Combining immune checkpoint inhibition plus tyrosine kinase inhibition as first and subsequent treatments for metastatic renal cell carcinoma

Cancer Med. 2022 Aug;11(16):3106-3114. doi: 10.1002/cam4.4679. Epub 2022 Mar 18.


Background: Immune checkpoint inhibitor/tyrosine kinase inhibitor (ICI/TKI) combinations are a new standard of care for the initial treatment of metastatic renal cell carcinoma (mRCC). Their efficacy and toxicity beyond the first-line setting remain poorly defined.

Methods: We retrospectively reviewed charts for 85 adults with mRCC of any histology receiving combination of ICI/TKI in any line of treatment at two academic centers as of 05/01/2020. We collected clinical, pathological, and treatment-related variables. Outcomes including objective response rate (ORR), progression-free survival (PFS), and toxicity were analyzed via descriptive statistics and the Kaplan-Meier method.

Results: Patients received pembrolizumab, nivolumab, avelumab, or nivolumab-ipilimumab, with concurrent use of sunitinib, axitinib, pazopanib, lenvatinib, or cabozantinib. Thirty-three patients received first-line ICI/TKI therapy, while 52 received ≥ second-line ICI/TKI. The efficacy of ICI/TKI therapy decreased with increasing lines of treatment (ORR: 56.7%, 37.5%, 21.4%, and 21%; median PFS [mPFS]: 15.2, 14.2, 10.1, and 6.8 months, for first, second, third, and ≥ fourth line therapy, respectively). In the ≥ second-line setting, ICI/TKI was most useful in patients who received ICI only, with an ORR of 50% and a mPFS of 9.1 months. Efficacy was limited in patients who received both TKI and ICI previously, with an ORR of 20% and a mPFS of 5.5 months. Overall, ≥ second-line ICI/TKI was tolerable with 25 of 52 (52%) patients developing grade ≥3 adverse events.

Conclusions: ICI/TKI combination therapy is feasible and safe beyond the first-line setting. Prior treatment history appears to impact efficacy but has a lesser effect on safety/tolerability.

Trial registration: NCT03793166 NCT04338269 NCT04987203.

Keywords: immune checkpoint inhibitor; immunotherapy; renal cell carcinoma; retrospective review; tyrosine kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Carcinoma, Renal Cell* / drug therapy
  • Carcinoma, Renal Cell* / pathology
  • Humans
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Kidney Neoplasms* / drug therapy
  • Kidney Neoplasms* / pathology
  • Nivolumab / therapeutic use
  • Protein-Tyrosine Kinases* / antagonists & inhibitors
  • Retrospective Studies


  • Immune Checkpoint Inhibitors
  • Nivolumab
  • Protein-Tyrosine Kinases

Associated data