Nivolumab/Ipilimumab Generates Worse Responses in Patients With Metastatic Clear Cell RCC With Low Serum Iron

The combination of nivolumab and ipilimumab (Yervoy) was associated with worse clinical benefit in patients with metastatic clear cell renal cell carcinoma who have low serum iron compared with patients with normal/high serum iron.

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was associated with worse clinical benefit in patients with metastatic clear cell renal cell carcinoma (RCC) who have low serum iron compared with patients with normal/high serum iron, according to a retrospective analysis presented at the 2022 Kidney Cancer Research Summit.1

Findings showed that 46.15% of patients with serum iron below the lower level of normal (LLN) were considered responders compared with 78.125% of patients with serum iron above the LLN (P = .012).

“Because of the current dataset size limitations, this study is currently only hypothesis generating. The study is also limited to response to ipilimumab/nivolumab rather than evaluating these in conjunction with other immune therapy combinations,” lead study author James Brundage, MS, a medical student at the University of Utah, and colleagues, wrote in a poster presentation of the data. “It is also possible that serum iron serves [as a] biomarker of aggressive disease biology rather than a pure marker of immune response.”

In April 2018, the FDA approved the combination of nivolumab and ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.2 However, approximately 20% of patients do not respond to this regimen, and no predictive biomarkers outline an unmet clinical need.

Since iron consumption can contribute to disease progression through the HIF pathways and can be consumed by tumor-associated macrophages in the tumor microenvironment, investigators hypothesized that low iron serum could be predictive of poor responses to ipilimumab/nivolumab.

The retrospective study identified patients with metastatic clear cell RCC who received treatment with ipilimumab/nivolumab from databases at Huntsman Cancer Institute at the University of Utah, as well as the University of Iowa, treated between December 2013 and June 2021.

Patients were required to have serum iron labs drawn prior to the start of treatment with ipilimumab/nivolumab or up to 1 month following the start of treatment. Treatment with ipilimumab/nivolumab was permitted in any line.

Eligible patients were then categorized as having low serum iron levels or normal serum iron levels. The primary end point of the study was duration of response (DOR) correlated with serum iron levels. DOR was defined as the time from treatment initiation to time of discontinuation or death, and responders were those who had a treatment duration of more than 4 months.

Secondary end points included response correlated to other iron indices, including total iron binding capacity (TIBC), ferritin, and transferrin.

Among the 81 patients included in the study, the median age was 61.17 years, the median body mass index was 29.33, 71.7% were male, and 88.9% were non-Hispanic White. Overall, 34.6% of patients had low serum iron, and 65.4% had normal serum iron.

Furthermore, 75.3% of patients had intermediate-risk disease, 8.6% had favorable-risk disease, and 16% had poor-risk disease. The line of treatment for ipilimumab/nivolumab included first (44.4%), second (28.4%), third (13.6%), fourth (11.1%), or fifth or later (2.5%).

Additional data showed that TIBC, ferritin, and transferrin were not predictive of clinical response. Patients with ferritin below the LLN (n = 51) experienced a response rate of 62.7% compared with 50% for those with ferritin above LLN (n = 2; P = .715). The response rates for patients with TIBC below the LLN (n = 25) and above the LLN (n = 33) had response rates of 52% and 72.7%, respectively (P = .104). Patients with transferrin below the LLN (n = 26) and above the LLN (n = 31) experienced response rates of 53.8% and 71.0%, respectively (P = .182).

“This is a hypothesis-generating, retrospective study. Therefore, these results need to be verified in future prospective studies or validated in banked samples of already conducted phase 3 clinical trials,” study authors concluded.


  1. Brundage J, Abuqayas B, Mani H, et al. Correlation of serum iron level and duration of response to ipilimumab and nivolumab in metastatic clear cell renal carcinoma (mccRCC). Presented at: Kidney Cancer Research Summit; October 6-7, 2022; Philadelphia, PA. Abstract 65. Accessed October 10, 2022.
  2. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. News release. FDA. April 16, 2018. Accessed October 10, 2022.
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