Refining Combination Strategies in Metastatic RCC - Episode 4

Metastatic RCC: Frontline TKI/IO Safety Data

March 17, 2021
Toni Choueiri, MD

Robert J. Motzer, MD

Treatment-related adverse events to be mindful of when treating patients with metastatic renal cell carcinoma with a TKI/IO regimen, such as lenvatinib and pembrolizumab, in the frontline setting.

Toni Choueiri, MD: One of the aspects of different therapies is safety. Of course, safety remains always a concern. With all of the approved combinations—axitinib/avelumab, [axitinib/pembrolizumab], [cabozantinib/nivolumab], as of today, and hopefully in the future, [lenvatinib/pembrolizumab], which is the VEGF/IO [immunotherapy]—the initial studies, despite some toxicities, made it to phase 3 and made it to FDA approval, in many situations. While the combinations with nivolumab of sunitinib and pazopanib didn’t make it.

This is somewhat safe, people have looked at it, but it doesn’t mean that there are no toxicities or that this is going to be something very easy to take. All of these treatments are not taken for a short amount of time. Usually, they’re continued until progression. If you look at [lenvatinib/pembrolizumab] and with everything else, and look at treatment-related AEs [adverse events], how we now report AEs with CTCAE [Common Terminology Criteria for Adverse Events][CM1] , it makes it hard to tease out what is related, what is not related, what does it mean. The good thing is that the grade 3 or 4 adverse events tend to be low. That’s the one important thing, usually less than 10%. The second thing is if there any toxicities we are not aware of.

Suddenly, is there a combination that led to an unusual degree of myelitis? And the answer is no. It seems that the toxicity comes from each single agent alone. Sometimes it’s hard to figure out what is causing what because there are some overlapping toxicities with diarrhea and LFTs [liver function test levels] that could be from the TKI [tyrosine kinase inhibitor] or the immune checkpoint inhibitor. What I rely on with this continuous treatment, is the treatment-related adverse event that led to complete treatment discontinuation of 1 or 2 drugs. We can see with all of the combinations, even if you look at [lenvatinib/pembrolizumab], it’s around 10% that lead to both drugs being discontinued because of AEs. Each drug alone is higher, between 18% and 25%. There are dose reductions. There are dose reductions with [pembrolizumab] overall in the [lenvatinib/pembrolizumab] CLEAR study. One of the reasons is we don’t know the dose of the TKI. This is not only lenvatinib, but also [cabozantinib] and others; we do not know.

[Cabozantinib] at 60 mg, once a day approved, 40 mg in combination with [nivolumab]. [Lenvatinib/pembrolizumab], I have seen 20 mg in combination, 20 mg of [lenvatinib]. That is what the phase 3 did. But then, if you look at the combination with everolimus, it’s 18 mg. And if you look at some of the studies with [lenvatinib]/everolimus, it’s between 14 and 18 mg; 18 mg seems to be a bit better, but then you have 20 mg in combination with [pembrolizumab]. The most important message is that it’s fine to start high, but be careful. You may need to dose reduce in the majority of the patients. That’s not a bad thing, as long as you know how to manage toxicities and how to provide the best exposure to patients. Some patients can stay on the lenvatinib at 20 mg, others may need to decrease to 18 mg or 14 mg or even lower, as long as the disease is controlled.

That would be the main message with toxicities, rather than comparing across trial the grade 3/4 [adverse events], it doesn’t help much, and may be confusing. How you would know that is by simply looking at the toxicity of the sunitinib control arm across all studies. There is a difference in toxicities. Look at the LFTs, diarrhea, treatment-related and not related, then say that’s the same arm, that is sunitinib. It was started at 50 mg, 4 weeks on 2 weeks off, how across the studies are there differences in reporting? That is one of the limitations of the toxicity grading we have in oncology.

Transcript edited for clarity.