in the clinic. I’m often surprised that what we see in clinical trials isn’t necessarily what we see in clinical practice in terms of discontinuations, where we don’t have to stick to a protocol as strictly.

I believe the rates of discontinuation for lenvatinib or pembrolizumab in the CLEAR trial were 20%-plus for each. That tells me 2 things. No. 1, it tells me that despite what we see from the tornado plots or the AE figures, it seems to be a more toxic regimen, or a regimen that might be more challenging to be on for a longer period. I believe that’s the question you asked regarding taking that into consideration when choosing a regimen. But the flipside to that is it also tells me how effective this regimen and combination is. It tells me that despite a relatively high discontinuation rate and a high dose reduction rate of lenvatinib of around 68%, the efficacy was there.

There are 2 things I’d like to see before I clearly say that the rates of discontinuation will drive my decision-making. First, I’d like to see how well the patients who discontinued their therapy did in the long run. Did we see the upfront benefit only because the TKI was on and then it came off and then we’re down to an IO monotherapy? Maybe it’s just an additive benefit. I’d also like to see the long-term data for patients who had dose reductions. I set expectations and I tell patients that the dose will need to be reduced in most of them. But can I clearly say that if we require a dose reduction in an individual patient from 20 mg to 14 mg that it won’t impact long-term efficacy? The upfront efficacy is well established, but I’d like to see the long-term data.

In summary, to answer the questions about discontinuation, in some ways it’s concerning because a high rate [of patients] are discontinuing. But despite that discontinuation, it appears that the efficacy in the population at large is sustained. But we need more data before we can clearly say that this should be the factor that drives deciding between one treatment vs another.

Transcript edited for clarity.

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