Patients undergoing first-line treatment for advanced or metastatic renal cell carcinoma (mRCC) are increasingly treated with immune checkpoint inhibitor (ICI)-based combination therapies. But with this trend comes the need for their oncology team to be familiar with the possible adverse events and challenges associated with the use of these treatments, according to a study published in Current Opinion in Urology.

A team of researchers conducted a meta-analysis of 6 phase 3 randomized control trials involving a total of 5121 patients with mRCC. The meta-analysis assessed the following 7 therapeutic regimens:

  • Nivolumab plus ipilimumab
  • Avelumab plus axitinib
  • Pembrolizumab plus axitinib
  • Atezolizumab plus bevacizumab
  • Nivolumab plus cabozantinib
  • Lenvatinib plus pembrolizumab
  • Sunitinib

The existing body of research on treatment-related adverse events (TRAEs) associated with ICI-based combination therapies is scarce; therefore, the researchers sought to identify the adverse events associated with these treatment regimens.

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“We found generally low treatment-related mortality rates with all included combinations and no statistically significant difference were observed compared to sunitinib,” the researchers wrote. But some adverse effects of ICI-based combination treatments were associated with treatment discontinuation.

The regimen associated with the lowest likelihood of mortality related to treatment toxicity was nivolumab plus cabozantinib (P =.8057).

Patients who received lenvatinib plus pembrolizumab, nivolumab plus ipilimumab, or nivolumab plus cabozantinib were most likely to discontinue treatment due to TRAEs. Lenvatinib plus pembrolizumab was associated with the greatest likelihood of high-grade TRAEs (P =.9539). 

Rates of hepatotoxicity with ICI-based combinations were found to be significantly higher, with nivolumab plus ipilimumab and pembrolizumab plus axitinib associated with grade 3 or higher increase in ALT or AST. Rates of all-grade endocrine-related adverse events were higher with ICI-based combinations, but rates of high-grade endocrine-related AEs were low. Combinations that included axitinib tended to cause higher rates of diarrhea.

Although the study had limitations, including the fact that drug dosages and administration periods weren’t analyzed, the researchers concluded that their findings confirmed the importance of being aware of the potential adverse effects associated with the range of ICI-based combinations used to treat mRCC.

“With the increased use of ICIs in the management of mRCC, knowledge of their spectrum of toxicity and the management of TRAEs are essential skills,” the researchers concluded.


Quhal F, Mori K, Remzi M, Fajkovic H, Shariat SF, Schmidinger M. Adverse events of systemic immune-based combination therapies in the first-line treatment of patients with metastatic renal cell carcinoma: systematic review and network meta-analysis. Curr Opin Urol. Published online May 6, 2021. doi: 10.1097/mou.0000000000000889