Management of Serious Toxicities with Cabozantinib/Nivolumab in mRCC

Neeraj Agarwal, MD

Professor of Medicine

Presidential Endowed Chair of Cancer Research

University of Utah Huntsman Cancer Institute

Salt Lake City, Utah

Targeted Oncology: What toxicities are the most serious with the combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) compared with sunitinib (Sutent) based on the CheckMate 9ER trial (NCT03141177) in metastatic renal cell carcinoma (mRCC)?

AGARWAL: If you if you look at grade 3 or 4 toxicities, which is easy to compare, they are not very different [since] cabozantinib and sunitinib are both VEGF tyrosine kinase inhibitors [TKIs]. Diarrhea, hand-foot syndrome, and hypertension are the most common ones, and they’re very similar in both arms.¹ But I don’t think nivolumab was contributing much beyond isolated elevation of liver enzymes. These are quite common, mostly grade 1 or 2. I don’t change anything unless they keep rising. Or I hold off on nivolumab for some time, and then I restart and most patients do well. I see lipase elevation quite often, but it’s mostly asymptomatic lipase elevation without pancreatitis. But other than that, I don’t see much difference between the arms as far as grade 3 or 4 adverse events are concerned.

Do you commonly check lipase levels in your patients?

During the clinical trials we have to check lipase. In my regular clinic, I don’t check lipase. But we have to check lipase in trials, and they go up and you don’t know what to do with it because the patient is doing fine. They were getting scans, and there was no evidence of pancreatitis on the scan, and they were completely asymptomatic. So we don’t know what to do with it. If they are having pain, that’s a different story.

If aspartate aminotransferase [AST] or alanine aminotransferase [ALT] are increasing, how do you know if it is necessary to hold nivolumab or cabozantinib?

I stop cabozantinib first. Ninety percent of these patients have grade 1 or 2 AST/ALT elevation because of TKIs.... If you stop cabozantinib, AST goes down within 4 or 5 days. That’s the first test I do, whether it is because of the TKI, which is the most common cause of AST elevation.

But then I also keep in mind that there are 3% or 4% patients who will be developing immune-related hepatitis. I don’t want to miss that. I stop cabozantinib first, then nivolumab is automatically held when these patients come to the clinic. If they get better with holding off on cabozantinib, then I continue with nivolumab.

Very rarely we see AST/ALT keeps going up despite stopping cabozantinib. Because if it is because of nivolumab, holding off on 1 dose is not going to make a change in immune hepatitis. Even though nivolumab was given 4 weeks before, it will continue to work to cause immune hepatitis. So if they have a second elevation, I start them on prednisone. I don’t wait for grade 3 or grade 4. I stop cabozantinib and I recheck the liver enzymes and if they have continued elevation of liver enzymes, I start them on prednisone at 1 mg/kg, not 2 mg/kg. One milligram per kilogram often does the trick with isolated enzyme elevation. And I only do that if [it continues] despite cabozantinib discontinuation and 7 days after.

This is probably one of the most challenging situations we used to face during the clinical trials. If someone has diarrhea—cabozantinib, axitinib [Inlyta], and all of them cause diarrhea, and there were no guidelines at the time and we used to think, what should we do now? Then we realized axitinib, cabozantinib, lenvatinib [Lenvima] may have different half-lives, but when we hold them, diarrhea gets better in 2 days. That’s how I start contemplating starting steroids.

_Reference:

_{1. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl_6):350. doi:10.1200/JCO.2022.40.6_suppl.350}